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251. Immunological and genetic kinetics from diagnosis to clinical progression in chronic lymphocytic leukemia

Author: Marta Crespo, Bárbara Tazón-Vega, Clara Franco-Jarava, José A. García-Marco, Genís Parra, Gloria Iacoboni, Juan C. Nieto, Isabel Jiménez, Carles Palacio-García, Francesc Bosch, Anna Esteve-Codina, Rafael Valdés-Mas, Sabela Bobillo, Pau Abrisqueta, Lluis Puigdefàbregas, Júlia Carabia, Magdalena Munuera, María José Terol, Institut Català de la Salut, [Jiménez I, Nieto JC, Carabia J, Munuera M, Puigdefàbregas L, Crespo M] Experimental Hematology, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Tazón-Vega B, Abrisqueta P, Bobillo S, Palacio-García C, Iacoboni G, Bosch F] Departament de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain. Servei d’Hematologia, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Experimental Hematology, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Franco-Jarava C] Servei d’Immunologia, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Vall d’Hebron Hospital Universitari, Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: Chronic lymphocytic leukemia, T cell, Leucèmia limfocítica crònica - Diagnòstic, Clinical Biochemistry, Clinical progression, RM1-950, Somatic evolution in cancer, Asymptomatic, Immune system, Other subheadings::Other subheadings::/immunology [Other subheadings], medicine, Pathological Conditions, Signs and Symptoms::Pathologic Processes::Disease Attributes::Disease Progression [DISEASES], Immunologia, Otros calificadores::Otros calificadores::/inmunología [Otros calificadores], T cell exhaustion, Immune evasion, Mechanism (biology), business.industry, Research, Biochemistry (medical), Leucèmia, medicine.disease, afecciones patológicas, signos y síntomas::procesos patológicos::atributos de la enfermedad::progresión de la enfermedad [ENFERMEDADES], medicine.anatomical_structure, Neoplasms::Neoplasms by Histologic Type::Leukemia::Leukemia, Lymphoid::Leukemia, B-Cell::Leukemia, Lymphocytic, Chronic, B-Cell [DISEASES], Cancer research, Avaluació de resultats (Assistència sanitària), Molecular Medicine, Therapeutics. Pharmacology, medicine.symptom, business, Genètica, CLL, Ex vivo, CD8, neoplasias::neoplasias por tipo histológico::leucemia::leucemia linfoide::leucemia de células B::leucemia linfocítica crónica de células B [ENFERMEDADES]
Abstract: Progressió clínica; Evasió immune Progresión clínica; Evasión inmune Clinical progression; Immune evasion Background Mechanisms driving the progression of chronic lymphocytic leukemia (CLL) from its early stages are not fully understood. The acquisition of molecular changes at the time of progression has been observed in a small fraction of patients, suggesting that CLL progression is not mainly driven by dynamic clonal evolution. In order to shed light on mechanisms that lead to CLL progression, we investigated longitudinal changes in both the genetic and immunological scenarios. Methods We performed genetic and immunological longitudinal analysis using paired primary samples from untreated CLL patients that underwent clinical progression (sampling at diagnosis and progression) and from patients with stable disease (sampling at diagnosis and at long-term asymptomatic follow-up). Results Molecular analysis showed limited and non-recurrent molecular changes at progression, indicating that clonal evolution is not the main driver of clinical progression. Our analysis of the immune kinetics found an increasingly dysfunctional CD8+ T cell compartment in progressing patients that was not observed in those patients that remained asymptomatic. Specifically, terminally exhausted effector CD8+ T cells (T-betdim/−EomeshiPD1hi) accumulated, while the the co-expression of inhibitory receptors (PD1, CD244 and CD160) increased, along with an altered gene expression profile in T cells only in those patients that progressed. In addition, malignant cells from patients at clinical progression showed enhanced capacity to induce exhaustion-related markers in CD8+ T cells ex vivo mainly through a mechanism dependent on soluble factors including IL-10. Conclusions Altogether, we demonstrate that the interaction with the immune microenvironment plays a key role in clinical progression in CLL, thereby providing a rationale for the use of early immunotherapeutic intervention. This work was supported by the Instituto de Salud Carlos III, Fondo de Investigaciones Sanitarias (PI17/00950, M.C., PI18/01392, P.A. and PI17/00943, F.B.) and co-financed by the European Regional Development Fund (ERDF) and Fundación Asociación Española Contra el Cáncer (M.C. and P.A.), Gilead Fellowships (GLD16/00144, GLD18/00047, F.B.) and Fundació la Marató de TV3 (201905–30-31 F.B). S.B. is the recipient of a postdoctoral fellowship from Fundación Alfonso Martin Escudero. R.V-M. is supported by a Torres Quevedo fellowship from the Spanish Ministry of Science and Innovation (PTQ-16-08623). A.E-C. is funded by ISCIII/MINECO (PT17/0009/0019) which is co-funded by FEDER. M.C. holds a contract from Ministerio de Ciencia, Innovación y Universidades (RYC-2012-2018).
Published: 2021

252. Trifluridine/tipiracil in combination with oxaliplatin and either bevacizumab or nivolumab in metastatic colorectal cancer: a dose-expansion, phase I study

Author: Ronan Fougeray, Mark P Saunders, Catherine Leger, Antoine Hollebecque, Laetitia Dahan, Gerald W. Prager, Julien Edeline, Alexander Stein, Gábor Rubovszky, Alessandra Auriemma, Zsuzsanna Papai, Roberto Bordonaro, Aitana Calvo, Antonio Cubillo, Guillem Argiles, V. Cattan, Thierry André, Nadia Amellal, Josep Tabernero, ARNAS 'Garibaldi, S. Luigi-Currò, Ascoli-Tomaselli', Hospital General Universitario 'Gregorio Marañón' [Madrid], University of Verona (UNIVR), Département d’Innovation Thérapeutique et essais précoces [Gustave Roussy] (DITEP), Institut Gustave Roussy (IGR), National Institute of Oncology [Budapest, Hungary], The Christie NHS Foundation Trust [Manchester, Royaume-Uni], Medizinische Universität Wien = Medical University of Vienna, Microbes évolution phylogénie et infections (MEPHI), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), Service d'Oncologie Médicale [CHU Saint -Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Vall d'Hebron Institute of Oncology [Barcelone] (VHIO), Vall d'Hebron University Hospital [Barcelona], Hospital Universitario HM Sanchinarro [Madrid, Spain], Centre de Recherche en Cancérologie de Marseille (CRCM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Centre Eugène Marquis (CRLCC), Institut de Recherches Internationales Servier [Suresnes] (IRIS), Università degli studi di Verona = University of Verona (UNIVR), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Gestionnaire, HAL Sorbonne Université 5, Service d'Oncologie Médicale [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Català de la Salut, [Bordonaro R] Azienda Ospedaliera ARNAS Garibaldi, Catania, Italy. [Calvo A] Gregorio Marañon University General Hospital, Madrid, Spain. [Auriemma A] Azienda Ospedaliera Universitaria Integrat, University of Verona, Verona, Italy. [Hollebecque A] Drug Development Department, Gustave Roussy Cancer Campus, Villejuif, France. [Rubovszky G] Department of Medical Oncology and Clinical Pharmacology, National Institute of Oncology Hungary, Budapest, Hungary. [Saunders MP] Christie NHS Foundation Trust, Manchester, UK. [Argilés G] Vall d'Hebron Hospital Universitari, Barcelona, Spain. Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Tabernero J] Vall d'Hebron Hospital Universitari, Barcelona, Spain. Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain. UVic-UCC, IOB-Quiron, Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: Cancer Research, Pyrrolidines, Colorectal cancer, Other subheadings::Other subheadings::/drug therapy [Other subheadings], Otros calificadores::Otros calificadores::/efectos adversos [Otros calificadores], Gastroenterology, Trifluridine, trifluridine/tipiracil, Còlon - Càncer - Tractament, chemistry.chemical_compound, 0302 clinical medicine, Antineoplastic Combined Chemotherapy Protocols, Original Research, metastatic colorectal cancer, terapéutica::terapéutica::farmacoterapia::protocolos antineoplásicos::terapéutica::farmacoterapia::protocolos de quimioterapia antineoplásica combinada [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, neoplasias::neoplasias por localización::neoplasias del sistema digestivo::neoplasias gastrointestinales::neoplasias intestinales::neoplasias colorrectales [ENFERMEDADES], 3. Good health, [SDV.SP] Life Sciences [q-bio]/Pharmaceutical sciences, Bevacizumab, Nivolumab, Oncology, 030220 oncology & carcinogenesis, Cohort, medicine.symptom, Colorectal Neoplasms, medicine.drug, medicine.medical_specialty, Nausea, Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores], [SDV.CAN]Life Sciences [q-bio]/Cancer, Neutropenia, fluoropyrimidines, Quimioteràpia combinada, 03 medical and health sciences, Neoplasms::Neoplasms by Site::Digestive System Neoplasms::Gastrointestinal Neoplasms::Intestinal Neoplasms::Colorectal Neoplasms [DISEASES], [SDV.CAN] Life Sciences [q-bio]/Cancer, Therapeutics::Therapeutics::Drug Therapy::Antineoplastic Protocols::Therapeutics::Drug Therapy::Antineoplastic Combined Chemotherapy Protocols [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], Internal medicine, Recte - Càncer - Tractament, Other subheadings::Other subheadings::/adverse effects [Other subheadings], medicine, Humans, Tipiracil, business.industry, oxaliplatin, medicine.disease, Oxaliplatin, chemistry, business, Thymine, 030215 immunology
Abstract: Background In preclinical studies trifluridine/tipiracil (FTD/TPI) plus oxaliplatin (Industriestrasse, Holzkirchen, Germany) sensitised microsatellite stable (MSS) metastatic colorectal cancer (mCRC) to anti-programmed cell death protein-1; the addition of oxaliplatin or bevacizumab (F Hoffmann- la ROCHE AG, Kaiseraugst, Switzerland) enhanced the antitumour effects of FTD/TPI. This study aimed to investigate the safety and efficacy of FTD/TPI plus oxaliplatin and either bevacizumab or nivolumab (Uxbridge business Park, Uxbridge, United Kingdom) in patients with mCRC who had progressed after at least one prior line of treatment. Patients and methods In 14-day cycles, patients received FTD/TPI 35 mg/m2 (twice daily, days 1-5) plus oxaliplatin 85 mg/m2 (day 1), and, on day 1, either bevacizumab 5 mg/kg (cohort A) or nivolumab 3 mg/kg (cohort B). Patients in Cohort B had confirmed MSS status. Results In total, 54 patients were enrolled: 37 in cohort A and 17 in cohort B. Recruitment in cohort B was stopped early due to the low response rate (RR) observed at interim analyses of efficacy. The most common adverse events (AEs) in cohort A were neutropenia/decreased neutrophils (75.7%), nausea (59.5%), vomiting (40.5%), diarrhoea (37.8%), peripheral sensory neuropathy (37.8%), fatigue (35.1%) and decreased appetite (35.1%). In cohort B, the most common AEs were neutropenia/decreased neutrophils (70.6%), diarrhoea (58.8%), nausea (47.1%), vomiting (47.1%), fatigue (47.1%), asthenia (41.2%), paraesthesia (41.2%), thrombocytopenia/decreased platelets (35.3%) and decreased appetite (35.3%). Confirmed objective RR was 17.1% in cohort A and 7.1% in cohort B; the corresponding values for median progression-free survival in the two cohorts were 6.3 and 6.0 months. Conclusion FTD/TPI plus oxaliplatin and bevacizumab or nivolumab had an acceptable safety profile and demonstrated antitumour activity in previously treated patients with mCRC., Highlights • This study evaluated the safety and efficacy of FTD/TPI plus oxaliplatin and either bevacizumab or nivolumab in mCRC patients. • FTD/TPI plus oxaliplatin in combination with bevacizumab or nivolumab had an acceptable and manageable safety profile. • Antitumour activity was observed following treatment with FTD/TPI plus oxaliplatin and bevacizumab. • Despite a modest RR with the addition of nivolumab, survival data were promising in these poor-prognosis patients.
Published: 2021
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253. Brain Metastases in HER2-Positive Breast Cancer: Current and Novel Treatment Strategies

Author: Andri Papakonstantinou, Mafalda Oliveira, Alejandro Garcia-Alvarez, Institut Català de la Salut, [Garcia-Alvarez A] Servei d’Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Papakonstantinou A] Breast Cancer Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Department of Oncology-Pathology, Karolinska Institute, 17177 Stockholm, Sweden. Department of Breast Cancer, Endocrine Tumors and Sarcoma, Karolinska University Hospital, 17176 Stockholm, Sweden. [Oliveira M] Servei d’Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Breast Cancer Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: 0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores], tucatinib, Review, Other subheadings::Other subheadings::/drug therapy [Other subheadings], Lapatinib, 03 medical and health sciences, breast cancer, 0302 clinical medicine, Breast cancer, Metàstasi, Quality of life, pertuzumab, Trastuzumab, HER2, Internal medicine, Medicine, brain metastasis, lapatinib, skin and connective tissue diseases, RC254-282, business.industry, Neoplasms::Neoplastic Processes::Neoplasm Metastasis [DISEASES], Neoplasms. Tumors. Oncology. Including cancer and carcinogens, neoplasias::neoplasias por localización::neoplasias del sistema nervioso::neoplasias del sistema nervioso central::neoplasias cerebrales [ENFERMEDADES], medicine.disease, Metastatic breast cancer, metastatic, Neoplasms::Neoplasms by Site::Nervous System Neoplasms::Central Nervous System Neoplasms::Brain Neoplasms [DISEASES], neratinib, trastuzumab, 030104 developmental biology, Cervell - Càncer - Tractament, neoplasias::procesos neoplásicos::metástasis neoplásica [ENFERMEDADES], 030220 oncology & carcinogenesis, Neratinib, Pertuzumab, CNS, business, medicine.drug, Brain metastasis
Abstract: Simple Summary Development of brain metastases is an important event for patients with breast cancer, and it affects both their survival and their quality of life. Patients with HER2-positive breast cancer are more commonly affected by brain metastases compared to patients with HER2-negative/hormone receptor-positive breast cancer. It is essential to find proper therapies that reduce the risk for metastasis in the brain, as well as agents that are active when metastatic lesions develop. Management of HER2-positive breast cancer has drastically improved in recent years due to the development of several drugs targeting the HER2 receptor. This review aims to provide insight into current and novel treatment strategies for patients with brain metastases from HER2-positive breast cancer. Abstract Development of brain metastases can occur in up to 30–50% of patients with breast cancer, representing a significant impact on an individual patient in terms of survival and quality of life. Patients with HER2-positive breast cancer have an increased risk of developing brain metastases; however, screening for brain metastases is not currently recommended due to the lack of robust evidence to support survival benefit. In recent years, several novel anti-HER2 agents have led to significant improvements in the outcomes of HER2-positive metastatic breast cancer. Despite these advances, brain and leptomeningeal metastases from HER2-positive breast cancer remain a significant cause of morbidity and mortality, and their optimal management remains an unmet need. This review presents an update on the current and novel treatment strategies for patients with brain metastases from HER2-positive breast cancer and discusses the open questions in the field.
Published: 2021

254. The efficacy and safety of enzalutamide with trastuzumab in patients with HER2+and androgen receptor-positive metastatic or locally advanced breast cancer

Author: M.T. Huizing, Stephen Chan, Stefania Russo, Gail S. Wright, Joyce Steinberg, Andrew M Wardley, Ron Bose, Robyn R. Young, A. Jo Chien, Iulia Cristina Tudor, Andrea Rocca, Lowell L. Hart, Javier Cortes, Kathy D. Miller, Hope S. Rugo, Marie-Pascale Graas, Louise Provencher, Patrick Neven, Jennifer Sugg, Ian E. Krop, David Cameron, Vandana G. Abramson, Institut Català de la Salut, [Wardley A] NIHR Manchester Clinical Research Facility at The Christie NHS Foundation Trust and Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine, and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK. [Cortes J] Division of Breast Cancers and Gynecological Tumors, IOB Institute of Oncology, Quironsalud Group, Madrid and Barcelona, Spain. Breast Cancer & Melanoma Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Provencher L] Department of Surgery, Centre des Maladies du Sein, CHU de Québec-Université Laval, Québec, Canada. [Miller K] Indiana University Melvin and Bren Simon Cancer Center, Indiana University, Indianapolis, USA. [Chien AJ, Rugo HS] UCSF Comprehensive Cancer Center, University of California, San Francisco, USA, Vall d'Hebron Barcelona Hospital Campus, Wardley, Andrew, Cortes, Javier, Provencher, Louise, Miller, Kathy, Chien, A Jo, Rugo, Hope S, Steinberg, Joyce, Sugg, Jennifer, Tudor, Iulia C, Huizing, Manon, Young, Robyn, Abramson, Vandana, Bose, Ron, Hart, Lowell, Chan, Stephen, Cameron, David, Wright, Gail S, Graas, Marie-Pascale, Neven, Patrick, Rocca, Andrea, Russo, Stefania, and Krop, Ian E
Subjects: Oncology, Cancer Research, Human epidermal growth factor receptor 2, Receptor, ErbB-2, Neoplasms::Neoplasms by Site::Breast Neoplasms [DISEASES], epidemiología y bioestadística::epidemiología::usos de la epidemiología::eficacia [SALUD PÚBLICA], Phases of clinical research, Mama - Càncer - Quimioteràpia, chemistry.chemical_compound, Trastuzumab, Antineoplastic Combined Chemotherapy Protocols, terapéutica::farmacoterapia::farmacoterapia combinada [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Epidemiology and Biostatistics::Epidemiology::Uses of Epidemiology::Efficacy [PUBLIC HEALTH], skin and connective tissue diseases, Aged, 80 and over, DOCETAXEL, neoplasias::neoplasias por localización::neoplasias de la mama [ENFERMEDADES], education.field_of_study, Therapeutics::Drug Therapy::Drug Therapy, Combination [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], Androgen receptor, Enzalutamide, HER2, Metastatic breast cancer, Middle Aged, Evaluable Disease, OPEN-LABEL, Clinical Trial, Receptors, Androgen, Response Evaluation Criteria in Solid Tumors, Benzamides, TH3RESA, Female, Medicaments antineoplàstics - Eficàcia, Life Sciences & Biomedicine, medicine.drug, Adult, EXPRESSION, medicine.medical_specialty, Population, Breast Neoplasms, Breast cancer, Internal medicine, Nitriles, Phenylthiohydantoin, medicine, Humans, education, Aged, Science & Technology, business.industry, PHYSICIANS CHOICE, PERTUZUMAB, medicine.disease, chemistry, EMTANSINE, Human medicine, business
Abstract: Purpose Androgen receptor (AR) expression occurs in up to 86% of human epidermal growth factor receptor 2-positive (HER2+) breast cancers. In vitro, AR inhibitors enhance antitumor activity of trastuzumab, an anti-HER2 antibody, in trastuzumab-resistant HER2+ cell lines. This open-label, single-arm, phase II study evaluated the efficacy and safety of enzalutamide, an AR-signaling inhibitor, in patients with advanced HER2+ AR+ breast cancer previously treated with trastuzumab. Methods Eligible patients had measurable or non-measurable evaluable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, Eastern Cooperative Oncology Group status ≤ 1, no history of brain metastases, and previously received ≥ 1 anti-HER2 regimen for advanced disease. Patients received 160 mg oral enzalutamide daily and 6 mg/kg intravenous trastuzumab every 21 days until disease progression or unacceptable toxicity. Primary end point was clinical benefit rate at 24 weeks (CBR24); secondary end points included progression-free survival (PFS) and safety. Results Overall, 103 women were enrolled [median age 60 years (range 34–83)]; 62% had received ≥ 3 lines of prior anti-HER2 therapy. CBR24, comprising patients with confirmed partial responses (5%) and durable stable disease at 24 weeks (19%), was 24% in the efficacy evaluable set (n = 89). CBR24 did not seem related to AR-expression levels or hormone receptor status. Median PFS was 3.4 months (95% confidence interval 2.0–3.8). Overall, 97 (94%) patients experienced treatment-emergent adverse events (TEAEs), with fatigue most common (34%). Dyspnea (4%) and malignant neoplasm progression (3%) were the only TEAEs grade ≥ 3 reported in ≥ 3 patients. 22 patients (21%) reported serious TEAEs. Four patients (4%) experienced fatal, non-drug-related TEAEs. Conclusions Enzalutamide plus trastuzumab was well tolerated, and a subset of patients in this heavily pretreated population had durable disease control. Determination of biomarkers is needed to identify patients most likely to benefit from this combination. ClinicalTrials.gov number NCT02091960
Published: 2021
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255. Breast-Gynaecological & Immuno-Oncology International Cancer Conference (BGICC) Consensus and Recommendations for the Management of Triple-Negative Breast Cancer

Author: Jessica W.T. Leung, Sana Al-Sukhun, Omalkhair Abulkhair, Benjamin O. Anderson, Meteb Foheidi, Nagi S. El Saghir, Hany Abdel Aziz, Joseph Gligorov, Mohamed Sabry, Hamdy A. Azim, Hagar Elghazawy, Edith A. Perez, Frédérique Penault-Llorca, Bahadir M. Gulluoglu, Joaira Bakkach, Khaled Abdel Karim, Banu Arun, Pierfranco Conte, Valentina Guarneri, Hope S. Rugo, Hesham Elghazaly, Mohamed A Shehata, Mona Frolova, Philip Poortmans, Cheng Har Yip, Sandra M. Swain, Manal Mohamed El-mahdy, Nermean Bahie Eldin, Alaa Kandil, Mohamed El-Shinawi, Charles M. Balch, Marwan Ghosn, Wentao Yang, Matti Aapro, Heba M. El-Zawahry, Adel T. Aref, Armando E. Giuliano, Roberto Orecchia, Ruslan M. Paltuev, Ain Shams University (ASU), Department of Medicine, University of California San Francisco Comprehensive Cancer Center, San Francisco, CA 94158, Clinical Oncology Department, Kasr Alainy School of Medicine, Cairo University, Giza 12613, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, MedStar Health, Washington, DC 20007, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, Breast Center, Clinique de Genolier, 1272 Genolier, Department of Hematology & Oncology, Mayo Clinic, Jacksonville, FL 32224, University of Washington [Seattle], Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Department of Surgery, Oncology and Gastroenterology, University of Padova, Istituto Oncologico Veneto IOV IRCCS, 35128 Padova, Department of Internal Medicine, Division of Hematology Oncology, American University of Beirut Medical Center, Beirut 1107 2020, Subang Jaya Medical Centre, Kuala Lumpur 47500, Université Saint-Joseph de Beyrouth (USJ), University of Antwerp (UA), Clinical oncology Department, Menoufia University, Shebin Elkom 51132, Department of Surgery, Surgical Oncology Division, Cedars-Sinai Medical Center, Los Angeles, CA 90048, Department of Breast Imaging, Division of Diagnostic Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Breast & Endocrine Surgery Unit, Marmara University School of Medicine, University Hospital, Istanbul 34722, Federal State Budgetary Institution 'NN Blokhin National Medical Research Center of Oncology' of the Ministry of Health of the Russian Federation, 127994 Moscow, Surgical Oncology Department, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, Università degli Studi di Milano = University of Milan (UNIMI), Al Hyatt Oncology Practice, Amman 11183, Department of Clinical Oncology, Alexandria School of Medicine, Alexandria 21131, Russian Association of Oncological Mammology, Department of Breast Tumours of Federal State Budgetary Institution 'Petrov Research Institute of Oncology', 197758 Saint Petersburg, College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Adult Medical Oncology, Princess Noorah Oncology Center, King Abdulaziz Medical City, Ministry of National Guard Health Affairs-Western Region, Jeddah 22384, Vice President of Galala University, Galala University, Suez 435611, Oncology Department, Alfaisal university, Alhabib Hospital, Riyad 11533, Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai 200032, University of Adelaide, Biomedical Genomics & Oncogenetics Research Laboratory, Faculty of Sciences and Techniques of Tangier, Abdel Malek Essaadi University, Tangier 90000, Elghazaly, Hesham, Rugo, Hope S., Azim, Hamdy A., Swain, Sandra M., Arun, Banu, Aapro, Matti, Perez, Edith A., Anderson, Benjamin O., Penault-Llorca, Frederique, Conte, Pierfranco, El Saghir, Nagi S., Yip, Cheng-Har, Ghosn, Marwan, Poortmans, Philip, Shehata, Mohamed A., Giuliano, Armando E., Leung, Jessica W. T., Guarneri, Valentina, Gligorov, Joseph, Gulluoglu, Bahadir M., Abdel Aziz, Hany, Frolova, Mona, Sabry, Mohamed, Balch, Charles M., Orecchia, Roberto, El-Zawahry, Heba M., Al-Sukhun, Sana, Abdel Karim, Khaled, Kandil, Alaa, Paltuev, Ruslan M., Foheidi, Meteb, El-Shinawi, Mohamed, ElMahdy, Manal, Abulkhair, Omalkhair, Yang, Wentao, Aref, Adel T., Bakkach, Joaira, Bahie Eldin, Nermean, Elghazawy, Hagar, Clinical Oncology Department, Faculty of Medicine, Ain Shams University, Cairo 11566, Breast Health Global Initiative, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA 98195, Hematology and Oncology Department, Saint Joseph University, Beirut 1104 2020, Iridium Kankernetwerk and Faculty of Medicine and Health Sciences, University of Antwerp, 2610 Wilrijk-Antwer, Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Scientific Directorate, IRCCS European Institute of Oncology (IEO), and University of Milan, 20122 Milan, Department of General Surgery, Faculty of Medicine, Ain Shams University, Cairo 11566, Department of Pathology, Ain shams University, Cairo 11566, and The School of Public Health, University of Adelaide, Adelaide 5005
Subjects: 0301 basic medicine, Cancer Research, medicine.medical_specialty, POSTMASTECTOMY RADIOTHERAPY, medicine.medical_treatment, [SDV]Life Sciences [q-bio], education, COMPLETE RESPONSE PCR, Disease, MUTATION CARRIERS, Guidelines, 03 medical and health sciences, NEOADJUVANT CHEMOTHERAPY, 0302 clinical medicine, Breast cancer, ADJUVANT CHEMOTHERAPY, medicine, DISEASE-FREE SURVIVAL, TUMOR-INFILTRATING LYMPHOCYTES, platinum, LOCOREGIONAL RECURRENCE, AMERICAN SOCIETY, Triple-negative breast cancer, RC254-282, business.industry, BRCA mutations, Consensus, Immunotherapy, Platinum, Cancer conference, Consensus conference, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Evidence-based medicine, RANDOMIZED PHASE-III, medicine.disease, 3. Good health, Clinical trial, 030104 developmental biology, Oncology, consensus, 030220 oncology & carcinogenesis, Family medicine, triple-negative breast cancer, Human medicine, immunotherapy, business, Mastectomy
Abstract: Simple Summary Despite the impressive progress in the treatment of triple-negative breast cancer (TNBC), oncologists still face several provocative clinical scenarios in daily practice where clear evidence-based recommendations are lacking, and expert opinion is of utmost importance. In an attempt to seek guidance for these controversial topics in TNBC management, a consensus recommendations session for TNBC was held during the 12th round of the Breast-Gynaecological & Immuno-oncology International Cancer Conference (BGICC) Egypt, 2020. This special session convened a multidisciplinary committee of 35 panellists who specialize in breast cancer care from 13 countries. The consensus covered all the aspects of TNBC management starting from defining TNBC to the management of metastatic disease and highlighted the rapidly evolving landscape in this field. Consensus was reached in 70% of the statements (35/50). In addition, areas of warranted research were identified to guide future prospective clinical trials. Background: The management of patients with triple-negative breast cancer (TNBC) is challenging with several controversies and unmet needs. During the 12th Breast-Gynaecological & Immuno-oncology International Cancer Conference (BGICC) Egypt, 2020, a panel of 35 breast cancer experts from 13 countries voted on consensus guidelines for the clinical management of TNBC. The consensus was subsequently updated based on the most recent data evolved lately. Methods: A consensus conference approach adapted from the American Society of Clinical Oncology (ASCO) was utilized. The panellists voted anonymously on each question, and a consensus was achieved when >= 75% of voters selected an answer. The final consensus was later circulated to the panellists for critical revision of important intellectual content. Results and conclusion: These recommendations represent the available clinical evidence and expert opinion when evidence is scarce. The percentage of the consensus votes, levels of evidence and grades of recommendation are presented for each statement. The consensus covered all the aspects of TNBC management starting from defining TNBC to the management of metastatic disease and highlighted the rapidly evolving landscape in this field. Consensus was reached in 70% of the statements (35/50). In addition, areas of warranted research were identified to guide future prospective clinical trials.
Published: 2021
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256. Nivolumab and Ipilimumab as Maintenance Therapy in Extensive-Disease Small-Cell Lung Cancer: CheckMate 451

Author: Wen Hong Lin, Carlos H. Barrios, Martin Reck, Ramaswamy Govindan, Neal Ready, Dimple Pandya, Hye Ryun Kim, Taofeek K. Owonikoko, Alejandro Navarro, Keunchil Park, Laurent Greillier, Ivor John Percent, Vanesa Gutierrez, Miten Patel, Jong Seok Lee, Parul Doshi, Michael Schenker, Solange Peters, Shaker R. Dakhil, Jerónimo Rodríguez-Cid, Daniel Morgensztern, Christine Baudelet, Sofia Baka, Jonathan F. Baden, Giovanni Selvaggi, Institut Català de la Salut, [Owonikoko TK] Winship Cancer Institute of Emory University, Atlanta, GA. [Park K] Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea. [Govindan R] Alvin J Siteman Cancer Center at Washington University School of Medicine, St Louis, MO. [Ready N] Duke University Medical Center, Durham, NC. [Reck M] Department of Thoracic Oncology, Airway Research Center North, German Center for Lung Research, LungClinic, Grosshansdorf, Germany. [Peters S] Oncology Department, Lausanne University Hospital, Lausanne, Switzerland. [Navarro A] Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus, Emory University [Atlanta, GA], Samsung Medical Center Sungkyunkwan University School of Medicine, Institute Division of Hematology/Oncology, Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), Duke University Medical Center, German Center for Lung Research, Lausanne University Hospital, Vall d'Hebron Institute of Oncology [Barcelone] (VHIO), Vall d'Hebron University Hospital [Barcelona], Instituto Nacional de Enfermedades Respiratorias [México, Mexico], SF Nectarie Oncology Center [Craiova, Romania], Seoul National University Bundang Hospital (SNUBH), Hospital Regional Universitario de Málaga = Regional University Hospital of Malaga [Spain], Pontifical Catholic University of Rio Grande do Sul (PUC-RS), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hôpital Nord [CHU - APHM], Interbalkan Medical Center of Thessaloniki, Bristol-Myers Squibb [Princeton], and Yonsei University College of Medicine [Séoul, Corée du Sud]
Subjects: 0301 basic medicine, Oncology, Male, Cancer Research, Lung Neoplasms, medicine.medical_treatment, Checkmate, Other subheadings::Other subheadings::/drug therapy [Other subheadings], [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, 0302 clinical medicine, Maintenance therapy, Antineoplastic Combined Chemotherapy Protocols, Other subheadings::/therapeutic use [Other subheadings], Aged, 80 and over, terapéutica::terapéutica::farmacoterapia::protocolos antineoplásicos::terapéutica::farmacoterapia::protocolos de quimioterapia antineoplásica combinada [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Middle Aged, Nivolumab, 030220 oncology & carcinogenesis, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Non small cell, medicine.drug, Adult, medicine.medical_specialty, neoplasias::neoplasias por localización::neoplasias torácicas::neoplasias del tracto respiratorio::neoplasias pulmonares::neoplasias de los bronquios::carcinoma broncogénico::carcinoma pulmonar de células pequeñas [ENFERMEDADES], Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores], [SDV.CAN]Life Sciences [q-bio]/Cancer, Ipilimumab, Quimioteràpia combinada, 03 medical and health sciences, Double-Blind Method, Internal medicine, Therapeutics::Therapeutics::Drug Therapy::Antineoplastic Protocols::Therapeutics::Drug Therapy::Antineoplastic Combined Chemotherapy Protocols [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], medicine, Humans, Lung cancer, Aged, Chemotherapy, Extensive Disease, business.industry, Otros calificadores::/uso terapéutico [Otros calificadores], medicine.disease, Small Cell Lung Carcinoma, 030104 developmental biology, Neoplasms::Neoplasms by Site::Thoracic Neoplasms::Respiratory Tract Neoplasms::Lung Neoplasms::Bronchial Neoplasms::Carcinoma, Bronchogenic::Small Cell Lung Carcinoma [DISEASES], business, Pulmons - Càncer - Tractament
Abstract: PURPOSE In extensive-disease small-cell lung cancer (ED-SCLC), response rates to first-line platinum-based chemotherapy are robust, but responses lack durability. CheckMate 451, a double-blind phase III trial, evaluated nivolumab plus ipilimumab and nivolumab monotherapy as maintenance therapy following first-line chemotherapy for ED-SCLC. METHODS Patients with ED-SCLC, Eastern Cooperative Oncology Group performance status 0-1, and no progression after ≤ 4 cycles of first-line chemotherapy were randomly assigned (1:1:1) to nivolumab 1 mg/kg plus ipilimumab 3 mg/kg once every 3 weeks for 12 weeks followed by nivolumab 240 mg once every 2 weeks, nivolumab 240 mg once every 2 weeks, or placebo for ≤ 2 years or until progression or unacceptable toxicity. Primary end point was overall survival (OS) with nivolumab plus ipilimumab versus placebo. Secondary end points were hierarchically tested. RESULTS Overall, 834 patients were randomly assigned. The minimum follow-up was 8.9 months. OS was not significantly prolonged with nivolumab plus ipilimumab versus placebo (hazard ratio [HR], 0.92; 95% CI, 0.75 to 1.12; P = .37; median, 9.2 v 9.6 months). The HR for OS with nivolumab versus placebo was 0.84 (95% CI, 0.69 to 1.02); the median OS for nivolumab was 10.4 months. Progression-free survival HRs versus placebo were 0.72 for nivolumab plus ipilimumab (95% CI, 0.60 to 0.87) and 0.67 for nivolumab (95% CI, 0.56 to 0.81). A trend toward OS benefit with nivolumab plus ipilimumab was observed in patients with tumor mutational burden ≥ 13 mutations per megabase. Rates of grade 3-4 treatment-related adverse events were nivolumab plus ipilimumab (52.2%), nivolumab (11.5%), and placebo (8.4%). CONCLUSION Maintenance therapy with nivolumab plus ipilimumab did not prolong OS for patients with ED-SCLC who did not progress on first-line chemotherapy. There were no new safety signals.
Published: 2021
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257. Biomarker-Guided Anti-Egfr Rechallenge Therapy in Metastatic Colorectal Cancer

Author: Stefania Napolitano, Vincenzo Famiglietti, Vincenzo De Falco, J. Ros, Elena Elez Fernandez, Pietro Paolo Vitiello, Fortunato Ciardiello, Evaristo Maiello, Tiziana Latiano, Teresa Troiani, Giulia Martini, Davide Ciardiello, Erika Martinelli, Institut Català de la Salut, [Ciardiello D] Oncologia Medica, Dipartimento di Medicina di Precisione, Università degli Studi della Campania Luigi Vanvitelli, 80131 Naples, Italy. Oncologia Medica, Ospedale Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy. [Martini G, Famiglietti V, Napolitano S, De Falco V, Troiani T] Oncologia Medica, Dipartimento di Medicina di Precisione, Università degli Studi della Campania Luigi Vanvitelli, 80131 Naples, Italy. [Ros J] Oncologia Medica, Dipartimento di Medicina di Precisione, Università degli Studi della Campania Luigi Vanvitelli, 80131 Naples, Italy. Servei d’Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. IOB-Quiron, UVic-UCC, 08035 Barcelona, Spain. [Elez Fernandez E] Servei d’Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. IOB-Quiron, UVic-UCC, 08035 Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus, Ciardiello, D., Martini, G., Famiglietti, V., Napolitano, S., De Falco, V., Troiani, T., Latiano, T. P., Ros, J., Fernandez, E. E., Vitiello, P. P., Maiello, E., Ciardiello, F., and Martinelli, E.
Subjects: 0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, Colorectal cancer, medicine.medical_treatment, rechallenge, anti-EGFR monoclonal antibodies, Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores], Review, Other subheadings::Other subheadings::/drug therapy [Other subheadings], 03 medical and health sciences, 0302 clinical medicine, Neoplasms::Neoplasms by Site::Digestive System Neoplasms::Gastrointestinal Neoplasms::Intestinal Neoplasms::Colorectal Neoplasms [DISEASES], Growth factor receptor, Metàstasi, Anti-EGFR monoclonal antibodie, Internal medicine, Recte - Càncer - Tractament, Medicine, Panitumumab, Còlon - Càncer -Tractament, Other subheadings::/therapeutic use [Other subheadings], Liquid biopsy, RC254-282, Chemotherapy, Cetuximab, business.industry, Otros calificadores::/uso terapéutico [Otros calificadores], metastatic colorectal cancer, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, acciones y usos químicos::acciones farmacológicas::usos terapéuticos::antineoplásicos [COMPUESTOS QUÍMICOS Y DROGAS], medicine.disease, neoplasias::neoplasias por localización::neoplasias del sistema digestivo::neoplasias gastrointestinales::neoplasias intestinales::neoplasias colorrectales [ENFERMEDADES], 030104 developmental biology, 030220 oncology & carcinogenesis, Cancer cell, Biomarker (medicine), Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Antineoplastic Agents [CHEMICALS AND DRUGS], business, medicine.drug
Abstract: Simple Summary The survival of patients with metastatic colorectal cancer (mCRC) has been improved over the years and now reaches 30–40 months. However, few therapeutic options are available after failure of first- and second-line treatments. In fact, prognosis of chemo-refractory mCRC remains poor. Therefore, new therapeutic strategies are needed. Emerging evidence suggest that retreatment with epidermal growth factor (EGFR) inhibitors after a treatment break, in patients that obtained a clinical benefit by previous anti-EGFR, could lead to prolonged survival. The rationale beyond this “rechallenge” strategy is that after a “treatment holiday” EGFR resistant cancer cells decay, restoring the sensibility to EGFR blockade. In this review we analyze the current knowledge of retreatment with EGFR inhibitors, examine the role of novel biomarkers that can guide the appropriate selection of patients. Finally, we discuss future perspectives and on-going clinical trials. Abstract The prognosis of patients with metastatic colorectal cancer (mCRC) who progressed to the first and the second lines of treatment is poor. Thus, new therapeutic strategies are needed. During the last years, emerging evidence suggests that retreatment with anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (MAbs) in the third line of mCRC patients, that have previously obtained clinical benefit by first-line therapy with anti-EGFR MAbs plus chemotherapy, could lead to prolonged survival. The rationale beyond this “rechallenge” strategy is that, after disease progression to first line EGFR-based therapy, a treatment break from anti-EGFR drugs results in RAS mutant cancer cell decay, restoring the sensitivity of cancer cells to cetuximab and panitumumab. In fact, rechallenge treatment with anti-EGFR drugs has shown promising clinical activity, particularly in patients with plasma RAS and BRAF wild type circulating tumor DNA, as defined by liquid biopsy analysis at baseline treatment. The aim of this review is to analyze the current knowledge on rechallenge and to investigate the role of novel biomarkers that can guide the appropriate selection of patients that could benefit from this therapeutic strategy. Finally, we discuss on-going trials and future perspectives.
Published: 2021

258. Evaluation of the association of heterozygous germline variants in NTHL1 with breast cancer predisposition: an international multi-center study of 47,180 subjects

Author: Lisa Devereux, Douglas F. Easton, Simone McInerny, Melissa C. Southey, R. K. Schmutzler, Orland Diez, Muriel A. Adank, Tu Nguyen-Dumont, Alfons Meindl, Alejandro Moles-Fernández, Marjanka K. Schmidt, Rodney J. Scott, Martine Dumont, Paul A. James, Christoph Engel, Fabienne Lesueur, Penny Soucy, Yu Kuan Huang, N Li, Elad Ziv, Elodie Girard, Eric Hahnen, Magnus Zethoven, Jamie Allen, Kylie L. Gorringe, Susan L. Neuhausen, Irene L. Andrulis, Dane Cheasley, Jacques Simard, John L. Hopper, Ian G. Campbell, Niko Thio, Sara Gutiérrez-Enríquez, Institut Català de la Salut, [Li N] Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, Melbourne, Vic, Australia. Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Vic, Australia. Parkville Familial Cancer Centre, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, Vic, Australia. [Zethoven M] Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, Melbourne, Vic, Australia. Bioinformatics Core Facility, Peter MacCallum Cancer Centre, Melbourne, Vic, Australia. [McInerny S] Parkville Familial Cancer Centre, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, Vic, Australia. [Devereux L] Lifepool, Peter MacCallum Cancer Centre, Melbourne, Vic, Australia. [Huang YK] Upper Gastrointestinal Translational Research Laboratory, Peter MacCallum Cancer Centre, Melbourne, Vic, Australia. Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Melbourne, Vic, Australia. [Thio N] Bioinformatics Core Facility, Peter MacCallum Cancer Centre, Melbourne, Vic, Australia. [Gutiérrez-Enríquez S, Moles-Fernández A] Hereditary Cancer Genetics Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Diez O] Hereditary Cancer Genetics Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Àrea de Genètica Clínica i Molecular, Hospital Universitari Vall d’Hebron, Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus, Li, Na [0000-0003-1578-9561], Devereux, Lisa [0000-0003-2435-5888], Huang, Yu-Kuan [0000-0003-2262-7069], Cheasley, Dane [0000-0002-1170-4690], Gutiérrez-Enríquez, Sara [0000-0002-1711-6101], Simard, Jacques [0000-0001-6906-3390], Schmidt, Marjanka K [0000-0002-2228-429X], Andrulis, Irene L [0000-0002-4226-6435], Engel, Christoph [0000-0002-7247-282X], Lesueur, Fabienne [0000-0001-7404-4549], Easton, Douglas F [0000-0003-2444-3247], Scott, Rodney J [0000-0001-7724-3404], Gorringe, Kylie L [0000-0001-5681-2022], James, Paul A [0000-0002-4361-4657], Campbell, Ian G [0000-0002-7773-4155], Apollo - University of Cambridge Repository, Allen, Jamie [0000-0002-8677-2225], Schmidt, Marjanka K. [0000-0002-2228-429X], Andrulis, Irene L. [0000-0002-4226-6435], Easton, Douglas F. [0000-0003-2444-3247], Scott, Rodney J. [0000-0001-7724-3404], Gorringe, Kylie L. [0000-0001-5681-2022], James, Paul A. [0000-0002-4361-4657], and Campbell, Ian G. [0000-0002-7773-4155]
Subjects: 0301 basic medicine, Oncology, Mama - Càncer - Prognosi, Neoplasms::Neoplasms by Site::Breast Neoplasms [DISEASES], Genetic Phenomena::Genotype::Genetic Predisposition to Disease [PHENOMENA AND PROCESSES], Diàtesi, 32 Biomedical and Clinical Sciences, medicine.disease_cause, 631/208/737, Germline, 0302 clinical medicine, Other subheadings::/diagnosis [Other subheadings], Missense mutation, 2.1 Biological and endogenous factors, Pharmacology (medical), 631/208/68, RC254-282, Cancer, 2 Aetiology, Mutation, neoplasias::neoplasias por localización::neoplasias de la mama [ENFERMEDADES], medicine.diagnostic_test, article, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, 4203 Health Services and Systems, 3. Good health, 030220 oncology & carcinogenesis, Malalties congènites, Haploinsufficiency, medicine.medical_specialty, DNA repair, Otros calificadores::/diagnóstico [Otros calificadores], 631/67/69, 03 medical and health sciences, Breast cancer, Clinical Research, Internal medicine, Breast Cancer, medicine, Genetics, Radiology, Nuclear Medicine and imaging, Genetic Testing, Genetic testing, fenómenos genéticos::genotipo::predisposición genética a la enfermedad [FENÓMENOS Y PROCESOS], business.industry, Prevention, Human Genome, 42 Health Sciences, 631/67/1347, medicine.disease, 3211 Oncology and Carcinogenesis, 631/208/199, 030104 developmental biology, business
Abstract: Bi-allelic loss-of-function (LoF) variants in the base excision repair (BER) gene NTHL1 cause a high-risk hereditary multi-tumor syndrome that includes breast cancer, but the contribution of heterozygous variants to hereditary breast cancer is unknown. An analysis of 4985 women with breast cancer, enriched for familial features, and 4786 cancer-free women revealed significant enrichment for NTHL1 LoF variants. Immunohistochemistry confirmed reduced NTHL1 expression in tumors from heterozygous carriers but the NTHL1 bi-allelic loss characteristic mutational signature (SBS 30) was not present. The analysis was extended to 27,421 breast cancer cases and 19,759 controls from 10 international studies revealing 138 cases and 93 controls with a heterozygous LoF variant (OR 1.06, 95% CI: 0.82–1.39) and 316 cases and 179 controls with a missense variant (OR 1.31, 95% CI: 1.09–1.57). Missense variants selected for deleterious features by a number of in silico bioinformatic prediction tools or located within the endonuclease III functional domain showed a stronger association with breast cancer. Somatic sequencing of breast cancers from carriers indicated that the risk associated with NTHL1 appears to operate through haploinsufficiency, consistent with other described low-penetrance breast cancer genes. Data from this very large international multicenter study suggests that heterozygous pathogenic germline coding variants in NTHL1 may be associated with low- to moderate- increased risk of breast cancer.
Published: 2021

259. ctDNA-Based Liquid Biopsy of Cerebrospinal Fluid in Brain Cancer

Author: Laura Escudero, Francisco Martínez-Ricarte, Joan Seoane, Institut Català de la Salut, [Escudero L] Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Vall d’Hebron Hospital Universitari, Barcelona, Spain, Barcelona, Spain. [Martínez-Ricarte F] Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Vall d’Hebron Hospital Universitari, Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. [Seoane J] Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Vall d’Hebron Hospital Universitari, Barcelona, Spain, Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. CIBERONC (Centro de Investigación Biomédica en Red de Cáncer), Instituto de Salud Carlos III, 28029 Madrid, Spain. ICREA (Institució Catalana de Recerca i Estudis Avançats), 08010 Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: Neoplasms::Neoplasms by Site::Nervous System Neoplasms::Central Nervous System Neoplasms [DISEASES], 0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, neoplasias::neoplasias por localización::neoplasias del sistema nervioso::neoplasias del sistema nervioso central [ENFERMEDADES], Tumour heterogeneity, Review, Disease, Brain cancer, cerebrospinal fluid, Liquid biopsies, nucleótidos y nucleósidos de ácidos nucleicos::ácidos nucleicos::ácidos nucleicos libres de células::ADN tumoral circulante [COMPUESTOS QUÍMICOS Y DROGAS], 03 medical and health sciences, liquid biopsies, 0302 clinical medicine, Cerebrospinal fluid, Central nervous system malignancies, Internal medicine, Diagnosis::Diagnostic Techniques and Procedures::Clinical Laboratory Techniques::Cytological Techniques::Cytodiagnosis::Biopsy::Liquid Biopsy [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], Medicine, Liquid biopsy, central nervous system malignancies, RC254-282, Therapeutic strategy, brain cancer, Otros calificadores::Otros calificadores::/líquido cefalorraquídeo [Otros calificadores], Nucleic Acids, Nucleotides, and Nucleosides::Nucleic Acids::Cell-Free Nucleic Acids::Circulating Tumor DNA [CHEMICALS AND DRUGS], business.industry, Líquid cefaloraquidi - Biòpsia, circulating tumour DNA, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Research findings, Biomarker (cell), diagnóstico::técnicas y procedimientos diagnósticos::técnicas de laboratorio clínico::técnicas citológicas::citodiagnóstico::biopsia::biopsia líquida [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], 030104 developmental biology, 030220 oncology & carcinogenesis, Sistema nerviós central - Malalties - Diagnòstic, business, Other subheadings::Other subheadings::/cerebrospinal fluid [Other subheadings], Circulating tumour DNA
Abstract: Simple Summary The optimal treatment and management of patients with brain cancer depend on the molecular characteristics of their tumour. Since the tumour changes with time, it is, therefore, essential to characterise the tumour of each patient at the exact time of selecting the most suitable therapeutic strategy. However, obtaining a tumour biopsy for its characterisation is a risky and invasive procedure and, sometimes, not even feasible, leading to a lack of information about the tumour. These challenges can be overcome by using a liquid biopsy of cerebrospinal fluid. Brain cancer cells release DNA into the cerebrospinal fluid, and the analysis of the cell-free circulating tumour DNA can reveal the genetic profile of brain cancer in a relatively noninvasive manner. In this review, we revise the recent results in this field that show how circulating tumour DNA in cerebrospinal fluid can provide diagnostic and prognostic information, identify potential therapeutic targets, monitor the tumour response or resistance to treatment, and help to identify tumour relapse. Abstract The correct characterisation of central nervous system (CNS) malignancies is crucial for accurate diagnosis and prognosis and also the identification of actionable genomic alterations that can guide the therapeutic strategy. Surgical biopsies are performed to characterise the tumour; however, these procedures are invasive and are not always feasible for all patients. Moreover, they only provide a static snapshot and can miss tumour heterogeneity. Currently, monitoring of CNS cancer is performed by conventional imaging techniques and, in some cases, cytology analysis of the cerebrospinal fluid (CSF); however, these techniques have limited sensitivity. To overcome these limitations, a liquid biopsy of the CSF can be used to obtain information about the tumour in a less invasive manner. The CSF is a source of cell-free circulating tumour DNA (ctDNA), and the analysis of this biomarker can characterise and monitor brain cancer. Recent studies have shown that ctDNA is more abundant in the CSF than plasma for CNS malignancies and that it can be sequenced to reveal tumour heterogeneity and provide diagnostic and prognostic information. Furthermore, analysis of longitudinal samples can aid patient monitoring by detecting residual disease or even tracking tumour evolution at relapse and, therefore, tailoring the therapeutic strategy. In this review, we provide an overview of the potential clinical applications of the analysis of CSF ctDNA and the challenges that need to be overcome in order to translate research findings into a tool for clinical practice.
Published: 2021

260. Immune microenvironment characterisation and dynamics during anti-HER2-based neoadjuvant treatment in HER2-positive breast cancer

Author: Xavier Guardia, Garazi Serna, J. Cortés, Begoña Bermejo, Roberta Fasani, Patricia Galván, Gaia Griguolo, Nuria Chic, Luis Manso, Serafin Morales, N. Martínez, I Garau, Maria Vidal, Montse Muñoz, Antonio Llombart-Cussac, Mafalda Oliveira, Paolo Nuciforo, Aleix Prat, Laia Paré, Patricia Villagrasa, E Martínez, Sonia Pernas, J. Alarcón, Tomás Pascual, Ramon Lopez, Institut Català de la Salut, [Griguolo G] Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy. Division of Oncology 2, Istituto Oncologico Veneto IRCCS, Padova, Italy. Translational Genomics and Targeted Therapeutics in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain. [Serna G, Fasani R, Guardia X] Molecular Oncology Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Pascual T] Translational Genomics and Targeted Therapeutics in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain. Department of Medical Oncology, Hospital Clínic de Barcelona, Barcelona, Spain. SOLTI Breast Cancer Research Group, Barcelona, Spain. [Chic N] Translational Genomics and Targeted Therapeutics in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain. Department of Medical Oncology, Hospital Clínic de Barcelona, Barcelona, Spain. [Oliveira M] Servei d’Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Breast Cancer and Melanoma Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Nuciforo P] Molecular Oncology Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. SOLTI Breast Cancer Research Group, Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: 0301 basic medicine, Cancer Research, Stromal cell, Pronòstic mèdic, Tumour heterogeneity, CD3, Neoplasms::Neoplasms by Site::Breast Neoplasms [DISEASES], Article, Càncer de mama, 03 medical and health sciences, Breast cancer, 0302 clinical medicine, Immune system, medicine, skin and connective tissue diseases, RC254-282, Otros calificadores::/terapia [Otros calificadores], neoplasias::neoplasias por localización::neoplasias de la mama [ENFERMEDADES], biology, business.industry, FOXP3, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Other subheadings::/therapy [Other subheadings], Prognosis, medicine.disease, Expressió gènica, Neoadjuvant Therapy, Blockade, 030104 developmental biology, Oncology, Hormone receptor, 030220 oncology & carcinogenesis, Mama - Càncer - Tractament, biology.protein, Cancer research, Tumour immunology, terapéutica::tratamiento combinado::tratamiento neoadyuvante [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Gene expression, business, CD8
Abstract: Taca de plasma sec; Hepatitis C; Targeta de separació de plasma Mancha de plasma seco; Hepatitis C; Tarjeta de separación de plasma Dried plasma spot; Hepatitis C; Plasma separation card Despite their recognised role in HER2-positive (HER2+) breast cancer (BC), the composition, localisation and functional orientation of immune cells within tumour microenvironment, as well as its dynamics during anti-HER2 treatment, is largely unknown. We here investigate changes in tumour-immune contexture, as assessed by stromal tumour-infiltrating lymphocytes (sTILs) and by multiplexed spatial cellular phenotyping, during treatment with lapatinib-trastuzumab in HER2+ BC patients (PAMELA trial). Moreover, we evaluate the relationship of tumour-immune contexture with hormone receptor status, intrinsic subtype and immune-related gene expression. sTIL levels increase after 2 weeks of HER2 blockade in HR-negative disease and HER2-enriched subtype. This is linked to a concomitant increase in cell density of all four immune subpopulations (CD3+, CD4+, CD8+, Foxp3+). Moreover, immune contexture analysis showed that immune cells spatially interacting with tumour cells have the strongest association with response to anti-HER2 treatment. Subsequently, sTILs consistently decrease at the surgery in patients achieving pathologic complete response, whereas most residual tumours at surgery remain inflamed, possibly reflecting a progressive loss of function of T cells. Understanding the features of the resulting tumour immunosuppressive microenvironment has crucial implications for the design of new strategies to de-escalate or escalate systemic therapy in early-stage HER2+ BC. We thank all the patients and family members for participating in the PAMELA study. This study was supported, in part, by Instituto de Salud Carlos III—PI16/00904, The Breast Cancer Research Foundation and Fundación Científica Asociación Española Contra el Cáncer (Ayuda Postdoctoral AECC 2017), Fundación Merck—Immunología and Comprehensive Programme of Cancer Immunotherapy & Immunology (CAIMI) BBVA Foundation (grant number 89/2017). Acknowledgements to the Cellex Foundation for providing research facilities and equipment. G.G. acknowledges funding from a 2019 Conquer Cancer Foundation YIA in Breast Cancer. This work has been realised in the Surgery and Morphological Sciences Doctorate framework of Univ Autonoma de Barcelona.
Published: 2021

261. A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Author: Coignard, Juliette, Lush, Michael, Beesley, Jonathan, O’Mara, Tracy A., Dennis, Joe, Tyrer, Jonathan P., Barnes, Daniel R., McGuffog, Lesley, Leslie, Goska, Bolla, Manjeet K., Adank, Muriel A., Agata, Simona, Ahearn, Thomas, Aittomäki, Kristiina, Andrulis, Irene L., Anton-Culver, Hoda, Arndt, Volker, Arnold, Norbert, Aronson, Kristan J., Arun, Banu K., Augustinsson, Annelie, Azzollini, Jacopo, Barrowdale, Daniel, Baynes, Caroline, Becher, Heko, Bermisheva, Marina, Bernstein, Leslie, Białkowska, Katarzyna, Blomqvist, Carl, Bojesen, Stig E., Bonanni, Bernardo, Borg, Ake, Brauch, Hiltrud, Brenner, Hermann, Burwinkel, Barbara, Buys, Saundra S., Caldés, Trinidad, Caligo, Maria A., Campa, Daniele, Carter, Brian D., Castelao, Jose E., Chang-Claude, Jenny, Chanock, Stephen J., Chung, Wendy K., Claes, Kathleen B. M., Clarke, Christine L., Bertrand, Ophélie, Caputo, Sandrine, Dupré, Anaïs, le Mentec, Marine, Belotti, Muriel, Birot, Anne-Marie, Buecher, Bruno, Fourme, Emmanuelle, Gauthier-Villars, Marion, Golmard, Lisa, Houdayer, Claude, Moncoutier, Virginie, de Pauw, Antoine, Saule, Claire, Sinilnikova, Olga, Mazoyer, Sylvie, Damiola, Francesca, Barjhoux, Laure, Verny-Pierre, Carole, Léone, M. lanie, Boutry-Kryza, Nadia, Calender, Alain, Giraud, Sophie, Caron, Olivier, Guillaud-Bataille, Marine, Bressac-de-Paillerets, Brigitte, Bignon, Yves- Jean, Uhrhammer, Nancy, Lasset, Christine, Bonadona, Valérie, Berthet, Pascaline, Vaur, Dominique, Castera, Laurent, Noguchi, Tetsuro, Popovici, Cornel, Sobol, Hagay, Bourdon, Violaine, Remenieras, Audrey, Noguès, Catherine, Coupier, Isabelle, Pujol, Pascal, Dumont, Aurélie, Révillion, Françoise, Adenis, Claude, Muller, Danièle, Barouk-Simonet, Emmanuelle, Bonnet, Françoise, Bubien, Virginie, Sevenet, Nicolas, Longy, Michel, Toulas, Christine, Guimbaud, Rosine, Gladieff, Laurence, Feillel, Viviane, Leroux, Dominique, Dreyfus, H. lène, Rebischung, Christine, Peysselon, Magalie, Coron, Fanny, Faivre, Laurence, Baurand, Amandine, Jacquot, Caroline, Bertolone, Geoffrey, Lizard, Sarab, Prieur, Fabienne, Lebrun, Marine, Kientz, Caroline, Ferrer, Sandra Fert, Mari, V. ronique, Vénat-Bouvet, Laurence, Delnatte, Capucine, Bézieau, Stéphane, Mortemousque, Isabelle, Coulet, Florence, Colas, Chrystelle, Soubrier, Florent, Warcoin, Mathilde, Sokolowska, Johanna, Bronner, Myriam, Collonge-Rame, Marie-Agnès, Damette, Alexandre, Gesta, Paul, Lallaoui, Hakima, Chiesa, Jean, Molina-Gomes, Denise, Ingster, Olivier, Gregory, Helen, Miedzybrodzka, Zosia, Morrison, Patrick J., Ong, Kai-ren, Donaldson, Alan, Rogers, Mark T., Kennedy, M. John, Porteous, Mary E., Brewer, Carole, Davidson, Rosemarie, Izatt, Louise, Brady, Angela, Barwell, Julian, Adlard, Julian, Foo, Claire, Lalloo, Fiona, Side, Lucy E., Eason, Jacqueline, Henderson, Alex, Walker, Lisa, Eeles, Rosalind A., Cook, Jackie, Snape, Katie, Eccles, Diana, Murray, Alex, McCann, Emma, Collée, J. Margriet, Conroy, Don M., Czene, Kamila, Daly, Mary B., Devilee, Peter, Diez, Orland, Ding, Yuan Chun, Domchek, Susan M., Dörk, Thilo, dos-Santos-Silva, Isabel, Dunning, Alison M., Dwek, Miriam, Eccles, Diana M., Eliassen, A. Heather, Engel, Christoph, Eriksson, Mikael, Evans, D. Gareth, Fasching, Peter A., Flyger, Henrik, Fostira, Florentia, Friedman, Eitan, Fritschi, Lin, Frost, Debra, Gago-Dominguez, Manuela, Gapstur, Susan M., Garber, Judy, Garcia-Barberan, Vanesa, García-Closas, Montserrat, García-Sáenz, José A., Gaudet, Mia M., Gayther, Simon A., Gehrig, Andrea, Georgoulias, Vassilios, Giles, Graham G., Godwin, Andrew K., Goldberg, Mark S., Goldgar, David E., González-Neira, Anna, Greene, Mark H., Guénel, Pascal, Haeberle, Lothar, Hahnen, Eric, Haiman, Christopher A., Håkansson, Niclas, Hall, Per, Hamann, Ute, Harrington, Patricia A., Hart, Steven N., He, Wei, Hogervorst, Frans B. L., Hollestelle, Antoinette, Hopper, John L., Horcasitas, Darling J., Hulick, Peter J., Hunter, David J., Imyanitov, Evgeny N., Fox, Stephen, Campbell, Ian, Spurdle, Amanda, Webb, Penny, de Fazio, Anna, Tassell, Margaret, Kirk, Judy, Lindeman, Geoff, Price, Melanie, Southey, Melissa, Milne, Roger, Deb, Sid, Bowtell, David, van der Hout, Annemieke H., van den Ouweland, Ans M. W., Mensenkamp, Arjen R., van Deurzen, Carolien H. M., Kets, Carolien M., Seynaeve, Caroline, van Asperen, Christi J., Aalfs, Cora M., Gómez Garcia, Encarna B., van Leeuwen, Flora E., de Bock, G. H., Meijers-Heijboer, Hanne E. J., Obdeijn, Inge M., Gille, J. J. P., Oosterwijk, Jan C., Wijnen, Juul T., van der Kolk, Lizet E., Hooning, Maartje J., Ausems, Margreet G. E. M., Mourits, Marian J. E., Blok, Marinus J., Rookus, Matti A., van der Luijt, Rob B., van Cronenburg, T. C. T. E. F., van der Pol, Carmen C., Russell, Nicola S., Siesling, Sabine, Overbeek, Lucy, Wijnands, R., de Lange, Judith L., Clarke, Christine, Graham, Dinny, Sachchithananthan, Mythily, Marsh, Deborah, Scott, Rodney, Baxter, Robert, Yip, Desmond, Carpenter, Jane, Davis, Alison, Pathmanathan, Nirmala, Simpson, Peter, Jager, Agnes, Jakubowska, Anna, James, Paul A., Jensen, Uffe Birk, John, Esther M., Jones, Michael E., Kaaks, Rudolf, Kapoor, Pooja Middha, Karlan, Beth Y., Keeman, Renske, Khusnutdinova, Elza, Kiiski, Johanna I., Ko, Yon-Dschun, Kosma, Veli-Matti, Kraft, Peter, Kurian, Allison W., Laitman, Yael, Lambrechts, Diether, le Marchand, Loic, Lester, Jenny, Lesueur, Fabienne, Lindstrom, Tricia, Lopez-Fernández, Adria, Loud, Jennifer T., Luccarini, Craig, Mannermaa, Arto, Manoukian, Siranoush, Margolin, Sara, Martens, John W. M., Mebirouk, Noura, Meindl, Alfons, Miller, Austin, Milne, Roger L., Montagna, Marco, Nathanson, Katherine L., Neuhausen, Susan L., Nevanlinna, Heli, Nielsen, Finn C., O’Brien, Katie M., Olopade, Olufunmilayo I., Olson, Janet E., Olsson, H. kan, Osorio, Ana, Ottini, Laura, Park-Simon, Tjoung-Won, Parsons, Michael T., Pedersen, Inge Sokilde, Peshkin, Beth, Peterlongo, Paolo, Peto, Julian, Pharoah, Paul D. P., Phillips, Kelly-Anne, Polley, Eric C., Poppe, Bruce, Presneau, Nadege, Pujana, Miquel Angel, Punie, Kevin, Radice, Paolo, Rantala, Johanna, Rashid, Muhammad U., Rennert, Gad, Rennert, Hedy S., Robson, Mark, Romero, Atocha, Rossing, Maria, Saloustros, Emmanouil, Sandler, Dale P., Santella, Regina, Scheuner, Maren T., Schmidt, Marjanka K., Schmidt, Gunnar, Scott, Christopher, Sharma, Priyanka, Soucy, Penny, Southey, Melissa C., Spinelli, John J., Steinsnyder, Zoe, Stone, Jennifer, Stoppa-Lyonnet, Dominique, Swerdlow, Anthony, Tamimi, Rulla M., Tapper, William J., Taylor, Jack A., Terry, Mary Beth, Teulé, Alex, Thull, Darcy L., Tischkowitz, Marc, Toland, Amanda E., Torres, Diana, Trainer, Alison H., Truong, Thérèse, Tung, Nadine, Vachon, Celine M., Vega, Ana, Vijai, Joseph, Wang, Qin, Wappenschmidt, Barbara, Weinberg, Clarice R., Weitzel, Jeffrey N., Wendt, Camilla, Wolk, Alicja, Yadav, Siddhartha, Yang, Xiaohong R., Yannoukakos, Drakoulis, Zheng, Wei, Ziogas, Argyrios, Zorn, Kristin K., Park, Sue K., Thomassen, Mads, Offit, Kenneth, Schmutzler, Rita K., Couch, Fergus J., Simard, Jacques, Chenevix-Trench, Georgia, Easton, Douglas F., Andrieu, Nadine, Antoniou, Antonis C., German Cancer Research Center, National Health and Medical Research Council (Australia), United States of Department of Health & Human Services, National Institute for Health Research (Reino Unido), French National Cancer Institute, Ligue Nationale Contre le Cancer (Francia), Cancer Research UK (Reino Unido), Unión Europea. Comisión Europea, Canadian Institutes of Health Research, Cancer Council New South Wales (Australia), KWF Kankerbestrijding, Instituto de Salud Carlos III, Xunta de Galicia (España), Ministerio de Sanidad, Política Social e Igualdad (España), Helmholtz Association, California Breast Cancer Research Program, Federal Ministry of Education & Research (Alemania), Government of Netherlands, Russian Foundation for Basic Research, O’Mara, Tracy A. [0000-0002-5436-3232], Dennis, Joe [0000-0003-4591-1214], Tyrer, Jonathan P. [0000-0003-3724-4757], Barnes, Daniel R. [0000-0002-3781-7570], Leslie, Goska [0000-0001-5756-6222], Ahearn, Thomas [0000-0003-0771-7752], Andrulis, Irene L. [0000-0002-4226-6435], Arndt, Volker [0000-0001-9320-8684], Azzollini, Jacopo [0000-0002-9364-9778], Barrowdale, Daniel [0000-0003-1661-3939], Becher, Heko [0000-0002-8808-6667], Bernstein, Leslie [0000-0002-7692-6518], Bojesen, Stig E. [0000-0002-4061-4133], Bonanni, Bernardo [0000-0003-3589-2128], Brauch, Hiltrud [0000-0001-7531-2736], Caldés, Trinidad [0000-0002-1038-5392], Chanock, Stephen J. [0000-0002-2324-3393], Chung, Wendy K. [0000-0003-3438-5685], Claes, Kathleen B. M. [0000-0003-0841-7372], Collée, J. Margriet [0000-0002-9272-9346], Devilee, Peter [0000-0002-8023-2009], Dörk, Thilo [0000-0002-9458-0282], Dunning, Alison M. [0000-0001-6651-7166], Dwek, Miriam [0000-0001-7184-2932], Eliassen, A. Heather [0000-0002-3961-6609], Fritschi, Lin [0000-0002-7692-3560], García-Closas, Montserrat [0000-0003-1033-2650], García-Sáenz, José A. [0000-0001-6880-0301], Gayther, Simon A. [0000-0001-7937-5443], Giles, Graham G. [0000-0003-4946-9099], Greene, Mark H. [0000-0003-1852-9239], Guénel, Pascal [0000-0002-8359-518X], Håkansson, Niclas [0000-0001-7673-5554], Hart, Steven N. [0000-0001-7714-2734], He, Wei [0000-0003-0161-3274], Hollestelle, Antoinette [0000-0003-1166-1966], Hulick, Peter J. [0000-0001-8397-4078], Jakubowska, Anna [0000-0002-5650-0501], James, Paul A. [0000-0002-4361-4657], Jensen, Uffe Birk [0000-0002-6205-6355], Jones, Michael E. [0000-0001-7479-3451], Kapoor, Pooja Middha [0000-0001-5503-8215], Keeman, Renske [0000-0002-5452-9933], Kraft, Peter [0000-0002-4472-8103], Kurian, Allison W. [0000-0002-6175-9470], Lambrechts, Diether [0000-0002-3429-302X], Lesueur, Fabienne [0000-0001-7404-4549], Martens, John W. M. [0000-0002-3428-3366], Miller, Austin [0000-0001-9739-8462], Milne, Roger L. [0000-0001-5764-7268], Nathanson, Katherine L. [0000-0002-6740-0901], Nevanlinna, Heli [0000-0002-0916-2976], Olopade, Olufunmilayo I. [0000-0002-9936-1599], Olson, Janet E. [0000-0003-4944-7789], Ottini, Laura [0000-0001-8030-0449], Parsons, Michael T. [0000-0003-3242-8477], Pedersen, Inge Sokilde [0000-0002-9902-8040], Peshkin, Beth [0000-0002-2997-4701], Peterlongo, Paolo [0000-0001-6951-6855], Peto, Julian [0000-0002-1685-8912], Pharoah, Paul D. P. [0000-0001-8494-732X], Punie, Kevin [0000-0002-1162-7963], Radice, Paolo [0000-0001-6298-4111], Rennert, Gad [0000-0002-8512-068X], Robson, Mark [0000-0002-3109-1692], Romero, Atocha [0000-0002-1634-7397], Saloustros, Emmanouil [0000-0002-0485-0120], Sandler, Dale P. [0000-0002-6776-0018], Schmidt, Marjanka K. [0000-0002-2228-429X], Scott, Christopher [0000-0003-1340-0647], Stone, Jennifer [0000-0001-5077-0124], Toland, Amanda E. [0000-0002-0271-1792], Truong, Thérèse [0000-0002-2943-6786], Vachon, Celine M. [0000-0002-1962-9322], Vega, Ana [0000-0002-7416-5137], Vijai, Joseph [0000-0002-7933-151X], Weitzel, Jeffrey N. [0000-0001-6714-092X], Wolk, Alicja [0000-0001-7387-6845], Yadav, Siddhartha [0000-0003-4630-9903], Yannoukakos, Drakoulis [0000-0001-7509-3510], Ziogas, Argyrios [0000-0003-4529-3727], Zorn, Kristin K. [0000-0003-2143-8979], Park, Sue K. [0000-0001-5002-9707], Simard, Jacques [0000-0001-6906-3390], Easton, Douglas F. [0000-0003-2444-3247], Apollo - University of Cambridge Repository, Becher, Heiko [0000-0002-8808-6667], RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA KG Polikliniek (9), Klinische Genetica, German Cancer Research Center (DKFZ), National Health and Medical Research Council of Australia, United States Department of Health & Human Services National Institutes of Health (NIH) - USA, National Institute for Health Research (NIHR), Institut National du Cancer (INCA) France, Ligue nationale contre le cancer, Cancer Research UK, European Commision, Canadian Institutes of Health Research (CIHR), Cancer Council New South Wales, Accion Estrategica de Salud del Instituto de Salud Carlos III FIS Intrasalud, Xunta de Galicia, Fomento de la Investigacion Clinica Independiente, Ministerio de Sanidad, Servicios Sociales e Igualdad, Spain, Fondo de Investigacion Sanitario, California Breast Cancer Research Fund, Federal Ministry of Education & Research (BMBF), Netherlands Government, Russian Foundation for Basic Research (RFBR), O'Mara, Tracy A [0000-0002-5436-3232], Tyrer, Jonathan P [0000-0003-3724-4757], Barnes, Daniel R [0000-0002-3781-7570], Andrulis, Irene L [0000-0002-4226-6435], Bojesen, Stig E [0000-0002-4061-4133], Chanock, Stephen J [0000-0002-2324-3393], Chung, Wendy K [0000-0003-3438-5685], Claes, Kathleen BM [0000-0003-0841-7372], Collée, J Margriet [0000-0002-9272-9346], Dunning, Alison M [0000-0001-6651-7166], Eliassen, A Heather [0000-0002-3961-6609], García-Sáenz, José A [0000-0001-6880-0301], Gayther, Simon A [0000-0001-7937-5443], Giles, Graham G [0000-0003-4946-9099], Greene, Mark H [0000-0003-1852-9239], Hart, Steven N [0000-0001-7714-2734], Hulick, Peter J [0000-0001-8397-4078], James, Paul A [0000-0002-4361-4657], Jones, Michael E [0000-0001-7479-3451], Kurian, Allison W [0000-0002-6175-9470], Martens, John WM [0000-0002-3428-3366], Milne, Roger L [0000-0001-5764-7268], Nathanson, Katherine L [0000-0002-6740-0901], Olopade, Olufunmilayo I [0000-0002-9936-1599], Olson, Janet E [0000-0003-4944-7789], Parsons, Michael T [0000-0003-3242-8477], Pharoah, Paul DP [0000-0001-8494-732X], Sandler, Dale P [0000-0002-6776-0018], Schmidt, Marjanka K [0000-0002-2228-429X], Toland, Amanda E [0000-0002-0271-1792], Vachon, Celine M [0000-0002-1962-9322], Weitzel, Jeffrey N [0000-0001-6714-092X], Zorn, Kristin K [0000-0003-2143-8979], Park, Sue K [0000-0001-5002-9707], Easton, Douglas F [0000-0003-2444-3247], HUS Comprehensive Cancer Center, Department of Oncology, Clinicum, INDIVIDRUG - Individualized Drug Therapy, HUS Gynecology and Obstetrics, Department of Obstetrics and Gynecology, Institut Català de la Salut, [Coignard J] Genetic Epidemiology of Cancer team, Inserm, U900, Paris, France. Institut Curie Paris, Paris, France. Mines ParisTech Fontainebleau, Paris, France. Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. PSL University Paris, Paris, France. Paris Sud University, Orsay, France. [Lush M, Dennis J] Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. [Beesley J, O'Mara TA] Department of Genetics and Computational Biology QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia. [Tyrer JP] Centre for Cancer Genetic Epidemiology, Department of Oncology University of Cambridge, Cambridge, UK. [Diez O] Oncogenetics Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Àrea de Genètica Clínica i Molecular, Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Lopez-Fernández A] High Risk and Cancer Prevention Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus, Basic and Translational Research and Imaging Methodology Development in Groningen (BRIDGE), Life Course Epidemiology (LCE), Damage and Repair in Cancer Development and Cancer Treatment (DARE), Targeted Gynaecologic Oncology (TARGON), Human Genetics, ARD - Amsterdam Reproduction and Development, Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, CCA - Cancer biology and immunology, Clinical Genetics, Medical Oncology, Pathology, and Radiology & Nuclear Medicine
Subjects: 0301 basic medicine, Linkage disequilibrium, endocrine system diseases, Neoplasms::Neoplasms by Site::Breast Neoplasms [DISEASES], 45/43, General Physics and Astronomy, Genome-wide association study, Linkage Disequilibrium, Breast cancer, 0302 clinical medicine, 3123 Gynaecology and paediatrics, Risk Factors, Genotype, breast neoplasms, Medicine and Health Sciences, 631/208/68, skin and connective tissue diseases, Cancer genetics, adult, alleles, BRCA1 protein, BRCA2 protein, female, genetic predisposition to disease, genome-wide association study, genotype, humans, linkage disequilibrium, middle aged, mutation, quantitative trait loci, risk factors, polymorphism, single nucleotide, HEBON Investigators, Genetics, neoplasias::neoplasias por localización::neoplasias de la mama [ENFERMEDADES], education.field_of_study, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], Multidisciplinary, Otros calificadores::Otros calificadores::/genética [Otros calificadores], BRCA1 Protein, Genetic Predisposition to Disease/genetics, article, Single Nucleotide, Middle Aged, BRCA2 Protein/genetics, 3. Good health, Mama - Càncer - Factors de risc, 030220 oncology & carcinogenesis, Mutation (genetic algorithm), Genome-Wide Association Study/methods, Medical genetics, Female, Medical Genetics, 692/499, Adult, medicine.medical_specialty, 45/61, Science, 3122 Cancers, Population, Quantitative Trait Loci, Genetic Phenomena::Genetic Variation::Mutation [PHENOMENA AND PROCESSES], ABCTB Investigators, 631/67/2324, Breast Neoplasms, Biology, Breast Neoplasms/genetics, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Càncer de mama, GEMO Study Collaborators, 03 medical and health sciences, Cancer epidemiology, SDG 3 - Good Health and Well-being, Other subheadings::Other subheadings::/genetics [Other subheadings], medicine, Humans, Genetic Predisposition to Disease, Allele, Polymorphism, education, EMBRACE Collaborators, fenómenos genéticos::variación genética::mutación [FENÓMENOS Y PROCESOS], Alleles, Medicinsk genetik, BRCA2 Protein, Mutació (Biologia), General Chemistry, 631/67/1347, Genotype frequency, 030104 developmental biology, Mutation, Mama - Càncer - Aspectes genètics, BRCA1 Protein/genetics, 3111 Biomedicine, KConFab Investigators, Quantitative Trait Loci/genetics, Genètica, Genome-Wide Association Study
Abstract: Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P, Breast cancer risk for BRCA1/BRCA2 mutation carriers varies depending on other genetic factors. Here, the authors perform a case-only genome-wide association study and highlight novel loci associated with breast cancer risk for BRCA1/BRCA2 mutation carriers.
Published: 2021
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262. SEOM clinical guidelines for the treatment of malignant pleural mesothelioma (2020)

Author: J de Castro-Carpeño, Joaquim Bosch-Barrera, Ernest Nadal, Ana Laura Ortega, M. Guirado, Rosario García-Campelo, D Vicente, J. Coves, Susana Cedres, R. López-Castro, Institut Català de la Salut, [Nadal E] Department of Medical Oncology, Catalan Institute of Oncology, Hospital Duran i Reynals, Avda Gran Via 199-203, l’Hospitalet de Llobregat, Barcelona, Spain. [Bosch-Barrera J] Department of Medical Oncology, Catalan Institute of Oncology, Hospital Josep Trueta, Girona, Spain. [Cedrés S] Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Servei d’Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Coves J] Department of Medical Oncology, Hospital Son Llatzer, Palma de Mallorca, Spain. [García-Campelo R] Department of Medical Oncology, Complejo Hospitalario Universitario A Coruña, Coruña, Spain. [Guirado M] Department of Medical Oncology, Hospital General Universitario de Elche, Elche, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: 0301 basic medicine, Oncology, Mesothelioma, Clinical guidelines, Cancer Research, medicine.medical_treatment, Malignant pleural mesothelioma, Salvage therapy, Platinum Compounds, Càncer - Quimioteràpia, medicine.disease_cause, terapéutica::tratamiento combinado [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Medical Oncology, Deoxycytidine, 0302 clinical medicine, Diagnòstic, Diagnosis, neoplasias::neoplasias por tipo histológico::neoplasias glandulares y epiteliales::adenoma::mesotelioma [ENFERMEDADES], Societies, Medical, High-Throughput Nucleotide Sequencing, Vinorelbine, General Medicine, Cytoreduction Surgical Procedures, Combined Modality Therapy, Pemetrexed, 030220 oncology & carcinogenesis, Protocols clínics, Immunotherapy, medicine.drug, Neoplasms::Neoplasms by Histologic Type::Neoplasms, Glandular and Epithelial::Adenoma::Mesothelioma [DISEASES], medicine.medical_specialty, Pleural Neoplasms, Clinical Guides in Oncology, Antineoplastic Agents, Asbestos, 03 medical and health sciences, Internal medicine, medicine, Humans, Genetic Testing, Diagnostic, Neoplasm Staging, Chemotherapy, Radiotherapy, business.industry, Mesothelioma, Malignant, medicine.disease, Gemcitabine, respiratory tract diseases, Medical protocols, Therapeutics::Combined Modality Therapy [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], Treatment, Mesotelioma, 030104 developmental biology, Spain, Carcinogens, Càncer - Immunoteràpia, business
Abstract: Mesothelioma is a rare and aggressive tumour with dismal prognosis arising in the pleura and associated with asbestos exposure. Its incidence is on the rise worldwide. In selected patients with early-stage MPM, a maximal surgical cytoreduction in combination with additional antitumour treatment may be considered in selected patients assessed by a multidisciplinary tumor board. In patients with unresectable or advanced MPM, chemotherapy with platinum plus pemetrexed is the standard of care. Currently, no standard salvage therapy has been approved yet, but second-line chemotherapy with vinorelbine or gemcitabine is commonly used. Novel therapeutic approaches based on dual immunotherapy or chemotherapy plus immunotherapy demonstrated promising survival benefit and will probably be incorporated in the future., E. Nadal thanks the support of Health Institute Carlos III-FEDER (ISCIII) [PI14/01109 and PI18/00920].
Published: 2021
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263. Evolution of Angiogenic Factors in Pregnant Patients with Breast Cancer Treated with Chemotherapy

Author: Elisa Llurba, Cristina Saura, Maria Concepció Céspedes, O. Sánchez, Rodrigo Dienstmann, Ángeles Peñuelas, Javier Cortes, Sandra Patricia Martínez, Carmen Domínguez, Fiorella Ruiz-Pace, Octavi Cordoba, Institut Català de la Salut, [Saura C, Peñuelas Á] Servei d’Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Sánchez O] Maternal and Child Health and Development Network (SAMID), RD12/0026/16 and RD16/0022/0015, Institute of Health Carlos III, 28029 Madrid, Spain. Biochemistry and Molecular Biology Research Centre for Nanomedicine, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. [Martínez S] Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Domínguez C] Biochemistry and Molecular Biology Research Centre for Nanomedicine, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Center for Biomedical Research on Rare Diseases (CIBERER), 08028 Barcelona, Spain. [Dienstmann R, Ruíz-Pace F] Oncology Data Science (ODysSey), Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Céspedes MC] Servei de Pediatria, Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Cortés J] Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. International Breast Cancer Center, Quiron Group, Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: Placental growth factor, Cancer Research, medicine.medical_specialty, angiogenic factors, Intrauterine growth restriction, Placental insufficiency, chemotherapy, lcsh:RC254-282, Otros calificadores::/efectos de los fármacos [Otros calificadores], Article, Preeclampsia, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, breast cancer, Medicine, Other subheadings::/drug effects [Other subheadings], Prospective cohort study, Amino Acids, Peptides, and Proteins::Amino Acids, Peptides, and Proteins::Proteins::Pregnancy Proteins::Placenta Growth Factor [CHEMICALS AND DRUGS], neoplasias::complicaciones neoplásicas del embarazo [ENFERMEDADES], Pregnancy, 030219 obstetrics & reproductive medicine, aminoácidos, péptidos y proteínas::aminoácidos, péptidos y proteínas::proteínas::proteínas gestacionales::factor de crecimiento placentario [COMPUESTOS QUÍMICOS Y DROGAS], business.industry, Obstetrics, Medicaments - Efectes secundaris, Neoplasms::Pregnancy Complications, Neoplastic [DISEASES], Cancer, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, Càncer en l'embaràs, Oncology, 030220 oncology & carcinogenesis, embryonic structures, pregnancy, business
Abstract: High prevalence of placental-derived complications, such as preeclampsia and intrauterine growth restriction, has been reported in women with breast cancer (BC) treated with chemotherapy during pregnancy (PBC-CHT). Aim: To ascertain whether PBC-CHT is associated with an imbalance of angiogenic factors, surrogate markers for placental insufficiency, that could explain perinatal outcomes. Methods: Prospective study between 2012 and 2016 in a single institution. Soluble fms-like tyrosine kinase (sFlt-1), placental growth factor (PlGF), and soluble endoglin (sEng) in maternal blood were assessed throughout pregnancy in 12 women with BC and 215 controls. Results: Cancer patients were treated with doxorubicin-based regimes and with taxanes. Ten PBC-CHT (83%) developed obstetrical complications. At the end of the third trimester, significantly higher levels of sFlt-1, sFlt-1/PGF ratio, and sEng levels were observed in BC women as compared to controls. Moreover, there was a significant correlation between plasma levels of sFlt-1 and the number of chemotherapy cycles administered. Besides, more chemotherapy cycles correlated with lower birthweight and head circumference at birth. Conclusions: Women with BC treated during pregnancy showed an antiangiogenic state compatible with placental insufficiency. Angiogenic factors could be useful in the clinical obstetric management of these patients, although further studies will be required to guide clinical decision-making.
Published: 2021

264. BRAF, MEK and EGFR inhibition as treatment strategies in BRAF V600E metastatic colorectal cancer

Author: Guillem Argiles, Giulia Martini, Emilia Sardo, Davide Ciardiello, Josep Tabernero, Nuria Mulet, Javier Ros, Francesc Salvà, Elena Elez, Iosune Baraibar, Jose Luis Cuadra, Ros, Javier, Baraibar, Iosune, Sardo, Emilia, Mulet, Nuria, Salvà, Francesc, Argilés, Guillem, Martini, Giulia, Ciardiello, Davide, Cuadra, José Lui, Tabernero, Josep, Élez, Elena, Institut Català de la Salut, [Ros J, Baraibar I, Salvà F, Argilés G, Élez E] Servei d’Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Sardo E] Servei d’Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Mulet N] Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Department of Medical Oncology, Institut Català d’Oncologia, Barcelona, Spain. [Martini G, Ciardiello D] Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Medicine, Università degli Studi della Campania Luigi Vanvitelli, Naples, Caserta, Campania, Italy. [Tabernero J] Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Vall d’Hebron Hospital Universitari, Barcelona, Spain. UVic-UCC, Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: MAPK/ERK pathway, BRAF inhibitor, endocrine system diseases, Colorectal cancer, Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores], encorafenib, Review, Other subheadings::Other subheadings::/drug therapy [Other subheadings], Còlon - Càncer - Tractament, chemistry.chemical_compound, Neoplasms::Neoplasms by Site::Digestive System Neoplasms::Gastrointestinal Neoplasms::Intestinal Neoplasms::Colorectal Neoplasms [DISEASES], Metàstasi, Encorafenib, Recte - Càncer - Tractament, Medicine, neoplasms, EGFR inhibitors, MEK inhibitor, business.industry, Kinase, BEACON clinical trial, BRAF V600E mutation, Neoplasms::Neoplastic Processes::Neoplasm Metastasis [DISEASES], Binimetinib, neoplasias::neoplasias por localización::neoplasias del sistema digestivo::neoplasias gastrointestinales::neoplasias intestinales::neoplasias colorrectales [ENFERMEDADES], medicine.disease, digestive system diseases, BRAF V600E, EGFR inhibitor, Oncology, chemistry, colon cancer, neoplasias::procesos neoplásicos::metástasis neoplásica [ENFERMEDADES], binimetinib, Cancer research, business
Abstract: Inhibidor de BRAF; Binimetinib; Cáncer de colon BRAF inhibitor; Binimetinib; Colon cancer Inhibidor de BRAF; Binimetinib; Càncer de còlon Introduction: BRAF driver mutations are found in up to 15% of patients with colorectal cancer (CRC) and lead to constitutive activation of BRAF kinase and sustained RAS/RAF/MEK/ERK pathway signaling. BRAF mutations define a sub-population characterized by a poor prognosis and dismal median survival. Following successful outcomes with BRAF inhibition in BRAF mutant metastatic melanoma, this approach was evaluated in metastatic colorectal cancer (mCRC). The development and combination of targeted therapies against multiple signaling pathways has proved particularly successful, with improved survival and response rates. Areas covered: This review addresses the development of therapeutic strategies with inhibitors targeting MAPK/ERK and EGFR signaling in BRAF V600E mutated mCRC, focusing on encorafenib, binimetinib and cetuximab. A pharmacological and clinical review of these drugs and the therapeutic approaches behind their optimization are presented. Expert opinion: Exploiting knowledge of the mechanisms of resistance to BRAF inhibitors has been crucial to developing effective therapeutic strategies in BRAF-V600E mutant mCRC. The BEACON trial is a successful example of this approach, using encorafenib and cetuximab with or without binimetinib in patients with previously treated BRAF V600E mutant mCRC, showing an impressive improvement in clinical outcomes and tolerable toxicity compared with chemotherapy, establishing a new standard of care in this setting. The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by grants from Instituto de Salud Carlos III (ISCIII) FIS/FEDER (PI17/00947, PI20/00968) and from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 635342.
Published: 2021

265. Physician-perceived utility of the EORTC QLQ-GINET21 questionnaire in the treatment of patients with gastrointestinal neuroendocrine tumours: a multicentre, cross-sectional survey (QUALINETS)

Author: Teresa Alonso, Guillermo de la Cruz, Neus Canal, Lourdes García, Alberto Carmona, Javier Sastre, Javier Gallego, Isabel Sevilla, Guillermo Crespo, Jaume Capdevila, Ángel Segura, Marta Benavent, Ignacio García Escobar, Ipsen, [Benavent,M] Virgen Del Rocío University Hospital, Biomedicine Institut Biomedicina of Sevilla (IBIS), Sevilla, Spain. [Sastre,J] San Carlos Clinic Hospital, San Carlos Hospital Research Institute (IdISSC), Madrid, Spain. [García Escobar,I] San Pedro De Alcántara Hospital, Cáceres, Spain. [Segura,A] Politécnico La Fe University Hospital, Valencia, Spain. [Capdevila,J] Teknon Oncologic Institut (IOT), Teknon Medical Center, Vall Hebron University Hospital, Vall Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Carmona,A] Morales Meseguer General University Hospital, Murcia, Spain. [Sevilla,I] Clinical and Translational Research in Cancer, Biomedical Research Institut of Malaga (IBIMA), Regional University Hospital and Virgen de la Victoria University Hospital of Málaga, Málaga, Spain. [Alonso,T] Ramón y Cajal Hospital, Madrid, Spain. [Crespo,G] Burgos University Hospital, Burgos, Spain. [García,L] Segovia General Hospital, Segovia, Spain. [Canal,N] IQVIA Information S.A., Barcelona, Spain. [de la Cruz,G] Ipsen Pharma S.A., Barcelona, Spain. [Gallego,J] Hospital General Universitario de Elche, Elche, Alicante, Spain., This study was sponsored by Ipsen, Institut Català de la Salut, [Benavent M] Virgen Del Rocío University Hospital, Biomedicine Institut Biomedicina of Sevilla (IBIS), Sevilla, Spain. [Sastre J] San Carlos Clinic Hospital, San Carlos Hospital Research Institute (IdISSC), Madrid, Spain. [Escobar IG] San Pedro De Alcántara Hospital, Cáceres, Spain. [Segura A] Politécnico La Fe University Hospital, Valencia, Spain. [Capdevila J] Teknon Oncologic Institut (IOT), Teknon Medical Center. Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Carmona A] Morales Meseguer General University Hospital, Murcia, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: Male, Information Science::Information Science::Communication [Medical Subject Headings], Cross-sectional study, Health-related quality of life, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], 0302 clinical medicine, Neuroendocrine tumours, Neoplasms::Neoplasms by Site::Digestive System Neoplasms::Gastrointestinal Neoplasms [DISEASES], Investigative Techniques::Epidemiologic Methods::Data Collection::Surveys and Questionnaires::Health Care Surveys::Patient Reported Outcome Measures [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], Routine clinical practice, 030212 general & internal medicine, ambiente y salud pública::salud pública::medidas epidemiológicas::demografía::estado de salud::calidad de vida [ATENCIÓN DE SALUD], Persons::Persons::Age Groups::Adult::Aged [Medical Subject Headings], Gastrointestinal Neoplasms, Health Care::Health Care Facilities, Manpower, and Services::Health Facilities::Hospitals [Medical Subject Headings], Communication, Outcome measures, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Data Collection::Questionnaires [Medical Subject Headings], General Medicine, Health Care::Health Care Facilities, Manpower, and Services::Health Personnel::Physicians [Medical Subject Headings], Middle Aged, humanities, Tumors neuroendocrins, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Epidemiologic Study Characteristics as Topic::Epidemiologic Studies::Cross-Sectional Studies [Medical Subject Headings], Neuroendocrine Tumors, 030220 oncology & carcinogenesis, Anthropology, Education, Sociology and Social Phenomena::Social Sciences::Quality of Life [Medical Subject Headings], lcsh:R858-859.7, Female, Persons::Persons::Age Groups::Adult::Young Adult [Medical Subject Headings], Diseases::Neoplasms::Neoplasms by Histologic Type::Neoplasms, Germ Cell and Embryonal::Neuroectodermal Tumors::Neuroendocrine Tumors [Medical Subject Headings], Adult, medicine.medical_specialty, Attitude of Health Personnel, Pacients - Satisfacció, Check Tags::Male [Medical Subject Headings], lcsh:Computer applications to medicine. Medical informatics, 03 medical and health sciences, Young Adult, Quality of life (healthcare), neoplasias::neoplasias por localización::neoplasias del sistema digestivo::neoplasias gastrointestinales [ENFERMEDADES], Physicians, medicine, Humans, In patient, Patient Reported Outcome Measures, Persons::Persons::Age Groups::Adult [Medical Subject Headings], Diseases::Digestive System Diseases::Digestive System Neoplasms::Gastrointestinal Neoplasms [Medical Subject Headings], Quality of Life Research, Aged, Health related quality of life, Médicos, Geographical Locations::Geographic Locations::Europe::Spain [Medical Subject Headings], Portugal, técnicas de investigación::métodos epidemiológicos::recopilación de datos::encuestas y cuestionarios::encuestas sobre atención a la salud::medidas de resultados percibidos por los pacientes [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], business.industry, Research, Public Health, Environmental and Occupational Health, QLQ-GINET21 questionnaire, Persons::Persons::Age Groups::Adult::Middle Aged [Medical Subject Headings], Tumores neuroendocrinos, Clinical utility, Geographical Locations::Geographic Locations::Europe::Portugal [Medical Subject Headings], Environment and Public Health::Public Health::Epidemiologic Measurements::Demography::Health Status::Quality of Life [HEALTH CARE], Cross-Sectional Studies, Check Tags::Female [Medical Subject Headings], Spain, Psychiatry and Psychology::Behavior and Behavior Mechanisms::Attitude::Attitude of Health Personnel [Medical Subject Headings], Avaluació de resultats (Assistència sanitària), Physical therapy, Quality of Life, EORTC QLQ-GINET21, Calidad de Vida, business, Comunicación
Abstract: [Background and objective] Patient-reported outcome measures can provide clinicians with valuable information to improve doctor-patient communication and inform clinical decision-making. The aim of this study was to evaluate the physician-perceived utility of the QLQ-GINET21 in routine clinical practice in patients with gastrointestinal neuroendocrine tumours (GI-NETs). Secondary aims were to explore the patient, clinician, and/or centre-related variables potentially associated with perceived clinical utility., [Methods] Non-interventional, cross-sectional, multicentre study conducted at 34 hospitals in Spain and Portugal (NCT02853422). Patients diagnosed with GI-NETs completed two health-related quality of life (HRQoL) questionnaires (QLQ-C30, QLQ-GINET21) during a single routine visit. Physicians completed a 14-item ad hoc survey to rate the clinical utility of QLQ-GINET21 on three dimensions: 1)therapeutic and clinical decision-making, 2)doctor-patient communication, 3)questionnaire characteristics., [Results] A total of 199 patients at 34 centres were enrolled by 36 participating clinicians. The highest rated dimension on the QLQ-GINET21 was questionnaire characteristics (86.9% of responses indicating “high utility”), followed by doctor-patient communication (74.4%), and therapeutic and clinical decision-making (65.8%). One physician-related variable (GI-NET patient volume > 30 patients/year) was associated with high clinical utility and two variables (older age/less experience treating GI-NETs) with low clinical utility., [Conclusions] Clinician-perceived clinical utility of QLQ-GINET21 is high. Clinicians valued the instruments’ capacity to provide a better understanding of patient perspectives and to identify the factors that had the largest influence on patient HRQoL., This study was sponsored by Ipsen.
Published: 2021

266. Tumor expression of cyclin-dependent kinase 5 (Cdk5) is a prognostic biomarker and predicts outcome of oxaliplatin-treated metastatic colorectal cancer patients

Author: [Ruiz de Porras V, Bystrup S, Cabrero-de Las Heras S] Program of predictive and personalized cancer medicine (PMPPC), Germans Trias i Pujol Research Institute (IGTP), Badalona, Spain. Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology, Badalona, Spain. [Musulén E] Department of Pathology, Hospital Universitari Germans Trias i Pujol, Badalona, Spain. Department of Pathology, Hospital Universitari General de Catalunya, Grupo Quirónsalud, Sant Cugat del Valles, Spain. [Palomero L] Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology, L’Hospitalet del Llobregat, Spain. ONCOBELL Program, Bellvitge Institute for Biomedical Research, L’Hospitalet del Llobregat, Spain. [Henar Alonso M] ONCOBELL Program, Bellvitge Institute for Biomedical Research, L’Hospitalet del Llobregat, Spain. Oncology Data Analytics Program, Institut Català d’Oncologia (ICO), Barcelona, Sapin. Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid, Spain. Department of Clinical Sciences, Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain. [Nieto R, Arango D] Grup de Recerca en Investigació Biomèdica en Tumors de l'Aparell Digestiu, CIBBIM-Nanomedicine, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Universitat Autònoma de Barcelona, Barcelona, Spain and Hospital Universitari Vall d'Hebron
Subjects: Quinases dependents de ciclina, Marcadors tumorals, Digestive System Diseases::Digestive System Neoplasms::Gastrointestinal Neoplasms::Intestinal Neoplasms::Digestive System Diseases::Digestive System Diseases::Digestive System Diseases::Digestive System Diseases::Colorectal Neoplasms [DISEASES], Recte - Càncer, factores biológicos::biomarcadores::marcadores tumorales [COMPUESTOS QUÍMICOS Y DROGAS], Enfermedades del Sistema Digestivo::Neoplasias del Sistema Digestivo::Neoplasias Gastrointestinales::Neoplasias Intestinales::Enfermedades del Sistema Digestivo::Enfermedades del Sistema Digestivo::Enfermedades del Sistema Digestivo::Enfermedades del Sistema Digestivo::Neoplasias Colorrectales [ENFERMEDADES], Enzimas y Coenzimas::Enzimas::Transferasas::Fosfotransferasas::Fosfotransferasas (Aceptor de Grupo Alcohol)::Proteínas Quinasas::Proteínas Serina-Treonina Quinasas::Proteínas Quinasas Dirigidas por Prolina::Quinasas Ciclina-Dependientes::Quinasas CDC2-CDC28::Quinasa 5 Dependiente de la Ciclina [COMPUESTOS QUÍMICOS Y DROGAS], Biological Factors::Biomarkers::Biomarkers, Tumor [CHEMICALS AND DRUGS], Enzymes and Coenzymes::Enzymes::Transferases::Phosphotransferases::Phosphotransferases (Alcohol Group Acceptor)::Protein Kinases::Protein-Serine-Threonine Kinases::Proline-Directed Protein Kinases::Cyclin-Dependent Kinases::CDC2-CDC28 Kinases::Cyclin-Dependent Kinase 5 [CHEMICALS AND DRUGS]
Published: 2021

267. Recent advances in the targeting of epigenetic regulators in b-cell non- Hodgkin lymphoma

Author: [Ribeiro ML] Laboratory of Experimental Hematology, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain. Servei d’Hematologia, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Universitat Autònoma de Barcelona, Barcelona, Spain. Laboratory of Immunopharmacology and Molecular Biology, Sao Francisco University Medical School, Braganca Paulista, Brazil. [Reyes-Garau D, Armengol D, Fernández-Serrano M, Roué G] Laboratory of Experimental Hematology, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain. Servei d’Hematologia, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Universitat Autònoma de Barcelona, Barcelona, Spain and Hospital Universitari Vall d'Hebron
Subjects: fenómenos genéticos::regulación de la expresión génica::epigénesis genética [FENÓMENOS Y PROCESOS], Neoplasms::Neoplasms by Histologic Type::Lymphoma::Lymphoma, Non-Hodgkin::Lymphoma, B-Cell [DISEASES], Investigative Techniques::Genetic Techniques::Sequence Analysis::High-Throughput Nucleotide Sequencing [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], Genetic Phenomena::Gene Expression Regulation::Epigenesis, Genetic [PHENOMENA AND PROCESSES], Neoplasias::Neoplasias por Tipo Histológico::Linfoma::Linfoma no Hodgkin::Linfoma de Células B [ENFERMEDADES], Técnicas de Investigación::Técnicas Genéticas::Análisis de Secuencia::Secuenciación de Nucleótidos de Alto Rendimiento [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Cèl·lules B - Tumors, Epigenètica, Other subheadings::Other subheadings::/drug therapy [Other subheadings], Genètica - Tècnica, Otros calificadores::Otros calificadores::/tratamiento farmacológico [Otros calificadores]
Published: 2021

268. Targeting antitumoral proteins to breast cancer by local administration of functional inclusion bodies

Author: [Pesarrodona M] Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, Bellaterra, Spain. CIBER de Bioingeniería Biomateriales y Nanomedicina (CIBER-BBN), Instituto de Salud Carlos III (ISCIII), Madrid, Spain. [Jauset T, Beaulieu ME] Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain. Peptomyc S.L. Edifici Cellex, Barcelona, Spain. [Díaz-Riascos ZV, Mancilla S, Fernández Y, Abasolo I] CIBER de Bioingeniería Biomateriales y Nanomedicina (CIBER-BBN), Instituto de Salud Carlos III (ISCIII), Madrid, Spain. CIBBIM-Nanomedicina Àrea de Validació Funcional i Estudis Preclínics, Vall d'Hebron Institut de Recerca (VHIR), Barcelona, Spain. Universitat Autònoma de Barcelona, Barcelona Spain. CIBBIM-Nanomedicina Direccionament i Alliberament Farmacològic, Vall d'Hebron Institut de Recerca (VHIR), Barcelona, Spain. [Sánchez-Chardi A] Departament de Biologia Evolutiva Ecologia i Ciències Ambientals, Facultat de Biologia, Universitat de Barcelona, Barcelona Spain. [Seras-Franzoso J, Baltà-Foix R] CIBBIM-Nanomedicina Direccionament i Alliberament Farmacològic, Vall d'Hebron Institut de Recerca (VHIR), Barcelona, Spain. Universitat Autònoma de Barcelona, Barcelona, Spain. [Schwartz Jr S] CIBER de Bioingeniería Biomateriales y Nanomedicina (CIBER-BBN), Instituto de Salud Carlos III (ISCIII), Madrid, Spain. CIBBIM-Nanomedicina Direccionament i Alliberament Farmacològic, Vall d'Hebron Institut de Recerca (VHIR), Barcelona, Spain. Universitat Autònoma de Barcelona, Barcelona, Spain. [Soucek L] Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain. Peptomyc S.L. Edifici Cellex, Barcelona, Spain. Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain. Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra, Spain and Hospital Universitari Vall d'Hebron
Subjects: Mama - Càncer, Proteïnes recombinants, Neoplasms::Neoplasms by Site::Breast Neoplasms [DISEASES], acciones y usos químicos::acciones farmacológicas::usos terapéuticos::antineoplásicos [COMPUESTOS QUÍMICOS Y DROGAS], células::estructuras celulares::cuerpos de inclusión [ANATOMÍA], Neoplasias::Neoplasias por Localización::Neoplasias de la Mama [ENFERMEDADES], Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Antineoplastic Agents [CHEMICALS AND DRUGS], Cells::Cellular Structures::Inclusion Bodies [ANATOMY], Medicaments antineoplàstics
Published: 2021

269. Targeted multiplex proteomics for molecular prescreening and biomarker discovery in metastatic colorectal cancer

Author: [Garazi S, Fasani R, Jimenez J, Nuciforo PG] Grup d’Oncologia Molecular, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Ruiz-Pace F, Dienstmann R] Grup d’Oncology Data Science (ODysSey), Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Cecchi F, Thyparambil S] NantOmics, LLC, Rockville, MD, USA. [Landolfi S] Servei d’Anatomia Patològica, Vall d'Hebron Hospital Universitari, Barcelona, Spain. Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain. [Elez E, Tabernero J] Servei de Medicina Oncològica, Vall d'Hebron Hospital Universitari, Barcelona, Spain. [Vivancos, A] Grup de Genòmica del Càncer, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain and Hospital Universitari Vall d'Hebron
Subjects: Marcadors tumorals, Digestive System Diseases::Digestive System Neoplasms::Gastrointestinal Neoplasms::Intestinal Neoplasms::Digestive System Diseases::Digestive System Diseases::Digestive System Diseases::Digestive System Diseases::Colorectal Neoplasms [DISEASES], Còlon - Càncer - Diagnòstic, Other subheadings::/diagnosis [Other subheadings], Otros calificadores::/diagnóstico [Otros calificadores], factores biológicos::biomarcadores::marcadores tumorales [COMPUESTOS QUÍMICOS Y DROGAS], Enfermedades del Sistema Digestivo::Neoplasias del Sistema Digestivo::Neoplasias Gastrointestinales::Neoplasias Intestinales::Enfermedades del Sistema Digestivo::Enfermedades del Sistema Digestivo::Enfermedades del Sistema Digestivo::Enfermedades del Sistema Digestivo::Neoplasias Colorrectales [ENFERMEDADES], Biological Factors::Biomarkers::Biomarkers, Tumor [CHEMICALS AND DRUGS]
Published: 2021

270. Pharmacological targeting of BET bromodomain proteins in acute myeloid leukemia and malignant lymphomas: from molecular characterization to clinical applications

Author: [Reyes-Garau D, Roué G] Laboratori d’Hematologia Experimental, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Servei d’Hematologia, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Universitat Autònoma de Barcelona, Barcelona, Spain. [Ribeiro M] Laboratori d’Hematologia Experimental, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Servei d’Hematologia, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Universitat Autònoma de Barcelona, Barcelona, Spain. Laboratory of Immunopharmacology and Molecular Biology, Sao Francisco University Medical School, Braganca Paulista, Brazil and Hospital Universitari Vall d'Hebron
Subjects: drug effects, Farmacologia molecular, Therapeutics::Drug Therapy::Molecular Targeted Therapy [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], tratamiento farmacológico, Medicaments proteínics, fenómenos químicos::fenómenos bioquímicos::estructura molecular::conformación molecular::conformación de proteínas::fenómenos químicos::fenómenos bioquímicos::estructura molecular::conformación molecular::conformación de proteínas::estructura terciaria de las proteínas::dominios proteicos [FENÓMENOS Y PROCESOS], Terapéutica::Quimioterapia::Terapia Molecular Dirigida [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], efectos de los fármacos, Enfermedades Hematológicas y Linfáticas::Enfermedades Hematológicas::Neoplasias Hematológicas [ENFERMEDADES], drug therapy, Hematologia oncològica, Chemical Phenomena::Biochemical Phenomena::Molecular Structure::Molecular Conformation::Protein Conformation::Chemical Phenomena::Biochemical Phenomena::Molecular Structure::Molecular Conformation::Protein Conformation::Protein Structure, Tertiary::Protein Domains [PHENOMENA AND PROCESSES], Hemic and Lymphatic Diseases::Hematologic Diseases::Hematologic Neoplasms [DISEASES]
Published: 2021

271. Comorbidities at Diagnosis, Survival, and Cause of Death in Patients with Chronic Lymphocytic Leukemia: A Population-Based Study

Author: Villavicencio, Alicia, Solans, Marta, Zacarías-Pons, Lluís, Vidal, Anna, Puigdemont, Montse, Roncero, Josep Maria, Saez, Marc, Marcos-Gragera, Rafael, Universitat Autònoma de Barcelona, Institut Català de la Salut, [Villavicencio A] Epidemiology Unit and Girona Cancer Registry, Oncology Coordination Plan, Catalan Institute of Oncology, Girona, Spain. Research Group on Statistics, Econometrics and Health (GRECS), University of Girona, Girona, Spain. Descriptive Epidemiology, Genetics and Cancer Prevention Group, Biomedical Research Institute (IDIBGI), Girona, Spain. [Solans M] Research Group on Statistics, Econometrics and Health (GRECS), University of Girona, Girona, Spain. Descriptive Epidemiology, Genetics and Cancer Prevention Group, Biomedical Research Institute (IDIBGI), Girona, Spain. Centro de Investigación Biomédica en Red: Epidemiología y Salud Pública (CIBERESP), Madrid, Spain. [Zacarías-Pons Ll] Research Group on Aging, Disability and Health, Girona Biomedical Research Institute (IDIBGI), Girona, Spain. [Vidal A, Puigdemont M] Epidemiology Unit and Girona Cancer Registry, Oncology Coordination Plan, Catalan Institute of Oncology, Girona, Spain. Descriptive Epidemiology, Genetics and Cancer Prevention Group, Biomedical Research Institute (IDIBGI), Girona, Spain. [Roncero JM] Departament d’Hematologia, Hospital Universitari de Girona Doctor Josep Trueta, Institut Català de la Salut (ICS), Girona, Spain. [Saez M] Research Group on Statistics, Econometrics and Health (GRECS), University of Girona, Girona, Spain. Centro de Investigación Biomédica en Red: Epidemiología y Salud Pública (CIBERESP), Madrid, Spain. [Marcos-Gragera R] Epidemiology Unit and Girona Cancer Registry, Oncology Coordination Plan, Catalan Institute of Oncology, Girona, Spain. Research Group on Statistics, Econometrics and Health (GRECS), University of Girona, Girona, Spain. Descriptive Epidemiology, Genetics and Cancer Prevention Group, Biomedical Research Institute (IDIBGI), Girona, Spain. Centro de Investigación Biomédica en Red: Epidemiología y Salud Pública (CIBERESP), Madrid, Spain. Josep Carreras Leukemia Research Institute, Badalona, Spain, and Hospital Universitari de Girona Dr Josep Trueta
Subjects: Multivariate analysis, Other subheadings::Other subheadings::/epidemiology [Other subheadings], Health, Toxicology and Mutagenesis, Chronic lymphocytic leukemia, lcsh:Medicine, Comorbidity, 0302 clinical medicine, immune system diseases, Cause of Death, hemic and lymphatic diseases, Medicine, ambiente y salud pública::salud pública::factores epidemiológicos::comorbilidad [ATENCIÓN DE SALUD], Cause of death, education.field_of_study, Leucèmia limfoide, Relative survival, Otros calificadores::Otros calificadores::/epidemiología [Otros calificadores], Leucèmia limfoide - Epidemiologia, Leucèmia limfoide -- Mortalitat, 030220 oncology & carcinogenesis, neoplasias::neoplasias por tipo histológico::leucemia::leucemia linfoide::leucemia de células B::leucemia linfocítica crónica de células B [ENFERMEDADES], medicine.medical_specialty, Population, Mort - Causes, causes of death, comorbidities, survival, Article, 03 medical and health sciences, Comorbiditat, Diabetes mellitus, Internal medicine, Humans, Health Care Quality, Access, and Evaluation::Quality of Health Care::Epidemiologic Factors::Comorbidity [HEALTH CARE], education, Proportional Hazards Models, business.industry, lcsh:R, Public Health, Environmental and Occupational Health, medicine.disease, Leukemia, Lymphocytic, Chronic, B-Cell, Cancer registry, population-based, Lymphocytic leukemia, Neoplasms::Neoplasms by Histologic Type::Leukemia::Leukemia, Lymphoid::Leukemia, B-Cell::Leukemia, Lymphocytic, Chronic, B-Cell [DISEASES], Investigative Techniques::Epidemiologic Methods::Data Collection::Vital Statistics::Mortality::Cause of Death [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], Lymphocytic leukemia -- Mortality, Spain, chronic lymphocytic leukemia, business, técnicas de investigación::métodos epidemiológicos::recopilación de datos::estadísticas vitales::mortalidad::causas de muerte [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], 030215 immunology
Abstract: This study aimed to examine the prevalence of comorbidities in patients diagnosed with chronic lymphocytic leukemia (CLL), and to assess its influence on survival and cause-specific mortality at a population-based level. Incident CLL cases diagnosed in the Girona province (Spain) during 2008&ndash, 2016 were extracted from the Girona Cancer Registry. Rai stage and presence of comorbidities at diagnosis, further categorized using the Charlson comorbidity index (CCI), were obtained from clinical records. Observed (OS) and relative survival (RS) were estimated and Cox&rsquo, s proportional hazard models were used to explore the impact of comorbidity on mortality. Among the 400 cases included in the study, 380 (99.5%) presented at least one comorbidity at CLL diagnosis, with diabetes without end organ damage (21%) being the most common disease. 5-year OS and RS were 68.8 (95% CI: 64.4&ndash, 73.6) and 99.5 (95% CI 3.13&ndash, 106.0), respectively, which decreased markedly with increasing CCI, particularly in patients with CCI &ge, 3. Multivariate analysis identified no statistically significant association between the CCI and overall CLL-related or CLL-unrelated mortality. In conclusion, a high CCI score negatively influenced the OS and RS of CLL patients, yet its effect on mortality was statistically non-significant when also considering age and the Rai stage.
Published: 2021
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272. Biomarkers Associating with PARP Inhibitor Benefit in Prostate Cancer in the TOPARP-B Trial

Author: Chloe Baker, Emma Hall, Daniel Nava Rodrigues, Claudia Bertan, Susana Miranda, Nuria Porta, Ruth Riisnaes, Mateus Crespo, Alec Paschalis, Wei Yuan, Joaquin Mateo, Johann S. de Bono, Sara Arce-Gallego, Stephen J. Pettitt, Violeta Serra, Bora Gurel, Suzanne Carreira, Diletta Bianchini, Jane Goodall, Pasquale Rescigno, Christopher J. Lord, Alba Llop-Guevara, Ana Ferreira, Rita Pereira, Jan Rekowski, George Seed, Ines Figueiredo, Institut Català de la Salut, [Carreira S, Porta N, Seed G] The Institute of Cancer Research, London, UK. [Arce-Gallego S, Llop-Guevara A, Serra V] Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Mateo J] The Institute of Cancer Research, London, UK. The Royal Marsden NHS Foundation Trust, London, UK. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Vall d’Hebron Hospital Universitari, Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: 0301 basic medicine, Male, ADN - Reparació, Neoplasms::Neoplasms by Site::Urogenital Neoplasms::Genital Neoplasms, Male::Prostatic Neoplasms [DISEASES], Genetic Phenomena::DNA Repair [PHENOMENA AND PROCESSES], DNA Repair, DNA repair, PALB2, RAD51, Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores], Antineoplastic Agents, Poly(ADP-ribose) Polymerase Inhibitors, Other subheadings::Other subheadings::/drug therapy [Other subheadings], fenómenos genéticos::reparación del ADN [FENÓMENOS Y PROCESOS], Germline, Medicaments antineoplàstics, Olaparib, 03 medical and health sciences, Prostate cancer, chemistry.chemical_compound, 0302 clinical medicine, Medicine, Humans, business.industry, Prostatic Neoplasms, Pròstata - Càncer - Tractament, medicine.disease, 3. Good health, neoplasias::neoplasias por localización::neoplasias urogenitales::neoplasias de los genitales masculinos::neoplasias de la próstata [ENFERMEDADES], 030104 developmental biology, Oncology, chemistry, 030220 oncology & carcinogenesis, PARP inhibitor, Cancer research, Homologous recombination, business, Biomarkers
Abstract: Pròstata; PARP; Biomarcadors Próstata; PARP; Biomarcadores Prostate; PARP; biomarkers PARP inhibitors are approved for treating advanced prostate cancers (APCs) with various defective DNA repair genes; however, further studies to clinically qualify predictive biomarkers are warranted. Herein we analyzed TOPARP-B Phase II clinical trial samples, evaluating whole exome and low-pass whole genome sequencing and immunohistochemical assays evaluating ATM and RAD51 foci (testing homologous recombination repair function). BRCA1/2 germline and somatic pathogenic mutations associated with similar benefit from olaparib; greater benefit was observed with homozygous BRCA deletion. Biallelic, but not mono-allelic, PALB2 deleterious alterations were associated with clinical benefit. In the ATM cohort, loss of ATM protein by immunohistochemistry associated with better outcome. RAD51 foci loss identified tumors with biallelic BRCA and PALB2 alteration while most ATM- and CDK12-altered APCs had higher RAD51 foci levels. Overall, APCs with homozygous BRCA2 deletion are exceptional responders; PALB2 biallelic loss and loss of ATM immunohistochemical expression associated with clinical benefit. TOPARP is an investigator-initiated trial; we are grateful for the support and funding from AstraZeneca, and for the study grants from Cancer Research UK (CRUK/11/029; C12540/A12829; C12540/A13230; C12540/A20447). ICR-CTSU also receives program grant funding from Cancer Research UK (Grant number: C1491/A15955, C1491/A25351). We acknowledge research funding for this work from Cancer Research UK, Prostate Cancer UK, the Movember Foundation through the London Movember Centre of Excellence (CEO13_2-002), the Prostate Cancer Foundation, and the UK Department of Health through an Experimental Cancer Medicine Centre (ECMC) grant. Professor Johann de Bono is a National Institute for Health Research (NIHR) Senior Investigator. The views expressed in this article are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health; research at the Royal Marsden Hospital is supported by a Biomedical Research Centre grant. Pasquale Rescigno was supported by a PCF Young Investigator Award 19YOUN19. The authors affiliated to VHIO acknowledge funding from “La Caixa” Foundation and European Institute of Innovation and Technology/Horizon 2020 (LCF/TR/CC19/52470003), Fundacion FERO and Fundacion Cellex. J. Mateo, A. Llop-Guevara and V. Serra received grants from Fundacion Cientifica AECC (LABAE16020PORTT) and an ERAPERMED2019-215. J. Mateo gratefully acknowledges funding from the European Union’s Horizon 2020 research and innovation program (Marie Skłodowska-Curie grant 837900), Instituto de Salud Carlos III (Grant PI18/01384), Fundación AECC, CRIS Cancer Foundation and the US Department of Defense CDMRP (Impact Award PC170510P1). S. Arce-Gallego Research. Downloaded from cancerdiscovery.aacrjournals.org on July 1, 2021. © 2021 American Association for Cancer Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on May 27, 2021; DOI: 10.1158/2159-8290.CD-21-0007 3 and V. Serra were supported by Instituto de Salud Carlos III (FI19/00280, CPII19/00033).
Published: 2021

273. Clinical, Pathological, and Molecular Features of Breast Carcinoma Cutaneous Metastasis

Author: Belén Pérez-Mies, José Palacios, Tamara Caniego-Casas, Javier Cortés, Giuseppe Curigliano, Silvia González-Martínez, David Pizarro, Institut Català de la Salut, [González-Martínez S] Clinical Researcher, Hospital Ramón y Cajal, Madrid, Spain. Fundación Contigo contra el Cáncer de la Mujer, Madrid, Spain. [Pizarro D, Caniego-Casas T] Department of Pathology, Hospital Ramón y Cajal, Madrid, Spain. [Pérez-Mies B, Palacios J] Department of Pathology, Hospital Ramón y Cajal, Madrid, Spain. Institute Ramón y Cajal for Health Research (IRYCIS), Madrid, Spain. CIBER-ONC, Instituto de Salud Carlos III, Madrid, Spain. Faculty of Medicine, University of Alcalá de Henares, Alcalá de Henares, Madrid, Spain. [Curigliano G] European Institute of Oncology, IRCCS, Milan, Italy. Departament of Oncology and Hematology, University of Milan, Milan, Italy. [Cortés J] CIBER-ONC, Instituto de Salud Carlos III, Madrid, Spain. Department of Medicine, Faculty of Biomedical and Health Sciences, Universidad Europea de Madrid, Madrid, Spain. Department of Medicine, Faculty of Biomedical and Health Sciences, Universidad Europea de Madrid, Madrid, Spain. International Breast Cancer Center (IBCC), Quironsalud Group, Barcelona, Spain. Medica Scientia Innovation Research, Barcelona, Spain. Medica Scientia Innovation Research, Ridgewood, NJ, USA. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: Oncology, Cancer Research, medicine.medical_specialty, Poor prognosis, Mama - Càncer - Prognosis, skin, Neoplasms::Neoplasms by Site::Breast Neoplasms [DISEASES], CNV, Cèl·lules canceroses - Proliferació, Neoplasias cutáneas, Review, Metastasis, Breast cancer, breast cancer, Medicina preventiva, Metàstasi, Internal medicine, health services administration, medicine, metastasis, Cutaneous metastasis, Tecnología médica, Pathological, RC254-282, health care economics and organizations, neoplasias::neoplasias por localización::neoplasias de la mama [ENFERMEDADES], business.industry, Neoplasms::Neoplastic Processes::Neoplasm Metastasis [DISEASES], Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Cáncer, medicine.disease, Primary tumor, Other subheadings::Other subheadings::/pathology [Other subheadings], neoplasias::procesos neoplásicos::metástasis neoplásica [ENFERMEDADES], Metástasis de la neoplasia, immunohistochemistry, Neoplasias de la mama, Immunohistochemistry, pathology, mutation, Breast carcinoma, business, Otros calificadores::Otros calificadores::/patología [Otros calificadores]
Abstract: Simple Summary Metastasis is the last stage in the development of cancer and usually results in mortality. Cutaneous metastases (CMs) account for 2% of all skin malignancies. Nearly 70% of CMs in women originate from breast cancer (BC). Since CM is usually associated with poor prognosis, the development of management strategies for these patients remains an important clinical challenge. Identifying molecular markers in primary BC that predict CMs and determining the molecular differences between primary tumors and their metastases is of great interest for designing new therapeutic approaches. Abstract Cutaneous metastases (CMs) account for 2% of all skin malignancies, and nearly 70% of CMs in women originate from breast cancer (BC). CMs are usually associated with poor prognosis, are difficult to treat, and can pose diagnostic problems, such as in histopathological diagnosis when occurring long after development of the primary tumor. In addition, the molecular differences between the primary tumors and their CMs, and between CMs and metastases in other organs, are not well defined. Here, we review the main clinical, pathological, and molecular characteristics of breast cancer CMs. Identifying molecular markers in primary BC that predict CM and can be used to determine the molecular differences between primary tumors and their metastases is of great interest for the design of new therapeutic approaches.
Published: 2021

274. COVID-19 in breast cancer patients: a subanalysis of the OnCovid registry

Author: Laia Garrigós, Cristina Saura, Clara Martinez-Vila, Alberto Zambelli, Mark Bower, Barbara Pistilli, Matteo Lambertini, Diego Ottaviani, Nikolaos Diamantis, Ailsa Lumsden, Sonia Pernas, Daniele Generali, Elia Seguí, Gemma Viñas, Eudald Felip, Ana Sanchez, Gianpiero Rizzo, Armando Santoro, Alessio Cortellini, Ylenia Perone, John Chester, Maria Iglesias, Marta Betti, Bruno Vincenzi, Michela Libertini, Francesca Mazzoni, Federica Zoratto, Rossana Berardi, Annalisa Guida, Rachel Wuerstlein, Angela Loizidou, Rachel Sharkey, Juan Aguilar Company, Marta Matas, Chiara Saggia, Lorenzo Chiudinelli, Emeline Colomba-Blameble, Myria Galazi, Uma Mukherjee, Mieke Van Hemelrijck, Mar Marin, Carla Strina, Aleix Prat, Helena Pla, Eva Maria Ciruelos, Alexia Bertuzzi, Lucia del Mastro, Giampiero Porzio, Thomas Newsom-Davis, Isabel Ruiz, Maria Belen Delany, Marco Krengli, Vittoria Fotia, Alessandro Viansone, Neha Chopra, Margarita Romeo, Ramon Salazar, Ignacio Perez, Francesca d’Avanzo, Michela Franchi, Manuela Milani, Fanny Pommeret, Marco Tucci, Paolo Pedrazzoli, Nadia Harbeck, Daniela Ferrante, David J. Pinato, Alessandra Gennari, Garrigos, L., Saura, C., Martinez-Vila, C., Zambelli, A., Bower, M., Pistilli, B., Lambertini, M., Ottaviani, D., Diamantis, N., Lumsden, A., Pernas, S., Generali, D., Segui, E., Vinas, G., Felip, E., Sanchez, A., Rizzo, G., Santoro, A., Cortellini, A., Perone, Y., Chester, J., Iglesias, M., Betti, M., Vincenzi, B., Libertini, M., Mazzoni, F., Zoratto, F., Berardi, R., Guida, A., Wuerstlein, R., Loizidou, A., Sharkey, R., Aguilar Company, J., Matas, M., Saggia, C., Chiudinelli, L., Colomba-Blameble, E., Galazi, M., Mukherjee, U., Van Hemelrijck, M., Marin, M., Strina, C., Prat, A., Pla, H., Ciruelos, E. M., Bertuzzi, A., del Mastro, L., Porzio, G., Newsom-Davis, T., Ruiz, I., Delany, M. B., Krengli, M., Fotia, V., Viansone, A., Chopra, N., Romeo, M., Salazar, R., Perez, I., D'Avanzo, F., Franchi, M., Milani, M., Pommeret, F., Tucci, M., Pedrazzoli, P., Harbeck, N., Ferrante, D., Pinato, D. J., Gennari, A., Institut Català de la Salut, [Garrigós L] Servei d’Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Saura C] Vall d’Hebron Hospital Universitari, Barcelona, Spain. Head Breast Cancer Unit, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Martinez-Vila C] Department of Oncology, Hospital Althaia Manresa, Barcelona, Spain. [Zambelli A] Oncology Unit, ASST Papa Giovanni XXIII, Bergamo, Italy. [Bower M] Department of Oncology and National Centre for HIV Malignancy, Chelsea and Westminster Hospital, London, UK. [Pistilli B] Department of Medical Oncology, Institute Gustave-Roussy, Villejuif, France. [Aguilar Company J] Servei d’Oncologia Mèdica i Servei de Malalties Infeccioses, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Ruiz I] Servei de Malalties Infeccioses, Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Pla H] Departament d'Oncologia Institut Català d'Oncologia, Hospital Universitari de Girona Doctor Josep Trueta, Institut Català de la Salut (ICS), Girona, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: medicine.medical_specialty, Outcome assessment (Medical care), breast cancer, COVID-19, COVID-19 outcomes, OnCovid, SARS-CoV-2, Neoplasms::Neoplasms by Site::Breast Neoplasms [DISEASES], Population, Context (language use), COVID-19 (Malaltia) - Mortalitat, Disease, técnicas de investigación::métodos epidemiológicos::recopilación de datos::estadísticas vitales::mortalidad [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Càncer de mama, Otros calificadores::Otros calificadores::/complicaciones [Otros calificadores], Breast cancer, Mama - Càncer, Internal medicine, virosis::infecciones por virus ARN::infecciones por Nidovirales::infecciones por Coronaviridae::infecciones por Coronavirus [ENFERMEDADES], Medicine, education, COVID-19 outcome, RC254-282, COVID-19 (Malaltia) - Complicacions, Original Research, education.field_of_study, neoplasias::neoplasias por localización::neoplasias de la mama [ENFERMEDADES], business.industry, Mortality rate, Cancer, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Virus Diseases::RNA Virus Infections::Nidovirales Infections::Coronaviridae Infections::Coronavirus Infections [DISEASES], medicine.disease, Comorbidity, Oncology, Investigative Techniques::Epidemiologic Methods::Data Collection::Vital Statistics::Mortality [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], Avaluació de resultats (Assistència mèdica), business, Complication, Other subheadings::Other subheadings::/complications [Other subheadings]
Abstract: COVID-19; SARS-CoV-2; Cáncer de mama COVID-19; SARS-CoV-2; Càncer de mama COVID-19; SARS-CoV-2; Breast cancer Background: Cancer patients are at higher risk of COVID-19 complications and mortality than the rest of the population. Breast cancer patients seem to have better prognosis when infected by SARS-CoV-2 than other cancer patients. Methods: We report a subanalysis of the OnCovid study providing more detailed information in the breast cancer population. Results: We included 495 breast cancer patients with a SARS-CoV-2 infection. Mean age was 62.6 years; 31.5% presented more than one comorbidity. The most frequent breast cancer subtype was luminal-like (n = 245, 49.5%) and 177 (35.8%) had metastatic disease. A total of 332 (67.1%) patients were receiving active treatment, with radical intent in 232 (47.6%) of them. Hospitalization rate was 58.2% and all-cause mortality rate was 20.3%. One hundred twenty-nine (26.1%) patients developed one COVID-19 complication, being acute respiratory failure the most common (n = 74, 15.0%). In the multivariable analysis, age older than 70 years, presence of COVID-19 complications, and metastatic disease were factors correlated with worse outcomes, while ongoing anticancer therapy at time of COVID-19 diagnosis appeared to be a protective factor. No particular oncological treatment was related to higher risk of complications. In the context of SARS-CoV-2 infection, 73 (18.3%) patients had some kind of modification on their oncologic treatment. At the first oncological reassessment (median time: 46.9 days ± 36.7), 255 (51.6%) patients reported to be fully recovered from the infection. There were 39 patients (7.9%) with long-term SARS-CoV-2-related complications. Conclusion: In the context of COVID-19, our data confirm that breast cancer patients appear to have lower complications and mortality rate than expected in other cancer populations. Most breast cancer patients can be safely treated for their neoplasm during SARS-CoV-2 pandemic. Oncological treatment has no impact on the risk of SARS-CoV-2 complications, and, especially in the curative setting, the treatment should be modified as little as possible. D.J. Pinato is supported by grant funding from the Wellcome Trust Strategic Fund (PS3416) and acknowledges grant support from the Cancer Treatment and Research Trust (CTRT), infrastructural and grant support by the Cancer Research UK Imperial Centre and the NIHR Imperial Biomedical Research Centre. A. Gennari is supported by the AIRC IG Grant, No. 14230, Associazione Italiana per la Ricerca sul Cancro Foundation, Milan, Italy and acknowledge also support from the UPO Aging Project.
Published: 2021

275. Epidemiology, treatment, and survival in small cell lung cancer in Spain: Data from the Thoracic Tumor Registry

Author: Bartomeu Massuti, Paola García Coves, M. Guirado, Julia Calzas, Ana Ortega, R. López-Castro, Edel del Barco, Oscar Juan, Delvys Rodriguez-Abreu, Rosario García-Campelo, Jose Manuel Trigo, Francisco Aparisi, Enric Carcereny, Joaquim Bosch-Barrera, Mariano Provencio, Manuel Cobo, Fernando Faria Franco, José Luis González-Larriba, Manuel Domine, S. Cerezo, Marta Domenech, [Franco,F, Provencio,M] Hospital Universitario Puerta de Hierro-Majadahonda, Madrid, Spain. [Carcereny,E, Domènech,M] Catalan Institute of Oncology, Hospital Universitari Germans Trias i Pujol, B-ARGO, IGTP, Badalona, Spain. [Guirado,M, García Coves,P] Hospital General Universitario de Elche, Elche, Spain. [Ortega,AL] Hospital Universitario de Jaén, Jaén, Spain. [López-Castro,R] Hospital Clínico Universitario de Valladolid, Valladolid, Spain. [Rodríguez-Abreu,D] Hospital Universitario Insular de Gran Canaria, Las Palmas de Gran Canaria, Spain. [García-Campelo,R] Complejo Hospitalario Universitario A Coruña, A Coruña, Spain. [Del Barco,E] Hospital Universitario de Salamanca, Salamanca, Spain. [Juan,O] Hospital Universitario y Politécnico La Fe, Valencia, Spain. [Aparisi,F] Hospital General de Valencia, Valencia, Spain. [González-Larriba,JL] Hospital Universitario Clínico San Carlos, Madrid, Spain. [Domine,M] Hospital Universitario Fundación Jiménez Díaz, IIS-FJD, Madrid, Spain. [Trigo,JM, Cobo,M] Unidad de Gestión Clínica Intercentros de Oncología Médica, Hospitales Universitarios Regional y Virgen de la Victoria, IBIMA, Málaga, Spain. [Cerezo,S] Hospital General La Mancha Centro, Alcázar de San Juan, Spain. [Calzas,J] Hospital Universitario de Fuenlabrada, Fuenlabrada, Spain. [Massutí,B] Hospital General Universitario de Alicante, Alicante, Spain. [Bosch-Barrera,J] Catalan Institute of Oncology, Girona, Spain., The TTR registry was supported by Fundación GECP, AstraZeneca, Novartis, Roche, the European Union’s Horizon 2020 research and innovation program (CLARIFY 875160)., and Servicio de Oncología. Hospital Universitario de Fuenlabrada
Subjects: Central Nervous System, Male, Lung Neoplasms, Survival, Epidemiology, medicine.medical_treatment, Terapéutica, España, Cancer Treatment, Carcinoma pulmonar de células pequeñas, Nervous System, Lung and Intrathoracic Tumors, Metastasis, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], Small Cell Lung Cancer, chemistry.chemical_compound, STAGE, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Epidemiologic Study Characteristics as Topic::Epidemiologic Studies::Cohort Studies::Retrospective Studies [Medical Subject Headings], Basic Cancer Research, Medicine and Health Sciences, Registries, Health Care::Environment and Public Health::Public Health::Epidemiologic Methods::Epidemiologic Study Characteristics as Topic::Epidemiologic Studies::Cohort Studies::Follow-Up Studies [Medical Subject Headings], Neurological Tumors, Neoplasias torácicas, Etoposide, Persons::Persons::Age Groups::Adult::Aged [Medical Subject Headings], Multidisciplinary, Supervivencia (salud pública), Middle Aged, respiratory system, Prognosis, Combined Modality Therapy, humanities, Survival Rate, PROPHYLACTIC CRANIAL IRRADIATION, Oncology, Neurology, CISPLATIN-BASED CHEMOTHERAPY, Medicine, Female, Anatomy, Health Care::Population Characteristics::Demography::Vital Statistics::Mortality::Survival Rate [Medical Subject Headings], RADIOTHERAPY, Research Article, medicine.drug, medicine.medical_specialty, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Therapeutics::Combined Modality Therapy [Medical Subject Headings], Science, Check Tags::Male [Medical Subject Headings], Diseases::Neoplasms::Neoplasms by Site::Thoracic Neoplasms::Respiratory Tract Neoplasms::Lung Neoplasms [Medical Subject Headings], Diagnostic Medicine, Internal medicine, Cancer Detection and Diagnosis, medicine, Humans, Epidemiología, Lung cancer, neoplasms, Aged, Retrospective Studies, Thoracic tumor, Cisplatin, Geographical Locations::Geographic Locations::Europe::Spain [Medical Subject Headings], Chemotherapy, Diseases::Neoplasms::Neoplasms by Site::Thoracic Neoplasms::Respiratory Tract Neoplasms::Lung Neoplasms::Bronchial Neoplasms::Carcinoma, Bronchogenic::Small Cell Lung Carcinoma [Medical Subject Headings], Small cell lung cancer, business.industry, Cancers and Neoplasms, Biology and Life Sciences, Persons::Persons::Age Groups::Adult::Middle Aged [Medical Subject Headings], EFFICACY, medicine.disease, TRENDS, Small Cell Lung Carcinoma, Carboplatin, Non-Small Cell Lung Cancer, respiratory tract diseases, Treatment, chemistry, Check Tags::Female [Medical Subject Headings], Spain, Brain Metastasis, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Diagnosis::Prognosis [Medical Subject Headings], Observational study, 1ST-LINE, business, Follow-Up Studies
Abstract: Background Small-cell lung cancer (SCLC) is an aggressive disease with high metastatic potential and poor prognosis. Due to its low prevalence, epidemiological and clinical information of SCLC patients retrieved from lung cancer registries is scarce. Patients and methods This was an observational multicenter study that enrolled patients with lung cancer and thoracic tumors, recruited from August 2016 to January 2020 at 50 Spanish hospitals. Demographic and clinical data, treatment patterns and survival of SCLC patients included in the Thoracic Tumor Registry (TTR) were analyzed. Results With a total of 956 cases, the age of 64.7 ± 9.1 years, 78.6% were men, 60.6% smokers, and ECOG PS 0, 1 or ≥ 2 in 23.1%, 53.0% and 23.8% of cases, respectively. Twenty percent of patients had brain metastases at the diagnosis. First-line chemotherapy (CT), mainly carboplatin or cisplatin plus etoposide was administered to >90% of patients. In total, 36.0% and 13.8% of patients received a second and third line of CT, respectively. Median overall survival was 9.5 months (95% CI 8.8–10.2 months), with an estimated rate of 70.3% (95% CI 67.2–73.4%), 38.9% (95% CI 35.4–42.4%), and 14.8% (95% CI 11.8–17.8%) at 6, 12 and 24 months respectively. Median progression-free survival was 6.3 months. Higher mortality and progression rates were significantly associated with male sex, older age, smoking habit, and ECOG PS 1–2. Long-term survival (> 2 years) was confirmed in 6.6% of patients, showing a positive correlation with better ECOG PS, poor smoking and absence of certain metastases at diagnosis. Conclusion This study provides an updated overview of the clinical situation and treatment landscape of ES-SCLC in Spain. Our results might assist oncologists to improve current clinical practice towards a better prognosis for these patients.
Published: 2021

276. Lifetime alcohol intake, drinking patterns over time and risk of stomach cancer: A pooled analysis of data from two prospective cohort studies

Author: Fulvio Ricceri, Joseph A. Rothwell, Amanda J. Cross, Graham G. Giles, Elisabete Weiderpass, Tilman Kühn, Emily Sonestedt, Yi Yang, Rudolf Kaaks, Valeria Pala, Anna Karakatsani, Dallas R. English, Rosario Tumino, Pilar Amiano, Antonia Trichopoulou, John L. Hopper, Leila Lujan-Barroso, Allison M. Hodge, Bengt Wallner, Ruth C. Travis, María Dolores López, Anne Tjønneland, Hazel M. Mitchell, Kostas Tsilidis, Domenico Palli, Harindra Jayasekara, Elio Riboli, Antonio Agudo, Robin Room, Heiner Boeing, Eva Ardanaz, Bas Bueno-de-Mesquita, Torkjel M. Sandanger, Pietro Ferrari, Robert J. MacInnis, Susana Merino, Andrew Haydon, Eleni Peppa, Marie-Christine Boutron-Ruault, Salvatore Panico, María José Sánchez, Marc J. Gunter, Hanna Sternby, Roger L. Milne, Gianluca Severi, Ana Lucia Mayen-Chacon, Centre international de Recherche sur le Cancer (CIRC), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Institut Gustave Roussy (IGR), VicHealth Kræftens Bekæmpelse, DCS German Cancer Research Center, DKFZ Centre International de Recherche sur le Cancer, CIRC Wellcome Trust, WT Medical Research Council, MRC: MC‐UU_12015/1, MR/M012190/1, MR/N003284/1 British Heart Foundation, BHF Department of Health and Social Care, DH Cancer Research UK, CRUK: C570/ A16491, C8221/A19170, C864/A14136 World Cancer Research Fund, WCRF Food Standards Agency, FSA Stroke Association European Commission, EC National Health and Medical Research Council, NHMRC: 1074383, 209057, 396414, GNT1163120 Cancer Council Victoria Institut National de la Santé et de la Recherche Médicale, Inserm Bundesministerium für Bildung und Forschung, BMBF Cancerfonden Ministerie van Volksgezondheid, Welzijn en Sport, VWS Ligue Contre le Cancer Stavros Niarchos Foundation, SNF Vetenskapsrådet, VR Consiglio Nazionale delle Ricerche, CNR Ministère des Affaires Sociales et de la Santé: GR‐IARC‐2003‐09‐12‐01 Instituto de Salud Carlos III, ISCIII Associazione Italiana per la Ricerca sul Cancro, AIRC Deutsche Krebshilfe Rijksinstituut voor Volksgezondheid en Milieu, RIVM Institut Gustave-Roussy Mutuelle Générale de l'Education Nationale, MGEN Ministry of Health and Social Solidarity, Greece Foundation for Alcohol Research and Education, FARE Hellenic Health Foundation, HHF, Australian National Health and Medical Research Council, Grant/Award Numbers: 1074383, 209057, 396414, GNT1163120, Cancer Council Victoria (Australia), Cancer Research UK, Grant/Award Numbers: C570/ A16491, C8221/A19170, C864/A14136, Catalan Institute of Oncology ‐ ICO (Spain), Danish Cancer Society, Deutsche Krebshilfe, the Deutsches Krebsforschungszentrum (Germany), Dutch Ministry of Public Health, Welfare and Sports, European Commission (Directorate General for Health and Consumer Affairs), Foundation for Alcohol Research and Education (Australia), French Ministry of Health, Grant/Award Number: Grant GR‐IARC‐2003‐09‐12‐01, Health Research Fund (FIS) ‐ Instituto de Salud Carlos III (ISCIII), Regional Governments of Andalucía, Asturias, Basque Country, Murcia and Navarra, Hellenic Health Foundation (Greece), Hellenic Ministry of Health and Social Solidarity (Greece), Institut National de la Santé et de la Recherche Médicale (France), Italian Association for Research on Cancer and the National Research Council (Italy), Ligue Contre le Cancer (France), LK Research Funds, Dutch Prevention Funds, the Dutch Zorg Onderzoek Nederland, Medical Research Council (UK), Grant/Award Numbers: MC‐UU_12015/1, MR/M012190/1, MR/N003284/1, Mutuelle Générale de l'Education Nationale, National Institute for Public Health and the Environment (RIVM) (the Netherlands), Netherlands Cancer Registry, Stavros Niarchos Foundation (Greece), Stroke Association, the British Heart Foundation, the Department of Health, the Food Standards Agency and the Wellcome Trust (UK), Swedish Cancer Society, the Swedish Scientific Council and the Regional Government of Skåne (Sweden), the Federal Ministry of Education and Research (Germany), VicHealth (Australia), World Cancer Research Fund and Statistics Netherlands (the Netherlands), the Institut Gustave Roussy Funding information, We thank Carine Biessy and Bertrand Hemon for their technical contribution to EPIC data used in this work. We are also grateful to all the EPIC participants who have been part of the project, and to the many members of the study teams who enabled this research. We thank the original MCCS investigators and the diligent team, who recruited the participants and who continue working on follow‐up, for their contribution. We also express our gratitude to the many thousands of Melbourne residents who continue to participate in the study. This work was supported by the Direction Générale de la Santé (French Ministry of Health, Grant GR‐IARC‐2003‐09‐12‐01), by the European Commission (Directorate General for Health and Consumer Affairs) and the International Agency for Research on Cancer. The national cohorts are supported by the Danish Cancer Society (Denmark), the Ligue Contre le Cancer, the Institut Gustave Roussy, the Mutuelle Générale de l'Education Nationale and the Institut National de la Santé et de la Recherche Médicale (France), the Deutsche Krebshilfe, the Deutsches Krebsforschungszentrum and the Federal Ministry of Education and Research (Germany), the Hellenic Health Foundation, the Stavros Niarchos Foundation and the Hellenic Ministry of Health and Social Solidarity (Greece), the Italian Association for Research on Cancer and the National Research Council (Italy), the Dutch Ministry of Public Health, Welfare and Sports, the Netherlands Cancer Registry, LK Research Funds, Dutch Prevention Funds, the Dutch Zorg Onderzoek Nederland, the World Cancer Research Fund and Statistics Netherlands (the Netherlands), the National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands, for their contribution and ongoing support to the EPIC Study, the Health Research Fund (FIS) ‐ Instituto de Salud Carlos III (ISCIII), Regional Governments of Andalucía, Asturias, Basque Country, Murcia and Navarra, and the Catalan Institute of Oncology ‐ ICO (Spain), the Swedish Cancer Society, the Swedish Scientific Council and the Regional Government of Skåne (Sweden), Cancer Research UK (C864/A14136 to EPIC‐Norfolk, C570/A16491 and C8221/A19170 to EPIC‐Oxford), Medical Research Council (MR/N003284/1 and MC‐UU_12015/1 to EPIC‐Norfolk, MR/M012190/1 to EPIC‐Oxford, United Kingdom), the Stroke Association, the British Heart Foundation, the Department of Health, the Food Standards Agency and the Wellcome Trust (UK). MCCS cohort recruitment was funded by Cancer Council Victoria ( https://www.cancervic.org.au/ ) and VicHealth ( https://www.vichealth.vic.gov.au/ ). The MCCS was further supported by Australian National Health and Medical Research Council (NHMRC) ( https://www.nhmrc.gov.au/ ) grants 209057, 396414 and 1074383, and ongoing follow‐up and data management has been funded by Cancer Council Victoria since 1995. Cases and their vital status were ascertained through the Victorian Cancer Registry and the Australian Institute of Health and Welfare, including the National Death Index and the Australian Cancer Database. Harindra Jayasekara is supported by NHMRC grant GNT1163120. John L. Hopper is a NHMRC Senior Principal Research Fellow. Yi Yang is supported by a Melbourne Research Scholarship from the University of Melbourne. Robin Room's position was funded by the Foundation for Alcohol Research and Education. The sponsors had no role in the design and conduct of the study, collection, management, analysis, and interpretation of the data, preparation, review, or approval of the manuscript, and and decision to submit the manuscript for publication.
Subjects: Male, Cancer Research, Gastroenterology, 0302 clinical medicine, Prospective Studies, Stomach cancer, Prospective cohort study, stomach cancer, biology, Stomach, Incidence, Hazard ratio, Smoking, cardia cancer, Cardia cancer, Middle Aged, Lifetime alcohol intake, 3. Good health, European Prospective Investigation into Cancer and Nutrition, Europe, medicine.anatomical_structure, Oncology, Drinking of alcoholic beverages, 030220 oncology & carcinogenesis, Consum d'alcohol, Female, Life Sciences & Biomedicine, Cohort study, Adult, medicine.medical_specialty, Alcohol Drinking, [SDV.CAN]Life Sciences [q-bio]/Cancer, Helicobacter Infections, noncardia cancer, 03 medical and health sciences, Stomach Neoplasms, Internal medicine, medicine, Humans, 1112 Oncology and Carcinogenesis, Oncology & Carcinogenesis, Aged, Science & Technology, Helicobacter pylori, EPIC, lifetime alcohol intake, MCCS, business.industry, Càncer d'estómac, Kirurgi, Australia, Cancer, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Noncardia cancer, medicine.disease, biology.organism_classification, Surgery, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition
Abstract: Alcohol consumption is causally linked to several cancers but the evidence for stomach cancer is inconclusive. In our study, the association between long-term alcohol intake and risk of stomach cancer and its subtypes was evaluated. We performed a pooled analysis of data collected at baseline from 491 714 participants in the European Prospective Investigation into Cancer and Nutrition and the Melbourne Collaborative Cohort Study. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated for incident stomach cancer in relation to lifetime alcohol intake and group-based life course intake trajectories, adjusted for potential confounders including Helicobacter pylori infection. In all, 1225 incident stomach cancers (78% noncardia) were diagnosed over 7 094 637 person-years; 984 in 382 957 study participants with lifetime alcohol intake data (5 455 507 person-years). Although lifetime alcohol intake was not associated with overall stomach cancer risk, we observed a weak positive association with noncardia cancer (HR = 1.03, 95% CI: 1.00-1.06 per 10 g/d increment), with a HR of 1.50 (95% CI: 1.08-2.09) for ≥60 g/d compared to 0.1 to 4.9 g/d. A weak inverse association with cardia cancer (HR = 0.93, 95% CI: 0.87-1.00) was also observed. HRs of 1.48 (95% CI: 1.10-1.99) for noncardia and 0.51 (95% CI: 0.26-1.03) for cardia cancer were observed for a life course trajectory characterized by heavy decreasing intake compared to light stable intake (Phomogeneity = .02). These associations did not differ appreciably by smoking or H pylori infection status. Limiting alcohol use during lifetime, particularly avoiding heavy use during early adulthood, might help prevent noncardia stomach cancer. Heterogeneous associations observed for cardia and noncardia cancers may indicate etiologic differences., National Health and Medical Research Council of Australia 1074383 209057 396414 GNT1163120, Canadian Institutes of Health Research (CIHR) Cancer Council Victoria, Cancer Research UK C570/A16491 C8221/A19170 C864/A14136, Catalan Institute of Oncology - ICO (Spain), Danish Cancer Society, Deutsche Krebshilfe, Deutsches Krebsforschungszentrum (Germany), Dutch Ministry of Public Health, Welfare and Sports, European Commission European Commission Joint Research Centre, Foundation for Alcohol Research and Education (Australia), French Ministry of Health GR-IARC-2003-09-12-01, Health Research Fund (FIS) -Instituto de Salud Carlos III (ISCIII), Junta de Andalucía, Regional Government of Asturias, Basque Government, Regional Government of Murcia, Regional Government of Navarra, Hellenic Health Foundation (Greece), Hellenic Ministry of Health and Social Solidarity (Greece), Institut National de la Sante et de la Recherche Medicale (Inserm), Consiglio Nazionale delle Ricerche (CNR), Associazione Italiana per la Ricerca sul Cancro (AIRC), Ligue Contre le Cancer (France), LK Research Funds, Dutch Prevention Funds, Netherlands Organization for Scientific Research (NWO), UK Research & Innovation (UKRI) Medical Research Council UK (MRC) MC-UU_12015/1 MR/M012190/1 MR/N003284/, Mutuelle Generale de l'Education Nationale, National Institute for Public Health and the Environment (RIVM) (the Netherlands), Netherlands Cancer Registry, Stavros Niarchos Foundation (Greece), Stroke Association (UK), British Heart Foundation, Department of Health (UK), Food Standards Agency (UK), Wellcome Trust, Swedish Cancer Society, Swedish Scientific Council (Sweden), Regional Government of Skane (Sweden), Federal Ministry of Education & Research (BMBF), VicHealth (Australia), World Cancer Research Fund and Statistics Netherlands (the Netherlands), Institut Gustave Roussy
Published: 2021
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277. SEOM clinical guideline for the management of cutaneous melanoma (2020)

Author: Enrique Espinosa, Ivan Marquez-Rodas, Eva Muñoz-Couselo, K Mujika, Alfonso Berrocal, Jose Luis Manzano, L. de la Cruz-Merino, Maria Gonzalez-Cao, Elisabeth Pérez-Ruiz, Margarita Majem, Institut Català de la Salut, [Majem M] Department of Medical Oncology, Hospital de la Santa Creu i Sant Pau, 08025 Barcelona, Spain. [Manzano JL] Department of Medical Oncology, H. Germans Trias i Pujol, Catalan Institute of Oncology, ICO-Badalona, Badalona, Spain. [Marquez-Rodas I] Department of Medical Oncology, Instituto de Investigación Sanitaria Gregorio Marañón and CIBERONC, Madrid, Spain. [Mujika K] Department of Medical Oncology, UGC de Oncología de Gipuzkoa, OSI Donostialdea-Onkologikoa, Guipúzcoa, Spain. [Muñoz-Couselo E] Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Servei d’Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Pérez-Ruiz E] Department of Medical Oncology, Hospital Costa del Sol and UGC Oncol, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Universitario Regional Virgen Victoria, Málaga, Spain, Vall d'Hebron Barcelona Hospital Campus, and Universidad de Sevilla. Departamento de Medicina
Subjects: Oncology, Cancer Research, Skin Neoplasms, Staging, medicine.medical_treatment, Biopsy, Medical Oncology, Targeted therapy, Neoplasms::Neoplasms by Histologic Type::Neoplasms, Germ Cell and Embryonal::Neuroectodermal Tumors::Neuroendocrine Tumors::Melanoma [DISEASES], 0302 clinical medicine, Adjuvants immunològics - Ús terapèutic, 030212 general & internal medicine, Molecular Targeted Therapy, Stage (cooking), Melanoma, Otros calificadores::/terapia [Otros calificadores], Societies, Medical, neoplasias::neoplasias por tipo histológico::neoplasias de células germinales y embrionarias::tumores neuroectodérmicos::tumores neuroendocrinos::melanoma [ENFERMEDADES], Brain Neoplasms, terapéutica::terapia biológica::inmunomodulación::inmunoterapia [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Medicina clínica - Presa de decisions, General Medicine, Chemotherapy, Adjuvant, 030220 oncology & carcinogenesis, Immunotherapy, Adjuvant, formatos de publicación::guía::guía de práctica clínica [CARACTERÍSTICAS DE PUBLICACIONES], Proto-Oncogene Proteins B-raf, medicine.medical_specialty, Clinical Guides in Oncology, 03 medical and health sciences, Internal medicine, medicine, Humans, In patient, neoplasms, Neoplasm Staging, Publication Formats::Guideline::Practice Guideline [PUBLICATION CHARACTERISTICS], Therapeutics::Biological Therapy::Immunomodulation::Immunotherapy [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], business.industry, Melanoma - Tractament, Adjuvant treatment metastatic treatment, Other subheadings::/therapy [Other subheadings], Guideline, medicine.disease, Spain, Cutaneous melanoma, Lymph Node Excision, Radiotherapy, Adjuvant, business, Follow-Up Studies
Abstract: Tractament adjuvant; Melanoma; Escenificació Adjuvant treatment; Melanoma; Staging Tratamiento adyuvante; Melanoma; Escenificación Melanoma affects about 6000 patients a year in Spain. A group of medical oncologists from Spanish Society of Medical Oncology (SEOM) and Spanish Multidisciplinary Melanoma Group (GEM) has designed these guidelines to homogenize the management of these patients. The diagnosis must be histological and determination of BRAF status has to be performed in patients with stage ≥ III. Stage I–III resectable melanomas will be treated surgically. In patients with stage III melanoma, adjuvant treatment with immunotherapy or targeted therapy is also recommended. Patients with unresectable or metastatic melanoma will receive treatment with immunotherapy or targeted therapy, the optimal sequence of these treatments remains unclear. Brain metastases require a separate consideration, since, in addition to systemic treatment, they may require local treatment. Patients must be followed up closely to receive or change treatment as soon as their previous clinical condition changes, since multiple therapeutic options are available.
Published: 2021

278. Multiethnic genome-wide association study of differentiated thyroid cancer in the EPITHYR consortium

Author: Pierre Laurent-Puig, Yan Ren, Frédérique Rachédi, Pascal Guénel, Sandya Liyanarachchi, Asta Försti, Albert de la Chapelle, Om Kulkarni, Claire Mulot, Huiling He, Federica Gemignani, Julie Guibon, Anne-Valérie Guizard, Fabienne Lesueur, Rossella Elisei, Ausrele Kesminiene, Anthony F. Herzig, Mojgan Karimi, Pierre-Emmanuel Sugier, Thérèse Truong, Delphine Bacq-Daian, Anne-Louise Leutenegger, Constance Xhaard, Daniel F. Comiskey, Celia M Pereda, Evgenia Ostroumova, Florent de Vathaire, Elisabeth Adjadj, Françoise Borson-Chazot, Jean-François Deleuze, Carole Rubino, Anne Boland-Auge, Hauke Thomsen, Elise A. Lucotte, Marie-Christine Boutron-Ruault, Juan J Lence-Anta, Rosa Ortiz, Claire Schvartz, Institut Gustave Roussy (IGR), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Université Paris-Saclay, Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Épidémiologie des radiations, épidémiologie clinique des cancers et survie (U1018 (Équipe 3) ), Institut Gustave Roussy (IGR)-Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Centre d'investigation clinique plurithématique Pierre Drouin [Nancy] (CIC-P), Centre d'investigation clinique [Nancy] (CIC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Cardiovascular and Renal Clinical Trialists [Vandoeuvre-les-Nancy] (INI-CRCT), Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy], French-Clinical Research Infrastructure Network - F-CRIN [Paris] (Cardiovascular & Renal Clinical Trialists - CRCT ), Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Université Paris Diderot, Sorbonne Paris Cité, Paris, France, Université Paris Diderot - Paris 7 (UPD7), Institut Jean Godinot [Reims], UNICANCER, Registre Général des Tumeurs du Calvados, CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-UNICANCER, Unité de recherche interdisciplinaire pour la prévention et le traitement des cancers (ANTICIPE), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital de Taaone, Hôpital Louis Pradel [CHU - HCL], Hospices Civils de Lyon (HCL), Health Service and Performance Research (HESPER), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Institute of Oncology and Radiobiology, Ohio State University [Columbus] (OSU), University of Pisa - Università di Pisa, Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Hopp Children's Cancer Center Heidelberg [Heidelber, Germany] (KITZ), German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ)-Heidelberg University Hospital [Heidelberg], German Cancer Consortium [Heidelberg] (DKTK), Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Centre International de Recherche contre le Cancer - International Agency for Research on Cancer (CIRC - IARC), Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), Ministère de l'Enseignement supérieur, de la Recherche et de l'Innovation, MESRI: 2102 918823 National Institute of Ecology, NIE Agence Nationale de la Recherche, ANR: ANR‐10‐COHO‐0006 Fondation ARC pour la Recherche sur le Cancer, ARC: PGA120150202302 Ligue Contre le Cancer Fondation de France Institut National Du Cancer, INCa: 9533 Agence Nationale de Sécurité Sanitaire de l’Alimentation, de l’Environnement et du Travail, ANSES Mutuelle Générale de l'Education Nationale, MGEN Electricité de France, EDF: EP 2019‐01, We thank Dr Yannick Rougier and Dr Dominique Baron-Dubourdieu for providing pathological reports for the NC study, as well as Dr Sylvie Laumond, Dr Jean-Paul Grangeon (Direction des affaires sanitaires et sociales de Nouvelle-Cal?donie) and the country's provincial health authorities (DPASS Sud, DPASS Nord, DPASS Iles Loyaut?) for support during data collection in the NC study. We thank Milagros Velasco, Mae Chappe and Idalmis Infante (Institute of Oncology and Radiobiology, La Havana, Cuba) and Silvia Turcios (National Institute of Endocrinology, La Havana, Cuba) for helping in the collection of the data in the Cuban Study. We thank John Paoaafaite and Joseph Teuri who contacted and interviewed cases and controls for the study. Finally, we also thank P. Morales, J. Iltis, P. Giraud, P. Didiergeorge, M. Brisard, G. Soubiran, B. Caillou, P. Dupire, J. Ienfa, G. de Clermont, N. Cerf, B. Oddo, M. Bambridge, C. Baron, A. Mouchard-Rachet, O. Simonet, D. Lamarque, J. Vabret, J. Delacre, M.P. Darquier and J. Leninger, for their help in the collection of the cases or in the organization of study in French Polynesia. We would like to thank the Association Centre de Regroupement Informatique et Statistique en Anatomie Pathologique en Provence-Alpes-C?te d'Azur (CRISAP PACA), as well as Dr Arlette Danzon, Dr Genevi?ve Sasolas, Dr Marc Christophe Sattonnet, Dr Marc Colonna, Dr Brigitte Lacour, Dr Michel Velten, Dr Enora Clero, Dr St?phane Maillard, Dr Laurent Bailly, Dr Eug?nia Marin? Barjoan, Dr Jean-Luc Lassalle, Dr Z Hafdi-Nejjari, Dr P Delafosse, Dr Elisabeth Adjadj, Kami-Marie Moreau, Cyrielle Orenes, Laurianne Sarrazin, St?phanie Bonnay, Fr?d?rique Chatelain, Maryse Barouh, Evelyne Rapp, Julie Festra?ts, Julie Valbousquet, Yusuf Atilgan, Jean Chappellet, Lallia Bedhouche, Florent Dayet and Ziyan Fami, for their help in the collection of cases, the organization and the management of the Young-Thyr study. We acknowledge Stefano Landi for the Italian GWAS data and Subhayan Chattopadhyay and Yasmeen Niazi (Division of Molecular Genetic Epidemiology, German Cancer Research Center?DKFZ) for technical assistance in these data analysis. We are grateful to Dr Herv? Perdry for his help in using the GASTON package. The EPITHYR GWAS was supported by Institut National du Cancer (grant number 9533) and Fondation ARC (grant number PGA120150202302). The E3N cohort received support from the MGEN, Gustave Roussy and Ligue contre le cancer for its setup and maintenance. The E3N cohort was also supported by a state grant from the Agence Nationale pour la Recherche (ANR) (grant number ANR-10-COHO-0006) within the Investissement d'Avenir program and from the French Ministry of Higher Education, Research and Innovation (MESRI, grant number 2102 918823). The other participating studies were funded by Ligue Nationale Contre le Cancer, ANR, the Direction G?n?rale de la Sante, the Agence Fran?aise de S?curit? Sanitaire de l'alimentation, de l'environnement et du travail (ANSES), CHILDTHYR EEC program, and the Fondation de France. JG was the recipient of a PhD fellowship from R?gion Ile-de-France, part of OK was the recipient of a post-doc fellowship from Electricit? de France (conseil scientifique de Radioprotection d'EDF, grant EP 2019-01)., The EPITHYR GWAS was supported by Institut National du Cancer (grant number 9533) and Fondation ARC (grant number PGA120150202302). The E3N cohort received support from the MGEN, Gustave Roussy and Ligue contre le cancer for its setup and maintenance. The E3N cohort was also supported by a state grant from the Agence Nationale pour la Recherche (ANR) (grant number ANR‐10‐COHO‐0006) within the Investissement d'Avenir program and from the French Ministry of Higher Education, Research and Innovation (MESRI, grant number 2102 918823). The other participating studies were funded by Ligue Nationale Contre le Cancer, the Direction Générale de la Sante, the Agence Française de Sécurité Sanitaire de l'alimentation, and the Fondation de France. JG was the recipient of a PhD fellowship from Région Ile‐de‐France, part of OK was the recipient of a post‐doc fellowship from Electricité de France (conseil scientifique de Radioprotection d'EDF, grant EP 2019‐01)., Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)
Subjects: Male, Cancer Research, Native Hawaiian or Other Pacific Islander, [SDV]Life Sciences [q-bio], Ethnic group, Genome-wide association study, 0302 clinical medicine, Gene Frequency, Informed consent, Epidemiology, thyroid cancer, Chromosomes, Human, Medicine, Prospective cohort study, Thyroid cancer, Genetics, 0303 health sciences, education.field_of_study, Incidence (epidemiology), Middle Aged, Checklist, 3. Good health, Oncology, 030220 oncology & carcinogenesis, Pacific islanders, Female, Adult, medicine.medical_specialty, case-control study, education, Population, Biology, Pacific Islands, Polymorphism, Single Nucleotide, White People, 03 medical and health sciences, Humans, Genetic Predisposition to Disease, Thyroid Neoplasms, Aged, 030304 developmental biology, genome-wide association study, business.industry, Case-control study, medicine.disease, Clinical trial, Case-Control Studies, Family medicine, business
Abstract: Incidence of differentiated thyroid carcinoma (DTC) varies considerably between ethnic groups, with particularly high incidence rates in Pacific Islanders. Here, we conducted a genome-wide association study (GWAS) involving 1,554 cases/1,973 controls of European ancestry and 301 cases/348 controls of Oceanian ancestry from the EPITHYR consortium. Our results confirmed the association with the known DTC susceptibility loci at 2q35, 8p12, 9q22.33 and 14q13.3 in the European ancestry population and suggested two novel signals at 1p31.3 (rs334729) and 16q23.2 (rs16950982), which were associated with TSH levels in previous GWAS. We additionally replicated an association with 5p15.33 reported previously in Chinese and European populations. Except at 1p31.3, all associations were in the same direction in the population of Oceanian ancestry. The frequency of risk alleles at 2q35, 5p15.33 and 16q23.2 were significantly higher in Oceanians than in Europeans and may explain part of the highest DTC incidence observed in Oceanians.Competing Interest StatementThe authors have declared no competing interest.Funding StatementINCA (grant number 9533) and ARC (grant number PGA120150202302), Ligue Nationale Contre le Cancer, Agence Nationale pour la Recherche (ANR), the Direction Generale de la Sante, the Agence Francaise de Securite Sanitaire de l alimentation, de lenvironnement et du travail (ANSES), CHILDTHYR EEC program, and the Fondation de France. JG and CX were the recipient of a PhD fellowship from Region Ile-de-France.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:All participants provided informed consent and each study was approved by their governing ethics committee.All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesThe data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. (Less)
Published: 2021
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279. SOLTI-1805 TOT-HER3 Study Concept: A Window-of-Opportunity Trial of Patritumab Deruxtecan, a HER3 Directed Antibody Drug Conjugate, in Patients With Early Breast Cancer

Author: Tomás Pascual, Mafalda Oliveira, Eva Ciruelos, Meritxell Bellet Ezquerra, Cristina Saura, Joaquin Gavilá, Sonia Pernas, Montserrat Muñoz, Maria J. Vidal, Mireia Margelí Vila, Juan M. Cejalvo, Blanca González-Farré, Martin Espinosa-Bravo, Josefina Cruz, Francisco Javier Salvador-Bofill, Juan Antonio Guerra, Ana María Luna Barrera, Miriam Arumi de Dios, Stephen Esker, Pang-Dian Fan, Olga Martínez-Sáez, Guillermo Villacampa, Laia Paré, Juan M. Ferrero-Cafiero, Patricia Villagrasa, Aleix Prat, Servicio de Oncología. Hospital Universitario de Fuenlabrada, Institut Català de la Salut, [Pascual T] SOLTI Innovative Cancer Research, Barcelona, Spain. Medical Oncology Department, Hospital Clinic de Barcelona, Barcelona, Spain. Translational Genomics and Targeted Therapies in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (Instituto de Investigaciones Biomédicas August Pi i Sunyer), Barcelona, Spain. [Oliveira M, Bellet Ezquerra M, Saura C] SOLTI Innovative Cancer Research, Barcelona, Spain. Servei d’Oncologia Mèdica, Vall d'Hebron Hospital Universitari, Barcelona, Spain. Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain. Breast Cancer Program, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain. Vall d'Hebron Hospital Universitari, Barcelona, Spain. [Ciruelos E] SOLTI Innovative Cancer Research, Barcelona, Spain. Medical Oncology Department, Hospital 12 de Octubre, Madrid, Spain. [Gavilá J] SOLTI Innovative Cancer Research, Barcelona, Spain. Medical Oncology Department, IVO—Fundación Instituto Valenciano de Oncología, Valencia, Spain. [Espinosa-Bravo M] Unitat de Cirurgia de Càncer de Mama, Vall d'Hebron Hospital Universitari, Barcelona, Spain. [Arumi de Dios M] Servei d’Oncologia Mèdica, Vall d'Hebron Hospital Universitari, Barcelona, Spain. Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: 0301 basic medicine, Oncology, Cancer Research, Patritumab, Antibody-drug conjugate, medicine.medical_specialty, patritumab deruxtecan, Neoplasms::Neoplasms by Site::Breast Neoplasms [DISEASES], Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores], Translational research, Drug resistance, Hormone receptors, Other subheadings::Other subheadings::/drug therapy [Other subheadings], CelTIL Score, HER3-DXd, Càncer de mama, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Investigative Techniques::Investigative Techniques::Evaluation Studies as Topic::Drug Evaluation [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], HER3, Internal medicine, Medicaments - Assaigs clínics, Hypothesis and Theory, Breast Cancer, Clinical endpoint, medicine, ERBB3, skin and connective tissue diseases, RC254-282, Tumor microenvironment, neoplasias::neoplasias por localización::neoplasias de la mama [ENFERMEDADES], Models, Statistical, Receptors d'hormones, business.industry, Modelos Estadísticos, Neoplasias de la Mama, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, 030104 developmental biology, 030220 oncology & carcinogenesis, Mama - Càncer - Tractament, U3-1402, técnicas de investigación::técnicas de investigación::estudios de evaluación como asunto::evaluación de medicamentos [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Breast neoplasms, business
Abstract: Càncer de mama; Puntuació CelTIL; Patritumab deruxtecan Cáncer de mama; Puntuación CelTIL; Patritumab deruxtecan Breast Cancer; CelTIL Score; Patritumab deruxtecan Background: Preclinical data support a key role for the human epidermal growth factor receptor 3 (HER3) pathway in hormone receptor (HR)–positive breast cancer. Recently, new HER3 directed antibody drug conjugates have shown activity in breast cancer. Given the need to better understand the molecular biology, tumor microenvironment, and mechanisms of drug resistance in breast cancer, we designed this window-of-opportunity study with the HER3 directed antibody drug conjugate patritumab deruxtecan (HER3-DXd; U3-1402). Trial Design: Based on these data, a prospective, multicenter, single-arm, window-of-opportunity study was designed to evaluate the biological effect of patritumab deruxtecan in the treatment of naïve patients with HR-positive/HER2-negative early breast cancer whose primary tumors are ≥1 cm by ultrasound evaluation. Patients will be enrolled in four cohorts according to the mRNA-based ERBB3 expression by central assessment. The primary endpoint is a CelTIL score after one single dose. A translational research plan is also included to provide biological information and to evaluate secondary and exploratory objectives of the study. We thank Daiichi Sankyo for their provision of patritumab deruxtecan and their financial contribution to this clinical study. Pas a Pas and Save the Mama to AP. Fundación SEOM (SEOM 2018 Grant: Fellowship for Training in Research in Reference Centers) to TP.
Published: 2021

280. Tumor-Associated Microbiome: Where Do We Stand?

Author: Nuria Mulet-Margalef, Paolo Nuciforo, Joan Mas, Marc Oliva, Victor Moreno, Laia Alemany, Stefania Napoli, Maria Ochoa-De-Olza, Eric J. Duell, Berta Laquente, Institut Català de la Salut, [Oliva M, Mulet-Margalef N, Laquente B] Medical Oncology Department, Catalan Institute of Oncology L’Hospitalet de Llobregat, Catalonia, Spain. ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, Catalonia, Spain. [Ochoa-De-Olza M] Service of Immuno-Oncology, Department of Oncology, Lausanne University Hospital, Lausanne, Switzerland. Ludwig Institute for Cancer Research, University of Lausanne, Lausanne, Switzerland. [Napoli S, Nuciforo P] Molecular Oncology Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Mas J] ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, Catalonia, Spain. Oncology Data Analytics Program, Catalan Institute of Oncology (ICO), L’Hospitalet de Llobregat, Catalonia, Spain. Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: 0301 basic medicine, Cytoplasm, fenómenos microbiológicos::microbiota::microbiota intestinal [FENÓMENOS Y PROCESOS], Carcinogenesis, Treatment outcome, gut microbiome, Review, Bioinformatics, medicine.disease_cause, lcsh:Chemistry, Mice, Càncer - Microbiologia, 0302 clinical medicine, Neoplasms, RNA, Ribosomal, 16S, Tumor Microenvironment, Carcinogènesi, lcsh:QH301-705.5, Spectroscopy, Microbiological Phenomena::Microbiota::Gastrointestinal Microbiome [PHENOMENA AND PROCESSES], Cell Physiological Phenomena::Cellular Microenvironment::Tumor Microenvironment [PHENOMENA AND PROCESSES], Microbiota, Human microbiome, dysbiosis, General Medicine, Computer Science Applications, Gene Expression Regulation, Neoplastic, Cell Transformation, Neoplastic, 030220 oncology & carcinogenesis, Disease Progression, carcinogenesis, Gene Expression Regulation, Viral, Antineoplastic Agents, Catalysis, Other subheadings::Other subheadings::/microbiology [Other subheadings], Inorganic Chemistry, neoplasias [ENFERMEDADES], 03 medical and health sciences, medicine, Animals, Humans, cancer, Intestins - Microbiologia, Microbiome, Physical and Theoretical Chemistry, Molecular Biology, Tumors, metagenomics, business.industry, Organic Chemistry, fenómenos fisiológicos celulares::microambiente celular::microambiente tumoral [FENÓMENOS Y PROCESOS], Immunity, Computational Biology, Cancer, Gene Expression Regulation, Bacterial, medicine.disease, tumor microbiome, Gut microbiome, Gastrointestinal Microbiome, Neoplasms [DISEASES], 030104 developmental biology, lcsh:Biology (General), lcsh:QD1-999, Metagenomics, Metagenome, Otros calificadores::Otros calificadores::/microbiología [Otros calificadores], business, Dysbiosis
Abstract: Dysbiosis; Gut microbiome; Tumor Disbiosis; Microbioma intestinal; Tumor Disbiosi; Microbioma intestinal; Tumor The study of the human microbiome in oncology is a growing and rapidly evolving field. In the past few years, there has been an exponential increase in the number of studies investigating associations of microbiome and cancer, from oncogenesis and cancer progression to resistance or sensitivity to specific anticancer therapies. The gut microbiome is now known to play a significant role in antitumor immune responses and in predicting the efficacy of immune-checkpoint inhibitors in cancer patients. Beyond the gut, the tumor-associated microbiome-microbe communities located either in the tumor or within its body compartment-seems to interact with the local microenvironment and the tumor immune contexture, ultimately impacting cancer progression and treatment outcome. However, pre-clinical research focusing on causality and mechanistic pathways as well as proof-of-concept studies are still needed to fully understand the potential clinical utility of microbiome in cancer patients. Moreover, there is a need for the standardization of methodology and the implementation of quality control across microbiome studies to allow for a better interpretation and greater comparability of the results reported between them. This review summarizes the accumulating evidence in the field and discusses the current and upcoming challenges of microbiome studies.
Published: 2021

281. The Impact of Excluding Nonrandomized Studies From Systematic Reviews in Rare Diseases: 'The Example of Meta-Analyses Evaluating the Efficacy and Safety of Enzyme Replacement Therapy in Patients With Mucopolysaccharidosis'

Author: Miguel Sampayo-Cordero, Bernat Miguel-Huguet, Andrea Malfettone, José Manuel Pérez-García, Antonio Llombart-Cussac, Javier Cortés, Almudena Pardo, Jordi Pérez-López, Institut Català de la Salut, [Sampayo-Cordero M, Malfettone A] Medica Scientia Innovation Research (MedSIR), Barcelona, Spain. [Miguel-Huguet B] Colorectal Unit, Department of Surgery, Hospital de Bellvitge, Barcelona, Spain. [Pérez-García JM] Medica Scientia Innovation Research (MedSIR), Barcelona, Spain. IOB Institute of Oncology, Quiron Salud Group, Madrid, Spain. [Llombart-Cussac A] Medica Scientia Innovation Research (MedSIR), Barcelona, Spain. Hospital Arnau de Vilanova, Universidad Católica de Valencia San Vicente Mártir, Valencia, Spain. [Cortés J] Medica Scientia Innovation Research (MedSIR), Barcelona, Spain. IOB Institute of Oncology, Quiron Salud Group, Madrid, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Pérez-López J] Servei de Medicina Interna, Vall d’Hebron Hospital Universitari, Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: 0301 basic medicine, Other subheadings::/methods [Other subheadings], Review, Disease, Biochemistry, 0302 clinical medicine, afecciones patológicas, signos y síntomas::procesos patológicos::atributos de la enfermedad::enfermedades raras [ENFERMEDADES], Clinical trials, systematic review, Otros calificadores::/métodos [Otros calificadores], case reports, nonrandomized study, Clinical endpoint, Molecular Biosciences, Biology (General), terapéutica::farmacoterapia::terapia enzimática::tratamiento de sustitución enzimática [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], media_common, mucopolysaccharidosis, Enzyme replacement therapy, Rare diseases, Systematic review, Mucopolisacàrids, Meta-analysis, Malalties rares, enzyme replacement therapy, medicine.medical_specialty, QH301-705.5, media_common.quotation_subject, rare disease, Mucopolysaccharides, Biochemistry, Genetics and Molecular Biology (miscellaneous), 03 medical and health sciences, medicine, Generalizability theory, Intensive care medicine, Molecular Biology, Selection bias, business.industry, Pathological Conditions, Signs and Symptoms::Pathologic Processes::Disease Attributes::Rare Diseases [DISEASES], Enzims - Ús terapèutic, diagnóstico::pronóstico::resultado del tratamiento [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Diagnosis::Prognosis::Treatment Outcome [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], meta-analysis, 030104 developmental biology, Avaluació de resultats (Assistència sanitària), business, 030217 neurology & neurosurgery, Therapeutics::Drug Therapy::Enzyme Therapy::Enzyme Replacement Therapy [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], Rare disease, Assaigs clínics
Abstract: Estudi no aleatoritzat; Malaltia rara; Revisió sistemàtica Estudio no aleatorizado; Enfermedad rara; Revisión sistemática Nonrandomized study; Rare disease; Systematic review Nonrandomized studies are usually excluded from systematic reviews. This could lead to loss of a considerable amount of information on rare diseases. In this article, we explore the impact of excluding nonrandomized studies on the generalizability of meta-analyses results on mucopolysaccharidosis (MPS) disease. A comprehensive search of systematic reviews on MPS patients up to May 2020 was carried out (CRD42020191217). The primary endpoint was the rate of patients excluded from systematic reviews if only randomized studies were considered. Secondary outcomes included the differences in patient and study characteristics between randomized and nonrandomized studies, the methods used to combine data from studies with different designs, and the number of patients excluded from systematic reviews if case reports were not considered. More than 50% of the patients analyzed have been recruited in nonrandomized studies. Patient characteristics, duration of follow-up, and the clinical outcomes evaluated differ between the randomized and nonrandomized studies. There are feasible strategies to combine the data from different randomized and nonrandomized designs. The analyses suggest the relevance of including case reports in the systematic reviews, since the smaller the number of patients in the reference population, the larger the selection bias associated to excluding case reports. Our results recommend including nonrandomized studies in the systematic reviews of MPS to increase the representativeness of the results and to avoid a selection bias. The recommendations obtained from this study should be considered when conducting systematic reviews on rare diseases.
Published: 2021

282. Systemic pro-inflammatory response identifies patients with cancer with adverse outcomes from SARS-CoV-2 infection: the OnCovid Inflammatory Score

Author: Dettorre, Gino M., Dolly, Saoirse, Loizidou, Angela, Chester, John, Jackson, Amanda, Mukherjee, Uma, Zambelli, Alberto, Aguilar Company, Juan, Bower, Mark, Sng, Christopher C. T., Salazar Soler, Ramón, Bertuzzi, Alexia, Brunet, Joan, Mesia, Ricard, Sita-Lumsden, Ailsa, Seguí, Elia, Biello, Federica, Generali, Daniele, Grisanti, Salvatore, Seeva, Pavetha, Rizzo, Gianpiero, Libertini, Michela, Maconi, Antonio, Moss, Charlotte, Russell, Beth, Harbeck, Nadia, Vincenzi, Bruno, Bertulli, Rossella, Ottaviani, Diego, Liñan, Raquel, Marrari, Andrea, Carmona García, M. Carmen, Chopra, Neha, Tondini, Carlo Alberto, Mirallas, Oriol, Tovazzi, Valeria, Fotia, Vittoria, Cruz, Claudia Andrea, Saoudi González, Nadia, Felip, Eudald, Roqué, Ariadna, Lee, Alvin J. X., Newsom-Davis, Tom, García Illescas, David, Reyes, Roxana, Wong, Yien Ning Sophia, Ferrante, Daniela, Scotti, Lorenza, Marco Hernández, Javier, Ruiz Camps, Isabel, Patriarca, Andrea, Rimassa, Lorenza, Chiudinelli, Lorenzo, Franchi, Michela, Santoro, Armando, Prat Aparicio, Aleix, Gennari, Alessandra, Van Hemelrijck, Mieke, Tabernero Caturla, Josep, Diamantis, Nikolaos, Pinato, David J., OnCovid study group, Dettorre, G. M., Dolly, S., Loizidou, A., Chester, J., Jackson, A., Mukherjee, U., Zambelli, A., Aguilar-Company, J., Bower, M., Sng, C. C. T., Salazar, R., Bertuzzi, A., Brunet, J., Mesia, R., Sita-Lumsden, A., Segui, E., Biello, F., Generali, D., Grisanti, S., Seeva, P., Rizzo, G., Libertini, M., Maconi, A., Moss, C., Russell, B., Harbeck, N., Vincenzi, B., Bertulli, R., Ottaviani, D., Linan, R., Marrari, A., Carmen Carmona-Garcia, M., Chopra, N., Tondini, C. A., Mirallas, O., Tovazzi, V., Fotia, V., Cruz, C. A., Saoudi-Gonzalez, N., Felip, E., Roque, A., Lee, A. J. X., Newsom-Davis, T., Garcia-Illescas, D., Reyes, R., Wong, Y. N. S., Ferrante, D., Scotti, L., Marco-Hernandez, J., Ruiz-Camps, I., Patriarca, A., Rimassa, L., Chiudinelli, L., Franchi, M., Santoro, A., Prat, A., Gennari, A., Van Hemelrijck, M., Tabernero, J., Diamantis, N., Pinato, D. J., Wellcome Trust, Institut Català de la Salut, [Dettorre GM] Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, UK. [Dolly S] Medical Oncology, Guy’s and St Thomas’ NHS Foundation Trust (GSTT), London, UK. [Loizidou A] Department of Infectious Diseases, Internal Medicine, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium. [Chester J] Medical Oncology, School of Medicine, Cardiff University, Cardiff, UK. Medical Oncology, Velindre Cancer Centre, Cardiff, UK. [Jackson A] Clinical Trials, Velindre Cancer Centre, Cardiff, UK. [Mukherjee U] Medical Oncology, Barts Health NHS Trust, London, UK. [Aguilar-Company J] Servei d’Oncologia Mèdica, Vall d'Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Servei de Malalties Infeccioses, Vall d'Hebron Hospital Universitari, Barcelona, Spain. [Mirallas O, Saoudi-Gonzalez N, García-Illescas D] Servei d’Oncologia Mèdica, Vall d'Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Ruiz-Camps I] Servei de Malalties Infeccioses, Vall d'Hebron Hospital Universitari, Barcelona, Spain. [Tabernero J] Servei d’Oncologia Mèdica, Vall d'Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. IOB-Quiron, UVic-UCC, Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: Male, 0301 basic medicine, Oncology, Cancer Research, Comorbidity, Systemic inflammation, Otros calificadores::Otros calificadores::/complicaciones [Otros calificadores], COVID-19 Testing, 0302 clinical medicine, Neoplasms, Immunotherapy Biomarkers, virosis::infecciones por virus ARN::infecciones por Nidovirales::infecciones por Coronaviridae::infecciones por Coronavirus [ENFERMEDADES], 80 and over, Immunology and Allergy, Medicine, Hypoalbuminemia, Young adult, Càncer, Multivariate Analysi, RC254-282, COVID-19 (Malaltia) - Complicacions, Cancer, Aged, 80 and over, OnCovid study group, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Virus Diseases::RNA Virus Infections::Nidovirales Infections::Coronaviridae Infections::Coronavirus Infections [DISEASES], Middle Aged, Prognosis, Inflamació, Systemic Inflammatory Response Syndrome, 030220 oncology & carcinogenesis, Cohort, Pathological Conditions, Signs and Symptoms::Pathologic Processes::Inflammation::Systemic Inflammatory Response Syndrome [DISEASES], Molecular Medicine, Female, medicine.symptom, Life Sciences & Biomedicine, Human, Adult, medicine.medical_specialty, Prognosi, Càncer - Epidemiologia, Immunology, neoplasias [ENFERMEDADES], inflammation mediator, Young Adult, 03 medical and health sciences, Internal medicine, Humans, afecciones patológicas, signos y síntomas::procesos patológicos::inflamación::síndrome de respuesta inflamatoria sistémica [ENFERMEDADES], Aged, Pharmacology, Science & Technology, business.industry, SARS-CoV-2, COVID-19, medicine.disease, inflammation, inflammation mediators, Blood Cell Count, Multivariate Analysis, Neoplasms [DISEASES], Systemic inflammatory response syndrome, 030104 developmental biology, Neoplasm, Lymphocytopenia, business, Other subheadings::Other subheadings::/complications [Other subheadings]
Abstract: Coronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Inflamació; Mediadors d'inflamació Coronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Inflamación; Mediadores de la inflamación Coronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Inflammation; Inflammation mediators Background Patients with cancer are particularly susceptible to SARS-CoV-2 infection. The systemic inflammatory response is a pathogenic mechanism shared by cancer progression and COVID-19. We investigated systemic inflammation as a driver of severity and mortality from COVID-19, evaluating the prognostic role of commonly used inflammatory indices in SARS-CoV-2-infected patients with cancer accrued to the OnCovid study. Methods In a multicenter cohort of SARS-CoV-2-infected patients with cancer in Europe, we evaluated dynamic changes in neutrophil:lymphocyte ratio (NLR); platelet:lymphocyte ratio (PLR); Prognostic Nutritional Index (PNI), renamed the OnCovid Inflammatory Score (OIS); modified Glasgow Prognostic Score (mGPS); and Prognostic Index (PI) in relation to oncological and COVID-19 infection features, testing their prognostic potential in independent training (n=529) and validation (n=542) sets. Results We evaluated 1071 eligible patients, of which 625 (58.3%) were men, and 420 were patients with malignancy in advanced stage (39.2%), most commonly genitourinary (n=216, 20.2%). 844 (78.8%) had ≥1 comorbidity and 754 (70.4%) had ≥1 COVID-19 complication. NLR, OIS, and mGPS worsened at COVID-19 diagnosis compared with pre-COVID-19 measurement (p
Published: 2021

283. Immune cell profiling of the cerebrospinal fluid enables the characterization of the brain metastasis microenvironment

Author: Paolo Nuciforo, Domenica Marchese, Carlota Rubio-Perez, Juan L. Trincado, Juan Sahuquillo, Josep Tabernero, Estela Pineda, Ester Bonfill-Teixidor, Holger Heyn, Francisco Martínez-Ricarte, Josep Maria Mesquida González, Genís Parra, Sara Ruiz, Leire Pedrosa, Marta Cicuendez, Joan Seoane, Catia Moutinho, Garazi Serna, Ester Planas-Rigol, Esteban Cordero, Laura Escudero, Alexandra Arias, Raffaella Iurlaro, Institut Català de la Salut, [Rubio-Perez C, Planas-Rigol E, Bonfill-Teixidor E, Arias A, Serna G, Iurlaro R, Escudero L, Nuciforo P] Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Trincado JL] CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain. Josep Carreras Leukemia Research Institute and Department of Biomedicine, School of Medicine, University of Barcelona, Barcelona, Spain. [Marchese D] CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain. [Martínez-Ricarte F, Cordero E, Cicuendez M, Sahuquillo J] Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Hospital Universitari, Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. [Tabernero J] Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Vall d’Hebron Hospital Universitari, Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. CIBERONC, Barcelona, Spain. [Seoane J] Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Vall d’Hebron Hospital Universitari, Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. CIBERONC, Barcelona, Spain. Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: 0301 basic medicine, Cancer microenvironment, Lung Neoplasms, Science, Immune checkpoint inhibitors, General Physics and Astronomy, Adenocarcinoma of Lung, CD8-Positive T-Lymphocytes, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, 0302 clinical medicine, Metàstasi, Political science, Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Antineoplastic Agents::Antineoplastic Agents, Immunological [CHEMICALS AND DRUGS], Leukocytes, Tumor Microenvironment, Humans, Sistema nerviós -- Càncer, Immune Checkpoint Inhibitors, Cerebrospinal Fluid, Multidisciplinary, Brain Neoplasms, Neoplasms::Neoplastic Processes::Neoplasm Metastasis [DISEASES], Brain, neoplasias::neoplasias por localización::neoplasias del sistema nervioso::neoplasias del sistema nervioso central::neoplasias cerebrales [ENFERMEDADES], General Chemistry, Prognosis, Cervell - Tumors, Neoplasms::Neoplasms by Site::Nervous System Neoplasms::Central Nervous System Neoplasms::Brain Neoplasms [DISEASES], 030104 developmental biology, neoplasias::procesos neoplásicos::metástasis neoplásica [ENFERMEDADES], 030220 oncology & carcinogenesis, Càncer - Immunoteràpia, Tumour immunology, Christian ministry, acciones y usos químicos::acciones farmacológicas::usos terapéuticos::antineoplásicos::inmunoterapia antineoplásica [COMPUESTOS QUÍMICOS Y DROGAS], Humanities, Genètica
Abstract: Brain metastases are the most common tumor of the brain with a dismal prognosis. A fraction of patients with brain metastasis benefit from treatment with immune checkpoint inhibitors (ICI) and the degree and phenotype of the immune cell infiltration has been used to predict response to ICI. However, the anatomical location of brain lesions limits access to tumor material to characterize the immune phenotype. Here, we characterize immune cells present in brain lesions and matched cerebrospinal fluid (CSF) using single-cell RNA sequencing combined with T cell receptor genotyping. Tumor immune infiltration and specifically CD8+ T cell infiltration can be discerned through the analysis of the CSF. Consistently, identical T cell receptor clonotypes are detected in brain lesions and CSF, confirming cell exchange between these compartments. The analysis of immune cells of the CSF can provide a non-invasive alternative to predict the response to ICI, as well as identify the T cell receptor clonotypes present in brain metastasis., The use of CSF for diagnosis of metastatic brain tumors could be of clinical and patient benefit. Here the authors undertake a single-cell RNA analysis of CSF and brain to determine whether the phenotype in the CSF is reflective of the phenotype in the tumor.
Published: 2021

284. Phase 1b/2a study of galunisertib, a small molecule inhibitor of transforming growth factor-beta receptor I, in combination with standard temozolomide-based radiochemotherapy in patients with newly diagnosed malignant glioma

Author: Susan C. Guba, Jordi Rodon, Tiana L. Burkholder, Ann Cleverly, David Capper, Antje Wick, Peter A. Forsyth, Cristina Suarez, Michael Lahn, Annick Desjardins, Shawn T. Estrem, Shuaicheng Wang, Ivelina Gueorguieva, Institut Català de la Salut, [Wick A] Clinical Cooperation Unit Neuro-oncology, German Cancer Research Center, Heidelberg University Medical Center, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany. [Desjardins A] The Preston Robert Tisch Brain Tumor Center at Duke, Duke University, Durham, NC, USA. [Suarez C] Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. [Forsyth P] H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA. [Gueorguieva I] Eli Lilly and Company, Erl Wood, UK 6 Eli Lilly and Company, Indianapolis, IN, USA. [Burkholder T] Eli Lilly and Company, Indianapolis, IN, USA. [Rodon J] Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, U. T. M. D. Anderson Cancer Center, Houston, TX, USA, and Vall d'Hebron Barcelona Hospital Campus
Subjects: 0301 basic medicine, Oncology, Male, Receptor, Transforming Growth Factor-beta Type I, Phase II Studies, Cervell - Càncer - Quimioteràpia, Cervell - Càncer - Radioteràpia, neoplasias::neoplasias por tipo histológico::neoplasias de células germinales y embrionarias::tumores neuroectodérmicos::neoplasias neuroepiteliales::glioma [ENFERMEDADES], 0302 clinical medicine, T-Lymphocyte Subsets, Gliomes, Therapeutics::Combined Modality Therapy::Chemoradiotherapy [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], Antineoplastic Combined Chemotherapy Protocols, Pharmacology (medical), Brain Neoplasms, Chemoradiotherapy, Glioma, Middle Aged, Tolerability, Neoplasms::Neoplasms by Histologic Type::Neoplasms, Germ Cell and Embryonal::Neuroectodermal Tumors::Neoplasms, Neuroepithelial::Glioma [DISEASES], 030220 oncology & carcinogenesis, Quinolines, Female, medicine.drug, medicine.medical_specialty, Galunisertib, T cells, Antineoplastic Agents, Newly diagnosed, 03 medical and health sciences, Pharmacokinetics, Internal medicine, medicine, Biomarkers, Tumor, Temozolomide, Humans, Protein Kinase Inhibitors, Radiochemotherapy, Aged, Pharmacology, business.industry, medicine.disease, terapéutica::tratamiento combinado::quimiorradioterapia [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Regimen, 030104 developmental biology, Pharmacodynamics, Pyrazoles, business, Glioblastoma, Biomarkers
Abstract: SummaryPurpose Galunisertib, a TGF-β inhibitor, has demonstrated antitumor effects in preclinical and radiographic responses in some patients with malignant glioma. This Phase 1b/2a trial investigated the clinical benefit of combining galunisertib with temozolomide-based radiochemotherapy (TMZ/RTX) in patients with newly diagnosed malignant glioma (NCT01220271). Methods This is an open-label, 2-arm Phase 1b/2a study (N = 56) of galunisertib (intermittent dosing: 14 days on/14 days off per cycle of 28 days) in combination with TMZ/RTX (n = 40), versus a control arm (TMZ/RTX, n = 16). The primary objective of Phase 1b was to determine the safe and tolerable Phase 2 dose of galunisertib. The primary objective of Phase 2a was to confirm the tolerability and pharmacodynamic profile of galunisertib with TMZ/RTX, and the secondary objectives included determining the efficacy and pharmacokinetic (PK) profile of galunisertib with TMZ/RTX in patients with glioblastoma. This study also characterized the changes in the major T-cell subsets during TMZ/RTX plus galunisertib treatment. Results In the Phase 2a study, efficacy results for patients treated with galunisertib plus TMZ/RTX or TMZ/RTX were: median overall survival (18.2 vs 17.9 months), median progression-free survival (7.6 vs 11.5 months), and disease control rate (80% [32/40] vs 56% [9/16] patients) respectively. PK profile of galunisertib plus TMZ/RTX regimen was consistent with previously published PK data of galunisertib. The overall safety profile across treatment arms was comparable. Conclusion No differences in efficacy, safety or pharmacokinetic variables were observed between the two treatment arms.
Published: 2021

285. Dietary intake and plasma phospholipid concentrations of saturated, monounsaturated and trans fatty acids and colorectal cancer risk in the European Prospective Investigation into Cancer and Nutrition cohort

Author: Joseph A. Rothwell, Giovanna Masala, José María Huerta, Aurora Perez-Cornago, Elisabete Weiderpass, Anja Olsen, Magritt Brustad, Claudia Agnoli, Corinne Casagrande, Guri Skeie, Ulrika Ericson, Verena Katzke, Mazda Jenab, Christina C. Dahm, Anne Tjønneland, Geneviève Nicolas, Rudolf Kaaks, Inge Huybrechts, Veronika Fedirko, Carlotta Sacerdote, Neil Murphy, Maria Wennberg, Veronique Chajes, Jeroen W.G. Derksen, Matthias B. Schulze, Elom K. Aglago, Bas Bueno-de-Mesquita, Alicia K Heath, Pilar Amiano, Salvatore Panico, Paula Jakszyn, Rosario Tumino, Marc J. Gunter, Inger T. Gram, María José Sánchez, Centre International de Recherche contre le Cancer - International Agency for Research on Cancer (CIRC - IARC), Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, 1000143, MR/M012190/1, Kræftens Bekæmpelse, DCS, Deutsches Krebsforschungszentrum, DKFZ, Centre International de Recherche sur le Cancer, CIRC, National Research Council, NRC, University of Maryland School of Public Health, SPH, Cancer Research UK, CRUK: 14136, C8221/A29017, World Cancer Research Fund, WCRF, Imperial College London, Institut National de la Santé et de la Recherche Médicale, Inserm, Bundesministerium für Bildung und Forschung, BMBF, Cancerfonden, Ministerie van Volksgezondheid, Welzijn en Sport, VWS, Ligue Contre le Cancer, Vetenskapsrådet, VR, Instituto de Salud Carlos III, ISCIII, Associazione Italiana per la Ricerca sul Cancro, AIRC, Deutsche Krebshilfe, Rijksinstituut voor Volksgezondheid en Milieu, RIVM, Institut Gustave-Roussy, Mutuelle Générale de l'Education Nationale, MGEN, NIHR Imperial Biomedical Research Centre, BRC, World Cancer Research Fund, Grant/Award Number: WCRF 2013/1002 Funding information trans, The authors would like to thank the EPIC study participants and staff for their valuable contribution to this research. The authors would also like to thank Ms Beatrice Vozar, Mr Bertrand Hemon and Ms Carine Biessy for the analysis of plasma samples, and the preparation of the databases. The coordination of EPIC is financially supported by International Agency for Research on Cancer (IARC) and also by the Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London which has additional infrastructure support provided by the NIHR Imperial Biomedical Research Centre (BRC). The national cohorts are supported by: Danish Cancer Society (Denmark), Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l'Education Nationale, Institut National de la Santé et de la Recherche Médicale (INSERM) (France), German Cancer Aid, German Cancer Research Center (DKFZ), German Institute of Human Nutrition PotsdamRehbruecke (DIfE), Federal Ministry of Education and Research (BMBF) (Germany), Associazione Italiana per la Ricerca sul Cancro‐AIRC‐Italy, Compagnia di SanPaolo and National Research Council (Italy), Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands), Health Research Fund (FIS)—Instituto de Salud Carlos III (ISCIII), Regional Governments of Andalucía, Asturias, Basque Country, Murcia and Navarra, and the Catalan Institute of Oncology—ICO (Spain), Swedish Cancer Society, Swedish Research Council and County Councils of Skåne and Västerbotten (Sweden), Cancer Research UK (14136 to EPIC‐Norfolk, C8221/A29017 to EPIC‐Oxford), MedicalResearch Council (1000143 to EPIC‐Norfolk, MR/M012190/1 to EPIC‐Oxford). (United Kingdom), the National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands. The EPIC‐Norfolk study (DOI 10.22025/2019.10.105.00004) has received funding from the Medical Research Council (MR/N003284/1, MC‐PC_13048 and MC‐UU_12015/1). We are grateful to all the participants who have been part of the project and to the many members of the study teams at the University of Cambridge who have enabled this research. The authors would like to acknowledge the use of data and samples from EPIC centres in Cambridge, France, Asturias, and Navarro. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the article. Our study was funded by a grant from the World Cancer Research Fund to Marc Gunter (Grant number: WCRF 2013/1002)., Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle G?n?rale de l'Education Nationale, Institut National de la Sant? et de la Recherche M?dicale (INSERM) (France), Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy, Compagnia di SanPaolo and National Research Council (Italy), Health Research Fund (FIS)?Instituto de Salud Carlos III (ISCIII), Regional Governments of Andaluc?a, Asturias, Basque Country, Murcia and Navarra, and the Catalan Institute of Oncology?ICO (Spain), Swedish Cancer Society, Swedish Research Council and County Councils of Sk?ne and V?sterbotten (Sweden), Cancer Research UK (14136 to EPIC-Norfolk, C8221/A29017 to EPIC-Oxford), MedicalResearch Council (1000143 to EPIC-Norfolk, and MR/M012190/1 to EPIC-Oxford). (United Kingdom), the National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands. The EPIC-Norfolk study (DOI 10.22025/2019.10.105.00004) has received funding from the Medical Research Council (MR/N003284/1, MC-PC_13048 and MC-UU_12015/1). We are grateful to all the participants who have been part of the project and to the many members of the study teams at the University of Cambridge who have enabled this research. The authors would like to acknowledge the use of data and samples from EPIC centres in Cambridge, France, Asturias, and Navarro. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the article. Our study was funded by a grant from the World Cancer Research Fund to Marc Gunter (Grant number: WCRF 2013/1002).
Subjects: Cancer Research, medicine.medical_specialty, Colorectal cancer, Myristic acid, [SDV.CAN]Life Sciences [q-bio]/Cancer, colorectal cancer, Gastroenterology, fatty acids, DISEASE, Palmitic acid, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, COLON, medicine, 2 SIDES, 2. Zero hunger, chemistry.chemical_classification, business.industry, Fatty acid, Odds ratio, ASSOCIATION, medicine.disease, Elaidic acid, 3. Good health, European Prospective Investigation into Cancer and Nutrition, Oncology, chemistry, 030220 oncology & carcinogenesis, biomarker, Stearic acid, business, dietary intake, LIPIDS
Abstract: International audience; Epidemiologic studies examining the association between specific fatty acids and colorectal cancer (CRC) risk are inconclusive. We investigated the association between dietary estimates and plasma levels of individual and total saturated (SFA), monounsaturated (MUFA), industrial-processed trans (iTFA), and ruminant-sourced trans (rTFA) fatty acids, and CRC risk in the European Prospective Investigation into Cancer and Nutrition (EPIC). Baseline fatty acid intakes were estimated in 450 112 participants (6162 developed CRC, median follow-up = 15 years). In a nested case-control study, plasma phospholipid fatty acids were determined by gas chromatography in 433 colon cancer cases and 433 matched controls. Multivariable-adjusted hazard ratios (HRs) and odds ratios (ORs) with 95% confidence intervals (CIs) were computed using Cox and conditional logistic regression, respectively. Dietary total SFA (highest vs lowest quintile, HRQ5vsQ1 = 0.80; 95%CI:0.69-0.92), myristic acid (HRQ5vsQ1 = 0.83, 95%CI:0.74-0.93) and palmitic acid (HRQ5vsQ1 = 0.81, 95%CI:0.70-0.93) were inversely associated with CRC risk. Plasma myristic acid was also inversely associated with colon cancer risk (highest vs lowest quartile, ORQ4vsQ1 = 0.51; 95%CI:0.32-0.83), whereas a borderline positive association was found for plasma stearic acid (ORQ4vsQ1 = 1.63; 95%CI:1.00-2.64). Dietary total MUFA was inversely associated with colon cancer (per 1-SD increment, HR1-SD = 0.92, 95%CI: 0.85-0.98), but not rectal cancer (HR1-SD = 1.04, 95%CI:0.95-1.15, Pheterogeneity = 0.027). Dietary iTFA, and particularly elaidic acid, was positively associated with rectal cancer (HR1-SD = 1.07, 95%CI:1.02-1.13). Our results suggest that total and individual saturated fatty acids and fatty acids of industrial origin may be relevant to the aetiology of CRC. Both dietary and plasma myristic acid levels were inversely associated with colon cancer risk, which warrants further investigation.
Published: 2021
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286. Acquired cancer cell resistance to T cell bispecific antibodies and CAR T targeting HER2 through JAK2 down-modulation

Author: Arenas, Enrique J., Martínez-Sabadell, Alex, Rius Ruiz, Irene, Román Alonso, Macarena, Escorihuela, Marta, Luque, Antonio, Fajardo, Carlos Alberto, Gros, Alena, Klein, Christian, Arribas, Joaquín V, Universitat Autònoma de Barcelona, Institut Català de la Salut, [Arenas EJ, Rius Ruiz I] Preclinical Research Program, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid 28029, Spain. [Martínez-Sabadell A, Román Alonso M, Escorihuela M, Luque A] Preclinical Research Program, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Fajardo CA, Gros A] Tumor Immunology & Immunotherapy Group, VHIO, Barcelona, Spain. [Arribas J] Preclinical Research Program, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid 28029, Spain. Tumor Immunology & Immunotherapy Group, VHIO, Barcelona, Spain. Cancer Research Program, IMIM (Hospital del Mar Medical Research Institute), Barcelona 08003, Spain. Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona 08010, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: 0301 basic medicine, Cytotoxicity, Immunologic, Receptor, ErbB-2, medicine.medical_treatment, T-Lymphocytes, General Physics and Astronomy, Cancer immunotherapy, Mice, 0302 clinical medicine, Neoplasms, Antibodies, Bispecific, Cytotoxic T cell, Otros calificadores::Otros calificadores::/inmunología [Otros calificadores], Multidisciplinary, Receptors, Chimeric Antigen, Cancer therapeutic resistance, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Signal Transduction, Physiological Phenomena::Pharmacological and Toxicological Phenomena::Pharmacological Phenomena::Drug Resistance::Drug Resistance, Neoplasm [PHENOMENA AND PROCESSES], T cell, Science, Down-Regulation, Biology, General Biochemistry, Genetics and Molecular Biology, Article, Cell Line, neoplasias [ENFERMEDADES], 03 medical and health sciences, Interferon-gamma, Other subheadings::Other subheadings::/immunology [Other subheadings], medicine, Animals, Humans, Resistència als medicaments, fenómenos fisiológicos::fenómenos farmacológicos y toxicológicos::fenómenos farmacológicos::resistencia a medicamentos::resistencia a los antineoplásicos [FENÓMENOS Y PROCESOS], Cancer, General Chemistry, Immunotherapy, Janus Kinase 2, medicine.disease, Chimeric antigen receptor, Neoplasms [DISEASES], 030104 developmental biology, Immunoediting, Tumor progression, Drug Resistance, Neoplasm, Cancer cell, Cancer research, Càncer - Immunoteràpia, Transcriptome
Abstract: Immunotherapy has raised high expectations in the treatment of virtually every cancer. Many current efforts are focused on ensuring the efficient delivery of active cytotoxic cells to tumors. It is assumed that, once these active cytotoxic cells are correctly engaged to cancer cells, they will unfailingly eliminate the latter, provided that inhibitory factors are in check. T cell bispecific antibodies (TCBs) and chimeric antigen receptors (CARs) offer an opportunity to test this assumption. Using TCB and CARs directed against HER2, here we show that disruption of interferon-gamma signaling confers resistance to killing by active T lymphocytes. The kinase JAK2, which transduces the signal initiated by interferon-gamma, is a component repeatedly disrupted in several independently generated resistant models. Our results unveil a seemingly widespread strategy used by cancer cells to resist clearance by redirected lymphocytes. In addition, they open the possibility that long-term inhibition of interferon-gamma signaling may impair the elimination phase of immunoediting and, thus, promote tumor progression., Several mechanisms of resistance to T cell-engaging therapies have been described for solid tumors. Here, by using T cell bispecific antibodies and chimeric antigen receptors (CAR) T cells targeting HER2, the authors show that cancer cell intrinsic disruption of interferon-gamma signalling, including downregulation of JAK2, confers resistance to T-cell mediated cytotoxicity.
Published: 2021

287. Human DNA decays faster with time than viral dsDNA: an analysis on HPV16 using pathology archive samples spanning 85 years

Author: Nicolás Párraga, Sara, Torres, Montserrat, Alemany, Laia, Félix, Ana, Cruz, Eugenia, Sanjosé Llongueras, Silvia de, Bosch José, Francesc Xavier, 1947, Bravo, Ignacio G., RIS HPV TT study groups, Virostyle (MIVEGEC-Virostyle), Perturbations, Evolution, Virulence (PEV), Maladies infectieuses et vecteurs : écologie, génétique, évolution et contrôle (MIVEGEC), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Maladies infectieuses et vecteurs : écologie, génétique, évolution et contrôle (MIVEGEC), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud]), Centre de Recherche en Ecologie et Evolution de la Santé (CREES), Institut de Recherche pour le Développement (IRD)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Catalan Institute of Oncology (ICO), Portuguese Institute of Oncology Francisco Gentil, and Universitat Oberta de Catalunya (UOC)
Subjects: 0301 basic medicine, Human dna, ADN, Uterine Cervical Neoplasms, papillomavirus, Degradation, chemistry.chemical_compound, 0302 clinical medicine, Cervix cancer, Invasive cervical carcinoma, Paraffin Embedding, Fixation (population genetics), Infectious Diseases, 030220 oncology & carcinogenesis, Viruses, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Biomarker (medicine), Female, Stability, papilomavirus, HPV, VPH, Integrity, Formalin fixed paraffin embedded, Càncer de coll uterí, Papillomaviruses, virus, DNA Fragmentation, Biology, Real-Time Polymerase Chain Reaction, Sample storage, Human Papillomavirus 16, lcsh:Infectious and parasitic diseases, Specimen Handling, 03 medical and health sciences, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Virology, Humans, lcsh:RC109-216, Papil·lomavirus, Gene, Research, Papillomavirus Infections, DNA, Formalin-Fixed Paraffin Embedded, Transformation (genetics), 030104 developmental biology, chemistry, DNA, Viral, Nucleic acid
Abstract: Background Quality of the nucleic acids extracted from Formalin Fixed Paraffin Embedded (FFPE) samples largely depends on pre-analytic, fixation and storage conditions. We assessed the differential sensitivity of viral and human double stranded DNA (dsDNA) to degradation with storage time. Methods We randomly selected forty-four HPV16-positive invasive cervical cancer (ICC) FFPE samples collected between 1930 and 1935 and between 2000 and 2004. We evaluated through qPCR the amplification within the same sample of two targets of the HPV16 L1 gene (69 bp, 134 bp) compared with two targets of the human tubulin-β gene (65 bp, 149 bp). Results Both viral and human, short and long targets were amplified from all samples stored for 15 years. In samples archived for 85 years, we observed a significant decrease in the ability to amplify longer targets and this difference was larger in human than in viral DNA: longer fragments were nine times (CI 95% 2.6–35.2) less likely to be recovered from human DNA compared with 1.6 times (CI 95% 1.1–2.2) for viral DNA. Conclusions We conclude that human and viral DNA show a differential decay kinetics in FFPE samples. The faster degradation of human DNA should be considered when assessing viral DNA prevalence in long stored samples, as HPV DNA detection remains a key biomarker of viral-associated transformation.
Published: 2021
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288. BARD1 Pathogenic Variants Are Associated with Triple-Negative Breast Cancer in a Spanish Hereditary Breast and Ovarian Cancer Cohort

Author: Rofes, Paula, Del Valle, Jesús, Torres Esquius, Sara, Feliubadaló, Lídia, Stradella, Agostina, Moreno-Cabrera, José Marcos, López-Doriga, Adriana, Munté, Elisabet, de Cid, R., Campos, Olga, Cuesta, Raquel, Teulé, Álex, Grau, Èlia, Sanz, Judit, Capellá, G. (Gabriel), Diez, Orland, Brunet, Joan, Balmaña Gelpí, Judith, Lázaro, Conxi, Universitat Autònoma de Barcelona, Institut Català de la Salut, [Rofes P, Del Valle J, Feliubadaló L, Moreno-Cabrera JM] Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, L’Hospitalet de Llobregat, Spain. Program in Molecular Mechanisms and Experimental Therapy in Oncology (Oncobell), IDIBELL, L’Hospitalet de Llobregat, Spain. Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain. [Torres-Esquius S, Balmaña J] Hereditary Cancer Genetics Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Servei d’Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. [Stradella A] Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, L’Hospitalet de Llobregat, Spain. Program in Molecular Mechanisms and Experimental Therapy in Oncology (Oncobell), IDIBELL, L’Hospitalet de Llobregat, Spain. Medical Oncology Department, Catalan Institute of Oncology, IDIBELL, L’Hospitalet de Llobregat, Spain. [Díez O] Institut Català de la Salut, Barcelona, Spain. Vall d’Hebron Hospital Universitari, Barcelona, Spain. Hereditary Cancer Genetics Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: 0301 basic medicine, Oncology, medicine.medical_specialty, lcsh:QH426-470, Moderate cancer risk, Hereditary breast and ovarian cancer, Càncer d'ovari, Genetic Phenomena::Genotype::Genetic Predisposition to Disease [PHENOMENA AND PROCESSES], Ovaris - Càncer - Aspectes genètics, hereditary breast and ovarian cancer, Germline, Article, Càncer de mama, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, breast cancer, Triple-negative breast cancer, Ovarian cancer, Internal medicine, Genetics, medicine, BARD1, Genetics (clinical), Genetic testing, fenómenos genéticos::genotipo::predisposición genética a la enfermedad [FENÓMENOS Y PROCESOS], moderate cancer risk, medicine.diagnostic_test, business.industry, Odds ratio, medicine.disease, Penetrance, neoplasias::neoplasias por localización::neoplasias de la mama::neoplasias de mama triple negativos [ENFERMEDADES], lcsh:Genetics, 030104 developmental biology, Neoplasms::Neoplasms::Neoplasms::Neoplastic Syndromes, Hereditary::Hereditary Breast and Ovarian Cancer Syndrome [DISEASES], ovarian cancer, 030220 oncology & carcinogenesis, Cohort, Neoplasms::Neoplasms by Site::Breast Neoplasms::Triple Negative Breast Neoplasms [DISEASES], triple-negative breast cancer, Mama - Càncer - Aspectes genètics, neoplasias::neoplasias::neoplasias::síndromes neoplásicos hereditarios::síndrome hereditario de cáncer de mama y ovario [ENFERMEDADES], business
Abstract: Only a small fraction of hereditary breast and/or ovarian cancer (HBOC) cases are caused by germline variants in the high-penetrance breast cancer 1 and 2 genes (BRCA1 and BRCA2). BRCA1-associated ring domain 1 (BARD1), nuclear partner of BRCA1, has been suggested as a potential HBOC risk gene, although its prevalence and penetrance are variable according to populations and type of tumor. We aimed to investigate the prevalence of BARD1 truncating variants in a cohort of patients with clinical suspicion of HBOC. A comprehensive BARD1 screening by multigene panel analysis was performed in 4015 unrelated patients according to our regional guidelines for genetic testing in hereditary cancer. In addition, 51,202 Genome Aggregation Database (gnomAD) non-Finnish, non-cancer European individuals were used as a control population. In our patient cohort, we identified 19 patients with heterozygous BARD1 truncating variants (0.47%), whereas the frequency observed in the gnomAD controls was 0.12%. We found a statistically significant association of truncating BARD1 variants with overall risk (odds ratio (OR) = 3.78, CI = 2.10&ndash, 6.48, p = 1.16 &times, 10&minus, 5). This association remained significant in the hereditary breast cancer (HBC) group (OR = 4.18, 7.70, p = 5.45 &times, 5). Furthermore, deleterious BARD1 variants were enriched among triple-negative BC patients (OR = 5.40, CI = 1.77&ndash, 18.15, p = 0.001) compared to other BC subtypes. Our results support the role of BARD1 as a moderate penetrance BC predisposing gene and highlight a stronger association with triple-negative tumors.
Published: 2021

289. Weight change in middle adulthood and risk of cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort

Author: Amanda J. Cross, Kristin Benjaminsen Borch, Renée T. Fortner, Vittorio Simeon, Paul Brennan, Guri Skeie, Elio Riboli, Rosario Tumino, Elisabete Weiderpass, Gianluca Severi, Carlotta Sacerdote, Kim Overvad, Manuela M. Bergmann, Isabel Drake, Sara Grioni, Panagiota Pagoni, Giovanna Masala, Pietro Ferrari, Heinz Freisling, Matthias B. Schulze, Maria Dolores Chirlaque, Pilar Amiano, Mattias Johansson, Ioanna Tzoulaki, Konstantinos K. Tsilidis, Timothy J. Key, J. Ramón Quirós, Eva Ardanaz, Antonio Agudo, Neil Murphy, Marie-Christine Boutron-Ruault, Christel Häggström, Sofia Christakoudi, Rudolf Kaaks, Merete Ellingjord-Dale, Sophia Harlid, Charlotta Rylander, Tanja Stocks, Anne Tjønneland, Fanny Artaud, Laure Dossus, Jytte Halkjær, Miguel Rodríguez-Barranco, Aurora Perez-Cornago, David C. Muller, Centre International de Recherche contre le Cancer - International Agency for Research on Cancer (CIRC - IARC), Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Kræftens Bekæmpelse, DCS German Cancer Research Center, DKFZ Centre International de Recherche sur le Cancer, CIRC National Research Council, NRC Medical Research Council, MRC: MC_UU_00011/6, MR/M012190/1 Cancer Research UK, CRUK: C570/A16491, C8221/A19170 World Cancer Research Fund, WCRF European Commission, EC Institut National de la Santé et de la Recherche Médicale, Inserm Bundesministerium für Bildung und Forschung, BMBF Cancerfonden Ministerie van Volksgezondheid, Welzijn en Sport, VWS Ligue Contre le Cancer Vetenskapsrådet, VR Associazione Italiana per la Ricerca sul Cancro, AIRC Deutsche Krebshilfe Rijksinstituut voor Volksgezondheid en Milieu, RIVM Institut Gustave-Roussy Mutuelle Générale de l'Education Nationale, MGEN NIHR Imperial Biomedical Research Centre, BRC Fondation Gustave Roussy, The authors thank the National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands, for their contribution and ongoing support to the EPIC study. The coordination of EPIC is financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer. The national cohorts are supported by Danish Cancer Society (Kr?ftens Bek?mpelse) (Denmark), Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle G?n?rale de l'Education Nationale, Institut National de la Sant? et de la Recherche M?dicale (INSERM) (France), German Cancer Aid (Deutsche Krebshilfe), German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ), Federal Ministry of Education and Research (Bundesministerium f?r Bildung und Forschung, BMBF) (Germany), Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy and National Research Council (Italy), Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands), Health Research Fund (FIS-ISCIII), Regional Governments of Andaluc?a, Asturias, Basque Country, Murcia, Navarra, and the Catalan Institute of Oncology (Barcelona) (Spain), Swedish Cancer Society (Cancerfonden), Swedish Research Council (Vetenskapsr?det), County Councils of Sk?ne and V?sterbotten (Sweden), Cancer Research UK (C570/A16491 and C8221/A19170 to EPIC-Oxford), Medical Research Council (MR/M012190/1 to EPIC-Oxford) (United Kingdom). Panagiota Pagoni is funded by Medical Research Council (grant reference MC_UU_00011/6). Infrastructure support for the Department of Epidemiology and Biostatistics at Imperial College London (UK) was provided by the NIHR Imperial Biomedical Research Centre (BRC). The funders had no role in the design and conduct of the study, the collection, analysis and interpretation of the data, or the preparation, review and approval of the manuscript, or in the decision to submit the manuscript for publication., The authors thank the National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands, for their contribution and ongoing support to the EPIC study. The coordination of EPIC is financially supported by the European Commission (DG‐SANCO) and the International Agency for Research on Cancer. The national cohorts are supported by Danish Cancer Society (Kræftens Bekæmpelse) (Denmark), Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l'Education Nationale, Institut National de la Santé et de la Recherche Médicale (INSERM) (France), German Cancer Aid (Deutsche Krebshilfe), German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ), Federal Ministry of Education and Research (Bundesministerium für Bildung und Forschung, BMBF) (Germany), Associazione Italiana per la Ricerca sul Cancro‐AIRC‐Italy and National Research Council (Italy), Health Research Fund (FIS‐ISCIII), Regional Governments of Andalucía, Asturias, Basque Country, Murcia, Navarra, and the Catalan Institute of Oncology (Barcelona) (Spain), Swedish Cancer Society (Cancerfonden), Swedish Research Council (Vetenskapsrådet), County Councils of Skåne and Västerbotten (Sweden), Cancer Research UK (C570/A16491 and C8221/A19170 to EPIC‐Oxford), Medical Research Council (MR/M012190/1 to EPIC‐Oxford) (United Kingdom). Panagiota Pagoni is funded by Medical Research Council (grant reference MC_UU_00011/6). Infrastructure support for the Department of Epidemiology and Biostatistics at Imperial College London (UK) was provided by the NIHR Imperial Biomedical Research Centre (BRC). The funders had no role in the design and conduct of the study, the collection, analysis and interpretation of the data, or the preparation, review and approval of the manuscript, or in the decision to submit the manuscript for publication., Associazione Italiana per la Ricerca sul Cancro, Bundesministerium für Bildung und Forschung, Cancer Research UK, Grant/Award Numbers: C570/A16491, C8221/A19170, Cancerfonden, Catalan Institute of Oncology Barcelona, Centre International de Recherche sur le Cancer, County Council of Skåne Sweden, County Council of Västerbotten Sweden, Deutsche Krebshilfe, Deutsches Krebsforschungszentrum, Directorate‐General for Health and Consumers, Dutch Ministry of Public Health, Welfare and Sports (VWS), Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), Health Research Fund (FIS‐ISCIII) Spain, Institut Gustave‐Roussy, Institut National de la Santé et de la Recherche Médicale, Kræftens Bekæmpelse, Ligue Contre le Cancer, LK Research Funds, Medical Research Council, Grant/Award Numbers: MC_UU_00011/6, MR/M012190/1, Mutuelle Générale de l'Education Nationale, National Research Council Italy, Netherlands Cancer Registry, Regional Government of Andalucía, Regional Government of Asturias, Regional Government of Basque Country, Regional Government of Murcia, Regional Government of Navarra, Statistics Netherlands, Vetenskapsrådet, World Cancer Research Fund (WCRF), Institut Gustave Roussy, International Agency for Research on Cancer, European Commission (DG‐SANCO) Funding information, Christakoudi, S., Pagoni, P., Ferrari, P., Cross, A. J., Tzoulaki, I., Muller, D. C., Weiderpass, E., Freisling, H., Murphy, N., Dossus, L., Turzanski Fortner, R., Agudo, A., Overvad, K., Perez-Cornago, A., Key, T. J., Brennan, P., Johansson, M., Tjonneland, A., Halkjaer, J., Boutron-Ruault, M. -C., Artaud, F., Severi, G., Kaaks, R., Schulze, M. B., Bergmann, M. M., Masala, G., Grioni, S., Simeon, V., Tumino, R., Sacerdote, C., Skeie, G., Rylander, C., Borch, K. B., Quiros, J. R., Rodriguez-Barranco, M., Chirlaque, M. -D., Ardanaz, E., Amiano, P., Drake, I., Stocks, T., Haggstrom, C., Harlid, S., Ellingjord-Dale, M., Riboli, E., Tsilidis, K. K., and Cancer Research UK
Subjects: Male, Cancer Research, middle adulthood, Overweight, Body Mass Index, Cohort Studies, 0302 clinical medicine, Weight loss, Risk Factors, Neoplasms, Prospective Studies, Correlation of Data, 2. Zero hunger, Ovarian Neoplasms, Obstetrics, Hazard ratio, PROLIFERATION, WOMEN, weight gain, Middle Aged, Kidney Neoplasms, 3. Good health, European Prospective Investigation into Cancer and Nutrition, BMI change, Europe, Oncology, 030220 oncology & carcinogenesis, ddc:540, Female, SQUAMOUS-CELL CARCINOMA, medicine.symptom, Life Sciences & Biomedicine, EXPRESSION, medicine.medical_specialty, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, 03 medical and health sciences, LEPTIN, FATNESS, medicine, Humans, cancer, 1112 Oncology and Carcinogenesis, Oncology & Carcinogenesis, Obesity, Risk factor, Proportional Hazards Models, Cancer och onkologi, Science & Technology, business.industry, Weight change, Endometrial Neoplasms, BODY-MASS INDEX, ESTROGEN-RECEPTORS, Pancreatic Neoplasms, Nutrition Assessment, Cancer and Oncology, Institut für Ernährungswissenschaft, GAIN, weight loss, business, Weight gain, Body mass index
Abstract: International audience; Obesity is a risk factor for several major cancers. Associations of weight change in middle adulthood with cancer risk, however, are less clear. We examined the association of change in weight and body mass index (BMI) category during middle adulthood with 42 cancers, using multivariable Cox proportional hazards models in the European Prospective Investigation into Cancer and Nutrition cohort. Of 241 323 participants (31% men), 20% lost and 32% gained weight (>0.4 to 5.0 kg/year) during 6.9 years (average). During 8.0 years of follow-up after the second weight assessment, 20 960 incident cancers were ascertained. Independent of baseline BMI, weight gain (per one kg/year increment) was positively associated with cancer of the corpus uteri (hazard ratio [HR] = 1.14; 95% confidence interval: 1.05-1.23). Compared to stable weight (±0.4 kg/year), weight gain (>0.4 to 5.0 kg/year) was positively associated with cancers of the gallbladder and bile ducts (HR = 1.41; 1.01-1.96), postmenopausal breast (HR = 1.08; 1.00-1.16) and thyroid (HR = 1.40; 1.04-1.90). Compared to maintaining normal weight, maintaining overweight or obese BMI (World Health Organisation categories) was positively associated with most obesity-related cancers. Compared to maintaining the baseline BMI category, weight gain to a higher BMI category was positively associated with cancers of the postmenopausal breast (HR = 1.19; 1.06-1.33), ovary (HR = 1.40; 1.04-1.91), corpus uteri (HR = 1.42; 1.06-1.91), kidney (HR = 1.80; 1.20-2.68) and pancreas in men (HR = 1.81; 1.11-2.95). Losing weight to a lower BMI category, however, was inversely associated with cancers of the corpus uteri (HR = 0.40; 0.23-0.69) and colon (HR = 0.69; 0.52-0.92). Our findings support avoiding weight gain and encouraging weight loss in middle adulthood.
Published: 2021
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290. COVID-19 infection in adult patients with hematological malignancies:a European Hematology Association Survey (EPICOVIDEHA)

Author: Pagano, Livio, Salmanton-García, Jon, Marchesi, Francesco, Busca, Alessandro, Corradini, Paolo, Hoenigl, Martin, Klimko, Nikolai, Koehler, Philipp, Pagliuca, Antonio, Passamonti, Francesco, Verga, Luisa, Víšek, Benjamin, Ilhan, Osman, Nadali, Gianpaolo, Weinbergerová, Barbora, Córdoba-Mascuñano, Raúl, Marchetti, Monia, Collins, Graham P., Farina, Francesca, Cattaneo, Chiara, Cabirta, Alba, Gomes-Silva, Maria, Itri, Federico, van Doesum, Jaap, Ledoux, Marie-Pierre, Čerňan, Martin, Jakšić, Ozren, Duarte, Rafael F., Magliano, Gabriele, Omrani, Ali S., Fracchiolla, Nicola S., Kulasekararaj, Austin, Valković, Toni, Poulsen, Christian Bjørn, Machado, Marina, Glenthøj, Andreas, Stoma, Igor, Ráčil, Zdeněk, Piukovics, Klára, Navrátil, Milan, Emarah, Ziad, Sili, Uluhan, Maertens, Johan, Blennow, Ola, Bergantim, Rui, García-Vidal, Carolina, Prezioso, Lucia, Guidetti, Anna, del Principe, Maria Ilaria, Popova, Marina, de Jonge, Nick, Ormazabal-Vélez, Irati, Fernández, Noemí, Falces-Romero, Iker, Cuccaro, Annarosa, Meers, Stef, Buquicchio, Caterina, Antić, Darko, Al-Khabori, Murtadha, García-Sanz, Ramón, Biernat, Monika M., Tisi, Maria Chiara, Sal, Ertan, Rahimli, Laman, Čolović, Natasa, Schönlein, Martin, Calbacho, Maria, Tascini, Carlo, Miranda-Castillo, Carolina, Khanna, Nina, Méndez, Gustavo-Adolfo, Petzer, Verena, Novák, Jan, Besson, Caroline, Duléry, Rémy, Lamure, Sylvain, Nucci, Marcio, Zambrotta, Giovanni, Žák, Pavel, Seval, Guldane Cengiz, Bonuomo, Valentina, Mayer, Jiří, López-García, Alberto, Sacchi, Maria Vittoria, Booth, Stephen, Ciceri, Fabio, Oberti, Margherita, Salvini, Marco, Izuzquiza, Macarena, Nunes-Rodrigues, Raquel, Ammatuna, Emanuele, Obr, Aleš, Herbrecht, Raoul, Núñez-Martín-Buitrago, Lucía, Mancini, Valentina, Shwaylia, Hawraa, Sciumè, Mariarita, Essame, Jenna, Nygaard, Marietta, Batinić, Josip, Gonzaga, Yung, Regalado-Artamendi, Isabel, Karlsson, Linda Katharina, Shapetska, Maryia, Hanakova, Michaela, El-Ashwah, Shaimaa, Borbényi, Zita, Çolak, Gökçe Melis, Nordlander, Anna, Dragonetti, Giulia, Maraglino, Alessio Maria Edoardo, Rinaldi, Amelia, De Ramón-Sánchez, Cristina, Cornely, Oliver A., Finizio, Olimpia, Fazzi, Rita, Sapienza, Giuseppe, Chauchet, Adrien, Van Praet, Jens, Prattes, Juergen, Dargenio, Michelina, Rossi, Cédric, Shirinova, Ayten, Malak, Sandra, Tafuri, Agostino, Ommen, Hans-Beier, Bologna, Serge, Khedr, Reham Abdelaziz, Choquet, Sylvain, Joly, Bertrand, Ceesay, M. Mansour, Philippe, Laure, Kho, Chi Shan, Desole, Maximilian, Tsirigotis, Panagiotis, Otašević, Vladimir, Borducchi, Davimar M. M., Antoniadou, Anastasia, Gaziev, Javid, Almaslamani, Muna A., García-Poutón, Nicole, Paterno, Giovangiacinto, Torres-López, Andrea, Tarantini, Giuseppe, Mellinghoff, Sibylle, Gräfe, Stefanie, Börschel, Niklas, Passweg, Jakob, Merelli, Maria, Barać, Aleksandra, Wolf, Dominik, Shaikh, Mohammad Usman, Thiéblemont, Catherine, Bernard, Sophie, Funke, Vaneuza Araújo Moreira, Daguindau, Etienne, Khostelidi, Sofya, Nucci, Fabio Moore, Martín-González, Juan-Alberto, Landau, Marianne, Soussain, Carole, Laureana, Cécile, Lacombe, Karine, Kohn, Milena, Aliyeva, Gunay, Piedimonte, Monica, Fouquet, Guillemette, Rêgo, Mayara, Hoell-Neugebauer, Baerbel, Cartron, Guillaume, Pinto, Fernando, Alburquerque, Ana Munhoz, Passos, Juliana, Yilmaz, Asu Fergun, Redondo-Izal, Ana-Margarita, Altuntaş, Fevzi, Heath, Christopher, Kolditz, Martin, Schalk, Enrico, Guolo, Fabio, Karthaus, Meinolf, Della Pepa, Roberta, Vinh, Donald, Noël, Nicolas, Deau Fischer, Bénédicte, Drenou, Bernard, Mitra, Maria Enza, Meletiadis, Joseph, Bilgin, Yavuz M., Jindra, Pavel, Espigado, Ildefonso, Drgoňa, Ľuboš, Serris, Alexandra, Di Blasi, Roberta, Ali, Natasha, EPICOVIDEHA working group, [missing], Pagano, Livio, Salmanton-Garcia, Jon, Marchesi, Francesco, Busca, Alessandro, Corradini, Paolo, Hoenigl, Martin, Klimko, Nikolai, Koehler, Philipp, Pagliuca, Antonio, Passamonti, Francesco, Verga, Luisa, Visek, Benjamin, Ilhan, Osman, Nadali, Gianpaolo, Weinbergerova, Barbora, Cordoba-Mascunano, Raul, Marchetti, Monia, Collins, Graham P., Farina, Francesca, Cattaneo, Chiara, Cabirta, Alba, Gomes-Silva, Maria, Itri, Federico, van Doesum, Jaap, Ledoux, Marie-Pierre, Cernan, Martin, Jaksic, Ozren, Duarte, Rafael F., Magliano, Gabriele, Omrani, Ali S., Fracchiolla, Nicola S., Kulasekararaj, Austin, Valkovic, Toni, Poulsen, Christian Bjorn, Machado, Marina, Glenthoj, Andreas, Stoma, Igor, Racil, Zdenek, Piukovics, Klara, Navratil, Milan, Emarah, Ziad, Sili, Uluhan, Maertens, Johan, Blennow, Ola, Bergantim, Rui, Garcia-Vidal, Carolina, Prezioso, Lucia, Guidetti, Anna, del Principe, Maria Ilaria, Popova, Marina, de Jonge, Nick, Ormazabal-Velez, Irati, Fernandez, Noemi, Falces-Romero, Iker, Cuccaro, Annarosa, Meers, Stef, Buquicchio, Caterina, Antic, Darko, Al-Khabori, Murtadha, Garcia-Sanz, Ramon, Biernat, Monika M., Tisi, Maria Chiara, Sal, Ertan, Rahimli, Laman, Colovic, Natasa, Schonlein, Martin, Calbacho, Maria, Tascini, Carlo, Miranda-Castillo, Carolina, Khanna, Nina, Mendez, Gustavo-Adolfo, Petzer, Verena, Novak, Jan, Besson, Caroline, Dulery, Remy, Lamure, Sylvain, Nucci, Marcio, Zambrotta, Giovanni, Zak, Pavel, Seval, Guldane Cengiz, Bonuomo, Valentina, Mayer, Jiri, Lopez-Garcia, Alberto, Sacchi, Maria Vittoria, Booth, Stephen, Ciceri, Fabio, Oberti, Margherita, Salvini, Marco, Izuzquiza, Macarena, Nunes-Rodrigues, Raquel, Ammatuna, Emanuele, Obr, Ales, Herbrecht, Raoul, Nunez-Martin-Buitrago, Lucia, Mancini, Valentina, Shwaylia, Hawraa, Sciume, Mariarita, Essame, Jenna, Nygaard, Marietta, Batinic, Josip, Gonzaga, Yung, Regalado-Artamendi, Isabel, Karlsson, Linda Katharina, Shapetska, Maryia, Hanakova, Michaela, El-Ashwah, Shaimaa, Borbenyi, Zita, Colak, Gokce Melis, Nordlander, Anna, Dragonetti, Giulia, Maraglino, Alessio Maria Edoardo, Rinaldi, Amelia, De Ramon-Sanchez, Cristina, Cornely, Oliver A., Pagano, L., Salmanton-Garcia, J., Marchesi, F., Busca, A., Corradini, P., Hoenigl, M., Klimko, N., Koehler, P., Pagliuca, A., Passamonti, F., Verga, L., Visek, B., Ilhan, O., Nadali, G., Weinbergerova, B., Cordoba-Mascunano, R., Marchetti, M., Collins, G. P., Farina, F., Cattaneo, C., Cabirta, A., Gomes-Silva, M., Itri, F., van Doesum, J., Ledoux, M. -P., Cernan, M., Jaksic, O., Duarte, R. F., Magliano, G., Omrani, A. S., Fracchiolla, N. S., Kulasekararaj, A., Valkovic, T., Poulsen, C. B., Machado, M., Glenthoj, A., Stoma, I., Racil, Z., Piukovics, K., Navratil, M., Emarah, Z., Sili, U., Maertens, J., Blennow, O., Bergantim, R., Garcia-Vidal, C., Prezioso, L., Guidetti, A., del Principe, M. I., Popova, M., de Jonge, N., Ormazabal-Velez, I., Fernandez, N., Falces-Romero, I., Cuccaro, A., Meers, S., Buquicchio, C., Antic, D., Al-Khabori, M., Garcia-Sanz, R., Biernat, M. M., Tisi, M. C., Sal, E., Rahimli, L., Colovic, N., Schonlein, M., Calbacho, M., Tascini, C., Miranda-Castillo, C., Khanna, N., Mendez, G. -A., Petzer, V., Novak, J., Besson, C., Dulery, R., Lamure, S., Nucci, M., Zambrotta, G., Zak, P., Seval, G. C., Bonuomo, V., Mayer, J., Lopez-Garcia, A., Sacchi, M. V., Booth, S., Ciceri, F., Oberti, M., Salvini, M., Izuzquiza, M., Nunes-Rodrigues, R., Ammatuna, E., Obr, A., Herbrecht, R., Nunez-Martin-Buitrago, L., Mancini, V., Shwaylia, H., Sciume, M., Essame, J., Nygaard, M., Batinic, J., Gonzaga, Y., Regalado-Artamendi, I., Karlsson, L. K., Shapetska, M., Hanakova, M., El-Ashwah, S., Borbenyi, Z., Colak, G. M., Nordlander, A., Dragonetti, G., Maraglino, A. M. E., Rinaldi, A., De Ramon-Sanchez, C., Cornely, O. A., Finizio, O., Fazzi, R., Sapienza, G., Chauchet, A., Van Praet, J., Prattes, J., Dargenio, M., Rossi, C., Shirinova, A., Malak, S., Tafuri, A., Ommen, H. -B., Bologna, S., Khedr, R. A., Choquet, S., Joly, B., Ceesay, M. M., Philippe, L., Kho, C. S., Desole, M., Tsirigotis, P., Otasevic, V., Borducchi, D. M. M., Antoniadou, A., Gaziev, J., Almaslamani, M. A., Garcia-Pouton, N., Paterno, G., Torres-Lopez, A., Tarantini, G., Mellinghoff, S., Grafe, S., Borschel, N., Passweg, J., Merelli, M., Barac, A., Wolf, D., Shaikh, M. U., Thieblemont, C., Bernard, S., Funke, V. A. M., Daguindau, E., Khostelidi, S., Nucci, F. M., Martin-Gonzalez, J. -A., Landau, M., Soussain, C., Laureana, C., Lacombe, K., Kohn, M., Aliyeva, G., Piedimonte, M., Fouquet, G., Rego, M., Hoell-Neugebauer, B., Cartron, G., Pinto, F., Alburquerque, A. M., Passos, J., Yilmaz, A. F., Redondo-Izal, A. -M., Altuntas, F., Heath, C., Kolditz, M., Schalk, E., Guolo, F., Karthaus, M., Della Pepa, R., Vinh, D., Noel, N., Deau Fischer, B., Drenou, B., Mitra, M. E., Meletiadis, J., Bilgin, Y. M., Jindra, P., Espigado, I., Drgona, L., Serris, A., Di Blasi, R., Ali, N., Stem Cell Aging Leukemia and Lymphoma (SALL), Salvy-Córdoba, Nathalie, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Università cattolica del Sacro Cuore = Catholic University of the Sacred Heart [Roma] (Unicatt), University Hospital of Cologne [Cologne], Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, IFO - Istituto Nazionale Tumori Regina Elena [Roma] (IRE), Città della Salute e della Scienza University-Hospital, IRCCS Istituto Nazionale dei Tumori [Milano], University of California [San Diego] (UC San Diego), University of California (UC), Medical University of Graz, Odessa National I.I.Mechnikov University, Faculty of Medicine [Cologne], University Hospital of Cologne [Cologne]-University of Cologne, King's College Hospital (KCH), Universitá degli Studi dell’Insubria = University of Insubria [Varese] (Uninsubria), Dipartimento di Medicina e Chirurgia = School of Medicine and Surgery [Monza], Università degli Studi di Milano-Bicocca = University of Milano-Bicocca (UNIMIB), Faculty of Medicine in Hradec Kralove [Republique Tchèque], Charles University [Prague] (CU), Ankara University School of Medicine [Turkey], Azienda Ospedaliera Universitaria Integrata of Verona, Masaryk University [Brno] (MUNI), Fundación Jiménez Díaz, Fundacion Jimenez Diaz [Madrid] (FJD), Ospedale SS Antonio e Biagio e Cesare Arrigo, Churchill Hospital Oxford Centre for Haematology, IRCCS San Raffaele Scientific Institute [Milan, Italie], ASST Spedali Civili of Brescia, Vall d'Hebron Institute of Oncology [Barcelone] (VHIO), Vall d'Hebron University Hospital [Barcelona], Universitat Autònoma de Barcelona (UAB), Instituto Português de Oncologia de Lisboa Francisco Gentil, Ospedale San Luigi Gonzaga, University Medical Center Groningen [Groningen] (UMCG), Institut de Cancérologie de Strasbourg Europe (ICANS), Palacky University Olomouc, Zagreb School of Medicine [Zagreb, Croatia] (Dubrava University Hospital), University of Zagreb, Hospital Universitario Puerta de Hierro-Majadahonda [Madrid, Spain], ASST Great Metropolitan Niguarda / ASST Grande Ospedale Metropolitano Niguarda [Milan, Italia], Hamad Medical Corporation [Doha, Qatar], Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, University of Rijeka, Croatian Cooperative Group for Hematological Diseases (CROHEM), Zealand University Hospital [Roskilde, Denmark], Hospital General Universitario 'Gregorio Marañón' [Madrid], Department of Clinical Microbiology [Rigshospitalet], Rigshospitalet [Copenhagen], Copenhagen University Hospital-Copenhagen University Hospital, Homieĺ State Medical University (GSMU), Institute of Hematology and Blood Transfusion [Prague, Czech Republic], University of Szeged [Szeged], University Hospital Ostrava, Mansoura University [Egypt], Marmara University [Kadıköy - İstanbul], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Karolinska University Hospital [Stockholm], Instituto de Investigação e Inovação em Saúde (I3S), Universidade do Porto = University of Porto, Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), Hospital de São João [Porto], Faculdade de Medicina da Universidade do Porto (FMUP), Clinic Barcelona Hospital Universitari, Department of Public Health and Cell Biology, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy, Pavlov First Saint Petersburg State Medical University [St. Petersburg], Vrije Universiteit Medical Centre (VUMC), Vrije Universiteit Amsterdam [Amsterdam] (VU), Complejo Hospitalario de Navarra, Hospital Universitario Marqués de Valdecilla [Santander], La Paz University Hospital, Azienda Usl Toscana centro [Firenze], AZ Klina, Clinical Center of Serbia (KCS), University of Belgrade [Belgrade], Sultan Qaboos University Hospital, Partenaires INRAE, Hospital Universitario de Salamanca, Servicio de Haematologia, Centro de Investigación del Cáncer-IBMCC (USAL-CSIC), University of Wrocław [Poland] (UWr), San Bortolo Hospital, Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), Hospital Universitario 12 de Octubre [Madrid], Azienda Sanitaria Universitaria Friuli Centrale (ASU FC), Universidad Rey Juan Carlos [Madrid] (URJC), University of Basel (Unibas), Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), University Hospital Kralovské Vinohrady, Centre Hospitalier de Versailles André Mignot (CHV), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut de Génétique Moléculaire de Montpellier (IGMM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Département Hématologie biologique [CHRU Montpellier], Pôle Biologie-Pathologie [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Universidade Federal do Estado do Rio de Janeiro (UNIRIO), San Gerardo Hospital of Monza, Oxford NIHR Biomedical Research Centre, IRCCS Ospedale San Raffaele [Milan, Italy], Assi Sette Llaghi Varese, Instituto Português de Oncologia do Porto / Portuguese Oncology Institute of Porto (IPO Porto), University Hospital Olomouc [Czech Republic], ASST Grande Ospedale Metropolitano Niguarda, University Hospital Centre Zagreb, Instituto Nacional do Câncer, Copenhagen University Hospital, Republican Scientific and Practical Center (RSPC) for organ and Tissue Transplantation, Minsk, Republican Scientific and Practical Center (RSPC) for Organ and Transplantation, German Centre for Infection Research (DZIF), Gilead Sciences, Pagano, Livio [0000-0001-8287-928X], Salmanton-García, Jon [0000-0002-6766-8297], Marchesi, Francesco [0000-0001-6353-2272], Busca, Alessandro [0000-0001-5361-5613], Corradini, Paolo [0000-0002-9186-1353], Hoenigl, Martin [0000-0002-1653-2824], Klimko, Nikolay [0000-0001-6095-7531], Koehler, Philipp [0000-0002-7386-7495], Pagliuca, Antonio [0000-0003-2519-0333], Passamonti, Francesco [0000-0001-8068-5289], Verga, Luisa [0000-0003-1142-8435], Víšek, Benjamin [0000-0001-8268-452X], Ilhan, Osman [0000-0003-1665-372X], Weinbergerová, Barbora [0000-0001-6460-2471], Córdoba, Raúl [0000-0002-7654-8836], Marchetti, Monia [0000-0001-7615-0572], Farina, Francesca [0000-0002-5124-6970], Cattaneo, Chiara [0000-0003-0031-3237], Cabirta, Alba [0000-0001-7198-8894], Gomes-Silva, Maria [0000-0002-6993-2450], Itri, Federico [0000-0002-3532-5281], Doesum, Jaap van [0000-0003-0214-3219], Ledoux, Marie-Pierre [0000-0002-3261-3616], Čerňan, Martin [0000-0003-2345-1229], Jakšić, Ozren [0000-0003-4026-285X], Magliano, Gabriel [0000-0002-9129-1530], Omrani, Ali S. [0000-0001-5309-6358], Fracchiolla, Nicola S. [0000-0002-8982-8079], Kulasekararaj, Austin G. [0000-0003-3180-3570], Valković, Toni [0000-0001-6083-8815], Poulsen, Christian Bjørn [0000-0001-9785-1378], Machado, Marina [0000-0002-8370-2248], Glenthøj, Andrea [0000-0003-2082-0738], Stoma, Igor [0000-0003-0483-7329], Ráčil, Zdeněk [0000-0003-3511-4596], Piukovics, Klára [0000-0003-4480-3131], Emarah, Ziad [0000-0003-0622-2598], Sili, Uluhan [0000-0002-9939-9298], Maertens, Johan [0000-0003-4257-5980], Bergantim, Rui [0000-0002-7811-9509], García-Vidal, Carolina [0000-0002-8915-0683], Prezioso, Lucia [0000-0003-1660-4960], Principe, Maria Ilaria del [0000-0002-3958-0669], Popova, Marina [0000-0001-8536-5495], Jonge, Nick de [0000-0002-9901-0887], Ormazabal-Vélez, Irati [0000-0003-1141-5546], Falces-Romero, Iker [0000-0001-5888-7706], Cuccaro, Annarosa [0000-0002-0237-1839], Meers, Stef [0000-0003-1754-2175], Buquicchio, Caterina [0000-0002-3683-5953], Antić, Darko [0000-0002-2608-1342], Al-Khabori, Murtadha [0000-0002-2937-8838], García-Sanz, Ramón [0000-0003-4120-2787], Biernat, Monika [0000-0003-3161-3398], Tisi, Maria Chiara [0000-0001-8231-6700], Sal, Ertan [0000-0003-2761-2675], Rahimli, Laman [0000-0003-2266-445X], Schönlein, Martin [0000-0002-1010-0975], Calbacho, María [0000-0001-8106-4863], Tascini, Carlo [0000-0001-9625-6024], Miranda-Castillo, Carolina [0000-0001-8763-9576], Khanna, Nina [0000-0002-2642-419X], Méndez, Gustavo-Adolfo [0000-0003-0514-7004], Petzer, Verena [0000-0002-9205-1440], Besson, Caroline [0000-0003-4364-7173], Duléry, Rémy [0000-0002-5024-1713], Lamure, Sylvain [0000-0001-5980-305X], Nucci, Marcio [0000-0003-4867-0014], Zambrotta, Giovanni [0000-0002-8612-2994], Žák, Pavel [0000-0003-4465-5343], Cengiz Seval, Guldane [0000-0001-9433-2054], Bonuomo, Valentina [0000-0001-6491-8337], Mayer, Jiří [0000-0003-0567-9887], López-García, Alberto [0000-0002-5354-5261], Sacchi, Maria Vittoria [0000-0001-8133-3357], Booth, Stephen [0000-0003-2687-0234], Ciceri, Fabio [0000-0003-0873-0123], Nunes-Rodrigues, Raquel [0000-0002-8347-4281], Ammatuna, Emanuele [0000-0001-8247-4901], Obr, Aleš [0000-0002-6758-3074], Herbrecht, Raoul [0000-0002-9381-4876], Shwaylia, Hawraa [0000-0002-4098-6092], Sciumè, Mariarita [0000-0001-7958-4966], Essame, Jenna [0000-0003-0926-5577], Batinić, Josip [0000-0001-5595-9911], Gonzaga, Yung [0000-0003-1416-2118], Regalado-Artamendi, Isabel [0000-0002-9673-9015], Karlsson, Linda Katharina [0000-0003-3317-7550], Shapetska, Maryia [0000-0002-1223-9161], El-Ashwah, Shaimaa [0000-0003-2210-1534], Çolak, Gökçe Melis [0000-0002-7662-7454], Dragonetti, Giulia [0000-0003-1775-6333], Rinaldi, Amelia [0000-0002-8211-5076], Ramón, Cristina de [0000-0002-8167-6410], Cornely, Oliver A. [0000-0001-9599-3137], Institut Català de la Salut, [Pagano L] Hematology, Fondazione Policlinico Universitario Agostino Gemelli - IRCCS – Università Cattolica del Sacro Cuore, Rome, Italy. Università Cattolica del Sacro Cuore, Rome, Italy. [Salmanton-García J] Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Excellence Center for Medical Mycology (ECMM), University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany. Cologne Excellence Cluster On Cellular Stress Responses in Aging Associated Diseases (CECAD), University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany. [Marchesi F] Hematology and Stem Cell Transplant Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy. [Busca A] Stem Cell Transplant Center, AOU Citta’ Della Salute E Della Scienza, Turin, Italy. [Corradini P] University of Milan and Fondazione IRCCS Istituto Nazionale Dei Tumori, Milan, Italy. [Hoenigl M] Division of Infectious Diseases and Global Public Health, Department of Medicine, University of California San Diego, San Diego, CA, USA. Clinical and Translational Fungal Working Group, University of California San Diego, La Jolla, CA, USA. Section of Infectious Diseases and Tropical Medicine, Department of Internal Medicine, Medical University of Graz, Graz, Austria. [Cabirta A, Izuzquiza M] Servei d’Hematologia, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Experimental Hematology, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Departament de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain, Vall d'Hebron Barcelona Hospital Campus, Hematology, Salmanton-García, Jon, Klimko, Nikolay, Víšek, Benjamin, Weinbergerová, Barbora, Córdoba, Raúl, Doesum, Jaap van, Čerňan, Martin, Jakšić, Ozren, Magliano, Gabriel, Kulasekararaj, Austin G., Valković, Toni, Poulsen, Christian Bjørn, Glenthøj, Andrea, Ráčil, Zdeněk, Piukovics, Klára, García-Vidal, Carolina, Principe, Maria Ilaria del, Jonge, Nick de, Ormazabal-Vélez, Irati, Antić, Darko, García-Sanz, Ramón, Biernat, Monika, Schönlein, Martin, Calbacho, María, Méndez, Gustavo-Adolfo, Duléry, Rémy, Žák, Pavel, Cengiz Seval, Guldane, Mayer, Jiří, López-García, Alberto, Obr, Aleš, Sciumè, Mariarita, Batinić, Josip, Çolak, Gökçe Melis, Ramón, Cristina de, and Universidad de Sevilla. Departamento de Medicina
Subjects: [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, Male, Cancer Research, MESH: Registries, Epidemiology, MESH: Hospitalization, Hematological malignancies, Otros calificadores::Otros calificadores::/complicaciones [Otros calificadores], MESH: Aged, 80 and over, MESH: Risk Factors, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Risk Factors, Malalties - Factors de risc, Risk of mortality, Medicine and Health Sciences, virosis::infecciones por virus ARN::infecciones por Nidovirales::infecciones por Coronaviridae::infecciones por Coronavirus [ENFERMEDADES], 80 and over, Medicine, MESH: COVID-19, Registries, Sang - Malalties - Complicacions, RC254-282, Cause of death, BIOMEDICINA I ZDRAVSTVO. Kliničke medicinske znanosti. Interna medicina, MESH: Aged, Aged, 80 and over, Hematology, MESH: Middle Aged, Mortality rate, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Myeloid leukemia, Virus Diseases::RNA Virus Infections::Nidovirales Infections::Coronaviridae Infections::Coronavirus Infections [DISEASES], [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Middle Aged, CANCER, Europe, Hospitalization, Intensive Care Units, Oncology, MESH: Young Adult, Hematologic Neoplasms, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Female, BIOMEDICINA I ZDRAVSTVO. Kliničke medicinske znanosti. Infektologija, Life Sciences & Biomedicine, Adult, medicine.medical_specialty, [SDV.CAN]Life Sciences [q-bio]/Cancer, COVID-19, EHA, Pandemic, Aged, Humans, SARS-CoV-2, Young Adult, técnicas de investigación::métodos epidemiológicos::estadística como asunto::probabilidad::riesgo::factores de riesgo [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], [SDV.CAN] Life Sciences [q-bio]/Cancer, Intensive care, Internal medicine, Diseases of the blood and blood-forming organs, MESH: SARS-CoV-2, neoplasias::neoplasias por localización::neoplasias hematológicas [ENFERMEDADES], Molecular Biology, BIOMEDICINE AND HEALTHCARE. Clinical Medical Sciences. Internal Medicine, pandemic, hematological malignancies, epidemiology, MESH: Humans, Science & Technology, business.industry, Myelodysplastic syndromes, Research, MESH: Adult, Neoplasms::Neoplasms by Site::Hematologic Neoplasms [DISEASES], medicine.disease, BIOMEDICINE AND HEALTHCARE. Clinical Medical Sciences. Infectology, Settore MED/15, MESH: Male, Settore MED/15 - MALATTIE DEL SANGUE, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, COVID-19 (Malaltia) - Diagnòstic, MESH: Intensive Care Units, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Investigative Techniques::Epidemiologic Methods::Statistics as Topic::Probability::Risk::Risk Factors [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], MESH: Europe, RC633-647.5, business, MESH: Female, Other subheadings::Other subheadings::/complications [Other subheadings], MESH: Hematologic Neoplasms
Abstract: Background Patients with hematological malignancies (HM) are at high risk of mortality from SARS-CoV-2 disease 2019 (COVID-19). A better understanding of risk factors for adverse outcomes may improve clinical management in these patients. We therefore studied baseline characteristics of HM patients developing COVID-19 and analyzed predictors of mortality. Methods The survey was supported by the Scientific Working Group Infection in Hematology of the European Hematology Association (EHA). Eligible for the analysis were adult patients with HM and laboratory-confirmed COVID-19 observed between March and December 2020. Results The study sample includes 3801 cases, represented by lymphoproliferative (mainly non-Hodgkin lymphoma n = 1084, myeloma n = 684 and chronic lymphoid leukemia n = 474) and myeloproliferative malignancies (mainly acute myeloid leukemia n = 497 and myelodysplastic syndromes n = 279). Severe/critical COVID-19 was observed in 63.8% of patients (n = 2425). Overall, 2778 (73.1%) of the patients were hospitalized, 689 (18.1%) of whom were admitted to intensive care units (ICUs). Overall, 1185 patients (31.2%) died. The primary cause of death was COVID-19 in 688 patients (58.1%), HM in 173 patients (14.6%), and a combination of both COVID-19 and progressing HM in 155 patients (13.1%). Highest mortality was observed in acute myeloid leukemia (199/497, 40%) and myelodysplastic syndromes (118/279, 42.3%). The mortality rate significantly decreased between the first COVID-19 wave (March–May 2020) and the second wave (October–December 2020) (581/1427, 40.7% vs. 439/1773, 24.8%, p value, EPICOVIDEHA has received funds from Optics COMMITTM (COVID-19 Unmet Medical Needs and Associated Research Extension) COVID-19 RFP program by GILEAD Science, United States (Project 2020-8223).
Published: 2021
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291. Social mobility and healthy behaviours from a gender perspective in the Spanish multicase-control study (MCC-Spain)

Author: Leire Gil-Majuelo, Tania Fernández-Villa, Nuria Aragonés, Pilar Amiano, Esther Gracia-Lavedan, Juan Alguacil, Inmaculada Salcedo-Bellido, A. Delgado-parrilla, Cristina O'Callaghan-Gordo, Virginia Lope, Maria Dolores Chirlaque, Marta Maria Rodriguez-Suarez, Rafael Marcos-Gragera, Marcela Guevara, Dolores Salas, Rosana Peiró-Pérez, Inés Gómez-Acebo, Gemma Castaño-Vinyals, Marina Pollán, Trinidad Dierssen-Sotos, M. Pinto-carbó, Manolis Kogevinas, Antonio J. Molina, Conchi Moreno-Iribas, Mercedes Vanaclocha-Espi, Beatriz Pérez-Gómez, Mireia Obón-Santacana, Ana Molina-Barceló, Universidad de Cantabria, Universitat Oberta de Catalunya (UOC), Universidad de Granada, Universidad de Huelva, Fundación para el Fomento de la Investigación Sanitaria y Biomédica (FISABIO), Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBEResp), Instituto de Salud Carlos III, European Regional Development Fund, Fundación Marqués de Valdecilla, International Cancer Genome Consortium, Ministerio de Economía y Competitividad (España), Red Temática de Investigación Cooperativa en Cáncer (España), Junta de Castilla y León (España), Regional Government of Andalusia (España), Generalitat Valenciana (España), Fundación La Caixa, Basque Government (España), Gobierno de Murcia, Unión Europea. Comisión Europea, Asociación Española Contra el Cáncer, Government of Catalonia (España), Fundación Caja de Ahorros de Asturias, University of Oviedo (España), [Pinto-Carbo,M, Molina-Barcelo,A, Vanaclocha-Espi,M, Salas,D] Cancer and Public Health Area, Foundation for the Promotion of the Research in Healthcare and Biomedicine (FISABIO-Salud Pública), Valencia, Valencian Community, Spain. [Peiró-Pérez,R] Inequalities Area, Foundation for the Promotion of the Research in Healthcare and Biomedicine (FISABIO-Salud Pública), Valencia, Valencian Community, Spain. [Peiró-Pérez,R, Salas,D] General Directorate of Public Health, Valencia, Valencian Community, Spain. [Peiró-Pérez,R, Alguacil,J, Castaño-Vinyals,G, O’Callaghan-Gordo,C, Gràcia-Lavedan,E, Pérez-Gómez,B, Lope,V, Aragonés,N, Amiano,P, Dierssen-Soto,T, Gómez-Acebo,I, Guevara,M, Obón-Santacana,M, Salcedo-Bellido,I, Marcos-Gragera,R, Chirlaque,MD, Kogevinas,M, Pollán,M, Salas,D] Consortium for Biomedical Research in Epidemiology and Public Health (CIBEResp), Madrid, Spain. [Alguacil,J, Delgado-Parrilla,A] Centre for Health and Environmental Research, Huelva University, Huelva, Andalucia, Spain. [Castaño-Vinyals,G, Kogevinas,M] Barcelona Institute for Global Health (ISGlobal), Barcelona, Catalonia, Spain. [Castaño-Vinyals,G, O’Callaghan-Gordo,G, Kogevinas,M] Universitat Pompeu Fabra, Plaça de la Mercè, Barcelona, Catalonia, Spain. [Castaño-Vinyals,G, Kogevinas,M] Hospital del Mar Medical Research Institute, Barcelona, Catalonia, Spain. [O’Callaghan-Gordo,C] Faculty of Health Science,Universitat Oberta de Catalunya, Barcelona, Catalonia, Spain. [Pérez-Gómez,B, Pollán,M] Department of Epidemiology of Chronic Diseases, National Center for Epidemiology, Carlos III Institute of Health, Madrid, Spain. [Aragonés,N] Epidemiology Section, Public Health Division, Department of Health of Madrid, Madrid, Spain. [Molina,AJ, Fernández-Villa,T] The Research Group in Gene—Environment and Health Interactions, Institute of Biomedicine (IBIOMED), University of León, León, Castilla y León, Spain. [Gil-Majuelo,L, Amiano,P] Ministry of Health of the Basque Government, Sub-Directorate for Public Health and Addictions of Gipuzkoa, San Sebastián, Gipuzkoa, Spain. [Gil-Majuelo,L, Amiano,P] Biodonostia Health Research Institute, Group of Epidemiology of Chronic and Communicable Diseases, San Sebastián, Gipuzkoa, Spain. [Dierssen-Sotos,T, Gómez-Acebo,I] Cantabria University, Santander, Cantabria, Spain. [Guevara,M, Moreno-Iribas,C] Navarra Public Health Institute, Pamplona, Navarra, Spain. [Guevara,M, Moreno-Iribas,C] Navarra Institute for Health Research (IdiSNA), Pamplona, Navarra, Spain. [Obón-Santacana,M] Oncology Data Analytics Program (ODAP), Catalan Institute of Oncology (ICO), Barcelona, Catalonia, Spain. [Obón-Santacana,M] ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain. [Rodríguez-Suárez,MM] Preventive Medicine and Public Health Area, Oviedo University, Oviedo, Asturias, Spain. [Rodríguez-Suárez,MM] Central University Hospital of Asturias, Public Health Service of the Principe de Asturias, Oviedo, Asturias, Spain. [Salcedo-Bellido,I] Instituto de Investigación Biosanitaria ibs.GRANADA, Granada, Andalucia, Spain. [Salcedo-Bellido,I] Departamento de Medicina Preventiva y Salud Publica, Universidad de Granada, Granada, Andalucia, Spain. [Marcos-Gragera,R] Epidemiology Unit and Girona Cancer Registry, Oncology Coordination Plan, Department of Health, Autonomous Government of Catalonia, Catalan Institute of Oncology, Girona, Catalonia, Spain. [Marcos-Gragera,R] Descriptive Epidemiology, Genetics and Cancer Prevention Group [Girona Biomedical Research Institute], Girona, Catalonia, Spain. [Chirlaque,D] Department of Epidemiology, Murcia Regional Health Council, IMIB-Arrixaca, El Palmar, Murcia, Spain., and This research was supported by the 'Acción Transversal del Cancer', approved by the Spanish Council of Ministers on 11th October 2007, by the Instituto de Salud Carlos III-FEDER [grant number:PI08/1770, PI08/0533, PI08/1359, PS09/00773-Cantabria, PS09/01286-León, PS09/01903-Valencia, PS09/02078-Huelva, PS09/ 01662-Granada, PI11/01403, PI11/01889-FEDER, PI11/00226, PI11/01810, PI11/02213, PI12/00488, PI12/00265, PI12/01270, PI12/00715, PI12/00150, PI14/01219, PI14/0613, PI15/00069, PI15/00914, PI15/01032, PI11/01810, PI14/01219, PI11/02213, PIE16/00049, PI17/01179, PI17-00092], by the Fundación Marqués de Valdecilla [grant number: API 10/09], by the ICGC International Cancer Genome Consortium CLL (The ICGC CLL-Genome Project is funded by Spanish Ministerio de Economía y Competitividad (MINECO) through the Instituto de Salud Carlos III (ISCIII)), by the Red Temática de Investigación del Cáncer (RTICC) del ISCIII [grant number: RD12/0036/0036], by the Junta de Castilla y León [grant number: LE22A10-2], by the Consejería de Salud of the Junta de Andalucía [grant number: PI-0571-2009, PI-0306-2011, salud201200057018tra], by the Conselleria de Sanitat of the Generalitat Valenciana [grant number: AP_061/10], by the Recercaixa [grant number: 2010ACUP00310], by the Regional Government of the Basque Country, by the Consejería de Sanidad de la Región de Murcia, by the European Commission [grant number: FOOD-CT-2006-036224-HIWATE], by the Spanish Association Against Cancer (AECC) Scientific Foundation [grant number: GCTRA18022MORE], by the Catalan Government-Agency for Management of University and Research Grants (AGAUR) [grant number: 2014SGR647, 2014SGR850 and 2017SGR723], by the Fundación Caja de Ahorros de Asturias and by the University of Oviedo.
Subjects: Male, Behavioral and social aspects of health, Health Behavior, España, Social Sciences, Psychiatry and Psychology::Behavior and Behavior Mechanisms::Behavior::Tobacco Use::Smoking [Medical Subject Headings], Gender perspective, healthy behaviours, Hàbits sanitaris, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], 0302 clinical medicine, Movilidad social, Sociology, Social mobility, Medicine and Health Sciences, Socioeconomic aspects of health, Public and Occupational Health, European commission, Alcohol consumption, Salut, 030212 general & internal medicine, Persons::Persons::Age Groups::Adult::Aged [Medical Subject Headings], Anthropology, Education, Sociology and Social Phenomena::Social Sciences::Sociology::Social Class [Medical Subject Headings], Perspectiva de género, Aged, 80 and over, Multidisciplinary, Estudios de casos y controles, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Epidemiologic Study Characteristics as Topic::Epidemiologic Studies::Case-Control Studies [Medical Subject Headings], Health Care::Health Care Quality, Access, and Evaluation::Quality of Health Care::Epidemiologic Factors::Sex Factors [Medical Subject Headings], multicase-control study, Psychiatry and Psychology::Behavior and Behavior Mechanisms::Behavior::Health Behavior [Medical Subject Headings], Middle Aged, Sexual and gender issues, Anthropology, Education, Sociology and Social Phenomena::Social Sciences::Sociology::Social Class::Social Mobility [Medical Subject Headings], Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Statistics as Topic::Models, Statistical::Logistic Models [Medical Subject Headings], Health, language, Medicine, Female, 0305 other medical science, Persons::Persons::Age Groups::Adult::Young Adult [Medical Subject Headings], Research Article, Adult, Science, Health Care::Environment and Public Health::Public Health::Epidemiologic Methods::Data Collection::Health Surveys::Nutrition Surveys::Diet Surveys [Medical Subject Headings], Healthy lifestyle, Clase social, Check Tags::Male [Medical Subject Headings], Genre studies, Education, socioeconomic status, 03 medical and health sciences, Young Adult, Sex Factors, Political science, Cancer genome, Anthropology, Education, Sociology and Social Phenomena::Social Sciences::Sociology::Socioeconomic Factors [Medical Subject Headings], Humans, social mobility, Persons::Persons::Age Groups::Adult [Medical Subject Headings], Health behavior, Exercise, Educational Attainment, Nutrition, Aged, Geographical Locations::Geographic Locations::Europe::Spain [Medical Subject Headings], 030505 public health, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Data Collection::Health Surveys [Medical Subject Headings], Physical activity, Biology and Life Sciences, Persons::Persons::Age Groups::Adult::Middle Aged [Medical Subject Headings], Health Surveys, language.human_language, Diet, Health Care, Check Tags::Female [Medical Subject Headings], Social Class, Socioeconomic Factors, Estudis de gènere, Persons::Persons::Age Groups::Adult::Aged::Aged, 80 and over [Medical Subject Headings], Phenomena and Processes::Musculoskeletal and Neural Physiological Phenomena::Musculoskeletal Physiological Phenomena::Musculoskeletal Physiological Processes::Movement::Motor Activity::Exercise [Medical Subject Headings], Spain, Case-Control Studies, Psychiatry and Psychology::Behavior and Behavior Mechanisms::Behavior::Drinking Behavior::Alcohol Drinking [Medical Subject Headings], Catalan, Gender studies, Estilo de vida saludable, Humanities
Abstract: This research was supported by the “Acción Transversal del Cancer”, approved by the Spanish Council of Ministers on 11th October 2007, by the Instituto de Salud Carlos III-FEDER [grant number:PI08/1770, PI08/0533, PI08/1359, PS09/00773-Cantabria, PS09/01286-León, PS09/01903-Valencia, PS09/02078-Huelva, PS09/ 01662-Granada, PI11/01403, PI11/01889-FEDER, PI11/00226, PI11/01810, PI11/02213, PI12/00488, PI12/00265, PI12/01270, PI12/00715, PI12/00150, PI14/01219, PI14/0613, PI15/00069, PI15/00914, PI15/01032, PI11/01810, PI14/01219, PI11/02213, PIE16/00049, PI17/01179, PI17-00092], by the Fundación Marqués de Valdecilla [grant number: API 10/09], by the ICGC International Cancer Genome Consortium CLL (The ICGC CLL-Genome Project is funded by Spanish Ministerio de Economía y Competitividad (MINECO) through the Instituto de Salud Carlos III (ISCIII)), by the Red Temática de Investigación del Cáncer (RTICC) del ISCIII [grant number: RD12/0036/0036], by the Junta de Castilla y León [grant number: LE22A10-2], by the Consejería de Salud of the Junta de Andalucía [grant number: PI-0571-2009, PI-0306-2011, salud201200057018tra], by the Conselleria de Sanitat of the Generalitat Valenciana [grant number: AP_061/10], by the Recercaixa [grant number: 2010ACUP00310], by the Regional Government of the Basque Country, by the Consejería de Sanidad de la Región de Murcia, by the European Commission [grant number: FOOD-CT-2006-036224-HIWATE], by the Spanish Association Against Cancer (AECC) Scientific Foundation [grant number: GCTRA18022MORE], by the Catalan Government-Agency for Management of University and Research Grants (AGAUR) [grant number: 2014SGR647, 2014SGR850 and 2017SGR723], by the Fundación Caja de Ahorros de Asturias and by the University of Oviedo. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript., There is evidence for the influence of socioeconomic status (SES) on healthy behaviours but the effect of social mobility (SM) is not yet well known. This study aims to analyse the influence of origin and destination SES (O-SES and D-SES) and SM on healthy behaviours and co-occurrence, from an integrated gender and age perspective. Data were obtained from the controls of MCC-Spain between 2008–2013 (3,606 participants). Healthy behaviours considered: healthy diet, moderate alcohol consumption, non-smoking and physical activity. SM was categorized as stable high, upward, stable medium, downward or stable low. Binary and multinomial logistic regression models were adjusted. Those aged, “Acción Transversal del Cancer” by the Spanish Council of Ministers, Instituto de Salud Carlos III-FEDER [grant number:PI08/1770, PI08/0533, PI08/1359, PS09/00773-Cantabria, PS09/01286-León, PS09/01903-Valencia, PS09/02078-Huelva, PS09/ 01662-Granada, PI11/01403, PI11/01889-FEDER, PI11/00226, PI11/01810, PI11/02213, PI12/00488, PI12/00265, PI12/01270, PI12/00715, PI12/00150, PI14/01219, PI14/0613, PI15/00069, PI15/00914, PI15/01032, PI11/01810, PI14/01219, PI11/02213, PIE16/00049, PI17/01179, PI17-00092, Fundación Marqués de Valdecilla [grant number: API 10/09], ICGC International Cancer Genome Consortium CLL (The ICGC CLL-Genome Project is funded by Spanish Ministerio de Economía y Competitividad (MINECO) through the Instituto de Salud Carlos III (ISCIII)), Red Temática de Investigación del Cáncer (RTICC) del ISCIII [grant number: RD12/0036/0036], Junta de Castilla y León [grant number: LE22A10-2], Consejería de Salud of the Junta de Andalucía [grant number: PI-0571-2009, PI-0306-2011, salud201200057018tra], Conselleria de Sanitat of the Generalitat Valenciana [grant number: AP_061/10], Recercaixa [grant number: 2010ACUP00310], Regional Government of the Basque Country, Consejería de Sanidad de la Región de Murcia, European Commission [grant number: FOOD-CT-2006-036224-HIWATE], Spanish Association Against Cancer (AECC) Scientific Foundation [grant number: GCTRA18022MORE, Catalan Government-Agency for Management of University and Research Grants (AGAUR) [grant number: 2014SGR647, 2014SGR850 and 2017SGR723], Fundación Caja de Ahorros de Asturias, University of Oviedo
Published: 2021

292. Advanced Prostate Cancer with ATM Loss: PARP and ATR Inhibitors

Author: Pasquale Rescigno, Lorenzo Buroni, Amanda Swain, Nicolás Herranz, Bora Gurel, Ruth Riisnaes, Alejandro Athie, Jan Rekowski, Natalia Castro, Wei Yuan, Christopher J. Lord, Adam Sharp, J. Carmichael, Sara Arce-Gallego, Joan Carles, Diletta Bianchini, Macarena Gonzalez, Ana Ferreira, Suzanne Carreira, Antje Neeb, Jesús Gil, Verena Wagner, George Seed, Alec Paschalis, Cristina Suarez, Daniel Nava Rodrigues, Veronica Gil, Maria de Los Dolores Fenor de la Maza, Caterina Aversa, Ines Figueiredo, Jian Ning, Irene Casanova-Salas, Johann S. de Bono, Teresa Casals, Rafael Morales-Barrera, Claudia Bertan, Joaquin Mateo, Sarai Cordoba, Khobe Chandran, Susana Miranda, Jon Welti, Violeta Serra, Institut Català de la Salut, [Neeb A, Miranda S, Buroni L, Yuan W] The Institute of Cancer Research, London, UK. [Herranz N, Arce-Gallego S, Serra V] Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. [Athie A, Casals T, Casanova-Salas I, Cordoba S, Castro N] Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Gonzalez M, Morales-Barrera R, Suarez C, Carles J, Mateo J] Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Vall d’Hebron Hospital Universitari, Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: Male, Genome instability, ADN - Reparació, Synthetic lethality, 030232 urology & nephrology, Medicaments antineoplàstics - Ús terapèutic, Ataxia Telangiectasia Mutated Proteins, DNA damage response, Chemical Phenomena::Biochemical Phenomena::DNA Repair [PHENOMENA AND PROCESSES], Prostate cancer, 0302 clinical medicine, Prostate, Tumor Cells, Cultured, Medicine, fenómenos químicos::fenómenos bioquímicos::reparación del ADN [FENÓMENOS Y PROCESOS], medicine.diagnostic_test, OLAPARIB, Urology & Nephrology, 3. Good health, medicine.anatomical_structure, 030220 oncology & carcinogenesis, DNA-REPAIR, Immunohistochemistry, Life Sciences & Biomedicine, Neoplasms::Neoplasms by Site::Urogenital Neoplasms::Genital Neoplasms, Male::Prostatic Neoplasms [DISEASES], DNA repair, Urology, Poly(ADP-ribose) Polymerase Inhibitors, ATR inhibition, 03 medical and health sciences, Biopsy, Humans, terapéutica::protocolos clínicos::protocolos antineoplásicos::protocolos de quimioterapia antineoplásica combinada [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Neoplasm Staging, Retrospective Studies, Science & Technology, Pròstata - Càncer, business.industry, PARP inhibition, Prostatic Neoplasms, 1103 Clinical Sciences, Therapeutics::Clinical Protocols::Antineoplastic Protocols::Antineoplastic Combined Chemotherapy Protocols [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], medicine.disease, Telomere, neoplasias::neoplasias por localización::neoplasias urogenitales::neoplasias de los genitales masculinos::neoplasias de la próstata [ENFERMEDADES], ATM, Cancer research, business
Abstract: Inhibició de l’ATR; Resposta de danys a l’ADN; Càncer de pròstata Inhibición de ATR; Respuesta al daño del ADN; Cancer de prostata ATR inhibition; DNA damage response; Prostate cancer Background Deleterious ATM alterations are found in metastatic prostate cancer (PC); PARP inhibition has antitumour activity against this subset, but only some ATM loss PCs respond. Objective To characterise ATM-deficient lethal PC and to study synthetic lethal therapeutic strategies for this subset. Design, setting, and participants We studied advanced PC biopsies using validated immunohistochemical (IHC) and next-generation sequencing (NGS) assays. In vitro cell line models modified using CRISPR-Cas9 to impair ATM function were generated and used in drug-sensitivity and functional assays, with validation in a patient-derived model. Outcome measurements and statistical analysis ATM expression by IHC was correlated with clinical outcome using Kaplan-Meier curves and log-rank test; sensitivity to different drug combinations was assessed in the preclinical models. Results and limitations Overall, we detected ATM IHC loss in 68/631 (11%) PC patients in at least one biopsy, with synchronous and metachronous intrapatient heterogeneity; 46/71 (65%) biopsies with ATM loss had ATM mutations or deletions by NGS. ATM IHC loss was not associated with worse outcome from advanced disease, but ATM loss was associated with increased genomic instability (NtAI:number of subchromosomal regions with allelic imbalance extending to the telomere, p = 0.005; large-scale transitions, p = 0.05). In vitro, ATM loss PC models were sensitive to ATR inhibition, but had variable sensitivity to PARP inhibition; superior antitumour activity was seen with combined PARP and ATR inhibition in these models. Conclusions ATM loss in PC is not always detected by targeted NGS, associates with genomic instability, and is most sensitive to combined ATR and PARP inhibition. We gratefully acknowledge research funding for this work from Cancer Research UK, Prostate Cancer UK, the Movember Foundation through the London Movember Centre of Excellence ( CEO13_2-002 ), the Prostate Cancer Foundation (including Young Investigator Awards to Joaquin Mateo, Pasquale Rescigno, and Adam Sharp), Stand Up To Cancer, and the UK Department of Health through an Experimental Cancer Medicine Centre grant. Professor Johann de Bono is a National Institute for Health Research (NIHR) Senior Investigator; research at the Royal Marsden Hospital is supported by a Biomedical Research Centre grant. Part of this work was also funded by a Deparment of Defense CDMRP Impact Award (W81XWH-18-1-0756) to Joaquin Mateo and by Instituto de Salud Carlos III through Grant FI19/00280 to Sara Arce-Gallego, Grant CP19/00170 to Nicolás Herranz, and Grant PI18/01384 to Joaquin Mateo. The authors affiliated to VHIO acknowledge the “la Caixa” Foundation ( ID 100010434 ) for funding under agreement LCF/PR/PR17/51120011 and funding from Fundacion FERO and Moventia . This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement 837900 . The funding organisations had no role in the design, conduction or data analysis of this project, neither in the manuscript preparation.
Published: 2021
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293. Precise enhancement quantification in post-operative MRI as an indicator of residual tumor impact is associated with survival in patients with glioblastoma

Author: Alonso Garcia-Ruiz, Mònica Cos, Nahum Calvo, Gerard Plans, Albert Pons-Escoda, Marta Ligero, Jordi Bruna, Raquel Perez-Lopez, Carles Majós, Pablo Naval-Baudin, Institut Català de la Salut, [Garcia-Ruiz A, Ligero M] Radiomics Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Naval-Baudin P] Department of Radiology, Institut de Diagnòstic Per La Imatge (IDI), Bellvitge University Hospital, Barcelona, Spain. [Pons-Escoda A] Department of Radiology, Institut de Diagnòstic Per La Imatge (IDI), Bellvitge University Hospital, Barcelona, Spain. Neuro Oncology Unit, Institut d’Investigació Biomèdica de Bellvitge (IDIBELL), Barcelona, Spain. [Bruna J] Neuro Oncology Unit, Institut d’Investigació Biomèdica de Bellvitge (IDIBELL), Barcelona, Spain. Department of Neurology, Bellvitge University Hospital, Barcelona, Spain. [Plans G] Neuro Oncology Unit, Institut d’Investigació Biomèdica de Bellvitge (IDIBELL), Barcelona, Spain. Department of Neurosurgery, Bellvitge University Hospital, Barcelona, Spain. [Perez-Lopez R] Radiomics Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Servei Radiodiagnòstic (IDI), Vall d’Hebron Hospital Universitari, Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: Male, Neoplasm, Residual, Mathematics and computing, medicine.medical_treatment, Neurosurgical Procedures, Quimioteràpia, Image Processing, Computer-Assisted, Càncer de cap, Multidisciplinary, medicine.diagnostic_test, Brain Neoplasms, Confounding, Hazard ratio, Middle Aged, Prognosis, Magnetic Resonance Imaging, neoplasias::neoplasias por tipo histológico::neoplasias de células germinales y embrionarias::tumores neuroectodérmicos::neoplasias neuroepiteliales::glioma::astrocitoma::glioblastoma [ENFERMEDADES], Tumor Burden, Survival Rate, Neurology, Oncology, Medicine, Female, Radiology, medicine.drug, Adult, medicine.medical_specialty, Prognosi, Science, Brain tumor, Radioteràpia, Glioblastoma multiforme, Neoplasms::Neoplasms by Histologic Type::Neoplasms, Germ Cell and Embryonal::Neuroectodermal Tumors::Neoplasms, Neuroepithelial::Glioma::Astrocytoma::Glioblastoma [DISEASES], Article, Head cancer, Young Adult, Diagnosis::Diagnostic Techniques and Procedures::Diagnostic Imaging::Tomography::Magnetic Resonance Imaging [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], medicine, Mortalitat, Humans, Chemotherapy, diagnóstico::técnicas y procedimientos diagnósticos::diagnóstico por imagen::tomografía::imagen por resonancia magnética [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Mortality, Diagnosis::Prognosis [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], Survival rate, diagnóstico::pronóstico [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Aged, Retrospective Studies, Temozolomide, Radiotherapy, business.industry, Magnetic resonance imaging, Retrospective cohort study, medicine.disease, Imatgeria per ressonància magnètica, Glioblastoma, business, Follow-Up Studies
Abstract: Matemàtiques i informàtica; Neurologia; Oncologia Matemáticas e informática; Neurología; Oncología Mathematics and computing; Neurology; Oncology Glioblastoma is the most common primary brain tumor. Standard therapy consists of maximum safe resection combined with adjuvant radiochemotherapy followed by chemotherapy with temozolomide, however prognosis is extremely poor. Assessment of the residual tumor after surgery and patient stratification into prognostic groups (i.e., by tumor volume) is currently hindered by the subjective evaluation of residual enhancement in medical images (magnetic resonance imaging [MRI]). Furthermore, objective evidence defining the optimal time to acquire the images is lacking. We analyzed 144 patients with glioblastoma, objectively quantified the enhancing residual tumor through computational image analysis and assessed the correlation with survival. Pathological enhancement thickness on post-surgical MRI correlated with survival (hazard ratio: 1.98, p
Published: 2021

294. A Prospective Diet-Wide Association Study for Risk of Colorectal Cancer in EPIC

Author: Ingegerd Johansson, David S. Lopez, Alicia K Heath, Amanda J. Cross, Anne Tjønneland, J. Ramón Quirós, Melissa A. Merritt, Paula Jakszyn, Bas Bueno-de-Mesquita, Pilar Amiano, Anne Kirstine Eriksen, Manuela M. Bergmann, Marc J. Gunter, Bernard Srour, David C. Muller, Piet A. van den Brandt, Matthias B. Schulze, Salvatore Panico, Claudia Agnoli, Pietro Ferrari, Marco Lukic, José María Huerta, Christina C. Dahm, Therese Haugdahl Nøst, Areti Papadopoulou, Aurelio Barricarte Gurrea, Rosario Tumino, María José Sánchez, Fulvio Ricceri, Nadia Bastide, Paolo Vineis, Ulrika Ericson, Eva Ardanaz, Gianluca Severi, Guri Skeie, Aurora Perez-Cornago, Nikos Papadimitriou, Emmanouil Bouras, Elisabete Weiderpass, Ellio Riboli, Ioanna Tzoulaki, Heiner Boeing, Stina Bodén, Giovanna Masala, Jeroen W.G. Derksen, Jonna Berntsson, Verena Katzke, Elena Critselis, Konstantinos K. Tsilidis, University of Ioannina, Maastricht University [Maastricht], Imperial College London, Biomedical Research Foundation of the Academy of Athens (BRFAA), International Agency for Cancer Research (IACR), German Institute of Human Nutrition Potsdam-Rehbrücke (DIfE), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, University of Hawai'i [Honolulu] (UH), The University of Texas Health Science Center at Houston (UTHealth), University of Oxford [Oxford], University of Potsdam, The Arctic University of Norway (UiT), German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Umeå University, Università degli studi di Torino = University of Turin (UNITO), Lund University [Lund], Instituto de Salud Carlos III [Madrid] (ISC), Aarhus University [Aarhus], IRCCS Istituto Nazionale dei Tumori [Milano], University of Copenhagen = Københavns Universitet (KU), National Institute for Public Health and the Environment [Bilthoven] (RIVM), University of Naples Federico II, La Salle [Ramon Llull University], Utrecht University [Utrecht], Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Kræftens Bekæmpelse, DCS, Deutsches Krebsforschungszentrum, DKFZ, Centre International de Recherche sur le Cancer, CIRC, International Council of Ophthalmology, ICO, National Research Council, NRC, University of Maryland School of Public Health, SPH, Medical Research Council, MRC: MR/M012190/1, Cancer Research UK, CRUK: C8221/A29017, World Cancer Research Fund, WCRF: WCRF 2014/1180, Institut National de la Santé et de la Recherche Médicale, Inserm, Bundesministerium für Bildung und Forschung, BMBF, Cancerfonden, Ministerie van Volksgezondheid, Welzijn en Sport, VWS, Ligue Contre le Cancer, Vetenskapsrådet, VR, Instituto de Salud Carlos III, ISCIII, Associazione Italiana per la Ricerca sul Cancro, AIRC, Deutsche Krebshilfe, Institut Gustave-Roussy, Mutuelle Générale de l'Education Nationale, MGEN, Funding This work was supported by the World Cancer Research Fund International Regular Grant Programme (WCRF 2014/1180 to Konstantinos K. Tsilidis). The coordination of EPIC is financially supported by International Agency for Research on Cancer and also by the Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London which has additional infrastructure support provided by the National Institute for Health Research Imperial Biomedical Research Centre. The national cohorts are supported by the Danish Cancer Society (Denmark), Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle G?n?rale de l'Education Nationale, Institut National de la Sant? et de la Recherche M?dicale (INSERM) (France), German Cancer Aid, German Cancer Research Center (DKFZ), German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), Federal Ministry of Education and Research (BMBF) (Germany), Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy, Compagnia di SanPaolo and National Research Council (Italy), Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands), Health Research Fund (FIS)?Instituto de Salud Carlos III (ISCIII), Regional Governments of Andaluc?a, Asturias, Basque Country, Murcia and Navarra, and the Catalan Institute of Oncology (ICO) (Spain), Swedish Cancer Society, Swedish Research Council and County Councils of Sk?ne and V?sterbotten (Sweden), and Cancer Research UK (14136 to EPIC-Norfolk, C8221/A29017 to EPIC-Oxford) and Medical Research Council (1000143 to EPIC-Norfolk, MR/M012190/1 to EPIC-Oxford) (United Kingdom). Where authors are identified as personnel of the International Agency for Research on Cancer/World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy, or views of the International Agency for Research on Cancer/World Health Organization., Funding This work was supported by the World Cancer Research Fund International Regular Grant Programme ( WCRF 2014/1180 to Konstantinos K. Tsilidis). The coordination of EPIC is financially supported by International Agency for Research on Cancer and also by the Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London which has additional infrastructure support provided by the National Institute for Health Research Imperial Biomedical Research Centre . The national cohorts are supported by the Danish Cancer Society (Denmark), Ligue Contre le Cancer , Institut Gustave Roussy , Mutuelle Générale de l’Education Nationale, Institut National de la Santé et de la Recherche Médicale (INSERM) (France), German Cancer Aid , German Cancer Research Center ( DKFZ ), German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), Federal Ministry of Education and Research ( BMBF ) (Germany), Dutch Ministry of Public Health , Welfare and Sports ( VWS ), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund ( WCRF ), Statistics Netherlands (The Netherlands), Health Research Fund (FIS)– Instituto de Salud Carlos III ( ISCIII ), Regional Governments of Andalucía, Asturias, Basque Country, Murcia and Navarra, and the Catalan Institute of Oncology ( ICO ) (Spain), Swedish Cancer Society , Swedish Research Council and County Councils of Skåne and Västerbotten (Sweden), Epidemiologie, and RS: GROW - R1 - Prevention
Subjects: medicine.medical_specialty, [SDV]Life Sciences [q-bio], Riboflavin, colorectal cancer, Lower risk, Cohort Studies, Animal science, beta-Carotene, Risk Factors, Epidemiology, medicine, cohort study, Humans, Prospective Studies, Hepatology, Gastroenterology & Hepatology, business.industry, Hazard ratio, Gastroenterology, food and beverages, 1103 Clinical Sciences, Confidence interval, European Prospective Investigation into Cancer and Nutrition, Diet, epidemiology, nutrition, business, Colorectal Neoplasms, Cohort study
Abstract: Background & Aims: Evidence regarding the association of dietary exposures with colorectal cancer (CRC) risk is not consistent with a few exceptions. Therefore, we conducted a diet-wide association study (DWAS) in the European Prospective Investigation into Cancer and Nutrition (EPIC) to evaluate the associations between several dietary exposures with CRC risk. Methods: The association of 92 food and nutrient intakes with CRC risk was assessed in 386,792 participants, 5069 of whom developed incident CRC. Correction for multiple comparisons was performed using the false discovery rate, and emerging associations were examined in the Netherlands Cohort Study (NLCS). Multiplicative gene-nutrient interactions were also tested in EPIC based on known CRC-associated loci. Results: In EPIC, alcohol, liquor/spirits, wine, beer/cider, soft drinks, and pork were positively associated with CRC, whereas milk, cheese, calcium, phosphorus, magnesium, potassium, riboflavin, vitamin B6, beta carotene, fruit, fiber, nonwhite bread, banana, and total protein intakes were inversely associated. Of these 20 associations, 13 were replicated in the NLCS, for which a meta-analysis was performed, namely alcohol (summary hazard ratio [HR] per 1-SD increment in intake: 1.07; 95% confidence interval [CI], 1.04–1.09), liquor/spirits (HR per 1-SD increment in intake, 1.04; 95% CI, 1.02–1.06), wine (HR per 1-SD increment in intake, 1.04; 95% CI, 1.02–1.07), beer/cider (HR per 1-SD increment in intake, 1.06; 95% CI, 1.04–1.08), milk (HR per 1-SD increment in intake, 0.95; 95% CI, 0.93–0.98), cheese (HR per 1-SD increment in intake, 0.96; 95% CI, 0.94–0.99), calcium (HR per 1-SD increment in intake, 0.93; 95% CI, 0.90–0.95), phosphorus (HR per 1-SD increment in intake, 0.92; 95% CI, 0.90–0.95), magnesium (HR per 1-SD increment in intake, 0.95; 95% CI, 0.92–0.98), potassium (HR per 1-SD increment in intake, 0.96; 95% CI, 0.94–0.99), riboflavin (HR per 1-SD increment in intake, 0.94; 95% CI, 0.92–0.97), beta carotene (HR per 1-SD increment in intake, 0.96; 95% CI, 0.93–0.98), and total protein (HR per 1-SD increment in intake, 0.94; 95% CI, 0.92–0.97). None of the gene-nutrient interactions were significant after adjustment for multiple comparisons. Conclusions: Our findings confirm a positive association for alcohol and an inverse association for dairy products and calcium with CRC risk, and also suggest a lower risk at higher dietary intakes of phosphorus, magnesium, potassium, riboflavin, beta carotene, and total protein.
Published: 2020
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295. Cobimetinib plus atezolizumab in BRAFV600 wild-type melanoma: primary results from the randomized phase III IMspire170 study

Author: Daniil Stroyakovskiy, Yu Guo, Isabelle Rooney, P. Francesco Ferrucci, Keith T. Flaherty, Zeynep Eroglu, Jacopo Pigozzo, S. Troutman, Jacek Mackiewicz, S. Mulla, Athina Voulgari, Piotr Rutkowski, Bethany Pitcher, Brigitte Dréno, Lev V. Demidov, J.M.G. Larkin, A. Arance, M. Castro, Helen Gogas, Yibing Yan, National and Kapodistrian University of Athens (NKUA), Centre hospitalier universitaire de Nantes (CHU Nantes), Centre d’Investigation Clinique de Nantes (CIC Nantes), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Royal Marsden NHS Foundation Trust, N.N. Blokhin Russian Cancer Research Center, Moscow City Oncology Hospital No. 62 [Moscow, Russia] (MCOH), H. Lee Moffitt Cancer Center and Research Institute, European Institute of Oncology [Milan] (ESMO), Veneto Institute of Oncology IOV-IRCCS [Padua, Italy], Maria Sklodowska-Curie National Research Institute of Oncology [Krakow, Poland], Poznan University of Medical Sciences [Poland] (PUMS), Genentech, Inc. [San Francisco], Roche Products Ltd, F. Hoffmann-La Roche [Basel], Massachusetts General Hospital Cancer Center [Boston, MA, USA], Harvard Medical School [Boston] (HMS), Hospital Clinic [Barcelona, Spain], and Malbec, Odile
Subjects: 0301 basic medicine, atezolizumab, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Population, Pembrolizumab, Gastroenterology, BRAF wild-type, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Atezolizumab, Interquartile range, Internal medicine, medicine, melanoma, education, Adverse effect, cobimetinib, Cobimetinib, education.field_of_study, business.industry, Hazard ratio, Hematology, Rash, [SDV] Life Sciences [q-bio], 030104 developmental biology, Oncology, chemistry, 030220 oncology & carcinogenesis, pembrolizumab, medicine.symptom, business
Abstract: International audience; Background: Emerging data suggest that the combination of MEK inhibitors and immunotherapeutic agents may result in improved efficacy in melanoma. We evaluated whether combining MEK inhibition and immune checkpoint inhibition was more efficacious than immune checkpoint inhibition alone in patients with previously untreated BRAF V600 wild-type advanced melanoma. Patients and methods: IMspire170 was an international, randomized, open-label, phase III study. Patients were randomized 1 : 1 to receive cobimetinib (60 mg, days 1-21) plus anti-programmed death-ligand 1 atezolizumab (840 mg every 2 weeks) in 28-day cycles or anti-programmed death-1 pembrolizumab (200 mg every 3 weeks) alone until loss of clinical benefit, unacceptable toxicity, or consent withdrawal. The primary outcome was progression-free survival (PFS), assessed by an independent review committee in the intention-to-treat population. Results: Between 11 December 2017, and 29 January 2019, 446 patients were randomized to receive cobimetinib plus atezolizumab (n ¼ 222) or pembrolizumab (n ¼ 224). Median follow-up was 7.1 months [interquartile range (IQR) 4.8-9.9] for cobimetinib plus atezolizumab and 7.2 months (IQR 4.9-10.1) for pembrolizumab. Median PFS was 5.5 months [95% confidence interval (CI) 3.8-7.2] with cobimetinib plus atezolizumab versus 5.7 months (95% CI 3.7-9.6) with pembrolizumab [stratified hazard ratio 1.15 (95% CI 0.88-1.50); P ¼ 0.30]. Hazard ratios for PFS were consistent across prespecified subgroups. In exploratory biomarker analyses, higher tumor mutational burden was associated with improved clinical outcomes in both treatment arms. The most common grade 3-5 adverse events (AEs) were increased blood creatine phosphokinase (10.0% with cobimetinib plus atezolizumab versus 0.9% with pembrolizumab), diarrhea (7.7% versus 1.9%), rash (6.8% versus 0.9%), hypertension (6.4% versus 3.7%), and dermatitis acneiform (5.0% versus 0). Serious AEs occurred in 44.1% of patients with cobimetinib plus atezolizumab and 20.8% with pembrolizumab. Conclusion: Cobimetinib plus atezolizumab did not improve PFS compared with pembrolizumab monotherapy in patients with BRAF V600 wild-type advanced melanoma.
Published: 2020
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296. TGFβ promotes widespread enhancer chromatin opening and operates on genomic regulatory domains

Author: Florian Koehler, Sandra Peiró, María Ceballos-Chávez, José C. Reyes, José A. Guerrero-Martínez, [Guerrero-Martínez,JA, Ceballos-Chávez,M, Reyes,JC] Centro Andaluz de Biología Molecular y Medicina Regenerativa-CABIMER, Consejo Superior de Investigaciones Científicas-Universidad de Sevilla-Universidad Pablo de Olavide (CSIC-USE-UPO), Seville, Spain. [Koehler, F] Division of Epigenetics, DKFZ-ZMBH Alliance, German Cancer Research Center, Heidelberg, Germany. [Koehler, F] Faculty of Biosciences, Heidelberg University, Heidelberg, Germany. [Peiró,S] Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain., This work was funded by the Spanish Ministry of Economy and Competitiveness (BFU2014-53543-P and BFU2017-85420-R to J.C. Reyes), the Junta de Andalucía (BIO-321), 'Fundación Vencer El Cancer' (VEC) and the European Union (FEDER). CABIMER is a Center partially funded by the Junta de Andalucía. S.P was supported by the FERO Foundation, La Caixa Foundation (LCF/PR/PR12/51070001) and Cellex Foundation., Ministerio de Economía y Competitividad (España), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Junta de Andalucía, Fundación Fero, Fundació Privada Cellex, Institut Català de la Salut, [Guerrero-Martínez JA, Ceballos-Chávez M, Reyes JC] Centro Andaluz de Biología Molecular y Medicina Regenerativa-CABIMER, Consejo Superior de Investigaciones Científicas-Universidad de SevillaUniversidad Pablo de Olavide (CSIC-USE-UPO), Avenida Americo Vespucio 24, 41092 Seville, Spain. [Koehler F] Division of Epigenetics, DKFZ-ZMBH Alliance, German Cancer Research Center, Heidelberg, Germany. Faculty of Biosciences, Heidelberg University, Heidelberg, Germany. [Peiró S] Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: 0301 basic medicine, Transcriptional regulatory elements, Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression Regulation [Medical Subject Headings], General Physics and Astronomy, Genome informatics, Anatomy::Cells::Epithelial Cells::HEK293 Cells [Medical Subject Headings], Cromatina, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], Mice, 0302 clinical medicine, Transcription (biology), Transforming Growth Factor beta, Elementos de facilitación genéticos, Organisms::Eukaryota::Animals [Medical Subject Headings], Regulation of gene expression, Gene expression regulation, Multidisciplinary, Genome, fenómenos genéticos::estructuras genéticas::estructuras cromosómicas::cromatina [FENÓMENOS Y PROCESOS], Chromatin, Cell biology, fenómenos genéticos::regulación de la expresión génica [FENÓMENOS Y PROCESOS], Enhancer Elements, Genetic, Multigene Family, MCF-7 Cells, Anatomy::Cells::Cells, Cultured::Cell Line::Cell Line, Tumor::MCF-7 Cells [Medical Subject Headings], Signal transduction, Transcription, Chemicals and Drugs::Biological Factors::Intercellular Signaling Peptides and Proteins::Transforming Growth Factors [Medical Subject Headings], Genetic Phenomena::Genetic Structures::Chromosome Structures::Chromatin [PHENOMENA AND PROCESSES], Science, Factor de crecimiento transformador beta, Biology, General Biochemistry, Genetics and Molecular Biology, Article, Phenomena and Processes::Genetic Phenomena::Genetic Structures::Genome [Medical Subject Headings], 03 medical and health sciences, Regulació genètica, Animals, Humans, RNA, Messenger, Enhancer, Gene, Genoma, Phenomena and Processes::Genetic Phenomena::Genetic Structures::Genome::Genome Components::Genes::Gene Components::Regulatory Elements, Transcriptional::Enhancer Elements, Genetic [Medical Subject Headings], Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Mice [Medical Subject Headings], Anatomy::Cells::Cellular Structures::Intracellular Space::Cell Nucleus::Cell Nucleus Structures::Intranuclear Space::Chromosomes::Chromosome Structures::Chromatin [Medical Subject Headings], HEK 293 cells, General Chemistry, Genetic Phenomena::Gene Expression Regulation [PHENOMENA AND PROCESSES], Chemicals and Drugs::Nucleic Acids, Nucleotides, and Nucleosides::Nucleic Acids::RNA::RNA, Messenger [Medical Subject Headings], 030104 developmental biology, HEK293 Cells, Regulación de la expresión génica, Gene Expression Regulation, Enhancer elements, genetic, Transforming growth factor beta, Phenomena and Processes::Genetic Phenomena::Genetic Structures::Genome::Genome Components::Genes::Multigene Family [Medical Subject Headings], 030217 neurology & neurosurgery, Transforming growth factor
Abstract: The Transforming Growth Factor-β (TGFβ) signaling pathway controls transcription by regulating enhancer activity. How TGFβ-regulated enhancers are selected and what chromatin changes are associated with TGFβ-dependent enhancers regulation are still unclear. Here we report that TGFβ treatment triggers fast and widespread increase in chromatin accessibility in about 80% of the enhancers of normal mouse mammary epithelial-gland cells, irrespective of whether they are activated, repressed or not regulated by TGFβ. This enhancer opening depends on both the canonical and non-canonical TGFβ pathways. Most TGFβ-regulated genes are located around enhancers regulated in the same way, often creating domains of several co-regulated genes that we term TGFβ regulatory domains (TRD). CRISPR-mediated inactivation of enhancers within TRDs impairs TGFβ-dependent regulation of all co-regulated genes, demonstrating that enhancer targeting is more promiscuous than previously anticipated. The area of TRD influence is restricted by topologically associating domains (TADs) borders, causing a bias towards co-regulation within TADs., This work was funded by the Spanish Ministry of Economy and Competitiveness (BFU2014-53543-P and BFU2017-85420-R to J.C. Reyes), the Junta de Andalucía (BIO-321), “Fundación Vencer El Cancer” (VEC) and the European Union (FEDER). CABIMER is a Center partially funded by the Junta de Andalucía. S.P was supported by the FERO Foundation, La Caixa Foundation (LCF/PR/PR12/51070001) and Cellex Foundation.
Published: 2020

297. Correlation of the tumour-stroma ratio with diffusion weighted MRI in rectal cancer

Author: Martin N. J. M. Wasser, Rodrigo Dienstmann, Stéphanie M. Zunder, Paolo Nuciforo, Rob A. E. M. Tollenaar, Alonso Garcia-Ruiz, Wilma E. Mesker, C. Arnoud Meijer, Gabi W. van Pelt, Maria Vittoria Raciti, Raquel Perez-Lopez, Hans Gelderblom, Bente M. de Kok, Institut Català de la Salut, [Zunder SM] Department of Surgery, Leiden University Medical Centre, Albinusdreef 2, 2300 RC, Leiden, The Netherlands. Department of Medical Oncology, Leiden University Medical Centre, Albinusdreef 2, 2300 RC, Leiden, The Netherlands. [Perez-Lopez R, Raciti MV, Garcia-Ruiz A] Radiomics Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [de Kok BM] Department of Radiology, Leiden University Medical Centre, Albinusdreef 2, 2300 RC Leiden, The Netherlands. [van Pelt GW] Department of Surgery, Leiden University Medical Centre, Albinusdreef 2, 2300 RC, Leiden, The Netherlands. [Dienstmann R] Department of Oncology Data Science, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Nuciforo P] Department of Molecular Oncology Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: Colorectal cancer, Rectal neoplasms, Spearman's rank correlation coefficient, 030218 nuclear medicine & medical imaging, Neoplasms::Neoplasms by Site::Digestive System Neoplasms::Gastrointestinal Neoplasms::Intestinal Neoplasms::Colorectal Neoplasms::Rectal Neoplasms [DISEASES], neoplasias::neoplasias por localización::neoplasias del sistema digestivo::neoplasias gastrointestinales::neoplasias intestinales::neoplasias colorrectales::neoplasias del recto [ENFERMEDADES], 03 medical and health sciences, 0302 clinical medicine, Biopsy, Recte - Càncer - Tractament, Investigative Techniques::Epidemiologic Methods::Epidemiologic Research Design::Reproducibility of Results [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], medicine, Tumor Microenvironment, Effective diffusion coefficient, Humans, Radiology, Nuclear Medicine and imaging, Netherlands, Retrospective Studies, Reproducibility, medicine.diagnostic_test, business.industry, Ressonància magnètica, Diagnosis::Diagnostic Techniques and Procedures::Diagnostic Imaging::Tomography::Magnetic Resonance Imaging::Diffusion Magnetic Resonance Imaging [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], Reproducibility of Results, Magnetic resonance imaging, Retrospective cohort study, General Medicine, técnicas de investigación::métodos epidemiológicos::diseño de la investigación epidemiológica::reproducibilidad de los resultados [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], medicine.disease, Magnetic Resonance Imaging, body regions, Diffusion Magnetic Resonance Imaging, Spain, 030220 oncology & carcinogenesis, Avaluació de resultats (Assistència sanitària), diagnóstico::técnicas y procedimientos diagnósticos::diagnóstico por imagen::tomografía::imagen por resonancia magnética::imagen de resonancia magnética de difusión [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], business, Nuclear medicine, Diffusion MRI
Abstract: Imatges per ressonància magnètica; Neoplàsies rectals; Microambient tumoral Imagen de resonancia magnética; Neoplasias rectales; Microambiente tumoral Magnetic Resonance Imaging; Rectal neoplasms; Tumor Microenvironment Objective This study evaluated the correlation between intratumoural stroma proportion, expressed as tumour-stroma ratio (TSR), and apparent diffusion coefficient (ADC) values in patients with rectal cancer. Methods This multicentre retrospective study included all consecutive patients with rectal cancer, diagnostically confirmed by biopsy and MRI. The training cohort (LUMC, Netherlands) included 33 patients and the validation cohort (VHIO, Spain) 69 patients. Two observers measured the mean and minimum ADCs based on single-slice and whole-volume segmentations. The TSR was determined on diagnostic haematoxylin & eosin stained slides of rectal tumour biopsies. The correlation between TSR and ADC was assessed by Spearman correlation ( r s ). Results The ADC values between stroma-low and stroma-high tumours were not significantly different. Intra-class correlation (ICC) demonstrated a good level of agreement for the ADC measurements, ranging from 0.84–0.86 for single slice and 0.86–0.90 for the whole-volume protocol. No correlation was observed between the TSR and ADC values, with ADC mean r s = -0.162 ( p= 0.38) and ADC min r s = 0.041 ( p= 0.82) for the single-slice and r s = -0.108 ( p= 0.55) and r s = 0.019 ( p= 0.92) for the whole-volume measurements in the training cohort, respectively. Results from the validation cohort were consistent; ADC mean r s = -0.022 ( p= 0.86) and ADC min r s = 0.049 ( p= 0.69) for the single-slice and r s = -0.064 ( p= 0.59) and r s = -0.063 ( p= 0.61) for the whole-volume measurements. Conclusions Reproducibility of ADC values is good. Despite positive reports on the correlation between TSR and ADC values in other tumours, this could not be confirmed for rectal cancer. This study received financial support from “ Genootschap Landgoed Keukenhof .” Author R.P.L.’s work is supported by a PCF-Young Investigator Award . The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
Published: 2020

298. Trastuzumab Emtansine Plus Non-Pegylated Liposomal Doxorubicin in HER2-Positive Metastatic Breast Cancer (Thelma): A Single-Arm, Multicenter, Phase Ib Trial

Author: Andrea Malfettone, Miguel Sampayo-Cordero, Joseph Gligorov, Simona Borštnar, Santiago Escrivá-de-Romaní, Serena Di Cosimo, Thomas M. Suter, Javier Cortes, Etienne Brain, Jose Perez-Garcia, Laura Calabuig, Maria Vidal, Maja Ravnik, Antonio Llombart-Cussac, Elena López-Miranda, Institut Català de la Salut, [López-Miranda E] Department of Medical Oncology, Hospital Universitario Ramón y Cajal, Madrid, Spain. Medical Department, Medica Scientia Innovation Research (MedSIR), Ridgewood, NJ, USA. Medical Department, Medica Scientia Innovation Research (MedSIR), Barcelona, Spain. [Pérez-García JM] Medical Department, Medica Scientia Innovation Research (MedSIR), Ridgewood, NJ, USA. Medical Department, Medica Scientia Innovation Research (MedSIR), Barcelona, Spain. International Breast Cancer Center (IBCC), Quiron Group, Medical Oncology Department, Barcelona, Spain. [Di Cosimo S] Medical Department, Medica Scientia Innovation Research (MedSIR), Ridgewood, NJ, USA. Medical Department, Medica Scientia Innovation Research (MedSIR), 08018 Barcelona, Spain. Biomarkers Unit, Department of Applied Research and Technological Development, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy. [Brain E] Department of Medical Oncology, Institut Curie, St. Cloud, France. [Ravnik M] Department of Oncology, University Medical Centre Maribor, Maribor, Slovenia. [Escrivá-de-Romaní S] Servei d’Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Cortés J] Medical Department, Medica Scientia Innovation Research (MedSIR), Ridgewood, NJ, USA. Medical Department, Medica Scientia Innovation Research (MedSIR), Barcelona, Spain. International Breast Cancer Center (IBCC), Quiron Group, Medical Oncology Department, Barcelona, Spain. Servei d’Oncologia Mèdica, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: 0301 basic medicine, Cardiac function curve, Oncology, musculoskeletal diseases, Cancer Research, medicine.medical_specialty, Liposomal Doxorubicin, T-DM1, Neoplasms::Neoplasms by Site::Breast Neoplasms [DISEASES], Otros calificadores::Otros calificadores::/efectos adversos [Otros calificadores], lcsh:RC254-282, Article, Pegylated Liposomal Doxorubicin, Càncer de mama, Metastasis, Medicaments antineoplàstics - Efectes secundaris, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Breast cancer, Pharmacokinetics, Mama - Càncer, Metàstasi, Trastuzumab, Internal medicine, Therapeutics::Therapeutics::Drug Therapy::Antineoplastic Protocols::Therapeutics::Drug Therapy::Antineoplastic Combined Chemotherapy Protocols [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], Other subheadings::Other subheadings::/adverse effects [Other subheadings], Medicine, skin and connective tissue diseases, neoplasms, trastuzumab emtansine, neoplasias::neoplasias por localización::neoplasias de la mama [ENFERMEDADES], business.industry, terapéutica::terapéutica::farmacoterapia::protocolos antineoplásicos::terapéutica::farmacoterapia::protocolos de quimioterapia antineoplásica combinada [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], medicine.disease, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Metastatic breast cancer, HER2-positive, 030104 developmental biology, chemistry, Trastuzumab emtansine, 030220 oncology & carcinogenesis, Maximum tolerated dose, metastatic breast cancer, business, medicine.drug, non-pegylated liposomal doxorubicin
Abstract: The paper assesses the dose-limiting toxicities and the maximum tolerated dose (MTD) of trastuzumab emtansine (T-DM1) combined with non-pegylated liposomal doxorubicin (NPLD) in HER2-positive (HER2+) metastatic breast cancer (MBC). This single-arm, open-label, phase Ib trial (NCT02562378) enrolled anthracycline-na&iuml, ve HER2+ MBC patients who had progressed on trastuzumab and taxanes. Patients received a maximum of 6 cycles of NPLD intravenously (IV) at various dose levels (45, 50, and 60 mg/m2) in the &ldquo, 3 plus 3&rdquo, dose-escalation part. During expansion, they received 60 mg/m2 of NPLD every 3 weeks (Q3W) plus standard doses of T-DM1. The MTD was T-DM1 3.6 mg/kg plus NPLD 60 mg/m2 administered IV Q3W. No clinically relevant worsening of cardiac function was observed. Among all evaluable patients, the overall response rate was 40.0% (95%CI, 16.3&ndash, 67.7) with a median duration of response of 6.9 months (95%CI, 4.8&ndash, 9.1). Clinical benefit rate was 66.7% (95%CI, 38.4&ndash, 88.2) and median progression-free survival was 7.2 months (95%CI, 4.5&ndash, 9.6). No significant influence of NPLD on T-DM1 pharmacokinetics was observed. The addition of NPLD to T-DM1 is feasible but does not seem to improve the antitumor efficacy of T-DM1 in HER2+ MBC patients.
Published: 2020

299. Phase 2 study of buparlisib (BKM120), a pan-class I PI3K inhibitor, in patients with metastatic triple-negative breast cancer

Author: Yisheng Li, Violeta Serra, Lewis C. Cantley, Begoña Bermejo, Ana C. Garrido-Castro, Gordon B. Mills, Patricia Villagrasa, Ian E. Krop, Nan Lin, Zhan Xu, Aleix Prat, Cristina Saura, Hao Guo, Eva Ciruelos, Romualdo Barroso-Sousa, Carlos L. Arteaga, David B. Solit, Laia Paré, Eric P. Winer, Joaquín Gavilá, Jennifer Savoie, Pamela Céliz, Jordi Rodon, Institut Català de la Salut, [Garrido-Castro AC] Department of Medical Oncology, Susan F. Smith Center for Women’s Cancers, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston, MA 02215, USA. [Saura C] Servei d’Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. SOLTI Breast Cancer Research Group, Barcelona, Spain. [Barroso-Sousa R] Department of Medical Oncology, Susan F. Smith Center for Women’s Cancers, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston, MA 02215, USA. Hospital Sírio-Libanês, Brasilia, Brazil. [Guo H] Division of Biostatistics, Department of Data Sciences, Dana-Farber Cancer Institute, Boston, MA, USA. [Ciruelos E] Hospital 12 de Octubre, Madrid, Spain. [Bermejo B] Clinic University Hospital, INCLIVA Biomedical Research Institute, CIBERONC-ISCIII, Valencia, Spain. [Serra V] Experimental Therapeutics Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Rodon J] Servei d’Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. SOLTI Breast Cancer Research Group, Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: Oncology, Proteomics, Buparlisib, Phases of clinical research, Aminopyridines, Medicaments antineoplàstics - Ús terapèutic, Triple Negative Breast Neoplasms, Other subheadings::Other subheadings::/drug therapy [Other subheadings], chemistry.chemical_compound, 0302 clinical medicine, Mama - Càncer, Antineoplastic Combined Chemotherapy Protocols, Clinical endpoint, Medicine, Neoplasm Metastasis, Triple-negative breast cancer, 0303 health sciences, Neoplasms::Neoplastic Processes::Neoplasm Metastasis [DISEASES], High-Throughput Nucleotide Sequencing, Middle Aged, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Metastatic breast cancer, Survival Rate, Treatment Outcome, 030220 oncology & carcinogenesis, Neoplasms::Neoplasms by Site::Breast Neoplasms::Triple Negative Breast Neoplasms [DISEASES], Disease Progression, Female, Patient Safety, Research Article, Adult, medicine.medical_specialty, Class I Phosphatidylinositol 3-Kinases, Morpholines, Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores], Phase 1, lcsh:RC254-282, 03 medical and health sciences, Breast cancer, Metàstasi, Internal medicine, Humans, Adverse effect, Protein Kinase Inhibitors, Response Evaluation Criteria in Solid Tumors, 030304 developmental biology, Aged, business.industry, medicine.disease, BKM120, neoplasias::neoplasias por localización::neoplasias de la mama::neoplasias de mama triple negativos [ENFERMEDADES], PI3K pathway, chemistry, neoplasias::procesos neoplásicos::metástasis neoplásica [ENFERMEDADES], business, Progressive disease
Abstract: BackgroundTreatment options for triple-negative breast cancer remain limited. Activation of the PI3K pathway via loss ofPTENand/orINPP4Bis common. Buparlisib is an orally bioavailable, pan-class I PI3K inhibitor. We evaluated the safety and efficacy of buparlisib in patients with metastatic triple-negative breast cancer.MethodsThis was a single-arm phase 2 study enrolling patients with triple-negative metastatic breast cancer. Patients were treated with buparlisib at a starting dose of 100 mg daily. The primary endpoint was clinical benefit, defined as confirmed complete response (CR), partial response (PR), or stable disease (SD) for ≥ 4 months, per RECIST 1.1. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and toxicity. A subset of patients underwent pre- and on-treatment tumor tissue biopsies for correlative studies.ResultsFifty patients were enrolled. Median number of cycles was 2 (range 1–10). The clinical benefit rate was 12% (6 patients, all SD ≥ 4 months). Median PFS was 1.8 months (95% confidence interval [CI] 1.6–2.3). Median OS was 11.2 months (95% CI 6.2–25). The most frequent adverse events were fatigue (58% all grades, 8% grade 3), nausea (34% all grades, none grade 3), hyperglycemia (34% all grades, 4% grade 3), and anorexia (30% all grades, 2% grade 3). Eighteen percent of patients experienced depression (12% grade 1, 6% grade 2) and anxiety (10% grade 1, 8% grade 2). Alterations inPIK3CA/AKT1/PTENwere present in 6/27 patients with available targeted DNA sequencing (MSK-IMPACT), 3 of whom achieved SD as best overall response though none with clinical benefit ≥ 4 months. Of five patients with paired baseline and on-treatment biopsies, reverse phase protein arrays (RPPA) analysis demonstrated reduction of S6 phosphorylation in 2 of 3 patients who achieved SD, and in none of the patients with progressive disease.ConclusionsBuparlisib was associated with prolonged SD in a very small subset of patients with triple-negative breast cancer; however, no confirmed objective responses were observed. Downmodulation of key nodes in the PI3K pathway was observed in patients who achieved SD. PI3K pathway inhibition alone may be insufficient as a therapeutic strategy for triple-negative breast cancer.Trial registrationNCT01790932. Registered on 13 February 2013;NCT01629615. Registered on 27 June 2012.
Published: 2020

300. Inclusion of non-inferiority analysis in superiority-based clinical trials with single-arm, two-stage Simon's design

Author: Sampayo-Cordero, Miguel, Miguel-Huguet, Bernat, Pérez-García, José, Páez, David, Guerrero-Zotano, Ángel L., Garde-Noguera, Javier, Aguirre, Elena, Holgado, Esther, López-Miranda, Elena, Huang, Xin, Malfettone, Andrea, Llombart-Cussac, Antonio, Cortés, Javier, Universitat Autònoma de Barcelona, Institut Català de la Salut, [Sampayo-Cordero M] Medica Scientia Innovation Research (MedSIR), Barcelona, Spain. Medica Scientia Innovation Research (MedSIR), Ridgewood, NJ, USA. [Miguel-Huguet B] Hospital Universitari de Bellvitge, L’Hospitalet, Barcelona, Spain. [Pérez-García J] Medica Scientia Innovation Research (MedSIR), Barcelona, Spain. IOB, Institute of Oncology, QuironSalud Group, Barcelona and Madrid, Spain. [Páez D] Medica Scientia Innovation Research (MedSIR), Barcelona, Spain. Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. Universitat Autònoma de Barcelona (UAB), Bellaterra, Spain. [Guerrero-Zotano ÁL] Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA. [Garde-Noguera J] Hospital Arnau de Vilanova, Valencia, Spain. [Cortés J] IOB, Institute of Oncology, QuironSalud Group, Barcelona and Madrid, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Medica Scientia Innovation Research (MedSIR), Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: técnicas de investigación::métodos::diseño de la investigación [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Group sequential designs, Other subheadings::/methods [Other subheadings], Monte Carlo method, Two-stage, Stochastic ordering, Article, Non-inferiority, neoplasias [ENFERMEDADES], 03 medical and health sciences, 0302 clinical medicine, Non inferiority, Minimum-variance unbiased estimator, Investigative Techniques::Epidemiologic Methods::Epidemiologic Study Characteristics::Clinical Studies as Topic::Clinical Trials as Topic::Clinical Trials, Phase II as Topic [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], Otros calificadores::/métodos [Otros calificadores], Statistics, Investigative Techniques::Methods::Research Design [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], técnicas de investigación::métodos epidemiológicos::características de los estudios epidemiológicos::estudios clínicos como asunto::ensayos clínicos como asunto::ensayos clínicos en fase II como asunto [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], 030212 general & internal medicine, Mathematics, Pharmacology, lcsh:R5-920, Càncer - Tractament, General Medicine, Phase II, Clinical trial, Single-arm, Neoplasms [DISEASES], Switching to non-inferiority, Medicina - Investigació, Early phase, lcsh:Medicine (General), 030217 neurology & neurosurgery, Response probability, Type I and type II errors, Assaigs clínics
Abstract: Introduction Non-inferiority (NI) analysis is not usually considered in the early phases of clinical development. In some negative phase II trials, a post-hoc NI analysis justified additional phase III trials that were successful. However, the risk of false positive achievements was not controlled in these early phase analyses. We propose to preplan NI analyses in superiority-based Simon's two-stage designs to control type I and II error rates. Methods Simulations have been proposed to assess the control of type I and II errors rates with this method. A total of 12,768 two-stage Simon's design trials were constructed based on different assumptions of rejection response probability, desired response probability, type I and II errors, and NI margins. P-value and type II error were calculated with stochastic ordering using Uniformly Minimum Variance Unbiased Estimator. Type I and II errors were simulated using the Monte Carlo method. The agreement between calculated and simulated values was analyzed with Bland-Altman plots. Results We observed the same level of agreement between calculated and simulated type I and II errors from both two-stage Simon's superiority designs and designs in which NI analysis was allowed. Different examples has been proposed to explain the utility of this method. Conclusion Inclusion of NI analysis in superiority-based single-arm clinical trials may be useful for weighing additional factors such as safety, pharmacokinetics, pharmacodynamic, and biomarker data while assessing early efficacy. Implementation of this strategy can be achieved through simple adaptations to existing designs for one-arm phase II clinical trials., Highlights • Inclusion of non-inferiority analysis in single-arm trials is useful for weighing activity with safety and other data. • This strategy has been previously used in proof-of-concept studies to design successful randomized phase III trials. • However, it was a post-hoc analysis to deal with negative findings in phase II trials. So, the type I error was inflated. • We propose to plan the non-inferiority analysis in the study protocol to control false positive findings. • It can be made through simple adaptations to the Simon's two-stage design and other existing designs for single-arm trials.
Published: 2020

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