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1. Determining PD-L1 Status in Patients With Triple-Negative Breast Cancer: Lessons Learned From IMpassion130

Author

Jary, Marine, Liu, Wen-Wei, Yan, Dongyao, Bai, Isaac, Muranyi, Andrea, Colle, Elise, Brocheriou, Isabelle, Turpin, Anthony, Radosevic-Robin, Nina, Bourgoin, Pierre, Penault-Llorca, Frédérique, Cohen, Romain, Vernerey, Dewi, André, Thierry, Borg, Christophe, Shanmugam, Kandavel, Svrcek, Magali, Liu, Wen‐wei, Cooperator Multidisciplinary Oncology Group (GERCOR), CHU Clermont-Ferrand, Ventana Medical Systems, Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service d'oncologie médicale (CHRU Lille), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), CHU Saint-Antoine [AP-HP], Service d'Oncologie Médicale [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC)-Université de Franche-Comté (UFC), Breast Cancer Translational Research Laboratory, Institut Jules Bordet [Bruxelles], Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB)-Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Translational Cancer Research Unit [Antwerp], Philipps Universität Marburg = Philipps University of Marburg, Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Division of Pathology and Laboratory Medicine, Università degli Studi di Milano = University of Milan (UNIMI)-European Institute of Oncology [Milan] (ESMO), University of the Sunshine Coast (USC), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Department of Pathology, Aberdeen University Medical School, Hospital Universitario Ramón y Cajal [Madrid], Universidad de Alcalá - University of Alcalá (UAH), VU Medical Center, Cell Biology and Biotherapy Unit, INT-Fondazione Pascale, Department of Oncology and Metabolism [Sheffield, UK], The University of Sheffield [Sheffield, U.K.], Institute for Surgical Pathology, University hospital of Zurich [Zurich], Service de pathologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Pathologie [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), Service d'Oncologie Médicale [CHU Saint -Antoine], Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté]), Service d'Anatomie et cytologie pathologiques = Service de Pathologie [CHU Pitié-Salpêtrière] (ACP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service d'Oncologie Médicale [CHU Saint-Antoine], HAL-SU, Gestionnaire, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), 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), and Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)

Subjects
Cancer Research, Biopsy, Best practice, BluePrint 80-gene signature, Predictive, DNA Mismatch Repair, pMMR, B7-H1 Antigen, Cohort Studies, Breast cancer, MESH: Tumor Microenvironment, Tumor Microenvironment, MESH: B7-H1 Antigen, Prospective Studies, MESH: Lymphocytes, Tumor-Infiltrating, MESH: Cohort Studies, Oligometastatic colorectal cancer, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, high/low risk, immune profile, General Medicine, Immunohistochemistry, External quality assessment, 3. Good health, MESH: DNA Mismatch Repair, Oncology, Cytological techniques, Colonic Neoplasms, Molecular Medicine, HER2-low, Colorectal Neoplasms, PD-L1, Histology, Serum proteins, T lymphocytes, [SDV.CAN]Life Sciences [q-bio]/Cancer, Prognostic, Non-small cell lung carcinoma, Lymphocytes, Tumor-Infiltrating, Molecular diagnostics, Genetics, Humans, early breast cancer, MESH: Colonic Neoplasms, MESH: Humans, Liquid biopsy, gene expression profiles, MammaPrint 70-gene signature, Plasma proteins, Biomarker, MESH: Prospective Studies, digestive system diseases, Next-generation sequencing, Trastuzumab-deruxtecan, MESH: Tissue Fixation, hallmarks of cancer, MESH: Colorectal Neoplasms, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; In the era of immune checkpoint inhibitors, understanding the metastatic microenvironment of proficient mismatch repair/microsatellite stable (pMMR/MSS) colorectal cancer (CRC) is of paramount importance to both prognostication and the development of more effective novel therapies. In this study, primary and paired metastasis tissue samples were collected from patients with resectable metastatic CRC treated with adjuvant FOLFOX or peri-operative chemotherapy in the MIROX phase III prospective study. In total, 74 cancer tissues were stained for CD3, CD8, Forkhead box protein 3 (FOXP3), programmed cell death protein-1 (PD-1, invasive front, stromal, intra-epithelial compartments), and programmed death-ligand 1 (PD-L1, tumor, immune cells). The immune profiling of primary CRC had a limited value to predict the immune context of paired metastases for all markers but CD3+. The expression of CD8 and PD-L1 was higher in metastases after neoadjuvant FOLFOX. In metastases, both CD3 T cells at the invasive front and PD-L1 expressions on immune cells were predictive of better disease-free survival. These results show that the effect of FOLFOX on modifying the immune microenvironment in resected CRC metastases and measurement of PD-L1 expression and tumor-infiltrating CD8 T cells in pMMR/MSS metastatic tissue samples could improve treatment strategies of metastatic CRC patients.

Published
2022
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2. 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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3. Immune Checkpoint Inhibition in Metastatic Colorectal Cancer Harboring Microsatellite Instability or Mismatch Repair Deficiency

Author

Maximilien Heran, Romain Cohen, Magali Svrcek, Alex Duval, Thierry André, Raphael Colle, Thomas Pudlarz, 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), 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), Instabilité des microsatellites et cancers [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)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), Service de Pathologie [CHU Saint-Antoine], Gestionnaire, Hal Sorbonne Université, Service d'Oncologie Médicale [CHU Saint-Antoine], CHU Saint-Antoine [AP-HP], 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), Instabilité des microsatellites et cancers [CRSA], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)

Subjects
0301 basic medicine, Cancer Research, deficient mismatch repair, Colorectal cancer, medicine.medical_treatment, [SDV]Life Sciences [q-bio], colorectal cancer, Review, lcsh:RC254-282, 03 medical and health sciences, 0302 clinical medicine, medicine, neoplasms, business.industry, Microsatellite instability, Immunotherapy, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, Phenotype, Immune checkpoint, Lynch syndrome, digestive system diseases, 3. Good health, [SDV] Life Sciences [q-bio], 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Cancer research, MISMATCH REPAIR DEFICIENCY, microsatellite instability, DNA mismatch repair, immunotherapy, business
Abstract

Simple Summary Microsatellite instability (MSI) is a molecular indicator of defective DNA mismatch repair (dMMR). MSI/dMMR status is observed in approximately 5% of metastatic colorectal cancers (mCRC) but 10–18% of localized colorectal cancers. MSI/dMMR status is a major predictive biomarker for the efficacy of immune checkpoint inhibitors (ICIs). This review presents the current and future challenges of ICIs for patients with MSI/dMMR colorectal cancer. Abstract Microsatellite instability (MSI) is a tumor phenotype related to a deficient DNA mismatch repair system (dMMR). This phenotype, observed in 5% of metastatic mCRC but 10–18% of localized CRC, is associated with high tumor mutational burden with highly immunogenic neoantigens. It has emerged as a major predictive biomarker for the efficacy of ICIs. In this review, we will present a comprehensive overview of the literature concerning the efficacy of ICIs in MSI/dMMR mCRC, with a focus on new developments in first-line metastatic setting. Then, we will present current and future challenges of immuno-oncology for patients with MSI/dMMR metastatic CRC.

Published
2021
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4. FOLFIRINEC: a randomized phase II trial of mFOLFIRINOX vs platinum-etoposide for metastatic neuroendocrine carcinoma of gastroenteropancreatic or unknown origin

Author

Véronique Lorgis, Eric Baudin, Romain Desgrippes, Frédéric Thuillier, Jean-Yves Scoazec, Côme Lepage, Pauline Afchain, Thomas Walter, David Tougeron, Carole Monterymard, Vincent Hautefeuille, Julien Hadoux, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR), 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), Hospices Civils de Lyon (HCL), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Service d'Hépato Gastroenterologie [CHU Amiens-Picardie], CHU Amiens-Picardie, Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Service d'Oncologie médicale [CHU Limoges], CHU Limoges, Département de biologie et pathologie médicales [Gustave Roussy], CH de Saint-Malo [Broussais], Service d'Oncologie Médicale [CHU Saint-Antoine], 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), and Gestionnaire, HAL Sorbonne Université 5

Subjects
Oncology, Male, FOLFIRINOX, medicine.medical_treatment, Leucovorin, Phases of clinical research, Platinum Compounds, 0302 clinical medicine, Antineoplastic Combined Chemotherapy Protocols, Prospective Studies, Neoplasm Metastasis, Etoposide, Gastroenterology, Evaluable Disease, Progression-Free Survival, 3. Good health, Oxaliplatin, Survival Rate, Neuroendocrine Tumors, Treatment Outcome, 030220 oncology & carcinogenesis, Neuroendocrine carcinoma, 030211 gastroenterology & hepatology, Female, Fluorouracil, medicine.drug, Adult, medicine.medical_specialty, Irinotecan, Gastroenteropancreatic, 03 medical and health sciences, Stomach Neoplasms, Internal medicine, Intestinal Neoplasms, medicine, Chemotherapy, Humans, Contraindication, Hepatology, Performance status, business.industry, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Carcinoma, Neuroendocrine, Pancreatic Neoplasms, Regimen, Quality of Life, Neoplasms, Unknown Primary, business, Biomarkers
Abstract

Background Poorly differentiated neuroendocrine carcinomas (NEC) are rare diseases with a poor prognosis. Platinum-etoposide (PE) has been the recommended first-line treatment for decades. FOLFIRINEC (NCT04325425) is a national multicenter randomized phase II study which aims to challenge this standard regimen. Methods The primary objective is to compare the median progression-free survival (PFS) under mFOLFIRINOX versus PE. The secondary objectives are to evaluate the objective response rates (ORR), median overall survival (OS), safety and quality of life. The associated real-time translational study will establish a molecular profile for each patient enrolled. Main inclusion criteria are NEC of gastroenteropancreatic (GEP) or unknown origin, metastatic and RECIST 1.1 evaluable disease, tumor sample available and no contraindication to chemotherapy. Patients will be randomized 1:1 between PE every 21 days for 6–8 cycles and mFOLFIRINOX every 14 days for up to 12 cycles and stratified according to center, performance status, Ki67 and pathological subtype. This trial will randomize 218 patients (24 months of follow-up) to have 80% power to detect an improvement of the median PFS from 5 months under PE to 7.5 months under mFOLFIRINOX (HR of 0.67, α =5%, two-sided). An intermediate analysis is planned at 50% of events. Recruitment started on October 20, 2020.

Published
2021
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5. Pseudoprogression in patients treated with immune checkpoint inhibitors for microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer

Author

Anna Pellat, Daniel Lopez-Tabada, Raphael Colle, Marine Cachanado, Alex Duval, Yves Menu, Magali Svrcek, Anna Radzik, Thierry André, Romain Cohen, 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), Unité de Recherche Clinique de l’Est Parisien [CHU Saint-Antoine] (URC-EST), Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts (CHNO)-CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Rothschild [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Radiologie [CHU Saint-Antoine], 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), Service de Pathologie [CHU Saint-Antoine], CCSD, Accord Elsevier, Service d'Oncologie Médicale [CHU Saint-Antoine], 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)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Direction de la Recherche Clinique et de l'Innovation [AP-HP] (DRCI), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Recherche Saint-Antoine (CRSA), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)

Subjects
0301 basic medicine, Oncology, Male, Cancer Research, medicine.medical_specialty, Drug-Related Side Effects and Adverse Reactions, Colorectal cancer, Immune checkpoint inhibitors, [SDV]Life Sciences [q-bio], Population, DNA Mismatch Repair, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Medicine, Humans, Neoplasm Metastasis, education, Pseudoprogression, Immune Checkpoint Inhibitors, Response Evaluation Criteria in Solid Tumors, Aged, Retrospective Studies, education.field_of_study, business.industry, Incidence (epidemiology), Microsatellite instability, Middle Aged, medicine.disease, Prognosis, Confidence interval, 3. Good health, Survival Rate, [SDV] Life Sciences [q-bio], 030104 developmental biology, 030220 oncology & carcinogenesis, Disease Progression, DNA mismatch repair, Female, Microsatellite Instability, business, Colorectal Neoplasms, Follow-Up Studies
Abstract

Background The efficacy of immune checkpoint inhibitors (ICIs) in microsatellite instability-high/DNA mismatch repair (MSI/dMMR) metastatic colorectal cancer (mCRC) is well established. ICIs are responsible for pseudoprogression (PSPD) that complicates clinical decisions. We evaluated the PSPD frequency in patients with MSI/dMMR mCRC treated with ICIs. Patients and methods Consecutive patients with MSI/dMMR mCRC treated with ICIs from February 2015 to December 2019 at Saint-Antoine Hospital were included. Imaging was retrospectively and centrally reviewed according to Response Evaluation Criteria in Solid Tumours, version 1.1 (RECIST 1.1) and immune RECIST (iRECIST). PSPD was defined as an unconfirmed disease progression by iRECIST. Results One hundred twenty-three patients with MSI/dMMR mCRC were included. Thirty-six patients (29%) had radiological PD according to RECIST 1.1 during the median follow-up of 22.3 months (95% confidence interval [CI], 1.5–62.2), including 22 in the first 3 months (the primary radiological PD). Twenty-nine patients continued ICIs beyond PD. Twelve patients experienced PSPD, representing 10% of the population and 52% of the primary radiological PD. The median time to PSPD was 5.7 weeks (95% CI, 4.1–11.4). No PSPD was observed after 3 months. The PSPD incidence was 14.8% in patients treated with anti-PD1 alone (n = 9/61) and 4.8% in case of anti-PD1 plus anti-CTLA-4 (n = 3/62). Eight patients with PSPD experienced an objective response. The 2-year progression-free survival and overall survival rates for patients with PSPD were 70.0% (95% CI, 32.9–89.2) and 75.0% (95% CI, 29.8–93.4), respectively. Conclusion Patients with MSI/dMMR mCRC treated with ICIs experienced PSPDs. PSPD occurred within the first 3 months and represented most of the primary radiological PDs. The use of iRECIST criteria should be questioned after 3 months.

Published
2021
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6. Adrenal gland as a sanctuary site for immunotherapy in patients with microsatellite instability-high metastatic colorectal cancer

Author

Magali Svrcek, Quentin Letourneur, Toky Ratovomanana, Adrien Buisson, Anna Pellat, François Paye, Lucile Armenoult, Christelle De La Fouchardiere, Thierry André, Romain Cohen, Alex Duval, Mira Ayadi, Matthieu Sarabi, Vincent Jonchère, Pierre Meeus, Raphael Colle, Gestionnaire, HAL Sorbonne Université 5, Service d'Oncologie Médicale [CHU Saint-Antoine], 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), 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), Centre Léon Bérard [Lyon], (le programme) Cartes d'identité des tumeurs (CIT), Ligue Nationales Contre le Cancer (LNCC), Service de chirurgie générale et digestive [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), Service d'Oncologie Médicale [CHU Saint -Antoine], Centre de Recherche Saint-Antoine (CR Saint-Antoine), and Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP]

Subjects
Male, 0301 basic medicine, Cancer Research, Colorectal cancer, medicine.medical_treatment, Adrenal Gland Neoplasms, Case Report, Metastasis, 0302 clinical medicine, Tumor Microenvironment, Immunology and Allergy, Immune Checkpoint Inhibitors, RC254-282, Adrenal gland, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Adrenalectomy, Middle Aged, 3. Good health, 2518 1619, genome Instability, Treatment Outcome, medicine.anatomical_structure, Oncology, Response Evaluation Criteria in Solid Tumors, 030220 oncology & carcinogenesis, Disease Progression, Molecular Medicine, Microsatellite Instability, immunotherapy, Colorectal Neoplasms, hormones, hormone substitutes, and hormone antagonists, Adult, tumor, Immunology, [SDV.CAN]Life Sciences [q-bio]/Cancer, Radiosurgery, gastrointestinal neoplasms, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, medicine, Humans, Aged, Pharmacology, business.industry, biomarkers, Cancer, Microsatellite instability, medicine.disease, 030104 developmental biology, Drug Resistance, Neoplasm, Cancer research, business, Progressive disease, Transcription Factors
Abstract

Metastatic colorectal cancers (mCRC) harboring microsatellite instability (MSI) are sensitive to immune checkpoint inhibitors (ICIs), but the mechanisms of resistance to ICIs remain unclear. Dissociated responses in patients with ICI-treated cancer suggest that certain organs may serve as sanctuary sites due to the tumor microenvironment. This case series describes five patients with ICI-treated MSI mCRC with disease progression limited to the adrenal glands. At ICI initiation, three patients were free of metastasis in the adrenal glands. Four patients experienced objective response per RECIST (Response Evaluation Criteria in Solid Tumors) while treated with ICI. ICI treatment was discontinued due to progressive disease limited to the adrenal glands (n=3) or toxicity (n=2). The time between ICI initiation and progression in the adrenal glands ranged from 11 to 39 months. Adrenalectomy (n=3) and stereotactic body radiation therapy (n=2) were performed. At the last follow-up, all patients were alive and progression free. Molecular analyses were performed in one patient. A significant impairment of the antigen presentation pathway was observed in the ICI-resistant lesion of the adrenal gland, which could be explained by the presence of glucocorticoids in the adrenal gland microenvironment. We also detected an overexpression of TSC22D3, a glucocorticoid-target gene that functions as a mediator of anti-inflammation and immunosuppression. This case series suggests that the adrenal glands may be the sanctuary sites for ICI-treated MSI mCRC through the glucocorticoid-induced impairment of the antigen presentation machinery.

Published
2021
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7. Combining tumor deposits with the number of lymph node metastases to improve the prognostic accuracy in stage III colon cancer: a post hoc analysis of the CALGB/SWOG 80702 phase III study (Alliance)

Author

Jeffrey P. Meyers, Magali Svrcek, Romain Cohen, Pankaj Kumar, Monica M. Bertagnolli, Kristen K. Ciombor, Eileen M. O'Reilly, Johanna C. Bendell, Jeffrey A. Meyerhardt, Charles D. Blanke, DeQuincy Andrew Lewis, Charles S. Fuchs, Anthony F. Shields, Félix Couture, P. Kuebler, Philip A. Philip, A. De Jesus-Acosta, Benjamin R. Tan, Q. Shi, Zhaohui Jin, 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), Mayo Clinic [Rochester], 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), Service de Pathologie [CHU Saint-Antoine], Yale University School of Medicine, Genentech, Inc., Genentech, Inc. [San Francisco], L'hôtel-Dieu de Québec [CHU Québec] (HDQ), CHU de Québec–Université Laval, Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval), Columbus Community Clinical Oncology Program [Columbus, OH, USA] (CCOP), Vanderbilt University [Nashville], Sarah Cannon Research Institute [Nashville, Tennessee], Johns Hopkins University (JHU), Illinois Cancercare, P.C. [Peoria, IL, USA] (IC), Cone Health Medical Group HeartCare [Asheboro, NC, USA] (CHMGH), Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), Brigham & Women’s Hospital [Boston] (BWH), Harvard Medical School [Boston] (HMS), Wayne State University School of Medicine, Oregon Health and Science University [Portland] (OHSU), Weill Medical College of Cornell University [New York], Dana-Farber Cancer Institute [Boston], Service d'Oncologie Médicale [CHU Saint-Antoine], CHU Saint-Antoine [AP-HP], 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), Yale School of Medicine [New Haven, Connecticut] (YSM), and HAL-SU, Gestionnaire

Subjects
Oncology, medicine.medical_specialty, Colorectal cancer, Lymphovascular invasion, stage III, Perineural invasion, tumor deposit, colorectal cancer, [SDV.CAN]Life Sciences [q-bio]/Cancer, Article, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, adjuvant, Internal medicine, Post-hoc analysis, medicine, Humans, 030212 general & internal medicine, Stage (cooking), Lymph node, Neoplasm Staging, Retrospective Studies, Extranodal Extension, business.industry, Proportional hazards model, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Hematology, medicine.disease, Lymphovascular, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, 3. Good health, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Lymphatic Metastasis, Colonic Neoplasms, Lymph Nodes, prognosis, business
Abstract

International audience; Background: In colon cancer, tumor deposits (TD) are considered in assigning prognosis and staging only in the absence of lymph node metastasis (i.e. stage III pN1c tumors). We aimed to evaluate the prognostic value of the presence and the number of TD in patients with stage III, node-positive colon cancer.Patients and methods: All participants from the CALGB/SWOG 80702 phase III trial were included in this post hoc analysis. Pathology reports were reviewed for the presence and the number of TD, lymphovascular and perineural invasion. Associations with disease-free survival (DFS) and overall survival (OS) were evaluated by multivariable Cox models adjusting for sex, treatment arm, T-stage, N-stage, lymphovascular invasion, perineural invasion and lymph node ratio.Results: Overall, 2028 patients were included with 524 (26%) TD-positive and 1504 (74%) TD-negative tumors. Of the TD-positive patients, 80 (15.4%) were node negative (i.e. pN1c), 239 (46.1%) were pN1a/b (

Published
2021
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8. Monitoring levels of circulating cell‐free DNA in patients with metastatic colorectal cancer as a potential biomarker of responses to regorafenib treatment

Author

Dewi Vernerey, Thierry André, Isabelle Trouilloud, Brice Pastor, Thibault Mazard, A.R. Thierry, Cynthia Sanchez, Audrey Bauer, Benoit Roch, Christophe Louvet, Marine Jary, Simon Azan, Christophe Tournigand, Antoine Adenis, Julie Henriques, Gestionnaire, Hal Sorbonne Université, Institut du Cancer de Montpellier (ICM), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Service d'Oncologie Médicale [CHU Saint-Antoine], 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), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), Cooperator Multidisciplinary Oncology Group (GERCOR), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), CHU Henri Mondor, Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté]), Institut mutualiste Monsouris (IMM), 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), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Franche-Comté (UFC), and Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])

Subjects
0301 basic medicine, Oncology, Neuroblastoma RAS viral oncogene homolog, Male, Cancer Research, Colorectal cancer, Pyridines, [SDV]Life Sciences [q-bio], Mutant, medicine.disease_cause, chemistry.chemical_compound, 0302 clinical medicine, Medicine, Neoplasm Metastasis, cfDNA, Research Articles, RC254-282, Regorafenib, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, General Medicine, Middle Aged, 3. Good health, [SDV] Life Sciences [q-bio], Predictive biomarker, 030220 oncology & carcinogenesis, Molecular Medicine, Female, KRAS, Colorectal Neoplasms, Cell-Free Nucleic Acids, Research Article, medicine.medical_specialty, Antineoplastic Agents, [SDV.CAN]Life Sciences [q-bio]/Cancer, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, Genetics, Biomarkers, Tumor, Humans, In patient, Mutant ctDNA, Aged, business.industry, Phenylurea Compounds, Liquid Biopsy, circulating DNA, medicine.disease, Survival Analysis, Circulating Cell-Free DNA, 030104 developmental biology, chemistry, Potential biomarkers, Tumor response, business
Abstract

Circulating cell‐free DNA (cfDNA) contains circulating tumor DNA (ctDNA), which can be obtained from serial liquid biopsies to enable tumor genome analysis throughout the course of treatment. We investigated cfDNA and mutant ctDNA as potential biomarkers to predict the best outcomes of regorafenib‐treated metastatic colorectal cancer (mCRC) patients. We analyzed longitudinally collected plasma cfDNA of 43 mCRC patients prospectively enrolled in the phase II TEXCAN trial by IntPlex qPCR. Qualitative (KRAS, NRAS, BRAFV600E mutations) and quantitative (total cfDNA concentration, mutant ctDNA concentration, mutant ctDNA fraction) parameters were correlated with overall survival (OS) and progression‐free survival (PFS). When examined as classes or continuous variables, the concentrations of total cfDNA, mutant ctDNA, and, partly, mutant ctDNA fraction prior to regorafenib treatment correlated with OS. Patients with baseline cfDNA > 26 ng·mL−1 had shorter OS than those with cfDNA value below this threshold (4.0 vs 6.9 months; log‐rank P = 0.0366). Patients with baseline mutant ctDNA > 2 ng·mL−1 had shorter OS than those with mutant ctDNA below this threshold (log‐rank P = 0.0154). We show that pretreatment cfDNA and mutant ctDNA levels may identify mCRC patients that may benefit from regorafenib treatment., Circulating cell‐free DNA (cfdNA) was extracted from longitudinal blood collection of 43 mCRC patients treated by regorafenib. Qualitative (RAS, BRAFV600E mutations) and quantitative (cfDNA concentration, mutant circulating tumor DNA (ctDNA) concentration, mutant ctDNA fraction) parameters were correlated with survival. We show that pretreatment cfDNA and mutant ctDNA levels may identify mCRC patients that may benefit from regorafenib treatment.

Published
2021
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9. Discordances entre les référentiels des collèges d’enseignants en médecine et leur impact sur les étudiants en médecine

Author

Cohen, Romain, Renaud, Marie-Christine, Huguet, Florence, André, Thierry, Duguet, Alexandre, Steichen, Olivier, 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), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), Service d'oncologie-radiothérapie [CHU Tenon], CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Pneumologie et Réanimation Médicale [CHU Pitié-Salpêtrière] (Département ' R3S '), CHU Pitié-Salpêtrière [AP-HP], Service de Médecine Interne [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service d'Oncologie Médicale [CHU Saint-Antoine], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Service de Médecine Interne = Hôpital de jour de médecine [CHU Tenon]

Subjects
Medical education, Textbooks, Students, Medical, Éducation médicale, [SDV]Life Sciences [q-bio], Oncologie, Anxiety, Medical Oncology, Référentiels, Divergence, Oncology, Reference Books, Medical, Humans, France, Textbooks as Topic, Discrepancy, Schools, Medical
Abstract

International audience; Background: Textbooks endorsed by national medical specialty societies and colleges are used as official references for faculty and national examinations. Oncology is transdisciplinary, practiced and taught by oncologists but also by other specialists. We aimed at identifying discrepancies between chapters on cancers in different official specialty textbooks and evaluating their impact on students.Material and methods: Volunteer 6th-year medical students of the Sorbonne University faculty were paired and asked to list the discrepancies between all official specialty textbooks addressing a given cancer and then individually asked to evaluate the impact of discrepancies on their learning experience.Results: In March 2018, the 17 cancers listed in the French medical school education program were addressed in 14 official specialty textbooks (2 to 4 textbooks/cancer). Out of a class of 390 students, 78 volunteered and were paired; each cancer was analyzed by 3 pairs of students (1 or 2 cancers/pair); 154 discrepancies were reported (range: 4-18 per cancer). Discrepancies induced doubt and anxiety in students; 85% considered that harmonization should be achieved for all topics of the national medical school program.Conclusions: Discrepancies between official textbook are frequent, generate anxiety in students and impact learning experience.; ContexteLes référentiels des sociétés savantes de médecine et des collèges des enseignants des spécialités médicales sont utilisés comme des références officielles pour les examens facultaires et les épreuves nationales. L’oncologie est une discipline transdisciplinaire, pratiquée et enseignées par les oncologues mais également des spécialistes d’organe. Ce travail avait pour objectif d’identifier les discordances entre les chapitres traitant du cancer dans les référentiels des collèges d’enseignants en médecine et d’en évaluer l’impact chez les étudiants.Matériel et méthodesLes discordances entre les chapitres traitant du cancer dans les référentiels des collèges d’enseignants en médecine ont été recensées par des étudiants, volontaires, en sixième année à la faculté de médecine Sorbonne université. Il leur était également demandé d’évaluer, de manière individuelle, l’impact de ces discordances sur leur apprentissage.RésultatsEn mars 2017, les 17 items de cancérologie du programme officiel du deuxième cycle des études médicales étaient traités dans 14 référentiels de collèges d’enseignants en médecine (deux à quatre référentiels par localisation tumorale). Soixante-dix-huit des 390 étudiants de sixième année se sont portés volontaires et ont travaillé en binômes. Chaque localisation était analysée par trois binômes (un à deux cancers par binôme). Cent cinquante-quatre discordances ont été relevées (quatre à dix-huit par cancer). L’ensemble des étudiants déclarait que l’existence de ces discordances était source de doute et d’anxiété. Quatre-vingt-cinq pour cent d’entre eux considéraient qu’une harmonisation des référentiels devrait être recherchée dans l’ensemble des domaines du programme des études médicales.ConclusionsLes discordances entre référentiels des collèges d’enseignants sont fréquentes, générant une anxiété chez les étudiants avec un impact ressenti sur leur apprentissage.

Published
2021
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10. RECIST and iRECIST criteria for the evaluation of nivolumab plus ipilimumab in patients with microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: the GERCOR NIPICOL phase II study

Author

Jaafar Bennouna, Magali Svrcek, Yves Menu, Thibault Mazard, Thierry André, Dewi Vernerey, David Tougeron, Christophe Tournigand, Christophe Borg, Benoist Chibaudel, Romain Cohen, Aurélia Meurisse, Marie-Line Garcia-Larnicol, Christelle De La Fouchardiere, 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), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Service d'Oncologie médicale [CHU Henri Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Henri Mondor, Centre Léon Bérard [Lyon], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Division of Medical Oncology - Franco-British Hospital Institute, Cooperator Multidisciplinary Oncology Group (GERCOR), Service de Pathologie [CHU Saint-Antoine], Service de Radiologie [CHU Saint-Antoine], Gestionnaire, Hal Sorbonne Université, Service d'Oncologie Médicale [CHU Saint-Antoine], CHU Saint-Antoine [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
0301 basic medicine, Oncology, Male, CTLA-4 antigen, Cancer Research, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Immunology, Phases of clinical research, Ipilimumab, DNA Mismatch Repair, programmed cell death 1 receptor, gastrointestinal neoplasms, 03 medical and health sciences, 0302 clinical medicine, Antineoplastic Agents, Immunological, Internal medicine, Immunology and Allergy, Medicine, Humans, Response Evaluation Criteria in Solid Tumors, Pharmacology, Clinical/Translational Cancer Immunotherapy, business.industry, Microsatellite instability, Middle Aged, medicine.disease, Lynch syndrome, digestive system diseases, 3. Good health, Oxaliplatin, [SDV] Life Sciences [q-bio], Irinotecan, 030104 developmental biology, Nivolumab, 030220 oncology & carcinogenesis, Molecular Medicine, Female, Microsatellite Instability, immunotherapy, business, Colorectal Neoplasms, medicine.drug
Abstract

BackgroundImmune checkpoint inhibitors (ICIs) are highly effective in patients with microsatellite instability/mismatch repair-deficient (MSI/dMMR) metastatic colorectal cancer (mCRC). Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria may underestimate response to ICIs due to the pseudoprogression phenomenon. The GERCOR NIPICOL phase II study aimed to evaluate the frequency of pseudoprogressions in patients with MSI/dMMR mCRC treated with nivolumab and ipilimumab.MethodsPatients with MSI/dMMR mCRC previously treated with fluoropyrimidines, oxaliplatin, and irinotecan with/without targeted therapies received nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four cycles then nivolumab 3 mg/kg every 2 weeks until progression or a maximum of 20 cycles. Computed tomography scan tumor assessments were done every 6 weeks for 24 weeks and then every 12 weeks. The primary endpoint was disease control rate at 12 weeks according to RECIST 1.1 and iRECIST by central review.ResultsOf 57 patients included between December 2017 and November 2018, 48.0% received ≥3 prior lines of chemotherapy, 18.0% had BRAFV600E mutation, and 56.0% had Lynch syndrome-related cancer. Seven patients (12.0%) discontinued treatment due to adverse events; one died due to a treatment-related adverse event. The disease control rate (DCR) at 12 weeks was 86.0% with RECIST 1.1% and 87.7% with iRECIST. Two pseudoprogressions (3.5%) were observed, at week 6 and at week 36, representing 18% of patients with disease progression per RECIST 1.1 criteria. With a median follow-up of 18.4 months, median progression-free survival (PFS) and overall survival (OS) were not reached. The 12-month PFS rate was 72.9% with RECIST 1.1% and 76.5% with iRECIST. The 12-month OS rate was 84%. Overall response rate was 59.7% with both criteria. RAS/BRAF status, sidedness, Lynch syndrome, and other baseline parameters were not associated with PFS.ConclusionPseudoprogression is rare in patients with MSI/dMMR mCRC treated with nivolumab and ipilimumab. This combined ICI therapy confirms impressive DCR and survival outcomes in these patients.Trial registration numberNCT03350126.

Published
2020
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11. Immune scores in colorectal cancer: Where are we?

Author

Astrid Lièvre, David Malka, Julien Taieb, Frédéric Bibeau, Thierry André, Michel Ducreux, Institut Gustave Roussy (IGR), Département de médecine oncologique [Gustave Roussy], Chemistry, Oncogenesis, Stress and Signaling (COSS), Institut National de la Santé et de la Recherche Médicale (INSERM)-CRLCC Eugène Marquis (CRLCC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), CHU Pontchaillou [Rennes], Sorbonne Université (SU), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), 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), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), CRC, Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CCSD, Accord Elsevier, Service d'Oncologie Médicale [CHU Saint-Antoine], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, Colorectal cancer, CD3, Immune score, [SDV.CAN]Life Sciences [q-bio]/Cancer, CD8-Positive T-Lymphocytes, 03 medical and health sciences, 0302 clinical medicine, Immune system, Lymphocytes, Tumor-Infiltrating, [SDV.CAN] Life Sciences [q-bio]/Cancer, Immunity, Internal medicine, medicine, Cytotoxic T cell, Humans, biology, business.industry, Cancer, medicine.disease, Acquired immune system, Prognosis, 3. Good health, 030104 developmental biology, 030220 oncology & carcinogenesis, biology.protein, business, Colorectal Neoplasms, Immunologic Memory, CD8
Abstract

International audience; There is growing evidence that the immune system may prevent the occurrence, growth and metastatic diffusion of colorectal cancer (CRC). The role played by the adaptive immune response at the tumour site is critical in the balance between tumour invasion and defence against cancer. Recent data have shown that the evaluation of this immune response may help to define the prognosis and possibly the treatment of localised CRC as well as metastatic CRC. Tumour infiltrates with T cells (CD3+), cytotoxic T cells (CD8+) and memory T cells (CD45RO+) are the immune parameters most consistently and strongly associated with good clinical outcome in CRC. Several scoring systems have been developed, including the Immunoscore®, based on the immunohistochemical determination with a digital image analysis system of the density of CD3+ and CD8+ lymphocytes in the centre and the invasive margin of the tumour. This review will focus on the different immunoscoring systems developed in CRC, their performance, their limitations and their potential for improving patients’ care in the future.

Published
2020
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12. Chemotherapy in resected neuroendocrine carcinomas of the digestive

Author

Pellat, Anna, Walter, Thomas, Augustin, Jeremy, Hautefeuille, Vincent, Hentic, Olivia, Do Cao, Christine, Lièvre, Astrid, Coriat, Romain, Hammel, Pascal, Dubreuil, Olivier, Cohen, R., Couvelard, A., André, T., Svrcek, M, Baudin, Emmanuel, Afchain, P., 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), 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), Service d'Oncologie Médicale [Centre hospitalier Lyon Sud - HCL], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Service d'Anatomie et cytologie pathologiques [CHU Pitié-Salpêtrière] (ACP), CHU Pitié-Salpêtrière [AP-HP], Service d'Hépato Gastroenterologie [CHU Amiens-Picardie], CHU Amiens-Picardie, Service de Gastroentérologie [Hôpital Beaujon], Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'endocrinologie pédiatrique [CHU Lille], Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut Curie [Paris], Service d'hépato-gastro-entérologie [Rennes] = Gastroenterology [Rennes], CHU Pontchaillou [Rennes], Service de Gastro-entérologie [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Cooperator Multidisciplinary Oncology Group (GERCOR), Service d'Hépato-Gastro-Entérologie [CHU Pitié-Salpêtrière], Département d'Anatomo-Pathologie [Hôpital Bichat], AP-HP - Hôpital Bichat - Claude Bernard [Paris], Service de Pathologie [CHU Saint-Antoine], Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Sorbonne Université, Service d’anatomie et cytologie pathologiques [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université, Service d'hépato-gastro-entérologie [Rennes], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Service de gastroentérologie et cancérologie digestive [CHU Pitié-Salpêtrière], Gestionnaire, HAL Sorbonne Université 5, 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), Service d'Oncologie Médicale [CHU Saint-Antoine], Service d'Anatomie et cytologie pathologiques = Service de Pathologie [CHU Pitié-Salpêtrière] (ACP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
ki-67 index 43 44 2, [SDV.CAN] Life Sciences [q-bio]/Cancer, neuroendocrine carcinomas, [SDV.CAN]Life Sciences [q-bio]/Cancer, chemotherapy
Abstract

International audience; Background: Neuroendocrine carcinomas (NECs) of the digestive tract are rare and aggressive tumours. In localised disease the treatment is surgery. Based on expert consensus, international guidelines recommend the administration of adjuvant chemotherapy combining etoposide and platinum derivatives, justified by the high risk of metastatic relapse. However, no clinical study has proven the benefit of neoadjuvant or adjuvant chemotherapy. Objectives: We aimed to evaluate the effect of neoadjuvant +/– adjuvant and adjuvant therapy in this indication. Methods: We performed a retrospective observational French study to evaluate overall survival (OS) and disease-free survival (DFS), prognostic factors for survival, and chemotherapy toxicity. Results: Seventy-three patients had surgical resection of a localised digestive NEC between January 1, 2000 and December 31, 2016. The majority of patients presented colorectal (35%) tumours and the median Ki-67 value was 70%. Forty-three patients received chemotherapy, either perioperative (neoadjuvant +/– adjuvant) or adjuvant. The median OS and DFS for the whole population was 24 and 9 months, respectively. The median OS and DFS for patients receiving chemotherapy was 62 and 13 months, respectively. Positive postoperative node status and Ki-67 ≥80% had a negative prognostic impact on OS and DFS. Administration of chemotherapy had a positive prognostic impact on OS and DFS. Sixteen grade 3/4 toxicities were reported without toxic death. Conclusions: Our results suggest a positive effect on survival of chemotherapy in resected digestive NECs, but further studies are needed to confirm these results.

Published
2020
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13. Fusions NTRK : une nouvelle piste dans les cancers digestifs ?

Author

Kaïssa, Ouali, Anna, Pellat, Romain, Cohen, Magali, Svrcek, Frédérique, Penault-Llorca, Thierry, André, 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), Service d'Oncologie Médicale [CHU Saint-Antoine], 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), Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), 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], Service d'Oncologie Médicale [CHU Saint -Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)

Subjects
Indazoles, Oncogene Proteins, Fusion, [SDV]Life Sciences [q-bio], [SDV.CAN]Life Sciences [q-bio]/Cancer, Entrectinib, Humans, Receptor, trkB, Receptor, trkC, Nerve Growth Factors, Receptor, trkA, Protein Kinase Inhibitors, In Situ Hybridization, Larotrectinib, Gastrointestinal Neoplasms, Oncogene Proteins, Membrane Glycoproteins, High-Throughput Nucleotide Sequencing, Immunohistochemistry, Pancreatic Neoplasms, Pyrimidines, Benzamides, Cancers digestifs, Microsatellite instability, Pyrazoles, Gene Fusion, Colorectal Neoplasms, Neurotrophic Tropomyosin Receptor Kinase (NTRK)
Abstract

International audience; The advent of molecular biology resulted in the discovery of new oncogenes that have led to the development of targeted therapies for the management of cancer patients. The development of these therapies has improved the prognosis of patients in various tumour localizations. The TRK receptor (tropomyosin receptor kinase) is a transmembrane receptor with a tyrosine kinase activity that plays a role in both cell proliferation and the physiology of the nervous system. Fusions involving the NTRK gene, which codes for this receptor, have been found in different types of solid tumours and lead to its constitutional activation. These fusions, however uncommon, are mainly found in rare pediatric tumours but can also be encountered in digestive cancers with high prevalence (such as colorectal cancer, especially in case of microsatellite instability, with a frequency of 2.5 to 38.5 %) or in aggressive cancers (such as pancreatic cancer). Therapies targeting TRK, such as larotrectinib or entrectinib, have shown significant response rates, usually greater than 6 months, for tumours from various primary sites presenting NTRK fusions and refractory to standard therapies. These fusions can be detected by different methods: immunohistochemistry, FISH (fluorescence in situ hybridization) as well as NGS (next generation sequencing). The intent of this review is to report on current knowledge on NTRK fusions in oncology and to discuss the role of these fusions in digestive cancers and potential therapeutic implications.

Published
2020
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14. Clinical and molecular characterisation of hereditary and sporadic metastatic colorectal cancers harbouring microsatellite instability/DNA mismatch repair deficiency

Author

Rachid Kaci, Magali Svrcek, Dewi Vernerey, Pascale Cervera, Alex Duval, Philippe Bertheau, Yann Parc, Sylvie Dumont, Thierry André, Frédéric Bibeau, Romain Cohen, Daniel Lopez-Trabada, Jean-Marc Gornet, J-B. Bachet, Armelle Bardier, Elisabeth Hain, Olivier Buhard, Florence Renaud, Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC), Service de Pathologie [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), Service d'Hépato-Gastro-Entérologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'hépato-gastroentérologie, Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-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), Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Gustave Roussy (IGR), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, UNICANCER - Institut régional du Cancer Montpellier Val d'Aurelle (ICM), CRLCC Val d'Aurelle - Paul Lamarque, Service de chirurgie générale et digestive [CHU Saint-Antoine], Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Service d'Oncologie Médicale [CHU Saint -Antoine], Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC)-Université de Franche-Comté (UFC), HAL-UPMC, Gestionnaire, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Service d'Oncologie Médicale [CHU Saint-Antoine]

Subjects
Male, 0301 basic medicine, Cancer Research, Heredity, Time Factors, Colorectal cancer, Kaplan-Meier Estimate, DNA Mismatch Repair, 0302 clinical medicine, Risk Factors, PMS2, Neoplasm Metastasis, Middle Aged, Lynch syndrome, Pedigree, 3. Good health, Phenotype, Treatment Outcome, Molecular Diagnostic Techniques, Oncology, 030220 oncology & carcinogenesis, Female, Microsatellite Instability, DNA mismatch repair, France, Colorectal Neoplasms, MutL Protein Homolog 1, Adult, Proto-Oncogene Proteins B-raf, congenital, hereditary, and neonatal diseases and abnormalities, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, MLH1, Disease-Free Survival, Diagnosis, Differential, 03 medical and health sciences, Germline mutation, [SDV.CAN] Life Sciences [q-bio]/Cancer, Predictive Value of Tests, Biomarkers, Tumor, medicine, Humans, Genetic Predisposition to Disease, neoplasms, Aged, Proportional Hazards Models, Retrospective Studies, nutritional and metabolic diseases, Cancer, Microsatellite instability, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, DNA Methylation, medicine.disease, Colorectal Neoplasms, Hereditary Nonpolyposis, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, digestive system diseases, 030104 developmental biology, Multivariate Analysis, Mutation, Cancer research
Abstract

International audience; Background: Patients treated with chemotherapy for microsatellite unstable (MSI) and/or mismatch repair deficient (dMMR) cancer metastatic colorectal cancer (mCRC) exhibit poor prognosis. We aimed to evaluate the relevance of distinguishing sporadic from Lynch syndrome (LS)-like mCRCs.Patients and methods: MSI/dMMR mCRC patients were retrospectively identified in six French hospitals. Tumour samples were screened for MSI, dMMR, RAS/RAF mutations and MLH1 methylation. Sporadic cases were molecularly defined as those displaying MLH1/PMS2 loss of expression with BRAFV600E and/or MLH1 hypermethylation and no MMR germline mutation.Results: Among 129 MSI/dMMR mCRC patients, 81 (63%) were LS-like and 48 (31%) had sporadic tumours; 22% of MLH1/PMS2-negative mCRCs would have been misclassified using an algorithm based on local medical records (age, Amsterdam II criteria, BRAF and MMR statuses when locally tested), compared to a systematical assessment of MMR, BRAF and MLH1 methylation statuses. In univariate analysis, parameters associated with better overall survival were age (P < 0.0001), metastatic resection (P = 0.001) and LS-like mCRC (P = 0.01), but not BRAFV600E. In multivariate analysis, age (hazard ratio (HR) = 3.19, P = 0.01) and metastatic resection (HR = 4.2, P = 0.001) were associated with overall survival, but not LS. LS-like patients were associated with more frequent liver involvement, metastatic resection and better disease-free survival after metastasectomy (HR = 0.28, P = 0.01). Median progression-free survival of first-line chemotherapy was similar between the two groups (4.2 and 4.2 months; P = 0.44).Conclusions: LS-like and sporadic MSI/dMMR mCRCs display distinct natural histories. MMR, BRAF mutation and MLH1 methylation testing should be mandatory to differentiate LS-like and sporadic MSI/dMMR mCRC, to determine in particular whether immune checkpoint inhibitors efficacy differs in these two populations.

Published
2017
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15. Prognostic value of the early change in neutrophil-to-lymphocyte ratio in metastatic pancreatic adenocarcinoma

Author

Pascal Hammel, Paul McLellan, Daniel Pietrasz, Dewi Vernerey, Feryel Ksontini, Solene Doat, Julie Henriques, Jérôme Desramé, Isabelle Trouilloud, Christophe Louvet, Jean-Baptiste Bachet, Service d'Hépato-Gastro-Entérologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [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), Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Institut Salah Azaiz [Tunis] (ISA), Service de Gastroentérologie [Hôpital Beaujon], Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Unité de Gastroentérologie, Hôpital Privé Jean Mermoz, Service d'Oncologie Médicale [CHU Saint-Antoine], CHU Saint-Antoine [AP-HP], Institut Mutualiste de Montsouris (IMM), Centre Hépato-Biliaire [Hôpital Paul Brousse] (CHB), Hôpital Paul Brousse-Assistance Publique - Hôpitaux de Paris, Gestionnaire, Hal Sorbonne Université, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté]), Service d'Oncologie Médicale [CHU Saint -Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)

Subjects
medicine.medical_specialty, Neutrophils, medicine.medical_treatment, Adenocarcinoma, Prognostic, Gastroenterology, law.invention, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, law, Internal medicine, Metastatic pancreatic cancer, medicine, Humans, Lymphocytes, Prospective Studies, Neutrophil to lymphocyte ratio, Prospective cohort study, Retrospective Studies, Chemotherapy, Hepatology, business.industry, fungi, Retrospective cohort study, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Biomarker, Metastatic Pancreatic Adenocarcinoma, Prognosis, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, 3. Good health, Pancreatic Neoplasms, 030220 oncology & carcinogenesis, Biomarker (medicine), 030211 gastroenterology & hepatology, business, Biomarkers
Abstract

International audience; In metastatic pancreatic adenocarcinoma, a high neutrophil-to-lymphocyte ratio (NLR) at diagnosis is a marker of poor prognosis. The prognostic role of baseline NLR and NLR change during first-line chemotherapy were determined. We conducted a retrospective study by using data from a single-center prospective cohort and a randomized open-label, multicenter, randomized trial. Two hundred and twelve patients were analyzed. Baseline NLR>5 was an independent marker of poor prognosis for overall survival (HR=2.01, 95% CI 1.33-3.05; P=0.001) and progression-free survival (PFS; HR=1.80, 95% CI 1.23-2.65; P=0.0026). According to NLR dynamics (n=172), patients with NLR≤5 on days 1 and 15 had a significantly better prognosis than those with NLR≤5 on day 1 and NLR>5 on day 15 (HR=2.23, 95% CI 1.18-4.21; P=0.013), NLR >5 on day 1 and NLR ≤5 on day 15 (HR=3.25, 95% CI 1.86-5.68; P5 on days 1 and 15 (HR=3.37, 95% CI 1.93-5.90; P6 months; group effect: P5 had circulating tumor DNA. This study confirmed the independent prognostic value of baseline NLR >5 in metastatic pancreatic cancer. The change in NLR early during chemotherapy was also a prognostic indicator in patients with NLR ≤5.

Published
2020
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16. Management of colorectal peritoneal metastases: Expert opinion

Author

Marc Ychou, François Quenet, Pascale Mariani, Olivia Sgarbura, Jérémie H. Lefevre, Thierry André, M. Brunel, Jean-Marc Gornet, Karine Abboud, A. Pinto, Marc Pocard, Michel Ducreux, C. Eveno, Olivier Glehen, Diane Goéré, 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), Lille Neurosciences & Cognition - U 1172 (LilNCog (ex-JPARC)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Ciblage thérapeutique en Oncologie (EA3738), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Service de chirurgie générale et digestive [CHU Saint-Antoine], Institut du Cancer de Montpellier (ICM), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier de Versailles André Mignot (CHV), Institut Gustave Roussy (IGR), Université Paris-Saclay, Lille Neurosciences & Cognition - U 1172 (LilNCog), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Hôpital Claude Huriez [Lille], CHU Lille, Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Curie [Paris], CArcinose Péritoine Paris-Technologies (ex-CART) (CAP Paris-Tech (UMR_S_1275)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Hôpital Lariboisière-Fernand-Widal [APHP], CCSD, Accord Elsevier, CHU Saint-Etienne, Service d'Oncologie Médicale [CHU Saint-Antoine], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
medicine.medical_specialty, Colorectal cancer, [SDV]Life Sciences [q-bio], Antineoplastic Agents, 03 medical and health sciences, 0302 clinical medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, Cytoreductive surgery, Radical surgery, Laparoscopy, Peritoneal Neoplasms, Carcinomatosis, medicine.diagnostic_test, HIPEC, business.industry, General surgery, Carcinoma, Cytoreduction Surgical Procedures, Hyperthermia, Induced, General Medicine, medicine.disease, Combined Modality Therapy, 3. Good health, Oxaliplatin, Colon cancer, [SDV] Life Sciences [q-bio], Chemotherapy, Cancer, Regional Perfusion, 030220 oncology & carcinogenesis, Expert opinion, 030211 gastroenterology & hepatology, Hyperthermic intraperitoneal chemotherapy, Peritoneal diseases, Colorectal Neoplasms, business, medicine.drug
Abstract

International audience; When peritoneal metastases are diagnosed (strong agreement of experts): (i) seek advice from a multidisciplinary coordination meeting (MCM) with large experience in peritoneal disease (e.g. BIG RENAPE network); (ii) transfer (or not) the patient to a referral center with experience in hyperthermic intraperitoneal chemotherapy (HIPEC), according to the advice of the MCM. With regard to systemic chemotherapy (strong agreement of experts): (i) it should be performed both before and after surgery, (ii) for no longer than 6 months; (iii) without postoperative anti-angiogenetic drugs. With regard to cytoreductive surgery (strong agreement of experts): (i) Radical surgery requires a xiphopubic midline incision; (ii) no cytoreductive surgery via laparoscopy. With regard to HIPEC: HIPEC can be proposed for trials outside an HIPEC referral center (weak agreement between experts): (i) if surgery is radical; (ii) if the expected morbidity is "reasonable"; (iii) if the indication for HIPEC was suggested by a MCM, and; (iv) mitomycin is preferred to oxaliplatin (which cannot be recommended) for this indication.

Published
2019
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17. BRAF Mutation Status in Circulating Tumor DNA from Patients with Metastatic Colorectal Cancer: Extended Mutation Analysis from the AGEO RASANC Study

Author

Anne Thirot-Bidault, Olivier Bouché, Romain Coriat, Jean-Marc Gornet, Julien Taieb, Lysiane Marthey, Pascal Artru, I. Baumgaertner, David Tougeron, Thierry Lecomte, Corinne Normand, Valérie Taly, Dewi Vernerey, Florence Mary, Hélène Blons, Jean-Baptiste Bachet, Romain Cohen, Aurélia Meurisse, Samy Louafi, Thomas Aparicio, Pierre Laurent-Puig, Léo Mas, Service d'Hépato-Gastro-Entérologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Association des Gastroentérologues Oncologues [Paris] (AGEO), Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC), 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)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Service d'Hépato-gastroentérologie [HU Robert Debré, Reims], Hôpital universitaire Robert Debré [Reims], Service de gastroenterologie [CHU HEGP], Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), 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), Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Service d'hépato-gastro-entérologie [Hôpital Saint-Louis, APHP], Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Gastroentérologie [Hôpital Privé Jean Mermoz, Lyon], Hôpital privé Jean-Mermoz [Lyon] (Ramsay-GDS), Service de Gastroenterologie [CH Sud Francilien, Corbeil-Essonnes], Centre Hospitalier Sud Francilien [Corbeil-Essonnes] (CH Sud Francilien), Service de Gastroenterologie [GH Nord Essonne, Longjumeau], Groupe Hospitalier Nord Essonne [Longjumeau], Service d'Hépato-gastro-entérologie [APHP Kremlin-Bicêtre], AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Service d'Oncologie médicale [CHU Henri Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Henri Mondor, Service de Gastro-entérologie [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d’hépato-gastro-entérologie et assistance nutritive [CHU de Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Service de Gastroentérologie [CHRU Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Service de Gastroenterologie [Hôpital Avicenne, APHP], Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance Publique - Hôpitaux de Paris, Service d'hépato-gastroentérologie [Hôpital Antoine Béclère, APHP], AP-HP - Hôpital Antoine Béclère [Clamart], Service de biochimie [AP-HP Hôpital Européen Georges Pompidou], Merck Serono S.A.S. (France), an aliate of Merck KGaA (Darmstadt, Germany), supported this trial through grants to AGEO, but had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The AGEO Group sponsored the trial and investigators were responsible for study design,data collection, data analysis, and data interpretation., Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Service d'Oncologie Médicale [CHU Saint-Antoine], CHU Saint-Antoine [AP-HP], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), TALY, Valerie, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Franche-Comté (UFC), and Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])

Subjects
0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, Colorectal cancer, Concordance, [SDV]Life Sciences [q-bio], colorectal cancer, [SDV.CAN]Life Sciences [q-bio]/Cancer, lcsh:RC254-282, Article, Metastasis, methylated biomarker, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, Medicine, Prospective cohort study, circulating tumor DNA, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, accuracy, business.industry, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, digestive system diseases, 3. Good health, [SDV] Life Sciences [q-bio], 030104 developmental biology, Circulating tumor DNA, 030220 oncology & carcinogenesis, NGS, Mutation (genetic algorithm), Mutation testing, Biomarker (medicine), business, liver metastases, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

In patients with metastatic colorectal cancer (mCRC), RAS and BRAF mutations are currently determined by tumor sample analysis. Here, we report BRAF mutation status analysis in paired tumor tissue and plasma samples of mCRC patients included in the AGEO RASANC prospective cohort study. Four hundred and twenty-five patients were enrolled. Plasma samples were analyzed by next-generation sequencing (NGS). When no mutation was identified, we used two methylated specific biomarkers (digital droplet PCR) to determine the presence or absence of circulating tumor DNA (ctDNA). Patients with conclusive ctDNA results were defined as those with at least one mutation or one methylated biomarker. The kappa coefficient and accuracy were 0.79 (95% CI: 0.67&ndash, 0.91) and 97.3% (95% CI: 95.2&ndash, 98.6%) between the BRAF status in plasma and tissue for patients with available paired samples (n = 405), and 0.89 (95% CI: 0.80&ndash, 0.99) and 98.5% (95% CI: 96.4&ndash, 99.5%) for those with conclusive ctDNA (n = 323). The absence of liver metastasis was the main factor associated to inconclusive ctDNA results. In patients with liver metastasis, the kappa coefficient was 0.91 (95% CI, 0.81&ndash, 1.00) and accuracy was 98.6% (95% CI, 96.5&ndash, 99.6%). We demonstrate satisfying concordance between tissue and plasma BRAF mutation detection, especially in patients with liver metastasis, arguing for plasma ctDNA testing for routine BRAF mutation analysis in these patients.

Published
2019
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18. Resection of small bowel adenocarcinoma metastases: Results of the ARCAD-NADEGE cohort study

Author

Cedric Lecaille, Mohamad Chehimi, Romain Coriat, Marc Pocard, Thomas Aparicio, Sylvain Manfredi, David Tougeron, Eric Terrebonne, Isabelle Baumgaertner, Aziz Zaanan, Jean-Louis Legoux, Jean-Baptiste Bachet, Olivier Bouché, Anne-Laure Villing, Pauline Afchain, Jean-Marc Gornet, Robert Benamouzig, Johan Gagnière, Corinne Sarda, Jean-Luc Faucheron, Pierre Rompteaux, J. Forestier, Nathalie Bonichon-Lamichhane, Thierry Lecomte, Service de Gastro-entérologie [Avicenne], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Sorbonne Paris Nord, Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Recherche en Nutrition Humaine d'Auvergne (CRNH d'Auvergne)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Clermont Auvergne (UCA), Service de Chirurgie Digestive et Hépatobiliaire [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Service d'Hépato-Gastro-Entérologie [Hôpital Saint-Louis, AP-HP], Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Gastro-entérologie et hépatologie [Hôpital Cochin], [AP-HP], Hôpital Cochin [AP-HP], Service de gastro-entérologie [Henri Mondor AP-HP, Créteil], Hôpital Henri Mondor-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Département d'hépato-gastro-entérologie [Hôpital Trousseau : CHRU Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), 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), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'Hépato-Gastro-Entérologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Clinique Tivoli Ducos [Bordeaux], CHU Robert Debré [Reims], Centre Hospitalier Universitaire [Grenoble] (CHU), Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL), Polyclinique Bordeaux Nord Aquitaine, Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Hôpital Saint-Quentin, Hôpital d'Auxerre, Partenaires INRAE, Hopital de castres, Service Hépato-gastro-entérologie et oncologie digestive [CHR Orléans], Centre Hospitalier Régional d'Orléans (CHRO), A.R.C.A.D. (Aide et Recherche en CAncerologie Digestive) fundation [NA2009], Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5), Service Chirurgie Disgestive, Centre Hospitalier Universitaire Estaing, Hôpital Saint-Louis, Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), AP HP, Departement Oncologie, Centre Hospitalier Universitaire Henri Mondor, Groupe innovation et ciblage cellulaire (GICC), EA 7501 [2018-...] (GICC EA 7501), Université de Tours, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Saint-Antoine [APHP], Cooperator Multidisciplinary Oncology Group (GERCOR), Service de Gastroentérologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Université de Reims Champagne-Ardenne (URCA), Unité de Chirurgie Colorectale, CHU Grenoble-Hôpital Michallon, Gestes Medico-chirurgicaux Assistés par Ordinateur (TIMC-IMAG-GMCAO), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-IMAG-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-IMAG-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Centre de Recherche en Cancérologie de Lyon (CRCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hôpital Pontchaillou, Service d'Hépato-Gastroentérologie [Rouen], Hôpital Charles Nicolle [Rouen]-CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Département d'hépatologie et de gastroentérologie [CHU Bordeaux], Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Hôpital Haut-Lévêque [CHU Bordeaux], Université de Picardie Jules Verne (UPJV), Regional Hospital of Orleans, Centre de Recherche en Nutrition Humaine, Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-CHU Trousseau [APHP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre de Recherche en Nutrition Humaine d'Auvergne (CRNH d'Auvergne), CHU Trousseau [APHP], Service d'Oncologie Médicale [CHU Saint-Antoine], and CHU Saint-Antoine [AP-HP]

Subjects
Male, Lymphovascular invasion, [SDV]Life Sciences [q-bio], Gastroenterology, Metastasis, 0302 clinical medicine, Duodenal Neoplasms, Positron Emission Tomography Computed Tomography, Clinical endpoint, Prospective Studies, Neoplasm Metastasis, Digestive System Surgical Procedures, Aged, 80 and over, Univariate analysis, Small bowel adenocarcinoma, General Medicine, Middle Aged, Prognosis, Magnetic Resonance Imaging, Primary tumor, 3. Good health, Survival Rate, medicine.anatomical_structure, Oncology, Metastases resection, 030220 oncology & carcinogenesis, Female, 030211 gastroenterology & hepatology, France, Cohort study, medicine.drug, Adult, Ampulla of Vater, medicine.medical_specialty, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.MHEP.CHI]Life Sciences [q-bio]/Human health and pathology/Surgery, Adenocarcinoma, Disease-Free Survival, 03 medical and health sciences, Internal medicine, medicine, Humans, Aged, Neoplasm Staging, Lung, business.industry, medicine.disease, Oxaliplatin, Adjuvant chemotherapy, Hepatic metastases, Surgery, business, Follow-Up Studies
Abstract

Introduction Data are lacking with regard to curative resection of metastasis from small bowel adenocarcinoma (SBA). This study evaluated outcomes and prognostic factors in patients with curatively resected metastatic SBA. Methods A series of 34 patients undergoing resection of metastatic SBA from January 2009 to November 2014 at French centers were included into this cohort study. The primary endpoint was overall survival (OS). Secondary endpoints were recurrence-free survival (RFS) and prognostic factors. Univariate analyses were performed to determine prognostic risk factors. Results The sites of SBA metastases were peritoneal (29.4%), liver (26.5%), lymph nodes (11.8%), lung (2.9%), multiple (14.7%), and other (14.7%). Thirty (88.2%) patients received adjuvant or perioperative chemotherapy, mainly was oxaliplatin-based (76.5%). The median OS was 28.6 months and RFS was 18.7 months. Fourteen (41.2%) patients survived for more than 36 months. In univariate analysis, poor differentiation (P = 0.006), invaded margins (P = 0.003), and lymphatic invasion in the primary tumor (P = 0.039) were associated with decreased OS. Conclusion Overall survival of patients after resection of metastatic SBA remains poor, but long-term survivors are observed. Resection of metastatic SBA should be consider if patients are expected to be operated on with curative intent and have moderately or well-differentiated tumors.

Published
2019
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19. Discordance between immunochemistry of mismatch repair proteins and molecular testing of microsatellite instability in colorectal cancer

Author

Audelaure Junca, Jean-François Fléjou, Eric Frouin, Alex Duval, J. Godet, S. Vignot, Lucie Karayan-Tapon, Florence Coulet, Pascale Cervera, Magali Svrcek, Violaine Randrian, David Tougeron, Gaëlle Tachon, Thierry André, Romain Cohen, A. Guyot D'Asnières De Salins, Olivier Lascols, Camille Evrard, Centre hospitalier universitaire de Poitiers (CHU Poitiers), Laboratoire de neurosciences expérimentales et cliniques (LNEC), Université de Poitiers-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Oncologie Médicale [CHU Saint-Antoine], 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), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), 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), Instabilité des microsatellites et cancers [CRSA], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Gestionnaire, Hal Sorbonne Université, 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), 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], Instabilité des microsatellites et cancers [CHU Saint-Antoine], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP]

Subjects
Oncology, congenital, hereditary, and neonatal diseases and abnormalities, Cancer Research, medicine.medical_specialty, deficient mismatch repair, [SDV]Life Sciences [q-bio], Concordance, colorectal cancer, MLH1, DNA Mismatch Repair, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, PMS2, Humans, molecular biology, neoplasms, 030304 developmental biology, 0303 health sciences, business.industry, Immunochemistry, Microsatellite instability, medicine.disease, digestive system diseases, 3. Good health, [SDV] Life Sciences [q-bio], MSH6, Molecular Diagnostic Techniques, MSH2, 030220 oncology & carcinogenesis, immunohistochemistry, Cohort, microsatellite instability, DNA mismatch repair, Colorectal Neoplasms, business
Abstract

International audience; Background: DNA mismatch repair system deficiency (dMMR) is found in 15% of colorectal cancers (CRCs). Two methods are used to determine dMMR, immunohistochemistry (IHC) of MMR proteins and molecular testing of microsatellite instability (MSI). Only studies with a low number of patients have reported rates of discordance between these two methods, ranging from 1% to 10%.Materials and methods: Overall, 3228 consecutive patients with CRCs from two centers were included. Molecular testing was carried out using the Pentaplex panel and IHC evaluated four (MLH1, MSH2, MSH6, and PMS2; cohort 1; n = 1085) or two MMR proteins (MLH1 and MSH2; cohort 2; n = 2143). The primary endpoint was the rate of discordance between MSI and MMR IHC tests.Results: Fifty-one discordant cases (1.6%) were initially observed. Twenty-nine out of 51 discordant cases were related to IHC misclassifications. In cohort 1, after re-reading IHC and/or carrying out new IHC, 16 discordant cases were reclassified as nondiscordant. In cohort 2, after the addition of MSH6/PMS2 IHC and re-examination, 13 were reclassified as nondiscordant. In addition, 10 misclassifications of molecular tests were identified. Finally, only 12 discordant cases (0.4%) remained: 5 were proficient MMR/MSI and 7 were dMMR/microsatellite stable.Conclusions: Our study confirmed the high degree of concordance between MSI and MMR IHC tests. Discordant cases must be reviewed, and if needed, tests must be repeated and analyzed by an expert team.

Published
2021
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20. MSI/MMR-deficient tumor diagnosis: Which standard for screening and for diagnosis? Diagnostic modalities for the colon and other sites: Differences between tumors

Author

Magali Svrcek, Alex Duval, Romain Cohen, Jean-François Fléjou, Olivier Lascols, Ada Collura, Vincent Jonchère, Olivier Buhard, Service de Pathologie [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), 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), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU), Service d'Oncologie Médicale [CHU Saint -Antoine], Gestionnaire, Hal Sorbonne Université, 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), and Service d'Oncologie Médicale [CHU Saint-Antoine]

Subjects
0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, Colorectal cancer, medicine.medical_treatment, Genetic counseling, [SDV.CAN]Life Sciences [q-bio]/Cancer, DNA Mismatch Repair, Polymerase Chain Reaction, Mismatch repair, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, medicine, Humans, Mass Screening, Radiology, Nuclear Medicine and imaging, neoplasms, Chemotherapy, business.industry, Cancer, Microsatellite instability, Immunohistochimie, Hematology, General Medicine, medicine.disease, Colorectal Neoplasms, Hereditary Nonpolyposis, Immunohistochemistry, Lynch syndrome, digestive system diseases, 3. Good health, Instabilité des microsatellites, 030104 developmental biology, DNA Repair Enzymes, 030220 oncology & carcinogenesis, Next-generation sequencing, DNA mismatch repair, Syndrome de lynch, business, Colorectal Neoplasms, Algorithms, Séquençage nouvelle génération
Abstract

International audience; Microsatellite instability (MSI), which is caused by deficiency of the DNA mismatch repair (MMR) system, is the molecular abnormality observed in tumors associated with Lynch syndrome. Lynch syndrome represents one of the most frequent conditions of cancer predisposition in human, thus requiring specific care and genetic counseling. Moreover, research has recently focused increasingly on MMR deficiency due to its positive predictive value for the efficacy of immune checkpoints inhibitors (ICKi) in metastatic tumors, regardless of their primary origin. MSI has also been demonstrated to constitute an independent prognostic factor in several tumor types, being also associated with alternative response to chemotherapy. These observations have led many professional medical organizations to recommend universal screening of all newly diagnosed colorectal cancers for dMMR/MSI status and increasing evidence support the evaluation of MSI in all human tumors regardless of the cancer tissue of origin. Currently, two standard reference methods, namely immunohistochemistry and polymerase chain reaction, are recommended for the detection of dMMR/MSI status. These methods are equally valid as the initial screening test for dMMR/MSI in colorectal cancer. To date, there is no recommendation for the detection of dMMR/MSI in other primary tumors. In this review, we will present a comprehensive overview of the methods used for evaluation of tumor dMMR/MSI status in colorectal cancer, as well as in other tumor sites. We will see that the evaluation of this status remains challenging in some clinical settings, with the need to improve the above methods in these specific contexts.

Published
2019
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21. Prospective validation of a lymphocyte infiltration prognostic test in stage III colon cancer patients treated with adjuvant FOLFOX

Author

Jean-François Emile, Catherine Julié, Karine Le Malicot, Come Lepage, Josep Tabernero, Enrico Mini, Gunnar Folprecht, Jean-Luc Van Laethem, Stéphanie Dimet, Camille Boulagnon-Rombi, Marc-Antoine Allard, Frédérique Penault-Llorca, Jaafar Bennouna, Pierre Laurent-Puig, Julien Taieb, Josef Thaler, Richard Greil, Johannes Gaenzer, Wolfgang Eisterer, Joerg Tschmelitsch, Felix Keil, Hellmut Samonigg, August Zabernigg, Franz Schmid, Günther Steger, Robert Steinacher, Johannes Andel, Björn Jagdt, Alois Lang, Michael Fridrik, Reinhold Függer, Friedrich Hofbauer, Ewald Woell, Dietmar Geissler, Alfred Lenauer, Manfred Prager, Geert D'Haens, Gauthier Demolin, Joseph Kerger, Guido Deboever, Gilbert Ghillebert, Marc Polus, Eric Van Cutsem, Hassan Rezaie Kalantari, Thierry Delaunoit, Jean Charles Goeminne, Marc Peeters, Philippe Vergauwe, Ghislain Houbiers, Yves Humblet, Jos Janssens, Dirk Schrijvers, Erik Vanderstraeten, Jan Vermorken, Daniel Van Daele, Michel Ferrante, Frederic Forget, Alain Hendlisz, Mette Yilmaz, Svend Erik Nielsen, Lene Vestermark, Jim Larsen, Mohamed-Ayman Zawadi, Olivier Bouche, Laurent Mineur, Jaafar Bennouna-Louridi, Louis Marie Dourthe, Marc Ychou, Eveline Boucher, Denis Pezet, Francoise Desseigne, Michel Ducreux, Patrick Texereau, Laurent Miglianico, Philippe Rougier, Serge Fratte, Charles-Briac Levache, Yacine Merrouche, Stephen Ellis, Christophe Locher, Jean-Francois Ramee, Claire Garnier, Frederic Viret, Bruno Chauffert, Isabelle Cojean-Zelek, Pierre Michel, Cedric Lecaille, Christian Borel, Jean-Francois Seitz, Denis Smith, Catherine Lombard-Bohas, Thierry Andre, Jean-Marc Gornet, Francine Fein, Marie-Aude Coulon-Sfairi, Marie-Christine Kaminsky, Jean-Paul Lagasse, Dominique Luet, Pierre-Luc Etienne, Mohamed Gasmi, Andre Vanoli, Suzanne Nguyen, Thomas Aparicio, Hervé Perrier, Noel Stremsdoerfer, Philippe Laplaige, Dominique Arsene, Dominique Auby, Laurent Bedenne, Romain Coriat, Bernard Denis, Patrick Geoffroy, Gilles Piot, Yves Becouarn, Gilbert Bordes, Gael Deplanque, Olivier Dupuis, Frederic Fruge, Rosine Guimbaud, Thierry Lecomte, Gérard Lledo, Iradej Sobhani, Amani Asnacios, Ahmed Azzedine, Christophe Desauw, Marie-Pierre Galais, Dany Gargot, You-Heng Lam, Abakar Abakar-Mahamat, Jean-Francois Berdah, Sylviane Catteau, Marie-Christine Clavero-Fabri, Jean-Francois Codoul, Jean-Louis Legoux, Denis Goldfain, Pierre Guichard, Denis Pere Verge, Jocelyne Provencal, Bruno Vedrenne, Catherine Brezault-Bonnet, Denis Cleau, Jean-Paul Desir, David Fallik, Bruno Garcia, Marie-Hélène Gaspard, Dominique Genet, Johannes Hartwig, Yves Krummel, Tamara Matysiak Budnik, Vanessa Palascak-Juif, Harizo Randrianarivelo, Yves Rinaldi, Albert Aleba, Ariane Darut-Jouve, Aimery de Gramont, Herve Hamon, Frederic Wendehenne, Axel Matzdorff, Michael Konrad Stahl, Wolfgang Schepp, Martin Burk, Lothar Mueller, Michael Geissler, Luisa Mantovani-Loeffler, Thomas Hoehler, Walter Asperger, Hendrik Kroening, Ludwig Fischer von Weikersthal, Stefan Fuxius, Matthias Groschek, Johannes Meiler, Tanja Trarbach, Jacqueline Rauh, Nicolas Ziegenhagen, Albrecht Kretzschmar, Ullrich Graeven, Arnd Nusch, Goetz von Wichert, Ralf-Dieter Hofheinz, Gerhard Kleber, Karl-Heinz Schmidt, Ursula Vehling-Kaiser, Claudia Baum, Jochen Schuette, Georg Martin Haag, Wilhelm Holtkamp, Jochen Potenberg, Tobias Reiber, Georg Schliesser, Hans-Joachim Schmoll, Wolfgang Schneider-Kappus, Wolfgang Abenhardt, Claudio Denzlinger, Jan Henning, Bartscht Marxsen, Hans Guenter Derigs, Helmut Lambertz, Ingulf Becker-Boost, Karel Caca, Christian Constantin, Thomas Decker, Henning Eschenburg, Sigrun Gabius, Holger Hebart, Albrecht Hoffmeister, Heinz-August Horst, Stephan Kremers, Malte Leithaeuser, Sebastian Mueller, Siegfried Wagner, Severin Daum, Frank Schlegel, Martina Stauch, Volker Heinemann, Evaristo Maiello, Luciano Latini, Alberto Zaniboni, Dino Amadori, Giuseppe Aprile, Sandro Barni, Rodolfo Mattioli, Andrea Martoni, Rodolfo Passalacqua, Mario Nicolini, Enzo Pasquini, Carla Rabbi, Enrico Aitini, Alberto Ravaioli, Carlo Barone, Guido Biasco, Stefano Tamberi, Angelo Gambi, Claudio Verusio, Marina Marzola, Giorgio Lelli, Corrado Boni, Stefano Cascinu, Paolo Bidoli, Massimo Vaghi, Giorgio Cruciani, Francesco Di Costanzo, Alberto Sobrero, Roberto Petrioli, Massimo Aglietta, Oscar Alabiso, Federico Capuzzo, Alfredo Falcone, Domenico Cristi Corsi, Roberto Labianca, Stefania Salvagni, Silvana Chiara, Libero Ciuffreda, Francesco Ferraù, Francesco Giuliani, Sara Lonardi, Nicola Gebbia, Giovanni Mantovani, Evaristo Sanches, Juan Carlos Mellidez, Pedro Santos, Joao Freire, Cristina Sarmento, Luis Costa, Antonio Moreira Pinto, Sergio Barroso, Jorge Espirito Santo, Fátima Guedes, Amélia Monteiro, Anabela Sa, Irene Furtado, Ramon Salazar, Enrique Aranda Aguilar, Fernando Rivera Herrero, Javier Sastre Valera, Manuel Valladares Ayerbes, Jaime Feliu Batlle, Silvia Gil, Albert Abad Esteve, Carlos Garcia-Giron, Guillermo Lopez Vivanco, Antonia Salud Salvia, Vicente Alonso Orduña, Ruth Vera Garcia, Javier Gallego, Bartomeu Massuti Sureda, Jordi Remon, Maria Jose Safont Aguilera, Luis Cirera Nogueras, Bernado Queralt Merino, Cristina Gravalos Castro, Purificacion Martinez de Prado, Carlos Pijaume Pericay, Manuel Constenla Figueiras, Inmaculada Guasch Jordan, Maria Jose Gome Reina, Amelia Lopez-Ladron Garcia, Antonio Arrivi Garcia-Ramos, Andres Cervantes, Carlos Fernandez Martos, Eugenio Marcuello Gaspar, Ines Cabezas Montero, Pilar Escudero Emperador, Ana Leon Carbonero, Manuel Gallen Castillo, Teresa Garcia Garcia, Jose Garcia Lopez, Encarnacion Gonzalez Flores, Monica Guillot Morales, Marta Llanos Muñoz, Ana López Martín, Joan Maurel, Juan Carlos Camara, Rosario Dueñas Garcia, Mercedes Salgado, Isabel Hernandez Busquier, Teresa Checa Ruiz, Adelaida Lacasta Muñoa, Miquel Nogue Aliguer, Amalia Velasco Ortiz de Taranco, Miguel Mendez Ureña, Ferran Losa Gaspa, Jose Juan Ponce, Carlos Bosch Roig, Pedro Valero Jimenez, Antonio Galan Brotons, Santiago Albiol Rodriguez, Jose Ales Martinez, Liliana Canosa Ruiz, Margarita Centelles Ruiz, John Bridgewater, Rob Glynne-Jones, Saad Tahir, Tamas Hickish, Jim Cassidy, Leslie Samuel, UE 1373 Fourrages Environnement Ruminants Lusignan, Institut National de la Recherche Agronomique ( INRA ) -Physiologie Animale et Systèmes d'Elevage ( PHASE ) -Environnement et Agronomie ( E.A. ) -Biologie et Amélioration des Plantes ( BAP ) -Fourrages Environnement Ruminants Lusignan ( FERLUS ), Service de pathologie [CHU Ambroise Paré], Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Ambroise Paré, Service de Biostatistique, Fédération Francophone de la Cancérologie Digestive, FFCD, Lipides - Nutrition - Cancer [Dijon - U1231] ( LNC ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service d'hépato-gastroentérologie et cancérologie digestive (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Vall d'Hebron University Hospital [Barcelona], Dpt of Internal Medicine, Section of Immunoallergology and Respiratory [Florence] Diseases, University of Florence, Carl Gustav Carus University Hospital, Erasme Hospital, Brussels, Centre Hepato-Biliaire, AP-HP Hôpital Paul Brousse, Modèles de Cellules Souches Malignes et Thérapeutiques, Université Paris-Sud - Paris 11 ( UP11 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris-Sud - Paris 11 ( UP11 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Imagerie Moléculaire et Stratégies Théranostiques - Clermont Auvergne ( IMoST ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Clermont Auvergne ( UCA ), Institut de cancérologie de l'Ouest - Nantes ( ICO Nantes ), CRLCC Paul Papin-CRLCC René Gauducheau, Centre de recherche de Cancérologie et d'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 ) -Institut de Recherche en Santé de l'Université de Nantes ( IRS-UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), Université de Nantes ( UN ), Médecine Personnalisée, Pharmacogénomique, Optimisation Thérapeutique ( MEPPOT - U1147 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Klinikum Wels Grieskirchen, Oncology department [Salzburg], Salzburger Landesklinikum - Uniklinikum Salzburg ( SALK ), Institute of Chemical Reaction Engineering, Hamburg University of Technology, Alfred-Wegener-Institut, Helmholtz-Zentrum für Polar- und Meeresforschung ( AWI ), Department of Medical Oncology, Medical University Vienna, Department of Internal Medicine, Hospital of Steyr, Department Internal Medicine 3, Centre for Hematology and Medical Oncology, General Hospital Linz, Department Medicine LKH, Institut für Festköperfirschung, Institut des Sciences Moléculaires de Marseille ( ISM2 ), Centre National de la Recherche Scientifique ( CNRS ) -Ecole Centrale de Marseille ( ECM ) -Aix Marseille Université ( AMU ), University Hospitals Leuven [Leuven], Katholieke Universiteit Leuven ( KU Leuven ), Pharmacology and Toxicology, Ahvaz Jundishapur University of Medical Sciences, Institut de Biologie Computationnelle ( IBC ), Centre de Coopération Internationale en Recherche Agronomique pour le Développement ( CIRAD ) -Institut National de la Recherche Agronomique ( INRA ) -Institut National de Recherche en Informatique et en Automatique ( Inria ) -Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut des Sciences Moléculaires ( ISM ), Université Montesquieu - Bordeaux 4-Université Sciences et Technologies - Bordeaux 1-École Nationale Supérieure de Chimie et de Physique de Bordeaux (ENSCPB)-Centre National de la Recherche Scientifique ( CNRS ), Faculty of Veterinary Medicine, Ghent University [Belgium] ( UGENT ), Medical Oncology, Antwerp University Hospital [Edegem], Recombinaison et Expression Génétique, Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre Hospitalier de L'Ardenne (Libramont), Department of Cardiology [Sivas, Turkey], Cumhuriyet University [Sivas, Turkey], Department of Earth Sciences, Durham University, Department of Oncology, Rigshospitalet [Copenhagen], Odense Hospital, CP Kelco ApS, Centre Hospitalier Universitaire de Reims ( CHU Reims ), Institut de Recherche en Cancérologie de Montpellier ( IRCM - U1194 Inserm - UM ), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ), Université du Québec à Montréal ( UQAM ), Université Panthéon-Sorbonne ( UP1 ), École nationale supérieure d'architecture de Nantes ( ENSA Nantes ), Department of Hepatogastroenterology and Oncology, Hopital Ambroise Pare, 9, Avenue Charles de Gaulle, 92104, Boulogne Cedex, France., Hôpital Ambroise Paré, CH Belfort-Montbéliard, Polyclinique Francheville, Institut de Cancérologie de la Loire Lucien Neuwirth, Centre Hospitalier Universitaire de Saint-Etienne ( CHU de Saint-Etienne ), Centre Hospitalier de Meaux, Service d'hématologie, Clinique Catherine de Sienne, Unité de recherche sur les Biopolymères, Interactions Assemblages ( BIA ), Institut National de la Recherche Agronomique ( INRA ), Université de la Méditerranée - Aix-Marseille 2, Centre hospitalier universitaire d'Amiens ( CHU Amiens-Picardie ), CHU Amiens-Picardie, Pôle oncologie médicale, Hôpital des Diaconesses, Génétique du cancer et des maladies neuropsychiatriques ( GMFC ), Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université de Bretagne Occidentale - École de sages-femmes ( UBO UFR MSS ESF ), Université de Brest ( UBO ) -Centre Hospitalier Régional Universitaire de Brest ( CHRU Brest ), Service d'oncologie digestive et hépato-gastro-entérologie [Hôpital de la Timone - APHM], Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ), Service d'Oncologie Médicale [Centre hospitalier Lyon Sud - HCL], Centre Hospitalier Lyon Sud [CHU - HCL] ( CHLS ), Hospices Civils de Lyon ( HCL ) -Hospices Civils de Lyon ( HCL ), Service d'Oncologie Médicale [CHU Saint -Antoine], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Saint-Antoine [APHP], Centre de Recherche Saint-Antoine ( CR Saint-Antoine ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ), Hôpital Saint-Louis, Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Diderot - Paris 7 ( UPD7 ), Service Gastro-Entérologie, CHU Besançon, Université de Franche-Comté ( UFC ) -Université de Franche-Comté ( UFC ), Centre Alexis Vautrin ( CAV ), Ecophysiologie Végétale, Agronomie et Nutritions ( EVA ), Université de Caen Normandie ( UNICAEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Institut National de la Recherche Agronomique ( INRA ), Image et ville ( IV ), Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique ( CNRS ), Département informatique ( INFO ), Université européenne de Bretagne ( UEB ) -Télécom Bretagne-Institut Mines-Télécom [Paris], Service de Gastro-entérologie [Avicenne], Université Paris 13 ( UP13 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Avicenne, Agence de l'Environnement et de la Maîtrise de l'Energie - ADEME, Service d'hépato-gastroentérologie, CHU Caen-Hôpital côte de nacre, Département de Médecine, Centre hospitalier de Libourne, Service d'Hépato-Gastro-Entérologie (CHU de Dijon), Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Fondation FondaMental, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor, Variabilité de réponse aux psychotropes ( VariaPsy - U1144 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Diderot - Paris 7 ( UPD7 ), Département d'oncologie digestive, Institut Bergonié - CRLCC Bordeaux, Hôpital St Joseph, Service de Gynécologie et d'Obstétrique ( CHU Lyon ), Hospices Civils de Lyon ( HCL ), Gastro - Entérologie et Nutrition, CHU Toulouse [Toulouse]-Hôpital de Rangueil, CHU Toulouse [Toulouse], Génétique, Immunothérapie, Chimie et Cancer ( GICC ), Université de Tours-Centre National de la Recherche Scientifique ( CNRS ), Université Montpellier 1 ( UM1 ), Service de gastro-entérologie - Hôpital Henri Mondor, Laboratoire Matière et Systèmes Complexes ( Laboratoire MSC ), Université Paris Diderot - Paris 7 ( UPD7 ) -UFR de Physique, France, Amériques, Espagne – Sociétés, pouvoirs, acteurs ( FRAMESPA ), Université Toulouse - Jean Jaurès ( UT2J ) -Centre National de la Recherche Scientifique ( CNRS ), Regional Hospital of Orleans, Histoire, Archéologie et littératures des Mondes chrétiens et musulmans médiévaux ( CIHAM ), École normale supérieure - Lyon ( ENS Lyon ) -Université Lumière - Lyon 2 ( UL2 ) -École des hautes études en sciences sociales ( EHESS ) -Université Jean Moulin - Lyon III ( UJML ) -Université d'Avignon et des Pays de Vaucluse ( UAPV ) -Centre National de la Recherche Scientifique ( CNRS ), Neurobiologie des signaux intercellulaires ( NSI ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Centre National de la Recherche Scientifique ( CNRS ), Dept Med Genet, Hôpital Erasme (Bruxelles), Polyclinique de Limoges - site François Chénieux [Limoges], Clinique Médicale B, CHU Strasbourg, Service de gastro-entérologie, Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Hôpital Jean Minjoz, Hôpital Européen [Fondation Ambroise Paré - Marseille], Asklepios Klinikum Uckermark GmbH, DESY, Notkestr 85, D-22607 Hamburg, Germany, NASA Ames Research Center ( ARC ), Department of Chemistry, Center for Structural Biology, Vanderbilt University [Nashville], Biostatistique et Processus Spatiaux ( BIOSP ), Institute of Ecology [Jena], Friedrich-Schiller-Universität Jena, University of Rostock [Germany], Universität Stuttgart [Stuttgart], Oneonta, Zentrum für Innere Medizin, Klinikum Schwäbisch Gmünd/Stauferklinik, Physiopathologie du stress pancréatique, Institut Armand Frappier ( INRS-IAF ), Institut National de la Recherche Scientifique [Québec] ( INRS ) -Réseau International des Instituts Pasteur ( RIIP ) -Institut Armand Frappier, Institut de Mathématiques de Marseille ( I2M ), Aix Marseille Université ( AMU ) -Ecole Centrale de Marseille ( ECM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre des Sciences du Goût et de l'Alimentation [Dijon] ( CSGA ), Institut National de la Recherche Agronomique ( INRA ) -Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique ( CNRS ), Department of Computer Science [Freiburg], University of Freiburg [Freiburg], Institut für Mathematik [Berlin], Technische Universität Berlin ( TUB ), Department of Information Engineering, Computer Science and Mathematics, Università degli Studi dell'Aquila [L'Aquila] ( UNIVAQ.IT ), Department of Animal Sciences, North Carolina Agricultural and Technical State University, FEEM, Romagna Cancer Registry, IRST, Luigi Pierantoni Hospital, Observatoire sociologique du changement ( OSC ), Sciences Po-Centre National de la Recherche Scientifique ( CNRS ), Dipartimento di Chimica, Fisica e Ambiente, Università degli Studi di Udine - University of Udine [Italie], Department of Nuclear Medicine, PET/CT Centre, Centre de Psychiatrie et Neurosciences ( CPN - U894 ), Clinica di Oncologia Medica, AO Ospedali Riuniti, Università Politecnica delle Marche [Ancona] ( UNIVPM ), Universidade Nova de Lisboa ( UNINOVA ), Ottawa Hospital Research Institute [Ottawa] ( OHRI ), Oncologia Medica, Ospedali Riuniti, Ospedale 'San Vincenzo', NIPE, CIPES, European Synchrotron Radiation Facility ( ESRF ), Departamento de Engenharia Informática, Faculdade de Engenharia [Porto] ( FEUP ), Universidade do Porto [Porto]-Universidade do Porto [Porto], 3Decide, Unité de recherche Amélioration, Génétique et Physiologie Forestières ( UAGPF ), Universidade Federal de Campina Grande [Campina Grande] ( UFCG ), Instituto de Engenharia de Sistemas e Computadores ( INESC ), Departamento de Ciências Biológicas, Universidade Regional do Cariri ( URCA Brasil ), Department of Biochemistry and Molecular Biology [Barcelona, Spain], Universitat de Barcelona ( UB ), Associated Unit to Consejo Superior de Investigaciones Científicas - CSIC [Barcelona, Spain], University of Barcelona-Institute of Biomedicine - IBUB [Barcelona, Spain], IRCELYON-Caractérisation et remédiation des polluants dans l'air et l'eau ( CARE ), Institut de recherches sur la catalyse et l'environnement de Lyon ( IRCELYON ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique ( CNRS ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique ( CNRS ), Laboratoire d'analyse et d'architecture des systèmes [Toulouse] ( LAAS ), Centre National de la Recherche Scientifique ( CNRS ) -Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National des Sciences Appliquées - Toulouse ( INSA Toulouse ), Institut National des Sciences Appliquées ( INSA ) -Institut National des Sciences Appliquées ( INSA ) -Institut National Polytechnique [Toulouse] ( INP ), Institut Charles Gerhardt Montpellier - Institut de Chimie Moléculaire et des Matériaux de Montpellier ( ICGM ICMMM ), Université Montpellier 1 ( UM1 ) -Université Montpellier 2 - Sciences et Techniques ( UM2 ) -Ecole Nationale Supérieure de Chimie de Montpellier ( ENSCM ) -Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Instituto de Ciencia de Materiales de Madrid [Madrid] ( ICMM ), Interactions, Corpus, Apprentissages, Représentations ( ICAR ), École normale supérieure - Lyon ( ENS Lyon ) -Université Lumière - Lyon 2 ( UL2 ) -INRP-Ecole Normale Supérieure Lettres et Sciences Humaines-Centre National de la Recherche Scientifique ( CNRS ), Institut d'Investigacions Biomèdiques August Pi i Sunyer ( IDIBAPS ), North Region Cancer Registry of Portugal, UMR 5805 Environnements et Paléoenvironnements Océaniques et Continentaux ( EPOC ), Observatoire aquitain des sciences de l'univers ( OASU ), Université Sciences et Technologies - Bordeaux 1-Institut national des sciences de l'Univers ( INSU - CNRS ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Sciences et Technologies - Bordeaux 1-Institut national des sciences de l'Univers ( INSU - CNRS ) -Centre National de la Recherche Scientifique ( CNRS ) -École pratique des hautes études ( EPHE ) -Centre National de la Recherche Scientifique ( CNRS ), Department of Paediatrics and Intensive Care, Hospital Universitari Sant Joan de Deu, Laboratoire de Psychologie Sociale ( LPS ), Aix Marseille Université ( AMU ), Universitat de València ( UV ), Instituto de Cienca de Materiales de Madrid [Madrid] ( ICMM ), Biology, New Mexico State University, New Mexico State University, Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ), Centre de recherche sur les Ions, les MAtériaux et la Photonique ( CIMAP - UMR 6252 ), Centre National de la Recherche Scientifique ( CNRS ) -Ecole Nationale Supérieure d'Ingénieurs de Caen ( ENSICAEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université de Caen Normandie ( UNICAEN ), Normandie Université ( NU ), Institut d'Electronique et de Télécommunications de Rennes ( IETR ), Université de Nantes ( UN ) -Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National des Sciences Appliquées - Rennes ( INSA Rennes ) -CentraleSupélec-Centre National de la Recherche Scientifique ( CNRS ), Computer Science Department - Carnegie Mellon University, University of Pittsburgh, Laboratoire de Sciences Actuarielle et Financière ( SAF ), Université de Lyon-Université de Lyon, Instituto de Oncologia Corachan ( IDOC ), Laboratoire d'informatique de l'école normale supérieure ( LIENS ), École normale supérieure - Paris ( ENS Paris ) -Centre National de la Recherche Scientifique ( CNRS ), Experimental Quantum Optics and Photonics Group, University of Strathclyde, Institut de recherches Asiatiques ( IrAsia ), Aix Marseille Université ( AMU ) -Centre National de la Recherche Scientifique ( CNRS ), Centre Européen de Réalité Virtuelle ( CERV ), École Nationale d'Ingénieurs de Brest ( ENIB ), Sol Agro et hydrosystème Spatialisation ( SAS ), Institut National de la Recherche Agronomique ( INRA ) -AGROCAMPUS OUEST, Grenoble Institut des Neurosciences ( GIN ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -CHU Grenoble-Université Joseph Fourier - Grenoble 1 ( UJF ), Centre de recherche cerveau et cognition ( CERCO ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Laboratoire Géomatériaux et Environnement ( LGE ), Université Paris-Est Marne-la-Vallée ( UPEM ), Hôpital Ambroise Paré [AP-HP], Université Paris-Saclay, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Ambroise Paré [AP-HP], Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Centre hépato-biliaire (CHB), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Université de Nantes (UN), Médecine Personnalisée, Pharmacogénomique, Optimisation Thérapeutique (MEPPOT - U1147), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Salzburger Landesklinikum - Uniklinikum Salzburg (SALK), Alfred-Wegener-Institut, Helmholtz-Zentrum für Polar- und Meeresforschung (AWI), Institut des Sciences Moléculaires de Marseille (ISM2), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-École Centrale de Marseille (ECM)-Institut de Chimie du CNRS (INC), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Institut de Biologie Computationnelle (IBC), Université de Montpellier (UM)-Institut National de la Recherche Agronomique (INRA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS), Institut des Sciences Moléculaires (ISM), Université Montesquieu - Bordeaux 4-Université Sciences et Technologies - Bordeaux 1-École Nationale Supérieure de Chimie et de Physique de Bordeaux (ENSCPB)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Universiteit Gent = Ghent University [Belgium] (UGENT), Antwerp University Hospital [Edegem] (UZA), Hillerød Hospital, Copenhagen University Hospital-Copenhagen University Hospital, Centre Hospitalier Universitaire de Reims (CHU Reims), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université du Québec à Montréal = University of Québec in Montréal (UQAM), Université Paris 1 Panthéon-Sorbonne (UP1), École nationale supérieure d'architecture de Nantes (ENSA Nantes), Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Unité de recherche sur les Biopolymères, Interactions Assemblages (BIA), Institut National de la Recherche Agronomique (INRA), Génétique du cancer et des maladies neuropsychiatriques (GMFC), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bretagne Occidentale - École de sages-femmes (UBO UFR MSS ESF), Université de Brest (UBO)-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), 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), Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Centre Alexis Vautrin (CAV), Ecophysiologie Végétale, Agronomie et Nutritions (EVA), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Recherche Agronomique (INRA), Image et ville (IV), Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS), Département informatique (INFO), Université européenne de Bretagne - European University of Brittany (UEB)-Télécom Bretagne-Institut Mines-Télécom [Paris] (IMT), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris 13 (UP13)-Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Agence de l'Environnement et de la Maîtrise de l'Energie (ADEME), Service d'Hépato-Gastro-Enterologie et Nutrition [CHU Caen], Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Centre Hospitalier Libourne, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Fondation FondaMental [Créteil], Variabilité de réponse aux Psychotropes (VariaPsy - U1144), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Bergonié [Bordeaux], UNICANCER-UNICANCER, Service de Gynécologie et d'Obstétrique (CHU Lyon), Hospices Civils de Lyon (HCL), Génétique, immunothérapie, chimie et cancer (GICC), UMR 7292 CNRS [2012-2017] (GICC UMR 7292 CNRS), Université de Tours-Centre National de la Recherche Scientifique (CNRS), Université Montpellier 1 (UM1), Service de gastro-entérologie [Henri Mondor AP-HP, Créteil], Hôpital Henri Mondor-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Matière et Systèmes Complexes (MSC (UMR_7057)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Hôpital privé Toulon Hyères : Sainte Marguerite, Clinique des Quatre Pavillons, Lormont, France, Neurobiologie des signaux intercellulaires (NSI), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB)-Faculté de Médecine [Bruxelles] (ULB), NASA Ames Research Center (ARC), Biostatistique et Processus Spatiaux (BioSP), Friedrich-Schiller-Universität = Friedrich Schiller University Jena [Jena, Germany], University of Rostock, State University of New York at Oneonta (SUNY Oneonta), State University of New York (SUNY), Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Armand Frappier (INRS-IAF), Réseau International des Instituts Pasteur (RIIP)-Institut National de la Recherche Scientifique [Québec] (INRS), Institut de Mathématiques de Marseille (I2M), Aix Marseille Université (AMU)-École Centrale de Marseille (ECM)-Centre National de la Recherche Scientifique (CNRS), Klinikum Deggendorf, Technische Universität Berlin (TU), Università degli Studi dell'Aquila (UNIVAQ), North Carolina A&T State University, University of North Carolina System (UNC)-University of North Carolina System (UNC), Observatoire sociologique du changement (OSC), Sciences Po (Sciences Po)-Centre National de la Recherche Scientifique (CNRS), Institut de psychiatrie et neurosciences (U894 / UMS 1266), Università Politecnica delle Marche [Ancona] (UNIVPM), Universidade Nova de Lisboa = NOVA University Lisbon (NOVA), Ottawa Hospital Research Institute [Ottawa] (OHRI), European Synchrotron Radiation Facility (ESRF), Departamento de Engenharia Informática [Porto], Faculdade de Engenharia da Universidade do Porto (FEUP), Universidade do Porto-Universidade do Porto, Universidade Federal de Campina Grande [Campina Grande] (UFCG), Instituto de Engenharia de Sistemas e Computadores (INESC), Universidade Regional do Cariri (URCA Brasil), Universitat de Barcelona (UB), IRCELYON-Catalytic and Atmospheric Reactivity for the Environment (CARE), Institut de recherches sur la catalyse et l'environnement de Lyon (IRCELYON), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Laboratoire d'analyse et d'architecture des systèmes (LAAS), Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse 1 Capitole (UT1), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées, Institut Charles Gerhardt Montpellier - Institut de Chimie Moléculaire et des Matériaux de Montpellier (ICGM ICMMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut de Chimie du CNRS (INC), Instituto de Ciencia de Materiales de Madrid (ICMM), Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), Interactions, Corpus, Apprentissages, Représentations (ICAR), École normale supérieure - Lyon (ENS Lyon)-Université Lumière - Lyon 2 (UL2)-INRP-Ecole Normale Supérieure Lettres et Sciences Humaines (ENS LSH)-Centre National de la Recherche Scientifique (CNRS), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), UMR 5805 Environnements et Paléoenvironnements Océaniques et Continentaux (EPOC), Observatoire aquitain des sciences de l'univers (OASU), Université Sciences et Technologies - Bordeaux 1-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Sciences et Technologies - Bordeaux 1-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Hospital Universitario de Valme, Anenida de Bellavista s/n, Sevilla 41014, Spain, Hospital Son Llatzer, Universitat de València (UV), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Hospital Universitari Son Espases, University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE)-Pennsylvania Commonwealth System of Higher Education (PCSHE), Instituto de Oncologia Corachan (IDOC), Laboratoire d'informatique de l'école normale supérieure (LIENS), École normale supérieure - Paris (ENS Paris), Institut de recherches Asiatiques (IrAsia), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Centre Européen de Réalité Virtuelle (CERV), École Nationale d'Ingénieurs de Brest (ENIB), Sol Agro et hydrosystème Spatialisation (SAS), Institut National de la Recherche Agronomique (INRA)-AGROCAMPUS OUEST, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de recherche cerveau et cognition (CERCO), Institut des sciences du cerveau de Toulouse. (ISCT), Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Géomatériaux et Environnement (LGE), Université Paris-Est Marne-la-Vallée (UPEM), Fédération Francophone de Cancérologie Digestive (FFCD), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Aix Marseille Université (AMU)-École Centrale de Marseille (ECM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Service d'Oncologie Médicale [CHU Saint-Antoine], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Institut National de la Recherche Agronomique (INRA)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Avicenne [AP-HP], Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor, Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP), Department of Information Engineering, Computer Science and Mathematics = Dipartimento di Ingegneria e Scienze dell'Informazione e Matematica [L'Aquila] (DISIM), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut Charles Gerhardt Montpellier - Institut de Chimie Moléculaire et des Matériaux de Montpellier (ICGM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Département d'informatique - ENS Paris (DI-ENS), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-École Centrale de Marseille (ECM)-Aix Marseille Université (AMU), Institute of Biomedicine - IBUB [Barcelona, Spain]-University of Barcelona, Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche en Informatique et en Automatique (Inria)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche en Informatique et en Automatique (Inria)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), AGROCAMPUS OUEST, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut National de la Recherche Agronomique (INRA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure de Chimie et de Physique de Bordeaux (ENSCPB)-Université Sciences et Technologies - Bordeaux 1-Université Montesquieu - Bordeaux 4-Institut de Chimie du CNRS (INC), AGROCAMPUS OUEST-Institut National de la Recherche Agronomique (INRA), Institut National de la Recherche Agronomique (INRA)-Physiologie Animale et Systèmes d'Elevage (PHASE), Institut National de la Recherche Agronomique (INRA)-Environnement et Agronomie (E.A.)-Biologie et Amélioration des Plantes (BAP)-Fourrages Environnement Ruminants Lusignan (FERLUS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Ambroise Paré, University of Florence (UNIFI), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Imagerie Moléculaire et Stratégies Théranostiques - Clermont Auvergne (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Institut de cancérologie de l'Ouest - Nantes (ICO Nantes), Université Montesquieu - Bordeaux 4-Université Sciences et Technologies - Bordeaux 1-École Nationale Supérieure de Chimie et de Physique de Bordeaux (ENSCPB)-Centre National de la Recherche Scientifique (CNRS), Ghent University [Belgium] (UGENT), CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université du Québec à Montréal (UQAM), Université Panthéon-Sorbonne (UP1), Centre hospitalier universitaire d'Amiens (CHU Amiens-Picardie), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Saint-Antoine [APHP], Centre de Recherche Saint-Antoine (CR Saint-Antoine), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Université de Franche-Comté (UFC)-Université de Franche-Comté (UFC), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris 13 (UP13)-Hôpital Avicenne, Optimisation Thérapeutique en Neuropsychopharmacologie (VariaPsy - U1144), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC), Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Hôpital Jean Minjoz, Biostatistique et Processus Spatiaux (BIOSP), Centre des Sciences du Goût et de l'Alimentation [Dijon] (CSGA), Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique (CNRS), Technische Universität Berlin (TUB), Università degli Studi dell'Aquila [L'Aquila] (UNIVAQ.IT), Universidade Nova de Lisboa (NOVA), Faculdade de Engenharia [Porto] (FEUP), Unité de recherche Amélioration, Génétique et Physiologie Forestières (UAGPF), IRCELYON-Caractérisation et remédiation des polluants dans l'air et l'eau (CARE), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse 1 Capitole (UT1)-Université Toulouse - Jean Jaurès (UT2J), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Consejo Superior de Investigaciones Científicas [Spain] (CSIC), École normale supérieure - Lyon (ENS Lyon)-Université Lumière - Lyon 2 (UL2)-INRP-Ecole Normale Supérieure Lettres et Sciences Humaines-Centre National de la Recherche Scientifique (CNRS), Université Sciences et Technologies - Bordeaux 1-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Sciences et Technologies - Bordeaux 1-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-École pratique des hautes études (EPHE)-Centre National de la Recherche Scientifique (CNRS), École normale supérieure - Paris (ENS Paris)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut des sciences du cerveau de Toulouse. (ISCT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse - Jean Jaurès (UT2J)-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-Institut National de la Santé et de la Recherche Médicale (INSERM), Emile, J, Julie, C, Le Malicot, K, Lepage, C, Tabernero, J, Mini, E, Folprecht, G, Van Laethem, J, Dimet, S, Boulagnon-Rombi, C, Allard, M, Penault-Llorca, F, Bennouna, J, Laurent-Puig, P, Taieb, J, Bidoli, P, Emile, J. -F., Julie, C., Le Malicot, K., Lepage, C., Tabernero, J., Mini, E., Folprecht, G., Van Laethem, J. -L., Dimet, S., Boulagnon-Rombi, C., Allard, M. -A., Penault-Llorca, F., Bennouna, J., Laurent-Puig, P., Taieb, J., Thaler, J., Greil, R., Gaenzer, J., Eisterer, W., Tschmelitsch, J., Keil, F., Samonigg, H., Zabernigg, A., Schmid, F., Steger, G., Steinacher, R., Andel, J., Jagdt, B., Lang, A., Fridrik, M., Fugger, R., Hofbauer, F., Woell, E., Geissler, D., Lenauer, A., Prager, M., D'Haens, G., Demolin, G., Kerger, J., Deboever, G., Ghillebert, G., Polus, M., Van Cutsem, E., Kalantari, H. R., Delaunoit, T., Goeminne, J. C., Peeters, M., Vergauwe, P., Houbiers, G., Humblet, Y., Janssens, J., Schrijvers, D., Vanderstraeten, E., Vermorken, J., Van Daele, D., Ferrante, M., Forget, F., Hendlisz, A., Yilmaz, M., Nielsen, S. E., Vestermark, L., Larsen, J., Zawadi, M. -A., Bouche, O., Mineur, L., Bennouna-Louridi, J., Dourthe, L. M., Ychou, M., Boucher, E., Pezet, D., Desseigne, F., Ducreux, M., Texereau, P., Miglianico, L., Rougier, P., Fratte, S., Levache, C. -B., Merrouche, Y., Ellis, S., Locher, C., Ramee, J. -F., Garnier, C., Viret, F., Chauffert, B., Cojean-Zelek, I., Michel, P., Lecaille, C., Borel, C., Seitz, J. -F., Smith, D., Lombard-Bohas, C., Andre, T., Gornet, J. -M., Fein, F., Coulon-Sfairi, M. -A., Kaminsky, M. -C., Lagasse, J. -P., Luet, D., Etienne, P. -L., Gasmi, M., Vanoli, A., Nguyen, S., Aparicio, T., Perrier, H., Stremsdoerfer, N., Laplaige, P., Arsene, D., Auby, D., Bedenne, L., Coriat, R., Denis, B., Geoffroy, P., Piot, G., Becouarn, Y., Bordes, G., Deplanque, G., Dupuis, O., Fruge, F., Guimbaud, R., Lecomte, T., Lledo, G., Sobhani, I., Asnacios, A., Azzedine, A., Desauw, C., Galais, M. -P., Gargot, D., Lam, Y. -H., Abakar-Mahamat, A., Berdah, J. -F., Catteau, S., Clavero-Fabri, M. -C., Codoul, J. -F., Legoux, J. -L., Goldfain, D., Guichard, P., Verge, D. P., Provencal, J., Vedrenne, B., Brezault-Bonnet, C., Cleau, D., Desir, J. -P., Fallik, D., Garcia, B., Gaspard, M. -H., Genet, D., Hartwig, J., Krummel, Y., Budnik, T. M., Palascak-Juif, V., Randrianarivelo, H., Rinaldi, Y., Aleba, A., Darut-Jouve, A., de Gramont, A., Hamon, H., Wendehenne, F., Matzdorff, A., Stahl, M. K., Schepp, W., Burk, M., Mueller, L., Geissler, M., Mantovani-Loeffler, L., Hoehler, T., Asperger, W., Kroening, H., von Weikersthal, L. F., Fuxius, S., Groschek, M., Meiler, J., Trarbach, T., Rauh, J., Ziegenhagen, N., Kretzschmar, A., Graeven, U., Nusch, A., von Wichert, G., Hofheinz, R. -D., Kleber, G., Schmidt, K. -H., Vehling-Kaiser, U., Baum, C., Schuette, J., Haag, G. M., Holtkamp, W., Potenberg, J., Reiber, T., Schliesser, G., Schmoll, H. -J., Schneider-Kappus, W., Abenhardt, W., Denzlinger, C., Henning, J., Marxsen, B., Derigs, H. G., Lambertz, H., Becker-Boost, I., Caca, K., Constantin, C., Decker, T., Eschenburg, H., Gabius, S., Hebart, H., Hoffmeister, A., Horst, H. -A., Kremers, S., Leithaeuser, M., Mueller, S., Wagner, S., Daum, S., Schlegel, F., Stauch, M., Heinemann, V., Maiello, E., Latini, L., Zaniboni, A., Amadori, D., Aprile, G., Barni, S., Mattioli, R., Martoni, A., Passalacqua, R., Nicolini, M., Pasquini, E., Rabbi, C., Aitini, E., Ravaioli, A., Barone, C., Biasco, G., Tamberi, S., Gambi, A., Verusio, C., Marzola, M., Lelli, G., Boni, C., Cascinu, S., Bidoli, P., Vaghi, M., Cruciani, G., Di Costanzo, F., Sobrero, A., Petrioli, R., Aglietta, M., Alabiso, O., Capuzzo, F., Falcone, A., Corsi, D. C., Labianca, R., Salvagni, S., Chiara, S., Ciuffreda, L., Ferrau, F., Giuliani, F., Lonardi, S., Gebbia, N., Mantovani, G., Sanches, E., Mellidez, J. C., Santos, P., Freire, J., Sarmento, C., Costa, L., Pinto, A. M., Barroso, S., Santo, J. E., Guedes, F., Monteiro, A., Sa, A., Furtado, I., Salazar, R., Aguilar, E. A., Herrero, F. R., Valera, J. S., Ayerbes, M. V., Batlle, J. F., Gil, S., Esteve, A. A., Garcia-Giron, C., Vivanco, G. L., Salvia, A. S., Orduna, V. A., Garcia, R. V., Gallego, J., Sureda, B. M., Remon, J., Safont Aguilera, M. J., Nogueras, L. C., Merino, B. Q., Castro, C. G., de Prado, P. M., Pericay, C. P., Figueiras, M. C., Jordan, I. G., Gome Reina, M. J., Garcia, A. L. -L., Garcia-Ramos, A. A., Cervantes, A., Martos, C. F., Gaspar, E. M., Montero, I. C., Emperador, P. E., Carbonero, A. L., Castillo, M. G., Garcia, T. G., Lopez, J. G., Flores, E. G., Morales, M. G., Munoz, M. L., Martin, A. L., Maurel, J., Camara, J. C., Garcia, R. D., Salgado, M., Busquier, I. H., Ruiz, T. C., Munoa, A. L., Aliguer, M. N., de Taranco, A. V. O., Urena, M. M., Gaspa, F. L., Ponce, J. J., Roig, C. B., Jimenez, P. V., Brotons, A. G., Rodriguez, S. A., Martinez, J. A., Ruiz, L. C., Ruiz, M. C., Bridgewater, J., Glynne-Jones, R., Tahir, S., Hickish, T., Cassidy, J., and Samuel, L.

Subjects
0301 basic medicine, Oncology, Male, Cancer Research, Organoplatinum Compounds, Colorectal cancer, medicine.medical_treatment, Medizin, Leucovorin, Prospective cohort study, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 0302 clinical medicine, FOLFOX, Organoplatinum Compounds/therapeutic use, Antineoplastic Combined Chemotherapy Protocols, tudy, Lymphocytes, Prospective Studies, Leucovorin/therapeutic use, Middle Aged, Prognosis, 3. Good health, Colorectal carcinoma, Fluorouracil, 030220 oncology & carcinogenesis, Predictive value of tests, Colonic Neoplasms, Biomarker (medicine), Lymphocytes/pathology, Female, Adjuvant, medicine.drug, Adult, medicine.medical_specialty, [SDV.CAN]Life Sciences [q-bio]/Cancer, Fluorouracil/therapeutic use, Biomarkers, Tumor/analysis, 03 medical and health sciences, Lymphocytes, Tumor-Infiltrating, Predictive Value of Tests, Biomarker, Immune response, Internal medicine, medicine, Biomarkers, Tumor, Humans, Survival analysis, Aged, business.industry, medicine.disease, Survival Analysis, Surgery, 030104 developmental biology, Prospective cohort&nbsp, Multivariate Analysis, Colonic Neoplasms/diagnosis, Antineoplastic Combined Chemotherapy Protocols/therapeutic use, business
Abstract

IF 6.029; International audience; BackgroundThe prognostic value of lymphocyte infiltration (LI) of colorectal carcinoma (CC) has been demonstrated by several groups. However, no validated test is currently available for clinical practice. We previously described an automated and reproducible method for testing LI and aimed to validate it for clinical use.Patients and methodsAccording to National Institutes of Health criteria, we designed a prospective validation of this biomarker in patients included in the PETACC8 phase III study. Primary objective was to compare percentage of patients alive and without recurrence at 2 years in patients with high versus low LI (#NCT02364024). Associations of LI with patient recurrence and survival were analysed, and multivariable models were adjusted for treatment and relevant factors. Automated testing of LI was performed on virtual slides without access to clinical data.ResultsAmong the 1220 CC patients enrolled, LI was high, low and not evaluable in 241 (19.8%), 790 (64.8%) and 189 (15.5%), respectively. Primary objective was met with a 2-year recurrence rate of 14.4% versus 21.1% in patients with high and low LI, respectively (p = 0.02). Patients with high LI also had better disease free survival (DFS) and overall survival (OS). Tumour stage, grade, RAS status and BRAF status were with LI the only prognostic markers in multivariable analysis for OS. Subgroup analyses revealed that high LI had better DFS and OS in mismatch repair (MMR) proficient patients, and in patients without RAS mutation, but not in MMR deficient and RAS mutated patients.ConclusionAlthough this is the first validation with high level of evidence (IIB) of the prognostic value of a LI test in colon cancers, it still needs to be confirmed in independent series of colon cancer patients.

Published
2017
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22. Guidelines for time-to-event end-point definitions in trials for pancreatic cancer. Results of the DATECAN initiative (Definition for the Assessment of Time-to-event End-points in CANcer trials)

Author

Manfred B. Lutz, Roberto Labianca, Patrick Pessaux, Bert A. Bonsing, Benoist Chibaudel, David Malka, Claudio Bassi, Sophie Gourgou-Bourgade, Geertjan van Tienhoven, Pascal Hammel, Carine Bellera, Laeticia Dahan, Jean-Luc Van Laethem, Daniela Aust, Emmanuel Chamorey, Jean Robert Delpero, Josep Tabernero, Adelaide Dousseau, Teresa Macarulla, Franck Bonnetain, Julien Taieb, Karin Haustermans, Laurence Collette, Thomas Aparicio, François Lacaine, John P. Neoptolemos, Simone Mathoulin-Pélissier, Bengt Glimelius, Thierry Conroy, Paula Ghaneh, Alain Sauvanet, Erich Gerber, Christos Dervenis, Aurélien Latouche, Murielle Mauer, Michel Ducreux, Valérie Jooste, Virginie Berger, Jocelyn Gal, Alain Hendlisz, Aimery de Gramont, Emmanuel Mitry, Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC (UR 3181) (CEF2P / CARCINO), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), UNICANCER, Leiden University Medical Center (LUMC), Maladies chroniques, santé perçue, et processus d'adaptation (APEMAC), Université Paris Descartes - Paris 5 (UPD5)-Université de Lorraine (UL), Institut de Cancérologie de Lorraine - Alexis Vautrin [Nancy] (UNICANCER/ICL), Université Victor Segalen - Bordeaux 2, CHU Bordeaux [Bordeaux], Uppsala Universitet [Uppsala], University Hospitals Leuven [Leuven], CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Service de Gastro-entérologie [Avicenne], Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Avicenne [AP-HP], Carl Gustav Carus University (DRESDEN - CGCU), Technische Universität Dresden = Dresden University of Technology (TU Dresden), G.B. Rossi Hospital, Verona University, Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Service d'Oncologie Médicale [CHU Saint-Antoine], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Cooperator Multidisciplinary Oncology Group (GERCOR), Service d'oncologie digestive et hépato-gastro-entérologie [Hôpital de la Timone - APHM], Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Agia Olga Hospital [Athènes] (Konstantopoulio ), Oncologie digestive, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Institut für Radioonkologie, Royal Liverpool University Hospital, University of Liverpool-Royal Liverpool and Broadgreen University Hospital NHS Trust, Service de Gastroentérologie [Hôpital Beaujon], Hôpital Beaujon [AP-HP], Institut Jules Bordet [Bruxelles], Registre Bourguignon des Cancers Digestifs, Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Azienda Ospedaleria Ospedali Riuniti di Bergamo, Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), CaritasKlinikum Saarbrücken, Vall d'Hebron University Hospital [Barcelona], European Organisation for Research and Treatment of Cancer [Bruxelles] (EORTC), European Cancer Organisation [Bruxelles] (ECCO), Institut Curie [Paris], CRLCC René Huguenin, L'Institut hospitalo-universitaire de Strasbourg (IHU Strasbourg), Institut National de Recherche en Informatique et en Automatique (Inria)-l'Institut de Recherche contre les Cancers de l'Appareil Digestif (IRCAD)-Les Hôpitaux Universitaires de Strasbourg (HUS)-La Fédération des Crédits Mutuels Centre Est (FCMCE)-L'Association pour la Recherche contre le Cancer (ARC)-La société Karl STORZ, Service d’Hépatologie [Hôpital Beaujon], Service de gastroenterologie [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Academisch Medisch Centrum bij, Universiteit van Amsterdam (UvA), Institut de recherche en cancérologie de Montpellier (IRCM - U896 Inserm - UM1), Université Montpellier 1 (UM1)-CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre d'Investigation Clinique - Epidemiologie Clinique / Essais Cliniques Bordeaux, Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Bergonié [Bordeaux], Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC ( CEF2P / CARCINO ), Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Université Bourgogne Franche-Comté ( UBFC ) -Université de Franche-Comté ( UFC ), Maladies chroniques, santé perçue, et processus d'adaptation. Approches épidémiologiques et psychologiques. ( APEMAC - EA 4360 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Université de Lorraine ( UL ), Institut de Cancérologie de Lorraine - Alexis Vautrin ( ICL ), CHU Tenon [APHP], Hôpital Erasme (Bruxelles), Université Paris 13 ( UP13 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Avicenne, Carl Gustav Carus University ( DRESDEN - CGCU ), Technische Universität Dresden ( TUD ), Institut de cancérologie de l'Ouest - Nantes ( ICO Nantes ), CRLCC Paul Papin-CRLCC René Gauducheau, CRLCC Antoine Lacassagne, Service d'Oncologie Médicale [CHU Saint -Antoine], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Saint-Antoine [APHP], Cooperator Multidisciplinary Oncology Group ( GERCOR ), Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ), Institut Paoli Calmettes, Agia Olga Hospital [Athènes] ( Konstantopoulio ), Institut Gustave Roussy ( IGR ) -Institut Gustave Roussy ( IGR ), Hôpital Beaujon, Institut Jules Bordet, Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ) -Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ) -Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Centre de recherche en épidémiologie et santé des populations ( CESP ), Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ) -Université Paris-Sud - Paris 11 ( UP11 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale ( INSERM ), European Organisation for Research and Treatment of Cancer [Bruxelles] ( EORTC ), European Cancer Organisation [Bruxelles] ( ECCO ), Institut Curie, L'Institut hospitalo-universitaire de Strasbourg ( IHU Strasbourg ), Institut National de Recherche en Informatique et en Automatique ( Inria ) -l'Institut de Recherche contre les Cancers de l'Appareil Digestif (IRCAD)-Les Hôpitaux Universitaires de Strasbourg (HUS)-La Fédération des Crédits Mutuels Centre Est (FCMCE)-L'Association pour la Recherche contre le Cancer (ARC)-La société Karl STORZ, Service de gastroenterologie [CHU Georges Pompidou], Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Universiteit van Amsterdam ( UvA ), Institut de recherche en cancérologie de Montpellier ( IRCM ), Université Montpellier 1 ( UM1 ) -CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ), Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut Bergonié - CRLCC Bordeaux, Universiteit Leiden, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Università degli studi di Verona = University of Verona (UNIVR), Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC (EA 3181) (CEF2P / CARCINO), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), and CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1)

Subjects
Oncology, Cancer Research, Pathology, Delphi Technique, MESH : Randomized Controlled Trials as Topic, MESH: Delphi Technique, MESH : Consensus, law.invention, Clinical trials, 0302 clinical medicine, Pancreatic cancer, Time to event end-point, Consensus, Guidelines, Methodology, Clinical trials, Randomized controlled trial, law, 030212 general & internal medicine, Time to event end-point, Randomized Controlled Trials as Topic, Event (probability theory), MESH: Endpoint Determination, [ SDV.SPEE ] Life Sciences [q-bio]/Santé publique et épidémiologie, 16. Peace & justice, 3. Good health, 030220 oncology & carcinogenesis, MESH : Disease-Free Survival, MESH : Endpoint Determination, MESH: Pancreatic Neoplasms, medicine.medical_specialty, Consensus, Endpoint Determination, Guidelines, Disease-Free Survival, 03 medical and health sciences, Internal medicine, Pancreatic cancer, medicine, Overall survival, Humans, MESH: Consensus, Distributed File System, neoplasms, MESH: Humans, End point, business.industry, MESH : Humans, Methodology, Cancer, medicine.disease, Pancreatic Neoplasms, Clinical trial, MESH: Randomized Controlled Trials as Topic, MESH : Delphi Technique, MESH: Disease-Free Survival, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, MESH : Pancreatic Neoplasms
Abstract

International audience; BACKGROUND:Using potential surrogate end-points for overall survival (OS) such as Disease-Free- (DFS) or Progression-Free Survival (PFS) is increasingly common in randomised controlled trials (RCTs). However, end-points are too often imprecisely defined which largely contributes to a lack of homogeneity across trials, hampering comparison between them. The aim of the DATECAN (Definition for the Assessment of Time-to-event End-points in CANcer trials)-Pancreas project is to provide guidelines for standardised definition of time-to-event end-points in RCTs for pancreatic cancer.METHODS:Time-to-event end-points currently used were identified from a literature review of pancreatic RCT trials (2006-2009). Academic research groups were contacted for participation in order to select clinicians and methodologists to participate in the pilot and scoring groups (>30 experts). A consensus was built after 2 rounds of the modified Delphi formal consensus approach with the Rand scoring methodology (range: 1-9).RESULTS:For pancreatic cancer, 14 time to event end-points and 25 distinct event types applied to two settings (detectable disease and/or no detectable disease) were considered relevant and included in the questionnaire sent to 52 selected experts. Thirty experts answered both scoring rounds. A total of 204 events distributed over the 14 end-points were scored. After the first round, consensus was reached for 25 items; after the second consensus was reached for 156 items; and after the face-to-face meeting for 203 items.CONCLUSION:The formal consensus approach reached the elaboration of guidelines for standardised definitions of time-to-event end-points allowing cross-comparison of RCTs in pancreatic cancer.

Published
2014
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23. Time to health-related quality of life score deterioration as a modality of longitudinal analysis for health-related quality of life studies in oncology: do we need RECIST for quality of life to achieve standardization?

Author

Sophie Paget-Bailly, Pascal Auquier, Amélie Anota, Virginie Westeel, Christophe Borg, Caroline Bascoul-Mollevi, Franck Bonnetain, Frédéric Fiteni, Benoist Chibaudel, Zeinab Hamidou, Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC (UR 3181) (CEF2P / CARCINO), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Cooperator Multidisciplinary Oncology Group (GERCOR), Service d'Oncologie Médicale [CHU Saint-Antoine], 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), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut du Cancer de Montpellier (ICM), Centre d'études et de recherche sur les services de santé et la qualité de vie (CEReSS), Aix Marseille Université (AMU), Service de Pneumologie, oncologie thoracique et allergologie respiratoire [CHRU Besançon], Service d'Oncologie Médicale [CHRU Besançon], KARLI, Mélanie, Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC (EA 3181) (CEF2P / CARCINO), Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), 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), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
Adult, Oncology, Gerontology, medicine.medical_specialty, Standardization, Health Status, Quantitative Methods Special Section, Health-related quality of life, MEDLINE, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Context (language use), Deoxycytidine, Clinical trials, Quality of life (healthcare), [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, medicine, Humans, Longitudinal Studies, Response Evaluation Criteria in Solid Tumors, Aged, Health Services Needs and Demand, Modality (human–computer interaction), business.industry, Public health, Public Health, Environmental and Occupational Health, Longitudinal analysis, Middle Aged, Gemcitabine, humanities, 3. Good health, Pancreatic Neoplasms, Clinical trial, Time to deterioration, Disease Progression, Quality of Life, Female, Colorectal Neoplasms, business
Abstract

Purpose Longitudinal analysis of health-related quality of life (HRQoL) remains unstandardized and compromises comparison of results between trials. In oncology, despite available statistical approaches, results are poorly used to change standards of care, mainly due to lack of standardization and the ability to propose clinical meaningful results. In this context, the time to deterioration (TTD) has been proposed as a modality of longitudinal HRQoL analysis for cancer patients. As for tumor response and progression, we propose to develop RECIST criteria for HRQoL. Methods Several definitions of TTD are investigated in this paper. We applied this approach in early breast cancer and metastatic pancreatic cancer with a 5-point minimal clinically important difference. In breast cancer, TTD was defined as compared to the baseline score or to the best previous score. In pancreatic cancer (arm 1: gemcitabine with FOLFIRI.3, arm 2: gemcitabine alone), the time until definitive deterioration (TUDD) was investigated with or without death as event. Results In the breast cancer study, 381 women were included. The median TTD was influenced by the choice of the reference score. In pancreatic cancer study, 98 patients were enrolled. Patients in Arm 1 presented longer TUDD than those in Arm 2 for most of HRQoL scores. Results of TUDD were slightly different according to the definition of deterioration applied. Conclusion Currently, the international ARCAD group supports the idea of developing RECIST for HRQoL in pancreatic and colorectal cancer with liver metastasis, with a view to using HRQoL as a co-primary endpoint along with a tumor parameter. Electronic supplementary material The online version of this article (doi:10.1007/s11136-013-0583-6) contains supplementary material, which is available to authorized users.

Published
2013
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24. PRODIGE 34-FFCD 1402-ADAGE Adjuvant chemotherapy in elderly patients ă with resected stage III colon cancer: A randomized phase 3 trial

Author

Aparicio, Thomas, Francois, Eric, Cristol-Dalstein, Laurence, Carola, Elisabeth, Maillard, Emilie, Paillaud, Elena, Retornaz, Frederique, Faroux, Roger, André, Thierry, Bedenne, Laurent, Seitz, Jean-François, Service de Gastro-entérologie [Avicenne], Université Paris 13 ( UP13 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Avicenne, Centre Antoine Lacassagne, CRLCC Antoine Lacassagne, UNICANCER - Institut régional du Cancer [Montpellier] ( ICM ), CRLCC Val d'Aurelle - Paul Lamarque, CH Creil/Senlis, Fédération Francophone de la Cancérologie Digestive, FFCD, Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Unité de médecine gériatrique ( Gériatrie - Henri Mondor ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, Centre Gérontologique Départemental de Marseille ( CGD 13 ), Service de chirurgie digestive (CH de La Roche-sur-Yon), Centre Hospitalier Départemental - Hôpital de La Roche-sur-Yon, Service d'Oncologie Médicale [CHU Saint -Antoine], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Saint-Antoine [APHP], Centre de Recherche Saint-Antoine ( CR Saint-Antoine ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service d'Hépato-Gastro-Entérologie (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Service d'oncologie digestive et hépato-gastro-entérologie [Hôpital de la Timone - APHM], Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris 13 (UP13)-Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), Université Côte d'Azur (UCA)-UNICANCER, UNICANCER - Institut régional du Cancer Montpellier Val d'Aurelle (ICM), Lipides - Nutrition - Cancer (U866) (LNC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Unité de médecine gériatrique (Gériatrie - Henri Mondor), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, Centre Gérontologique Départemental de Marseille (CGD 13), Service d'Oncologie Médicale [CHU Saint-Antoine], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Avicenne [AP-HP], UNICANCER-Université Côte d'Azur (UCA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)

Subjects
[ SHS.PSY ] Humanities and Social Sciences/Psychology, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, [ SDV.MHEP.PSM ] Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, [SHS.PSY]Humanities and Social Sciences/Psychology, [ SHS.ECO ] Humanities and Social Sciences/Economies and finances, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, [ SDV.SPEE ] Life Sciences [q-bio]/Santé publique et épidémiologie, [SHS.ECO]Humanities and Social Sciences/Economics and Finance, Quality, ComputingMilieux_MISCELLANEOUS
Abstract

International audience; no abstract

Published
2016

25. PEPCOL: a GERCOR randomized phase II study of nanoliposomal irinotecan PEP02 (MM-398) or irinotecan with leucovorin/5-fluorouracil as second-line therapy in metastatic colorectal cancer

Author

Chibaudel, Benoist, Maindrault-Goebel, Frédérique, Bachet, Jean-Baptiste, Louvet, Christophe, Khalil, Ahmed, Dupuis, Olivier, Hammel, Pascal, Garcia, Marie-Line, Bennamoun, Mostefa, Brusquant, David, Tournigand, Christophe, André, Thierry, Arbaud, Claire, Larsen, Annette K, Wang, Yi-Wen, Yeh, C. Grace, Bonnetain, Franck, de Gramont, Aimery, Service d'Oncologie Médicale [Institut Hospitalier Franco-Britannique], Division of Medical Oncology - Institut Hospitalier Franco-Britannique, CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), AAREC Filia Research (AFR), 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), Service d'Hépato-Gastro-Entérologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [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), Service d'Oncologie Médicale [Montsouris], Institut Mutualiste de Montsouris (IMM), Service d'Oncologie médicale [CHU Tenon], CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'Oncologie médicale [Clinique Victor Hugo], Clinique Victor Hugo, Service de Gastroentérologie [Hôpital Beaujon], Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'Oncologie médicale [CHU Henri Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Henri Mondor, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), PharmaEngine, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Henri Mondor [Créteil], Service d'Oncologie Médicale [CHU Saint-Antoine], and HAL UPMC, Gestionnaire

Subjects
Male, Sucrose, [SDV.SP.MED] Life Sciences [q-bio]/Pharmaceutical sciences/Medication, MM398, Leucovorin, [SDV.CAN]Life Sciences [q-bio]/Cancer, Irinotecan, nanoliposomal irinotecan, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.SP.MED]Life Sciences [q-bio]/Pharmaceutical sciences/Medication, Antineoplastic Combined Chemotherapy Protocols, Humans, Neoplasm Metastasis, Original Research, Cancer Biology, Aged, Aged, 80 and over, PEP02, Middle Aged, phase II, Combined Modality Therapy, Colorectal cancer, digestive system diseases, Drug Combinations, Treatment Outcome, Retreatment, Quality of Life, Camptothecin, Female, Fluorouracil, Colorectal Neoplasms
Abstract

International audience; A multicenter, open-label, noncomparative, randomized phase II study (PEPCOL) was conducted to evaluate the efficacy and safety of the irinotecan or PEP02 (MM-398, nanoliposomal irinotecan) with leucovorin (LV)/5-fluorouracil (5-FU) combination as second-line treatment in patients with metastatic colorectal cancer (mCRC). Patients with unresectable mCRC who had failed one prior oxaliplatin-based first-line therapy were randomized toirinotecan with LV/5-FU (FOLFIRI) or PEP02 with LV/5-FU (FUPEP; PEP02 80mg/m2 with LV 400mg/m2 on day 1 and 5-FU 2400mg/m2 on days 1–2). Bevacizumab (5mg/kg, biweekly) was allowed in both arms. The primary endpoint was 2-month response rate (RR). Fifty-five patients were randomized (FOLFIRI, n=27; FUPEP, n=28). In the intent-to-treat population (n=55), 2-month RR response rate was observed in two (7.4%) and three (10.7%) patients in the FOLFIRI and FUPEP arms, respectively. The most common grade 3–4 adverse events reported in the respective FOLFIRI and FUPEP arms were diarrhea (33% vs. 21%), neutropenia (30% vs. 11%), mucositis (11% vs. 11%), and grade 2 alopecia (26% vs. 25%). FUPEP has activity and acceptable safety profile in oxaliplatin-pretreated mCRC patients.

Published
2016
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26. New Therapeutic Opportunities Based on DNA Mismatch Repair and BRAF Status in Metastatic Colorectal Cancer

Author

Chantal Dreyer, Pascale Cervera, Marc Pocard, Alex Duval, Aimery de Gramont, Jean-François Fléjou, Thierry André, Romain Cohen, Magali Svrcek, HAL-UPMC, Gestionnaire, Service d'Oncologie Médicale [CHU Saint-Antoine], 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), Service de Pathologie [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), Université Pierre et Marie Curie - Paris 6 (UPMC), Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cooperator Multidisciplinary Oncology Group (GERCOR), Service de Chirurgie d'Oncologie Digestive [CHU Lariboisière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'Oncologie Médicale [Institut Hospitalier Franco-Britannique], Division of Medical Oncology - Institut Hospitalier Franco-Britannique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Service d'Oncologie Médicale [CHU Saint -Antoine]

Subjects
0301 basic medicine, MAPK/ERK pathway, Proto-Oncogene Proteins B-raf, Colorectal cancer, medicine.medical_treatment, [SDV.CAN]Life Sciences [q-bio]/Cancer, medicine.disease_cause, DNA Mismatch Repair, Targeted therapy, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, PD-L1, Antineoplastic Combined Chemotherapy Protocols, Biomarkers, Tumor, Medicine, Humans, Molecular Targeted Therapy, Mutation, biology, business.industry, Microsatellite instability, medicine.disease, Prognosis, PD-1, PD-L1, Immune checkpoint, digestive system diseases, 3. Good health, 030104 developmental biology, BRAF mutation, Oncology, 030220 oncology & carcinogenesis, Cancer research, biology.protein, DNA mismatch repair, business, Colorectal Neoplasms
Abstract

International audience; Recently, colorectal cancer (CRC) subtyping consortium identified four consensus molecular subtypes (CMS1–4). CMS1 is enriched for deficient mismatch repair (dMMR) and BRAF V600E tumors. Intriguingly, this subtype has better relapse-free survival but worse overall survival after relapse compared with the other subtypes. Growing evidence is accumulating on the benefit of specific therapeutic strategies such as immune checkpoint inhibition therapy in dMMR tumors and mitogen-activated protein kinase (MAPK) pathway targeted therapy in tumors harboring BRAF V600E mutation. After reviewing dMMR prognostic value, immune checkpoints as major targets for dMMR carcinomas will be highlighted. Following, BRAF V600E prognostic impact will be reviewed and therapeutic strategies with the combination of cytotoxic agents and especially the combinations of BRAF and MAPK inhibitors will be discussed.

Published
2016
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27. ERCC1, XRCC1 and GSTP1 Single Nucleotide Polymorphisms and Survival of Patients with Colon Cancer Receiving Oxaliplatin-Based Adjuvant Chemotherapy

Author

Christophe Louvet, Aimery de Gramont, Claire Goumard, Pierre Laurent-Puig, Julien Taieb, Jean-François Emile, Pierre Validire, Claire Calmel, Jean-François Fléjou, Hélène Blons, Aziz Zaanan, Françoise Praz, Cécile Dalban, Khalid Alhazmi, Melek Istanbullu, HAL UPMC, Gestionnaire, Université Paris Descartes - Paris 5 (UPD5), Cancer Research and Personalized Medicine - CARPEM [Paris], Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de gastroenterologie [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Service Biostatistiques et Informatique Médicale (CHU de Dijon) (DIM), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Biomarqueurs et essais cliniques en Cancérologie et Onco-Hématologie (BECCOH), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay, Service de pathologie [CHU Ambroise Paré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Ambroise Paré [AP-HP], Service de biologie [CHU HEGP], Service de Pathologie [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), Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Département d'Anatomo-Pathologie, Paris, Dpt pathologie, Institut Mutualiste de Montsouris (IMM), Service d'Oncologie Médicale [Montsouris], Service d'Oncologie Médicale [CHU Saint-Antoine], 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), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-CHU Necker - Enfants Malades [AP-HP], Service d'Oncologie Médicale [CHU Saint -Antoine], Université Paris Descartes - Paris 5 ( UPD5 ), Hôpital Européen Georges Pompidou [APHP] ( HEGP ) -CHU Cochin [AP-HP]-Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -CHU Necker - Enfants Malades [AP-HP], Centre de Recherche Saint-Antoine ( CR Saint-Antoine ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service de gastroenterologie [CHU Georges Pompidou], Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Service Biostatistiques et Informatique Médicale (CHU de Dijon) ( DIM ), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Laboratoire épidémiologie et oncogénèse des tumeurs digestives, Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Ambroise Paré, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Saint-Antoine [APHP], Institut Mutualiste de Montsouris ( IMM ), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
medicine.medical_specialty, XRCC1, [SDV.SP.MED] Life Sciences [q-bio]/Pharmaceutical sciences/Medication, Colorectal cancer, medicine.medical_treatment, Single-nucleotide polymorphism, [SDV.CAN]Life Sciences [q-bio]/Cancer, Gastroenterology, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, polymorphism, GSTP1, FOLFOX, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.SP.MED]Life Sciences [q-bio]/Pharmaceutical sciences/Medication, Internal medicine, medicine, Lymph node, Chemotherapy, business.industry, [ SDV.SP.MED ] Life Sciences [q-bio]/Pharmaceutical sciences/Medication, adjuvant FOLFOX, medicine.disease, 3. Good health, Oxaliplatin, medicine.anatomical_structure, Oncology, colon cancer, Immunology, ERCC1, business, Research Paper, medicine.drug
Abstract

International audience; Background: While single nucleotide polymorphisms (SNP) in genes involved in DNA repair or drug metabolism have been shown to influence survival of metastatic colon cancer patients treated with FOLFOX, data on adjuvant setting are scarce.Methods: This study evaluated the correlation between disease-free survival (DFS) of 210 unselected stage III colon cancer patients receiving FOLFOX chemotherapy, and ERCC1-118 (rs11615, c.354T>C), XRCC1-399 (rs25487, c.1196G>A) and GSTP1-105 (rs1695, c.313A>G) polymorphisms. SNP were determined on tumor DNA using a PCR-based RFLP technique.Results: In univariate analysis, a trend towards longer DFS was observed for ERCC1 (C/T + T/T) versus (C/C) (HR=2.29; p=0.06), and XRCC1 (A/A) versus (G/G + G/A) (HR=1.61; p=0.16), but not for GSTP1 genotypes; a statistically significant p value was obtained when combining ERCC1 and XRCC1 favorable genotypes (0 versus ≥ 1 favorable genotypes, HR=2.42; p=0.02). After adjustment on tumor stage, lymph node ratio and differentiation grade, multivariate analysis showed that combining ERCC1 and XRCC1 genotypes gave a p value slightly above the threshold for statistical significance (HR=2.03; p=0.06), which was lower than for tumor stage, lymph node ratio or differentiation grade.Conclusion: The association of ERCC1 and XRCC1 polymorphisms may influence the prognosis of stage III colon cancer patients treated with FOLFOX adjuvant chemotherapy. Yet, these findings need to be confirmed in independent prospective studies.

Published
2014
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28. Fusions NTRK : une nouvelle piste dans les cancers digestifs ?

Author

Frédérique Penault-Llorca, Magali Svrcek, Anna Pellat, Romain Cohen, Thierry André, Kaïssa Ouali, Service d'Oncologie Médicale [CHU Saint-Antoine], 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), Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, and CCSD, Accord Elsevier

Subjects
0301 basic medicine, Cancer Research, Colorectal cancer, [SDV]Life Sciences [q-bio], [SDV.CAN]Life Sciences [q-bio]/Cancer, Entrectinib, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Pancreatic cancer, medicine, Radiology, Nuclear Medicine and imaging, Larotrectinib, medicine.diagnostic_test, business.industry, Cancer, Microsatellite instability, Hematology, General Medicine, medicine.disease, 3. Good health, [SDV] Life Sciences [q-bio], 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Trk receptor, Cancers digestifs, Cancer research, business, Tyrosine kinase, Neurotrophic Tropomyosin Receptor Kinase (NTRK), Fluorescence in situ hybridization
Abstract

International audience; The advent of molecular biology resulted in the discovery of new oncogenes that have led to the development of targeted therapies for the management of cancer patients. The development of these therapies has improved the prognosis of patients in various tumour localizations. The TRK receptor (tropomyosin receptor kinase) is a transmembrane receptor with a tyrosine kinase activity that plays a role in both cell proliferation and the physiology of the nervous system. Fusions involving the NTRK gene, which codes for this receptor, have been found in different types of solid tumours and lead to its constitutional activation. These fusions, however uncommon, are mainly found in rare pediatric tumours but can also be encountered in digestive cancers with high prevalence (such as colorectal cancer, especially in case of microsatellite instability, with a frequency of 2.5 to 38.5 %) or in aggressive cancers (such as pancreatic cancer). Therapies targeting TRK, such as larotrectinib or entrectinib, have shown significant response rates, usually greater than 6 months, for tumours from various primary sites presenting NTRK fusions and refractory to standard therapies. These fusions can be detected by different methods: immunohistochemistry, FISH (fluorescence in situ hybridization) as well as NGS (next generation sequencing). The intent of this review is to report on current knowledge on NTRK fusions in oncology and to discuss the role of these fusions in digestive cancers and potential therapeutic implications.

Published
2020
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29. Patients atteints d’un cancer gastrique localisé MSI/dMMR, pas de chimiothérapie mais une immunothérapie périopératoire : l’essai de phase II GERCOR NEONIPIGA vient d’être ouvert au recrutement

Author

Thierry André, Aziz Zaanan, Christophe Borg, Alex Duval, David Tougeron, Marine Jary, Rosine Guimbaud, Lea Clavel, Romain Cohen, Thomas Aparicio, Antoine Adenis, Christophe Louvet, Christophe Tournigand, Benoist Chibaudel, Jaafar Benouna, Marie-Line Garcia-Larnicol, Xavier Dray, Harry Sokol, Magali Svrcek, Thomas Pudlarz, Dewi Vernerey, Guillaume Piessen, 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), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), Cooperator Multidisciplinary Oncology Group (GERCOR), Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté]), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital Claude Huriez [Lille], CHU Lille, Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Université Sorbonne Paris Cité (USPC), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Mutualiste de Montsouris (IMM), Service d'Oncologie médicale [CHU Henri Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Henri Mondor, Centre hospitalier universitaire de Poitiers (CHU Poitiers), CHU Toulouse [Toulouse], Centre hospitalier universitaire de Nantes (CHU Nantes), Institut du Cancer de Montpellier (ICM), 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), Service de Gastroentérologie et nutrition [CHU Saint-Antoine], Site de Recherche Intégrée en Cancérologie (SIRIC-ONCOLille), Université de Lille, Sciences et Technologies-Université de Lille, Sciences Humaines et Sociales-Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université Lille Nord de France (COMUE)-UNICANCER-Université Lille Nord de France (COMUE)-UNICANCER-Cancéropole Nord-Ouest-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Instabilité des microsatellites et cancers [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)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], and Service de Pathologie [CHU Saint-Antoine]

Subjects
0301 basic medicine, Cancer Research, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Ipilimumab, 03 medical and health sciences, 0302 clinical medicine, medicine, Radiology, Nuclear Medicine and imaging, 10. No inequality, Syndrome de Lynch, Gynecology, business.industry, Hematology, General Medicine, Instabilité des microsatellites, 3. Good health, Lynch syndrome, Nivolumab, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Microsatellite instability, Cancer de l’estomac, Gastric cancer, business, medicine.drug
Abstract

International audience; IntroductionPerioperative chemotherapy is the standard strategy for localized gastric cancers. Nevertheless, this strategy seems to be inefficient, if not deleterious, for patients with tumors harboring microsatellite instability (MSI) and/or mismatch repair deficiency (dMMR), a tumor phenotype predictive for the efficacy of immune checkpoint inhibitors (ICKi).AimThe GERCOR NEONIPIGA single-arm phase II study (NCT04006262; EUDRACT 2018-004712-22) aims at evaluating the efficacy of a peri-operative strategy with nivolumab and ipilimumab in neoadjuvant setting, then nivolumab alone after surgery for patients with resectable MSI/dMMR gastric cancer.Material and methodsMain inclusion criteria are: gastric and oesogastric junction adenocarcinoma (GOA), T2-T4, all N stage and M0, MSI/dMMR. Patients will be treated with nivolumab 240 mg Q2 W, 6 infusions, and ipilimumab 1 mg/kg Q6 W, 2 infusions in neoadjuvant setting. Following surgery, patients with TRG 1-2-3 (Mandard tumor regression grade), acceptable tolerance of neoadjuvant treatment and postoperative ECOG performance status 0–1, will be treated with adjuvant nivolumab 480 mg Q4 W, 9 infusions.ResultsThe primary endpoint is pathological complete response rate (pCR-R). Based on a Fleming design, with α = 5% and β = 20%, 27 patients have to be evaluated (H0 = 5%; H1 = 20%). Secondary endpoints include disease-free survival, overall survival and safety.ConclusionThis study is planned to include 32 patients to evaluate the pCR-R with the combination of nivolumab and ipilimumab in neoadjuvant setting for MSI/dMMR localized GOA. The MSI/MMR status should be systematically assessed on diagnostic biopsies of all GOA. If it meets its primary endpoint, the GERCOR NEONIPIGA study might mark a turning point in the management of localized MSI/dMMR GOA patients.; IntroductionLa chimiothérapie périopératoire est la stratégie de référence pour les cancers gastriques (CG) localisés, mais semble inefficace voire délétère pour les patients avec un cancer MSI/dMMR (microsatellites instables/MMR-déficient), biomarqueur prédictif de l’efficacité de l’immunothérapie.ObjectifL’essai de phase 2 mono-bras GERCOR NEONIPIGA (NCT04006262; EUDRACT 2018-004712-22) évalue l’efficacité du nivolumab plus ipilimumab en néo-adjuvant puis nivolumab seul en adjuvant pour les CG ou de la jonction œsogastrique (JOG) MSI/dMMR résécables.Matériel et méthodesLes principaux critères d’inclusion sont : CG/JOG, T2-4 tout N M0, MSI/dMMR. Les patients sont traités en néo-adjuvant par nivolumab 240 mg Q2 W, 6 perfusions, et ipilimumab 1 mg/kg Q6 W, deux injections. Les patients avec un degré de régression tumorale 1-3 selon Mandard, une tolérance acceptable du traitement néo-adjuvant et un indice de performance postopératoire ECOG 0-1 recevront neuf perfusions mensuelles de nivolumab 480 mg en adjuvant.RésultatsL’objectif principal est le taux de réponse complète pathologique (pCR). Selon un design de Fleming avec α = 5 % et β = 20 %, 27 patients évaluables sont à analyser (H0 = 5 % ; H1 = 20 %). Les critères secondaires de jugement sont la survie sans maladie, la survie globale et le profil de tolérance.ConclusionIl est prévu d’inclure 32 patients pour évaluer le taux de pCR pour les CG/JOG MSI/dMMR traités par nivolumab et ipilimumab néo-adjuvant. Le statut MSI/MMR doit être systématiquement analysé sur les biopsies diagnostiques de tout CG/JOG. L’étude NEONIPIGA pourrait marquer un tournant dans la prise en charge des CG/JOG MSI/dMMR si elle atteint son objectif principal.

Published
2020
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30. Bevacizumab as adjuvant treatment of colon cancer: updated results from the S-AVANT phase III study by the GERCOR Group

Author

Roberto Buzzoni, W.P. Yong, S. Reingold, Joseph McKendrick, G.J.M. Creemers, Fernando Rivera, Dewi Vernerey, David Cunningham, G. Ravit, E. Van Cutsem, Jin-Tung Liang, A. de Gramont, Pia Österlund, G. Bodoky, Thierry André, J. Tabernero, W. Scheithauer, Randi Isaacs, Manel Rakez, S-A. Im, G. Fountzilas, 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), Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), HUS Comprehensive Cancer Center, Department of Oncology, and Clinicum

Subjects
0301 basic medicine, medicine.medical_specialty, CARCINOMA, Organoplatinum Compounds, Bevacizumab, IRINOTECAN, [SDV]Life Sciences [q-bio], 3122 Cancers, Leucovorin, STAGE-II, CAPECITABINE, Sudden death, Gastroenterology, Disease-Free Survival, 03 medical and health sciences, 0302 clinical medicine, adjuvant, Interquartile range, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Adjuvant therapy, Humans, XELOX, OXALIPLATIN, Neoplasm Staging, Performance status, business.industry, Hazard ratio, Hematology, CHEMOTHERAPY, OPEN-LABEL, Chemotherapy regimen, 3. Good health, Oxaliplatin, FOLFOX, 030104 developmental biology, colon cancer, Oncology, Chemotherapy, Adjuvant, 030220 oncology & carcinogenesis, Colonic Neoplasms, TRIAL, Fluorouracil, business, medicine.drug
Abstract

Background The bevacizumab-Avastin® adjuVANT (AVANT) study did not meet its primary end point of improving disease-free survival (DFS) with the addition of bevacizumab to oxaliplatin-based chemotherapy in stage III colon cancer (CC). We report here the long-term survival results (S-AVANT). Patients and methods Patients with curatively resected stage III CC were randomly assigned to FOLFOX4, FOLFOX4-bevacizumab, or XELOX-bevacizumab. Results A total of 2867 patients were randomized: FOLFOX4: n = 955, FOLFOX4-bevacizumab: n = 960, XELOX-bevacizumab: n = 952. With a median of 6.73 years follow-up (interquartile range 5.51–10.54), 672 patients died, of whom 198 (20.7%), 250 (26.0%), and 224 (23.5%) were in the FOLFOX4, FOLFOX4-bevacizumab, and XELOX-bevacizumab arms, respectively. The 10-year overall survival (OS) rates were 74.6%, 67.2%, and 69.9%, (P = 0.003) and 5-year disease-free survival (DFS) rates were 73.2%, 68.5%, and 71.0% (P = 0.174), respectively. OS and DFS hazard ratios were 1.29 [95% confidence interval (CI) 1.07–1.55; P = 0.008] and 1.16 (95% CI 0.99–1.37; P = 0.063) for FOLFOX4-bevacizumab versus FOLFOX4 and 1.15 (95% CI 0.95–1.39; P = 0.147) and 1.1 (95% CI 0.93–1.29; P = 0.269) for XELOX-bevacizumab versus FOLFOX4, respectively. CC-related deaths (n = 542) occurred in 157 (79.3%) patients receiving FOLFOX4, 205 (82.0%) receiving FOLFOX4-bevacizumab, and 180 (80.4%) receiving XELOX-bevacizumab (P = 0.764), while non-CC-related deaths occurred in 41 (20.7%), 45 (18.0%), and 44 (19.6%) patients, respectively. Cardiovascular-related and sudden deaths during treatment or follow-up were reported in 13 (6.6%), 17 (6.8%), and 14 (6.3%) patients, in the FOLFOX4, FOLFOX4-bevacizuamb, and XELOX-bevacizumab arms, respectively (P = 0.789). Treatment arm, sex, age, histological differentiation, performance status, T/ N stages, and localization of primary tumor were independent prognostic factors of OS in stage III. Conclusions S-AVANT confirms the initial AVANT report. No benefit of the bevacizumab addition to FOLFOX4 adjuvant therapy in patients with stage III CC was observed in terms of DFS with a negative effect in OS, without increase in non-CC related deaths. Clinical trial identification NCT00112918.

Published
2020
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31. Ascites and resistance to immune checkpoint inhibition in dMMR/MSI-H metastatic colorectal and gastric cancers

Author

Fucà, Giovanni, Cohen, Romain, Lonardi, Sara, Shitara, Kohei, Elez, Elena, Fakih, Marwan, Chao, Joseph, Klempner, Samuel J., Emmett, Matthew, Jayachandran, Priya, Bergamo, Francesca, García, Marc Díez, Mazzoli, Giacomo, Provenzano, Leonardo, Colle, Raphael, Svrcek, Magali, Ambrosini, Margherita, Randon, Giovanni, Shah, Aakash Tushar, Salati, Massimiliano, Fenocchio, Elisabetta, Salvatore, Lisa, Chida, Keigo, Kawazoe, Akihito, Conca, Veronica, Curigliano, Giuseppe, Corti, Francesca, Cremolini, Chiara, Overman, Michael, Andre, Thierry, Pietrantonio, Filippo, Universitat Autònoma de Barcelona, Fondazione IRCCS Istituto Nazionale Tumori - National Cancer Institute [Milan], Service d'Oncologie Médicale [CHU Saint-Antoine], 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), Instabilité des microsatellites et cancers [CRSA], 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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Veneto Institute of Oncology IOV-IRCCS [Padua, Italy], Department of Gastroenterology and Gastrointestinal Oncology [Kashiwa, Japon], National Cancer Center Hospital East, Vall d'Hebron Institute of Oncology [Barcelone] (VHIO), Vall d'Hebron University Hospital [Barcelona], City of Hope Comprehensive Cancer Center [Duarte], Massachusetts General Hospital [Boston], Harvard Medical School [Boston] (HMS), USC/Norris Comprehensive Cancer Center, University of Southern California (USC), Baylor College of Medicine (BCM), Baylor University, Università degli Studi di Modena e Reggio Emilia = University of Modena and Reggio Emilia (UNIMORE), Candiolo Cancer Institute (IRCCS), Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Azienda Ospedaliero-Universitaria Pisana [Pisa, Italy], Department of Translational Research on New Technologies in Medicine and Surgery, University of Pisa - Università di Pisa, European Institute of Oncology [Milan] (ESMO), Università degli Studi di Milano = University of Milan (UNIMI), The University of Texas M.D. Anderson Cancer Center [Houston], Gestionnaire, Hal Sorbonne Université, Institut Català de la Salut, [Fucà G] Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. [Cohen R] Sorbonne Université, Department of Medical Oncology, Hôpital Saint-Antoine, APHP and INSERM, Unité Mixte de Recherche Scientifique 938, Centre de Recherche Saint-Antoine, Equipe Instabilité des Microsatellites et Cancer, Equipe labellisée par la Ligue Nationale contre le Cancer, Paris, France. [Lonardi S] Medical Oncology 3 Medical Oncology 1, Istituto Oncologico Veneto IOV-IRCSS, Padua, Italy. [Shitara K] Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan. [Elez ME, Díez García M] Servei d’Oncologia Mèdica, Vall d'Hebron Hospital Universitari, Barcelona, Spain. Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. [Fakih M] Department of Medical Oncology and Therapeutic Research, City of Hope Comprehensive Cancer Center, Duarte, California, USA, and Vall d'Hebron Barcelona Hospital Campus

Subjects
Male, Cancer Research, Immunology, Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores], [SDV.CAN]Life Sciences [q-bio]/Cancer, gastrointestinal neoplasms, immunotherapy, translational medical research, tumor biomarkers, Other subheadings::Other subheadings::/drug therapy [Other subheadings], Còlon - Càncer - Tractament, Neoplasms::Neoplasms by Site::Digestive System Neoplasms::Gastrointestinal Neoplasms::Intestinal Neoplasms::Colorectal Neoplasms [DISEASES], [SDV.CAN] Life Sciences [q-bio]/Cancer, Stomach Neoplasms, Recte - Càncer - Tractament, Immunology and Allergy, Humans, Neoplasm Metastasis, Immune Checkpoint Inhibitors, RC254-282, Aged, Retrospective Studies, Pharmacology, Settore MED/06 - ONCOLOGIA MEDICA, acciones y usos químicos::acciones farmacológicas::usos terapéuticos::antineoplásicos [COMPUESTOS QUÍMICOS Y DROGAS], Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Ascites, Tumor biomarkers, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, neoplasias::neoplasias por localización::neoplasias del sistema digestivo::neoplasias gastrointestinales::neoplasias intestinales::neoplasias colorrectales [ENFERMEDADES], Gastrointestinal neoplasms, Survival Analysis, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, afecciones patológicas, signos y síntomas::procesos patológicos::ascitis [ENFERMEDADES], Oncology, Molecular Medicine, Female, Microsatellite Instability, Immunotherapy, Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Antineoplastic Agents [CHEMICALS AND DRUGS], Translational medical research, [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy, Colorectal Neoplasms, Pathological Conditions, Signs and Symptoms::Pathologic Processes::Ascites [DISEASES]
Abstract

BackgroundDespite unprecedented benefit from immune checkpoint inhibitors (ICIs) in patients with mismatch repair deficient (dMMR)/microsatellite instability high (MSI-H) advanced gastrointestinal cancers, a relevant proportion of patients shows primary resistance or short-term disease control. Since malignant effusions represent an immune-suppressed niche, we investigated whether peritoneal involvement with or without ascites is a poor prognostic factor in patients with dMMR/MSI-H metastatic colorectal cancer (mCRC) and gastric cancer (mGC) receiving ICIs.MethodsWe conducted a global multicohort study at Tertiary Cancer Centers and collected clinic-pathological data from a cohort of patients with dMMR/MSI-H mCRC treated with anti-PD-(L)1 ±anti-CTLA-4 agents at 12 institutions (developing set). A cohort of patients with dMMR/MSI-high mGC treated with anti-PD-1 agents±chemotherapy at five institutions was used as validating dataset.ResultsThe mCRC cohort included 502 patients. After a median follow-up of 31.2 months, patients without peritoneal metastases and those with peritoneal metastases and no ascites had similar outcomes (adjusted HR (aHR) 1.15, 95% CI 0.85 to 1.56 for progression-free survival (PFS); aHR 0.96, 95% CI 0.65 to 1.42 for overall survival (OS)), whereas inferior outcomes were observed in patients with peritoneal metastases and ascites (aHR 2.90, 95% CI 1.70 to 4.94; aHR 3.33, 95% CI 1.88 to 5.91) compared with patients without peritoneal involvement. The mGC cohort included 59 patients. After a median follow-up of 17.4 months, inferior PFS and OS were reported in patients with peritoneal metastases and ascites (aHR 3.83, 95% CI 1.68 to 8.72; aHR 3.44, 95% CI 1.39 to 8.53, respectively), but not in patients with only peritoneal metastases (aHR 1.87, 95% CI 0.64 to 5.46; aHR 2.15, 95% CI 0.64 to 7.27) when compared with patients without peritoneal involvement.ConclusionsPatients with dMMR/MSI-H gastrointestinal cancers with peritoneal metastases and ascites should be considered as a peculiar subgroup with highly unfavorable outcomes to current ICI-based therapies. Novel strategies to target the immune-suppressive niche in malignant effusions should be investigated, as well as next-generation ICIs or intraperitoneal approaches.

Published
2022
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32. Neoadjuvant nivolumab plus ipilimumab and adjuvant nivolumab in patients (pts) with localized microsatellite instability-high (MSI)/mismatch repair deficient (dMMR) oeso-gastric adenocarcinoma (OGA): The GERCOR NEONIPIGA phase II study

Author

Thierry Andre, David Tougeron, Guillaume Piessen, Christelle De La Fouchardiere, Christophe Louvet, Antoine Adenis, Marine Jary, Christophe Tournigand, Thomas Aparicio, Jérôme Desrame, Astrid Lièvre, Marie-Line Garcia-Larnicol, Thomas Pudlarz, Julie Henriques, Romain Cohen, Jérémie Lefevre, Magali Svrcek, CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Léon Bérard [Lyon], Institut Mutualiste de Montsouris (IMM), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Oncogenesis, Stress, Signaling (OSS), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], Chemistry, Oncogenesis, Stress and Signaling (COSS), Instabilité des microsatellites et cancers [CRSA], 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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Bristol-Myers Squibb, Fondation ARCAD, GERCOR, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), and Service d'Anatomie et cytologie pathologiques [CHU Saint-Antoine]

Subjects
Cancer Research, Oncology, [SDV.CAN]Life Sciences [q-bio]/Cancer
Abstract

244 Background: In pts with resectable gastric adenocarcinoma or OGA, radical surgery is the only curative option and perioperative chemotherapy seems worthless for those with MSI/dMMR tumors. Methods: We conducted phase II study evaluating the efficacy of neo-adjuvant nivolumab and ipilimumab followed by adjuvant nivolumab in pts with resectable MSI/dMMR, T2-T4 NxM0 tumors. Treatment consisted of nivolumab 240 mg every 2 weeks (6 infusions) and ipilimumab 1 mg/kg every 6 weeks (2 infusions), followed by radical surgery 5 weeks (±1 week) after last injection of nivolumab. Pts with Becker tumor regression grade (TRG) < 3 were treated with adjuvant nivolumab 480 mg every 4 weeks (9 infusions). The primary objective was pathological complete response (pCR) rate. Results: From 10/2019 to 06/2021, a total of 32 pts were enrolled (all had dMMR±MSI-H status; 16 with gastric cancer and 16 with OGA). The median age was 65.5 years (range, 40-80). Initial stage was: usT3Nx = 22, usT2Nx = 4, and usTxNx = 6 (not evaluable by ultrasound endoscopy). At data lock, 32 pts had terminated neo-adjuvant period and 27 (84%) completed all 6 neo-adjuvant cycles. 8 pts (32%) experienced G3/4 adverse events (AEs) during neo-adjuvant treatment. 29 pts underwent surgery; 2 refused surgery and had complete endoscopic response with tumor-free biopsies, 1 had surgery not performed in relation with a metastatic progression. The median delay between last injection and surgery was 35 days (extreme, 25-170). Overall surgical morbidity (54%, n = 14) was related to: anastomotic leakage = 4, pancreatitis = 2, pneumonia = 2, and other = 6. The incidence of post-operative mortality was 3.8% (n = 1) due to cardiovascular AE at post-operative day 3. All the 29 pts who underwent surgery had R0 resection: 17 (59%) had pCR (i.e., TRG 1a as per Becker grade, ypT0N0) and 4 (14%) had TRG 1b as per Beker grade (< 10% residual tumor per tumor bed). 1 pt had TRG 2 (10-50% of residual tumor) and 7 pts had TRG 3 (˃50% of residual tumor) as per Becker grade, per local pathological assessment (central pathological review is awaited). With a median follow-up of 10.9 months, 1 pt had metastatic relapse, 1 pt died without relapse and 30 pts were recurrence/progression-free. Conclusions: Neo-adjuvant therapy with nivolumab and ipilimumab is feasible and is associated with a high pCR rate in pts with MSI/dMMR resectable OGA. Data will be updated for the congress. Clinical trial information: NCT04006262.

Published
2022
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33. Ovarian metastases of pancreatic adenocarcinoma: clinical presentation, role of surgery, and potential value of the mutational profile for the differential diagnosis with primary mucinous ovarian carcinoma

Author

Magali Svrcek, Thierry André, François Paye, Anne Kerbaol, Pascal Hammel, Jérôme Cros, Sandra Granier, Alice de Malet, Louis de Mestier, Nathalie Théou-Anton, Safi Dokmak, Hôpital Paul Brousse, Service de Pathologie [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), Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Service de chirurgie générale et digestive [CHU Saint-Antoine], and Service d'Oncologie Médicale [CHU Saint -Antoine]

Subjects
Pathology, medicine.medical_specialty, [SDV.CAN]Life Sciences [q-bio]/Cancer, 03 medical and health sciences, 0302 clinical medicine, ovarian metastases, Ovarian carcinoma, medicine, Ovarian Mucinous Carcinoma, RC254-282, Original Research, Pancreas adenocarcinoma, molecular testing, business.industry, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, KRAS mutation, Histology, ovarian mucinous carcinoma, medicine.disease, 3. Good health, pancreas adenocarcinoma, Oncology, 030220 oncology & carcinogenesis, Adenocarcinoma, 030211 gastroenterology & hepatology, Presentation (obstetrics), Differential diagnosis, business, Kras mutation
Abstract

Background: Ovarian metastases (OM) of pancreatic adenocarcinoma (PA) (OM-PA) can mimic primary ovarian mucinous carcinoma (POMC) on imaging and histology. These metastases are often symptomatic and not highly chemosensitive, so that oophorectomy may be considered. Aims: The aims of this study were to compare the characteristics of OM-PA and POMC, and discuss the role of surgery. Patients and Methods: Clinical, imaging, and histological data of patients with OM-PA and POMC (2000–2017) in three tertiary centers were reviewed. Twenty-six genes were analyzed by next generation sequencing (NGS) on both primary PA and OM-PA. Results: Twenty-two women with OM-PA ( n = 13, 11 with surgical resection) or POMC ( n = 9) were selected. OM-PA were smaller than POMC ( p = 0.02); imaging, histological, and immunohistochemistry data did not clearly differentiate OM-PA from POMC in 12 of 22 cases (54%). Seven PA/OM-PA pairs were analyzed, and a concordant KRAS mutation was identified in all cases. In four OM-PA, concordant mutations were also found in TP53 ( n = 3), SMAD4 ( n = 1), MET ( n = 1), and PDGFRA ( n = 1) genes. The aim of oophorectomy in 11 OM-PA was for antalgic ( n = 6) or curative ( n = 5) intent. Pain improved in 4/6 of the former patients, but 2/6 had significant morbidity, and 2/6 died of rapid tumor progression. After oophorectomy, median progression-free and overall survivals were 6 (0–11) and 8 months (1–131), respectively. Conclusion: Analysis of mutation profiles in both primary PA and ovarian tumors, especially KRAS, can help to determine the pancreatic origin of OM-PA. Surgical resection of OM-AP in highly selected patients may improve pelvic symptoms but may also cause significant morbidity. The benefit to survival requires further studies.

Published
2021
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34. Letter to the Editor from Colle et al

Author

Raphael Colle, Thierry André, Yves Menu, 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), Sorbonne Université - Faculté de Médecine (SU FM), and Sorbonne Université (SU)

Subjects
0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, tumor, Letter to the editor, Colorectal cancer, [SDV]Life Sciences [q-bio], Immunology, gastrointestinal neoplasms, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Immunology and Allergy, Medicine, In patient, Pseudoprogression, Objective response, RC254-282, Pharmacology, business.industry, Tumor shrinkage, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Microsatellite instability, biomarkers, medicine.disease, genome instability, 3. Good health, 030104 developmental biology, 030220 oncology & carcinogenesis, Cohort, genetic markers, Molecular Medicine, immunotherapy, business
Abstract

In their article, Fucà et al highlight that early tumor shrinkage and depth of response predict the prognosis of patients with metastatic colorectal cancer (mCRC) microsatellite instability (MSI-H)/deficient mismatch repair (dMMR) treated by immune checkpoint inhibitors (ICI). We are surprised that no cases of pseudoprogression (PSPD) were reported in their study. PSPDs were described under ICI in patients treated for MSI/dMMR mCRC. In a cohort of 123 patients treated with anti-PD1±antiCTL-4 for MSI/dMMR mCRC, we reported 12 patients with PSPD, representing 10% of the cohort. Of 12 patients with PSPD, 8 secondary achieved an objective response and were alive and free of progression at the data lock. Conversely, in Fucà’s article, no PSDP was observed and the patients with primary radiological progression (21.7%) had a poor overall survival. These differences between the two series could be probably explained by the following points. First, Fucà et al use RECIST 1.1 criteria for radiological evaluation. Second, the first imaging was done after 8–9 weeks of treatment in Fucà’s article, which may be late to detect PSPD. In conclusion, if the first evaluation is made during the first 3 months of treatment, using iRECIST criteria seems mandatory to avoid stopping treatment prematurely, especially in patients receiving anti-PD1 alone.

Published
2021
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35. Centralized multidisciplinary team assessment of metastasis resectability in patients with metastatic colorectal cancer: A fundamental necessity

Author

Thierry André, Service d'Oncologie Médicale [CHU Saint -Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)

Subjects
medicine.medical_specialty, Colorectal cancer, business.industry, Health Policy, General surgery, [SDV.CAN]Life Sciences [q-bio]/Cancer, medicine.disease, Multidisciplinary team, 3. Good health, Metastasis, 03 medical and health sciences, 0302 clinical medicine, Oncology, 030220 oncology & carcinogenesis, Commentary, Internal Medicine, medicine, In patient, 030212 general & internal medicine, Public aspects of medicine, RA1-1270, business, ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2021
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36. Microsatellite instability in stage III colon cancer patients receiving fluoropyrimidine ± oxaliplatin: an

Author

Cohen, Romain, Taieb, Julien, Fiskum, Jack, Yothers, Greg, Goldberg, Richard, Yoshino, Takayuki, Alberts, Steven, Allegra, Carmen, De Gramont, Aimery, Seitz, Jean-Francois, O'Connell, Michael, Haller, Daniel, Wolmark, Norman, Erlichman, Charles, Zaniboni, Alberto, Lonardi, Sara, Kerr, Rachel, Grothey, Axel, Sinicrope, Franck, André, Thierry, Shi, Qian, 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), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Mayo Clinic [Rochester], University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE), Center for Climate Systems Research [New York] (CCSR), Columbia University [New York], University of Tokyo [Kashiwa Campus], The University of Florida College of Medicine, Service d'Oncologie Médicale [Institut Hospitalier Franco-Britannique], Division of Medical Oncology - Institut Hospitalier Franco-Britannique, Service d'oncologie digestive et hépato-gastro-entérologie [Hôpital de la Timone - APHM], Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Hospital of the University of Pennsylvania (HUP), Perelman School of Medicine, University of Pennsylvania [Philadelphia]-University of Pennsylvania [Philadelphia], Fondazione Poliambulanza, Veneto Institute of Oncology IOV-IRCCS [Padua, Italy], University of Oxford [Oxford], and West German Cancer Center [Essen, Germany]

Subjects
deficient mismatch repair, oxaliplatin, microsatellite instability, [SDV.CAN]Life Sciences [q-bio]/Cancer, prognosis, neoplasms, digestive system diseases, Colon cancer
Abstract

International audience; PURPOSE:In patients with stage III colon cancer (CC) whose tumors demonstrate microsatellite instability (MSI), the efficacy of adjuvant fluoropyrimidine (FP) with or without oxaliplatin has not been clearly demonstrated and the prognostic value of MSI remains uncertain.MATERIALS AND METHODS:Individual patient data from the ACCENT database were used to evaluate the effect of FP with or without oxaliplatin on disease-free survival (DFS) and overall survival (OS) among patients with MSI stage III CC and the prognostic value of MSI in patients treated with FP plus oxaliplatin, by stratified Cox models adjusted for demographic and clinicopathological factors.RESULTS:MSI status was available for 5,457 patients (609 MSI, 11.2%; 4848 microsatellite stable [MSS], 88.8%) from 12 randomized clinical trials (RCTs). Oxaliplatin significantly improved OS of MSI patients from the two RCTs testing FP with or without oxaliplatin (n = 185; adjusted hazard ratio [aHR] = 0.52, 95% CI, 0.28 to 0.93). Among the 4,250 patients treated with FP plus oxaliplatin (461 MSI and 3789 MSS), MSI was associated with better OS in the N1 group compared with MSS (aHR = 0.66; 95% CI, 0.46 to 0.95) but similar survival in the N2 population (aHR = 1.13; 95% CI, 0.86 to 1.48; P interaction = .029). The main independent prognosticators of MSI patients treated with FP plus oxaliplatin were T stage (aHR = 2.09; 95% CI, 1.29 to 3.38) and N stage (aHR = 3.57; 95% CI, 2.32 to 5.48). Similar results were observed for DFS in all analyses.CONCLUSION:Adding oxaliplatin to FP improves OS and DFS in patients with MSI stage III CC. Compared with MSS, MSI patients experienced better outcomes in the N1 group but similar survival in the N2 group.

Published
2021
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37. Molecular Targets for the Treatment of Metastatic Colorectal Cancer

Author

Jean-François Delattre, Thierry André, Raphael Colle, Romain Cohen, Thomas Pudlarz, Service d'Oncologie Médicale [CHU Saint -Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)

Subjects
0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, Colorectal cancer, medicine.drug_class, [SDV]Life Sciences [q-bio], colorectal cancer, [SDV.CAN]Life Sciences [q-bio]/Cancer, Review, Monoclonal antibody, lcsh:RC254-282, BRAF, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, HER2, medicine, HER2 Amplification, neoplasms, Predictive biomarker, business.industry, Microsatellite instability, ctDNA, medicine.disease, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, digestive system diseases, 3. Good health, 030104 developmental biology, 030220 oncology & carcinogenesis, Molecular targets, microsatellite instability, business, NTRK
Abstract

Over the past years, colorectal cancer (CRC) was subtyped according to its molecular and genetic characteristics, allowing the development of therapeutic strategies, based on predictive biomarkers. Biomarkers such as microsatellite instability (MSI), RAS and BRAF mutations, HER2 amplification or NTRK fusions represent major tools for personalized therapeutic strategies. Moreover, the routine implementation of molecular predictive tests provides new perspectives and challenges for the therapeutic management of CRC patients, such as liquid biopsies and the reintroduction of anti-EGFR monoclonal antibodies. In this review, we summarize the current landscape of targeted therapies for metastatic CRC patients, with a focus on new developments for EGFR blockade and emerging biomarkers (MSI, HER2, NTRK).

Published
2020
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38. Immunotherapy for Early Stage Colorectal Cancer: A Glance into the Future

Author

Thierry André, Romain Cohen, Qian Shi, 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), Sorbonne Université (SU), and Mayo Clinic [Rochester]

Subjects
0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, Colorectal cancer, medicine.medical_treatment, [SDV]Life Sciences [q-bio], stage III, Disease, Review, immunoscore, lcsh:RC254-282, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Medicine, Stage (cooking), business.industry, mismatch repair deficiency, oxaliplatin, Microsatellite instability, Cancer, Immunotherapy, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, 3. Good health, Oxaliplatin, Clinical trial, 030104 developmental biology, 030220 oncology & carcinogenesis, microsatellite instability, business, medicine.drug
Abstract

International audience; Immune checkpoint inhibitors (ICI) have reshaped therapeutic strategies for cancer patients. The development of ICI for early stage colorectal cancer is accompanied by specific challenges: (i) the selection of patients who are likely to benefit from these treatments, i.e., patients with tumors harboring predictive factors of efficacy of ICI, such as microsatellite instability and/or mismatch repair deficiency (MSI/dMMR), or other potential parameters (increased T cell infiltration using Immunoscore® or others, high tumor mutational burden, POLE mutation), (ii) the selection of patients at risk of disease recurrence (poor prognostic features), and (iii) the choice of an accurate clinical trial methodological framework. In this review, we will discuss the ins and outs of clinical research of ICI for early stage MSI/dMMR CC patients in adjuvant and neoadjuvant settings. We will then summarize data that might support the development of ICI in localized colorectal cancer beyond MSI/dMMR.

Published
2020
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39. Treatments after Immune Checkpoint Inhibitors in Patients with dMMR/MSI Metastatic Colorectal Cancer

Author

Quang Loc Bui, Léo Mas, Antoine Hollebecque, David Tougeron, Christelle de la Fouchardière, Thomas Pudlarz, Emily Alouani, Rosine Guimbaud, Julien Taieb, Thierry André, Raphaël Colle, Romain Cohen, HAL-SU, Gestionnaire, Service d'Oncologie Médicale [CHU Saint-Antoine], 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), Bach Mai Hospital [Hanoi], Vietnam National University [Hanoï] (VNU), Institut Gustave Roussy (IGR), Département d’Innovation Thérapeutique et essais précoces [Gustave Roussy] (DITEP), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Centre Léon Bérard [Lyon], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Instabilité des microsatellites et cancers [CRSA], Centre de Recherche Saint-Antoine (CRSA), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)

Subjects
Cancer Research, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Oncology, mismatch repair deficiency, metastatic colorectal cancer, microsatellite instability, chemotherapy after immunotherapy, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282, Article, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, digestive system diseases
Abstract

Simple Summary Several studies suggested an enhanced efficacy of conventional treatments (CT, i.e., chemotherapy +/− targeted therapy) administered after immune checkpoint inhibitors (ICI) in certain tumor types, but no data are available concerning metastatic colorectal cancer (mCRC) patients harboring mismatch repair deficiency/microsatellite instability (dMMR/MSI). The aim of our study was to assess the outcomes of dMMR/MSI mCRC patients receiving CT after ICI failure. We retrospectively collected clinical data from a multicentric cohort of 31 patients. Although limited by the small number of patients, our results did not suggest improved outcomes with CT in our population, and no significant association with previous ICI efficacy or with anti-VEGF agents was evidenced. However, prolonged disease control was observed in several cases, suggesting that some patients might derive an unexpected benefit from post-ICI treatments. With ICI becoming the standard of care in patients newly diagnosed with dMMR/MSI mCRC, these results might help to inform clinical decision-making and to guide future therapeutic strategies for these patients. Abstract Background: Several studies reported improved outcomes with conventional treatments (CT, i.e., chemotherapy ± targeted therapy) administered after immune checkpoints inhibitors (ICI) in certain tumor types. No data are available concerning patients (pts) with metastatic colorectal cancer (mCRC) harboring mismatch repair deficiency/microsatellite instability (dMMR/MSI). We aimed to assess the outcomes of dMMR/MSI mCRC pts receiving CT after ICI failure. Methods: We conducted a retrospective multicenter study investigating the outcomes of all dMMR/MSI mCRC pts who received post-ICI CT between 2015 and 2020. Results: 31 pts (male 61%, median age 56 years) were included. ICI was an anti-PD(L)1 monotherapy in 71% of pts, and 61% received >2 lines before post-ICI CT. The overall response rate and disease control rate were 13% and 45%, with a median progression-free survival (PFS) and overall survival of 2.9 and 7.4 months, respectively. No association of the outcomes with either ICI efficacy or anti-angiogenic agents was observed. Prolonged PFS (range 16.1–21.3 months) was observed in 4 pts (13%). Conclusions: Although conducted on a limited number of patients, our results do not support an association of previous ICI treatment with an enhanced efficacy of CT in dMMR/MSI mCRC. However, prolonged disease control was observed in several cases, suggesting that some pts might derive an unexpected benefit from post-ICI treatments.

Published
2022
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40. Evaluation of the prognostic impact of pathologic response to preoperative chemotherapy using Mandard’s Tumor Regression Grade (TRG) in gastric adenocarcinoma

Author

Thibault Voron, Thierry André, François Paye, Julien Taieb, Anne Berger, Simon Derieux, Sarah Manela, Magali Svrcek, Christine Lagorce-Pagès, Service de chirurgie générale et digestive [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), Service de Pathologie [CHU Saint-Antoine], and Service d'Oncologie Médicale [CHU Saint -Antoine]

Subjects
Adult, Male, Oncology, medicine.medical_specialty, Multivariate analysis, Databases, Factual, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Adenocarcinoma, Disease-Free Survival, 03 medical and health sciences, 0302 clinical medicine, Gastrectomy, Stomach Neoplasms, Internal medicine, Adjuvant therapy, Humans, Preoperative chemotherapy, Medicine, Aged, Retrospective Studies, Tumor Regression Grade, Chemotherapy, Hepatology, business.industry, Gold standard, Gastroenterology, Cancer, Middle Aged, Prognosis, medicine.disease, Combined Modality Therapy, Neoadjuvant Therapy, 3. Good health, Treatment Outcome, Chemotherapy, Adjuvant, 030220 oncology & carcinogenesis, Multivariate Analysis, Female, 030211 gastroenterology & hepatology, France, Neoplasm Grading, business
Abstract

Background Perioperative chemotherapy is the gold standard in gastric cancer management. The prognostic significance of pathological response has been investigated in many malignancies, using Tumor Regression Grade (TRG). Its prognostic value in gastric cancer remains poorly known. Aims This study aimed to assess the prognostic value of pathological response to chemotherapy, using Mandard’s TRG in gastric cancer, and to identify factors predictive of response to chemotherapy. Methods We retrospectively identified patients with gastric adenocarcinoma from two institutional surgical databases, with preoperative chemotherapy and subsequent gastrectomy. Pathological response was centrally reviewed using Mandard’s TRG. Results From 325 patients resected from a gastric cancer between 1997 and 2016, 109 underwent a preoperative chemotherapy. 42% were pathologic responders (TRG1-3) and 58% non-responders (TRG4-5). Five-years overall survival (OS) was 35% for non-responders, and 73% for responders (p = 0,006). Five-years disease-free survival (DFS) was 34% for non-responders and 65% for responders (p = 0,013). In multivariate analysis, pathological response was an independent prognostic factor of poor OS: HR = 2.736 (CI95% = 1.335–5.608; p = 0.006) and DFS: HR = 2.241 (CI95% = 1.130–4.446; p = 0.021). Conclusion TRG after preoperative chemotherapy is an important prognostic factor in patients resected for a gastric adenocarcinoma. Further studies should be performed to evaluate if adjuvant therapy should be adapted to pathological response.

Published
2020
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41. Prognostic Value of Tumor Deposits for Disease-Free Survival in Patients With Stage III Colon Cancer: A Post Hoc Analysis of the IDEA France Phase III Trial (PRODIGE-GERCOR)

Author

Jérôme Dauba, S. Fratte, Olivier Dupuis, Julien Taieb, Jean-François Emile, Frédéric Bibeau, Jean François Delattre, Yves Becouarn, Magali Svrcek, Romain Cohen, Dewi Vernerey, Benoist Chibaudel, Julie Henriques, Antoine Falcoz, Christophe Louvet, Thierry André, 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), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bourgogne (UB), Service d'Oncologie Médicale [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Biomarqueurs et essais cliniques en Cancérologie et Onco-Hématologie (BECCOH), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay, Hôpital Ambroise Paré [AP-HP], Hôpital Nord Franche-Comté [Hôpital de Trévenans] (HNFC), Service d'Oncologie Médicale [Institut Hospitalier Franco-Britannique], Division of Medical Oncology - Institut Hospitalier Franco-Britannique, CHU Mont de Marsan, Service d'Oncologie médicale [Clinique Victor Hugo], Clinique Victor Hugo, Institut Bergonié [Bordeaux], UNICANCER, Département de Pathologie [CHU Caen], 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), Université de Paris - UFR Médecine Paris Centre [Santé] (UP Médecine Paris Centre), Université de Paris (UP), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Service d'Oncologie Médicale [Montsouris], Institut Mutualiste de Montsouris (IMM), and Service de Pathologie [CHU Saint-Antoine]

Subjects
Oncology, Male, Cancer Research, medicine.medical_specialty, Disease free survival, Colorectal cancer, [SDV]Life Sciences [q-bio], TNM staging system, Disease-Free Survival, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Post-hoc analysis, medicine, Humans, In patient, 030212 general & internal medicine, Aged, Neoplasm Staging, business.industry, Cancer, Middle Aged, medicine.disease, Prognosis, 3. Good health, Stage III Colon Cancer, 030220 oncology & carcinogenesis, Colonic Neoplasms, Female, business
Abstract

PURPOSE Tumor deposits (TDs) seem to affect the prognosis of patients with colon cancer (CC). In the seventh edition of the American Joint Committee on Cancer TNM staging system for CC, the presence of TDs is only considered in the absence of lymph node metastases (LNMs). In the era of personalized duration of histopathologic criteria-based adjuvant therapy, this could potentially lead to a decrease in the prognostic prediction accuracy. PATIENTS AND METHODS A post hoc analysis of all pathologic reports from patients with stage III CC included in the IDEA France phase III study (ClinicalTrials.gov identifier: NCT00958737 ) investigating the duration of adjuvant fluorouracil, leucovorin, and oxaliplatin or capecitabine and oxaliplatin therapy (3 v 6 months) was performed. The primary objective was to determine the prognostic impact of TD on disease-free survival (DFS). The effect of the addition of TD to LNM count on pN restaging was also evaluated. A multivariable analysis was performed to establish the association between TD and DFS. RESULTS Of 1,942 patients, 184 (9.5%) had TDs. The pN1a/b and pN1c populations showed similar DFS. TD-positive patients had worse prognosis compared with TD-negative patients, with 3-year DFS rates of 65.6% (95% CI, 58.0% to 72.1%) and 74.7% (95% CI, 72.6% to 76.7%; P = .0079), respectively. On multivariable analysis, TDs were associated with a higher risk of recurrence or death (hazard ratio [HR], 1.36; P = .0201). Other adverse factors included pT4 and/or pN2 disease (HR, 2.21; P < .001), the 3 months of adjuvant treatment (HR, 1.29; P = .0029), tumor obstruction (HR, 1.28; P = .0233), and male sex (HR, 1.24; P = .0151). Patients restaged as having pN2 disease (n = 35, 2.3%) had similar DFS as patients initially classified as pN2. CONCLUSION The presence of TDs is an independent prognostic factor for DFS in patients with stage III CC. The addition of TD to LNM may help to better define the duration of adjuvant therapy.

Published
2020
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42. Prognostic and predictive value of the Immunoscore in stage III colon cancer patients treated with oxaliplatin in the prospective IDEA France PRODIGE-GERCOR cohort study

Author

Julien Taieb, Jean-François Emile, Pierre Laurent-Puig, Magali Svrcek, Dewi Vernerey, Amos Kirilovsky, R. Ben Jannet, Alex Duval, Thierry André, Roger Faroux, Julie Henriques, Jaafar Bennouna, Florence Marliot, Laurent Mineur, Jérôme Galon, Christophe Borg, Franck Pagès, Aurelie Catteau, Jérôme Desramé, Christophe Louvet, Fabienne Hermitte, Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), 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), 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), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Biomarqueurs et essais cliniques en Cancérologie et Onco-Hématologie (BECCOH), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay, Hôpital Ambroise Paré [AP-HP], Institut Mutualiste de Montsouris (IMM), Institut Sainte Catherine [Avignon], Centre hospitalier universitaire de Nantes (CHU Nantes), Hôpital privé Jean Mermoz, Service de gastroentérologie (CHD Vendee - Hopital Les Oudairies, La Roche Sur Yon), CHD Vendee (La Roche Sur Yon), 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), Instabilité des microsatellites et cancers [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)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Institut National Du Cancer, INCa: 2012-218 Institut National de la Santé et de la Recherche Médicale, Inserm Ligue Contre le Cancer: AOM09 202 Université Paris Descartes Institut National de la Santé et de la Recherche Médicale, Inserm, This work was supported by the National Institute of Health and Medical Research (INSERM), AP-HP , University Paris Descartes , the Cancéropole Ile-de-France , the Cancer Research for Personalized Medicine (CARPEM), Paris Alliance of Cancer Research Institutes (PACRI), the LabEx Immuno-oncology , [no grant number] the National Cancer Institute of France (INCa, and ref 2012-218), La Ligue Contre le Cancer , the French Ministry of Health Program Hospitalier de Recherche Clinique 2009 (PHRC 2009) [grant number AOM09 202 ] for the IDEA clinical trial, and HalioDx for Immunoscore®.

Subjects
0301 basic medicine, medicine.medical_specialty, Organoplatinum Compounds, Colorectal cancer, Immunoscore, [SDV.CAN]Life Sciences [q-bio]/Cancer, chemotherapy, Gastroenterology, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, Adjuvant therapy, Medicine, Humans, Prospective Studies, predictive, Neoplasm Staging, Duration of Therapy, business.industry, Proportional hazards model, Hazard ratio, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Hematology, medicine.disease, Prognosis, Confidence interval, 3. Good health, Oxaliplatin, 030104 developmental biology, Oncology, colon cancer, Chemotherapy, Adjuvant, 030220 oncology & carcinogenesis, Cohort, Colonic Neoplasms, biomarker, Fluorouracil, France, business, prognostic, Cohort study, medicine.drug
Abstract

International audience; Background: The Immunoscore (IS), which prognostically classifies stage I–III colon cancer (CC) patients, was evaluated in the International Duration Evaluation of Adjuvant Therapy (IDEA) France cohort study investigating 3 versus 6 months of oxaliplatin-based adjuvant chemotherapy in stage III CC patients.Patients and methods: Densities of CD3+ and CD8+ T cells in the tumor and invasive margin were determined by immunohistochemistry, quantified by digital pathology, and converted to IS. Mismatch repair status was determined by immunohistochemistry or by pentaplex PCR. Prediction of disease-free survival (DFS) by IS was analyzed by a multivariable Cox regression model in each study arm. Harrell's C-statistics were used to investigate the IS performance.Results: Samples of 1322 patients were available. IS Low, Intermediate (Int), and High were observed in 43.6%, 47.0%, and 9.4% of patients, respectively. IS Low identified patients at higher risk of relapse or death compared with Int + High [hazard ratio (HR) = 1.54; 95% confidence interval (CI) 1.24–1.93, P = 0.0001]. The 3-year DFS was 66.80% (95% CI 62.23–70.94) for IS Low and 77.14% (95% CI 73.50–80.35) for IS Int + High. In multivariable analysis, IS remained significantly independently associated with DFS (P = 0.003) when adjusted for sex, histological grade, T/N stage, and microsatellite instability. For mFOLFOX6-treated patients (91.6% of the cohort), a statistical significant interaction was observed for the predictive value of IS for treatment duration (3 versus 6 months) in terms of DFS (P = 0.057). IS Int + High significantly predicted benefit of 6 months of treatment (HR = 0.53; 95% CI 0.37–0.75; P = 0.0004), including clinically low- and high-risk stage III CC (all P < 0.001). Conversely, patients with IS Low (46.4%) did not significantly benefit from the 6-month mFOLFOX6 versus the 3-month mFOLFOX6.Conclusions: The prognostic value of IS for DFS was confirmed in patients with stage III CC treated with oxaliplatin-based chemotherapy. Its predictive value for DFS benefit of longer duration of mFOLFOX6 adjuvant treatment was found in IS Int + High. These results will be validated in an external independent cohort. ClinicalTrials.gov registration: NCT03422601; EudraCT Number: 2009-010384-16.

Published
2020
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43. Immune Checkpoint Inhibition in Colorectal Cancer: Microsatellite Instability and Beyond

Author

Raphael Colle, Joana Vidal, Luis A. Diaz, Romain Cohen, Benoit Rousseau, Thierry André, 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), Sorbonne Université (SU), Memorial Sloane Kettering Cancer Center [New York], and Instituto de Salud Carlos III [Madrid] (ISC)

Subjects
0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, Colorectal cancer, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Population, [SDV.CAN]Life Sciences [q-bio]/Cancer, 03 medical and health sciences, 0302 clinical medicine, Immune system, Internal medicine, Medicine, Humans, Pharmacology (medical), education, Immune Checkpoint Inhibitors, education.field_of_study, Chemotherapy, business.industry, Immune escape, Microsatellite instability, Immunotherapy, medicine.disease, Immune checkpoint, digestive system diseases, 3. Good health, 030104 developmental biology, 030220 oncology & carcinogenesis, Microsatellite Instability, business, Colorectal Neoplasms
Abstract

International audience; Immune checkpoints inhibitors (ICIs) have been a breakthrough, with unique response and survival patterns compared with chemotherapy for patients with advanced Mismatch Repair-deficient/Microsatellite instable (dMMR/MSI) colorectal cancer, but have shown disappointing results in Mismatch Repair-proficient/Microsatellite stable (pMMR/MSS) colorectal cancer. As up to 50% of patients harboring dMMR/MSI advanced cancers will ultimately progress after PD-1 blockade, biomarkers are needed to predict response/resistance to immunotherapy and to select patients for immunomodulating combination therapies. Patients with pMMR/MSS colorectal cancer present with distinct immune profiles compared to dMMR/MSI tumors, giving evidence of different immune escape mechanisms, which could be overcome through individualized immunotherapeutic strategies. In this review we discuss the latest developments in the field of immunotherapy for dMMR/MSI and pMMR/MSS colorectal cancers, and unresolved questions and considerations concerning the use of ICI therapies in this population. Future immunomodulation strategies based on biomarker selection (tumor mutational burden, Immunoscore®, mutational profile) are discussed.

Published
2019
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44. Reasons for chemotherapy discontinuation and end-of-life in patients with gastrointestinal cancer: A multicenter prospective AGEO study

Author

Olivier Dubreuil, Frédérick Moryoussef, Bruno Landi, Jean-Baptiste Bachet, Lola-Jade Palmieri, Solene Doat, Géraldine Perkins, Vincent Hautefeuille, Romain Coriat, Christophe Locher, Isabelle Trouilloud, Service d'Hépato-Gastro-Entérologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), 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), Centre Hospitalier de Meaux, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), and CHU Amiens-Picardie

Subjects
Pediatrics, medicine.medical_specialty, Palliative care, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Cachexia, Sepsis, 03 medical and health sciences, 0302 clinical medicine, Drug Therapy, medicine, Humans, Gastrointestinal cancer, Prospective Studies, Gastrointestinal Neoplasms, Chemotherapy, Terminal Care, Hepatology, business.industry, Palliative Care, Gastroenterology, Jaundice, medicine.disease, 3. Good health, Discontinuation, Death, 030220 oncology & carcinogenesis, Cohort, 030211 gastroenterology & hepatology, medicine.symptom, business
Abstract

International audience; Background: Previous research on chemotherapy discontinuation has mainly focused on predictive factors and outcomes. Few data are available on the reasons for chemotherapy discontinuation. The main objective was to identify the reasons for chemotherapy discontinuation in patients with gastrointestinal cancer. The secondary objectives were to describe the announcement of chemotherapy discontinuation and the time between chemotherapy discontinuation and death.Methods: This prospective multicenter French cohort included patients with advanced gastrointestinal cancer, for whom chemotherapy was discontinued between May 2016 and January 2018.Results: One hundred and fourteen patients were analyzed. The first cause of chemotherapy discontinuation was the impairment of general condition (asthenia, cachexia). Complications such as sepsis, jaundice or occlusion, were the second most frequent cause. Progression was observed at chemotherapy discontinuation in two-thirds of cases. The announcement of the chemotherapy discontinuation was made formally in 74% of cases, with a follow-up by a palliative care team initiated in 50% of cases. Sixty-nine percent of the patients received chemotherapy during the last three months of life and 26% during the last month. The median time between chemotherapy discontinuation and death was 65 days (IQR: 36.5-109): 44% of patients died at the hospital, 39% in a palliative care unit and 16% at home.Conclusion: Impairment of general condition was the major reason for chemotherapy discontinuation in patients with gastrointestinal cancers. Complications such as jaundice, sepsis or occlusion, were important reasons for discontinuation and could explain our shorter time between chemotherapy discontinuation and death, compared to other oncology sub-specialties.

Published
2019
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45. Patients atteints d’un cancer gastrique localisé MSI/dMMR, pas de chimiothérapie mais une immunothérapie périopératoire : l’essai de phase II GERCOR NEONIPIGA vient d’être ouvert au recrutement

Author

Cohen, Romain, Pudlarz, Thomas, Garcia-Larnicol, Marie-Line, Vernerey, Dewi, Dray, Xavier, Clavel, Léa, Jary, Marine, Piessen, Guillaume, Zaanan, Aziz, Aparicio, Thomas, Louvet, Christophe, Tournigand, Christophe, Chibaudel, Benoist, Tougeron, David, Guimbaud, Rosine, Benouna, Jaafar, Adenis, Antoine, Sokol, Harry, Borg, Christophe, Duval, Alex, Svrcek, Magali, André, Thierry, 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), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), Cooperator Multidisciplinary Oncology Group (GERCOR), Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté]), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital Claude Huriez [Lille], CHU Lille, Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Université Sorbonne Paris Cité (USPC), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Mutualiste de Montsouris (IMM), Service d'Oncologie médicale [CHU Henri Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Henri Mondor, Centre hospitalier universitaire de Poitiers (CHU Poitiers), CHU Toulouse [Toulouse], Centre hospitalier universitaire de Nantes (CHU Nantes), Institut du Cancer de Montpellier (ICM), 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), Service de Gastroentérologie et nutrition [CHU Saint-Antoine], Site de Recherche Intégrée en Cancérologie (SIRIC-ONCOLille), Université de Lille, Sciences et Technologies-Université de Lille, Sciences Humaines et Sociales-Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université Lille Nord de France (COMUE)-UNICANCER-Université Lille Nord de France (COMUE)-UNICANCER-Cancéropole Nord-Ouest-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Instabilité des microsatellites et cancers [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)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Service de Pathologie [CHU Saint-Antoine], Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Henri Mondor [Créteil], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), 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), Université de Lille-UNICANCER-Université de Lille-UNICANCER-Cancéropole Nord-Ouest-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Instabilité des microsatellites et cancers [CRSA], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)

Subjects
[SDV]Life Sciences [q-bio], Patient Selection, Adenocarcinoma, DNA Mismatch Repair, Ipilimumab, Disease-Free Survival, Neoadjuvant Therapy, Perioperative Care, Instabilité des microsatellites, Lynch syndrome, Antineoplastic Agents, Immunological, Clinical Trials, Phase II as Topic, Nivolumab, Phenotype, Treatment Outcome, Chemotherapy, Adjuvant, Stomach Neoplasms, Humans, Multicenter Studies as Topic, Cancer de l’estomac, Microsatellite Instability, Gastric cancer, Syndrome de Lynch
Abstract

International audience; IntroductionPerioperative chemotherapy is the standard strategy for localized gastric cancers. Nevertheless, this strategy seems to be inefficient, if not deleterious, for patients with tumors harboring microsatellite instability (MSI) and/or mismatch repair deficiency (dMMR), a tumor phenotype predictive for the efficacy of immune checkpoint inhibitors (ICKi).AimThe GERCOR NEONIPIGA single-arm phase II study (NCT04006262; EUDRACT 2018-004712-22) aims at evaluating the efficacy of a peri-operative strategy with nivolumab and ipilimumab in neoadjuvant setting, then nivolumab alone after surgery for patients with resectable MSI/dMMR gastric cancer.Material and methodsMain inclusion criteria are: gastric and oesogastric junction adenocarcinoma (GOA), T2-T4, all N stage and M0, MSI/dMMR. Patients will be treated with nivolumab 240 mg Q2 W, 6 infusions, and ipilimumab 1 mg/kg Q6 W, 2 infusions in neoadjuvant setting. Following surgery, patients with TRG 1-2-3 (Mandard tumor regression grade), acceptable tolerance of neoadjuvant treatment and postoperative ECOG performance status 0–1, will be treated with adjuvant nivolumab 480 mg Q4 W, 9 infusions.ResultsThe primary endpoint is pathological complete response rate (pCR-R). Based on a Fleming design, with α = 5% and β = 20%, 27 patients have to be evaluated (H0 = 5%; H1 = 20%). Secondary endpoints include disease-free survival, overall survival and safety.ConclusionThis study is planned to include 32 patients to evaluate the pCR-R with the combination of nivolumab and ipilimumab in neoadjuvant setting for MSI/dMMR localized GOA. The MSI/MMR status should be systematically assessed on diagnostic biopsies of all GOA. If it meets its primary endpoint, the GERCOR NEONIPIGA study might mark a turning point in the management of localized MSI/dMMR GOA patients.; IntroductionLa chimiothérapie périopératoire est la stratégie de référence pour les cancers gastriques (CG) localisés, mais semble inefficace voire délétère pour les patients avec un cancer MSI/dMMR (microsatellites instables/MMR-déficient), biomarqueur prédictif de l’efficacité de l’immunothérapie.ObjectifL’essai de phase 2 mono-bras GERCOR NEONIPIGA (NCT04006262; EUDRACT 2018-004712-22) évalue l’efficacité du nivolumab plus ipilimumab en néo-adjuvant puis nivolumab seul en adjuvant pour les CG ou de la jonction œsogastrique (JOG) MSI/dMMR résécables.Matériel et méthodesLes principaux critères d’inclusion sont : CG/JOG, T2-4 tout N M0, MSI/dMMR. Les patients sont traités en néo-adjuvant par nivolumab 240 mg Q2 W, 6 perfusions, et ipilimumab 1 mg/kg Q6 W, deux injections. Les patients avec un degré de régression tumorale 1-3 selon Mandard, une tolérance acceptable du traitement néo-adjuvant et un indice de performance postopératoire ECOG 0-1 recevront neuf perfusions mensuelles de nivolumab 480 mg en adjuvant.RésultatsL’objectif principal est le taux de réponse complète pathologique (pCR). Selon un design de Fleming avec α = 5 % et β = 20 %, 27 patients évaluables sont à analyser (H0 = 5 % ; H1 = 20 %). Les critères secondaires de jugement sont la survie sans maladie, la survie globale et le profil de tolérance.ConclusionIl est prévu d’inclure 32 patients pour évaluer le taux de pCR pour les CG/JOG MSI/dMMR traités par nivolumab et ipilimumab néo-adjuvant. Le statut MSI/MMR doit être systématiquement analysé sur les biopsies diagnostiques de tout CG/JOG. L’étude NEONIPIGA pourrait marquer un tournant dans la prise en charge des CG/JOG MSI/dMMR si elle atteint son objectif principal.

Published
2019
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46. Folfirinox versus gemcitabine/nab-paclitaxel as first-line therapy in patients with metastatic pancreatic cancer: a comparative propensity score study

Author

Julien Taieb, Isabelle Trouilloud, Jean-Marc Phelip, David Tougeron, Christophe Locher, Simon Pernot, Vincent Hautefeuille, Anne Thirot Bidault, Pascal Artru, Bertrand Le Roy, Astrid Pozet, Angélique Saint, Nelson Lourenco, Anne-Laure Pointet, Dominique Béchade, Jérôme Desramé, Nicolas Williet, Denis Pezet, Service de gastroentérologie [CHU Saint-Etienne], Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Département de gastro-entérologie et d'oncologie digestive [HEGP - APHP], Université Paris Descartes - Paris 5 (UPD5)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC (EA 3181) (CEF2P / CARCINO), Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Département d'oncologie digestive, Institut Bergonié [Bordeaux], UNICANCER-UNICANCER, 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), Biomarqueurs et essais cliniques en Cancérologie et Onco-Hématologie (BECCOH), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay, CHU Amiens-Picardie, CHU Pontchaillou [Rennes], Center Jean Mermoz, Clinique Saint Jean, Chirurgie digestive et hépatobiliaire, CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Département de Gastroentérologie et hépatologie, and Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-Hôpital Michallon

Subjects
0301 basic medicine, Oncology, medicine.medical_specialty, FOLFIRINOX, survival, 03 medical and health sciences, Study Protocol, 0302 clinical medicine, First line therapy, Internal medicine, Metastatic pancreatic cancer, medicine, pancreatic adenocarcinoma, In patient, lcsh:RC799-869, ComputingMilieux_MISCELLANEOUS, Nab-paclitaxel, business.industry, gemcitabine/nab-paclitaxel, Gastroenterology, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Gemcitabine, 3. Good health, metastatic, 030104 developmental biology, 030220 oncology & carcinogenesis, Propensity score matching, Folfirinox, lcsh:Diseases of the digestive system. Gastroenterology, business, medicine.drug
Abstract

Background: Folfirinox (FFX) and gemcitabine/nab-paclitaxel (GN) are both standard first-line treatments in patients with metastatic pancreatic cancer (mPC). However, data comparing these two chemotherapeutic regimens and their sequential use remain scarce. Methods: Data from two independent cohorts enrolling patients treated with FFX ( n = 107) or GN ( n = 109) were retrospectively pooled. Primary endpoint was overall survival (OS). Progression-free survival (PFS) was the secondary endpoint. A propensity score based on age, gender, performance status (PS), and presence of liver metastases was used to make groups comparable. Results: In the whole study population, OS was significantly higher in FFX (14 months; 95% CI: 10–21) than in GN groups (9 months; 95% CI: 8–12) before ( p = 0.008) and after ( p = 0.021) adjusting for age, number of metastatic sites, liver metastases, peritoneal carcinomatosis and CA19.9 level at baseline. PFS tends to be higher in FFX (6 months) than GN groups (5 months; p = 0.053). After matching ( n = 49/group), patients were comparable for all baseline characteristics including PS. In the matched population, there was a trend toward greater OS in patients treated with FFX (HR = 0.67; p = 0.097). However, survival in each group was not solely a result of the first-line regimen. The proportion of patients who were fit for GN after FFX failure (FFX–GN sequence) was higher (46.9%) than the reverse sequence (20.4%; p = 0.01), which suggests a higher feasibility for the FFX–GN sequence. Corresponding median OS were 19 months versus 9.5 months, respectively ( p = 0.094). Conclusion: This study shows greater OS with FFX than with GN in patients with mPC. GN after FFX failure appears more feasible than the reverse sequence.

Published
2019
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47. Épidémiologie des tumeurs MSI : fréquence des tumeurs MSI en fonction de la localisation du cancer et de son stade

Author

Romain Cohen, Raphael Colle, Service d'Oncologie Médicale [CHU Saint -Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)

Subjects
0301 basic medicine, congenital, hereditary, and neonatal diseases and abnormalities, Cancer Research, Colorectal cancer, [SDV]Life Sciences [q-bio], 03 medical and health sciences, 0302 clinical medicine, medicine, Radiology, Nuclear Medicine and imaging, neoplasms, business.industry, Endometrial cancer, nutritional and metabolic diseases, Cancer, Microsatellite instability, Hematology, General Medicine, medicine.disease, Phenotype, digestive system diseases, Lynch syndrome, Immune checkpoint, 3. Good health, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Cancer research, DNA mismatch repair, business
Abstract

Microsatellite instability (MSI) is a predictive biomarker for the efficacy of immune checkpoint inhibitors, regardless of the tumor type. While clinical characteristics of MSI cancer patients have been largely described in tumor localizations frequently associated with this genetic phenotype (i.e. colorectal cancer, endometrial cancer), it remains poorly characterized in other neoplasms. Pan-tumor high-throughput genome sequence analyses have contributed to the broadening of knowledge about the landscape of MSI. This review aims at synthetizing the literature concerning the frequency of MSI status in solid cancers, according to the cancer stage and the hereditary or sporadic origin of the mismatch repair deficiency. We then check for other cancers frequently associated with MSI and describe the clinical and pathological characteristics that should suggest a MSI phenotype.

Published
2019
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48. Immunotherapy and metastatic colorectal cancers with microsatellite instability or mismatch repair deficiency

Author

Helene Boussion, Thierry André, Anna Pellat, Magali Svrcek, Romain Cohen, Isabelle Trouilloud, Daniel Lopez-Trabada, Pauline Afchain, 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), and Service d'Anatomopathologie [CHU Saint-Antoine]

Subjects
0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, Colorectal cancer, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Antineoplastic Agents, Antibodies, Monoclonal, Humanized, DNA Mismatch Repair, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Humans, Radiology, Nuclear Medicine and imaging, neoplasms, Rectal Neoplasms, business.industry, Microsatellite instability, Hematology, General Medicine, Immunotherapy, medicine.disease, Ipilimumab, digestive system diseases, Lynch syndrome, Immune checkpoint, 3. Good health, Clinical trial, Nivolumab, 030104 developmental biology, 030220 oncology & carcinogenesis, Colonic Neoplasms, MISMATCH REPAIR DEFICIENCY, Microsatellite Instability, DNA mismatch repair, business
Abstract

Microsatellite instability (MSI) is a molecular indicator of defective DNA mismatch repair (dMMR) and is observed in approximately 5% of metastatic colorectal cancers (mCRC). MSI is a major predictive biomarker for the efficacy of immune checkpoint inhibitors (ICKi) amongst mCRC patients. After summarizing the literature about the efficacy of conventional cytotoxic regimens, we will highlight studies that have demonstrated the clinical activity of ICKi for patients with chemoresistant MSI/dMMR mCRC. Then we will focus on ongoing clinical trials and emerging challenges for the treatment of patients with MSI/dMMR mCRC.

Published
2019
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49. Gemcitabine and Oxaliplatin Chemotherapy or Surveillance in Resected Biliary Tract Cancer (PRODIGE 12-ACCORD 18-UNICANCER GI): A Randomized Phase III Study

Author

Jean-Paul Joly, Eric Assenat, Veronique Guerin-Meyer, Aurélie Bertaut, Jean-Louis Jouve, Jérôme Watelet, Christelle De La Fouchardiere, Catherine Lombard-Bohas, Trevor Stanbury, Karim Boudjema, Eveline Boucher, Laetitia Fartoux, Jean-Marc Phelip, Pascal Hammel, Jean-François Seitz, Karine Bouhier-Leporrier, Jean-Emmanuel Kurtz, M. Benabdelghani, Isabelle Baumgaertner, David Malka, David Tougeron, Roger Faroux, Julien Edeline, Christophe Louvet, Centre Eugène Marquis (CRLCC), Centre Paul Strauss, CRLCC Paul Strauss, Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Service d'Hépato-gastro-entérologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Hôpital Beaujon, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Amiens-Picardie, CHU Pontchaillou [Rennes], 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), Hôpital Côte de Nacre [CHU Caen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Hôpital du Bocage, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre Hospitalier Départemental - Hôpital de La Roche-sur-Yon, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), CHU Strasbourg, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service d'oncologie digestive et hépato-gastro-entérologie [Hôpital de la Timone - APHM], Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Service d'Oncologie médicale [CHU Henri Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Henri Mondor, Centre hospitalier universitaire de Poitiers (CHU Poitiers), Centre Léon Bérard [Lyon], Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL), UNICANCER [Paris], Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Institut Mutualiste de Montsouris (IMM), Institut Gustave Roussy (IGR), Département de médecine oncologique [Gustave Roussy], Service de gastroentérologie [CHU Saint-Etienne], and Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne)

Subjects
Adult, Male, Cancer Research, medicine.medical_specialty, Time Factors, medicine.medical_treatment, [SDV.CAN]Life Sciences [q-bio]/Cancer, Gastroenterology, MESH: Antineoplastic Combinated Chemotherapy Protocol / therapeutic uses, Biliary Tract Neoplasms / drug therapy, Biliary Tract Neoplasms / surgery, Deoxycytidine / analogs & derivatives, Oxaliplatin / administration & dosage, Watchful waiting, Deoxycytidine, law.invention, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, law, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, Progression-free survival, Watchful Waiting, Aged, Aged, 80 and over, Chemotherapy, Biliary tract cancer, business.industry, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, Middle Aged, Gemcitabine, Progression-Free Survival, 3. Good health, Oxaliplatin, Clinical trial, Biliary Tract Surgical Procedures, Biliary Tract Neoplasms, Oncology, Chemotherapy, Adjuvant, 030220 oncology & carcinogenesis, Quality of Life, 030211 gastroenterology & hepatology, Female, France, business, Adjuvant, medicine.drug
Abstract

PURPOSE No standard adjuvant treatment currently is recommended in localized biliary tract cancer (BTC) after surgical resection. We aimed to assess whether gemcitabine and oxaliplatin chemotherapy (GEMOX) would increase relapse-free survival (RFS) while maintaining health-related quality of life (HRQOL) in patients who undergo resection. PATIENTS AND METHODS We performed a multicenter, open-label, randomized phase III trial in 33 centers. Patients were randomly assigned (1:1) within 3 months after R0 or R1 resection of a localized BTC to receive either GEMOX (gemcitabine 1,000 mg/m2 on day 1 and oxaliplatin 85 mg/m2 infused on day 2 of a 2-week cycle) for 12 cycles (experimental arm A) or surveillance (standard arm B). Primary end points were RFS and HRQOL. RESULTS Between July 2009 and February 2014, 196 patients were included. Baseline characteristics were balanced between the two arms. After a median follow-up of 46.5 months (95% CI, 42.6 to 49.3 months), 126 RFS events and 82 deaths were recorded. There was no significant difference in RFS between the two arms (median, 30.4 months in arm A v 18.5 months in arm B; hazard ratio [HR], 0.88; 95% CI, 0.62 to 1.25; P = .48). There was no difference in time to definitive deterioration of global HRQOL (median, 31.8 months in arm A v 32.1 months in arm B; HR, 1.28; 95% CI, 0.73 to 2.26; log-rank P = .39). Overall survival was not different (median, 75.8 months in arm A v 50.8 months in arm B; HR, 1.08; 95% CI, 0.70 to 1.66; log-rank P = .74). Maximal adverse events were grade 3 in 62% (arm A) versus 18% (arm B) and grade 4 in 11% versus 3% ( P < .001). CONCLUSION There was no benefit of adjuvant GEMOX in resected BTC despite adequate tolerance and delivery of the regimen.

Published
2019
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50. « Mourir guéri » : « l’impensable » de la mort dans le cadre de l’allogreffe de cellules souches hématopoïétiques

Author

A. Polomeni, Service d'Oncologie Médicale [CHU Saint -Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)

Subjects
03 medical and health sciences, Psychiatry and Mental health, Clinical Psychology, 0302 clinical medicine, Oncology, Oncology (nursing), [SDV]Life Sciences [q-bio], 030220 oncology & carcinogenesis, 030215 immunology, 3. Good health
Abstract

Seul traitement susceptible de se constituer en projet curatif pour des hemopathies malignes a pronostic pejoratif, les allogreffes de cellules souches hematopoietiques comportent des risques accrus de morbimortalite. Par le biais de ces complications, la visee therapeutique de l’allogreffe peut se trouver subvertie par ses propres consequences: gueri de la pathologie initiale, le patient peut venir a deceder du fait des complications liees a la procedure therapeutique. Nous abordons le vecu des soignants face a ces deces.

Published
2016
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