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151. Tumor mutational burden in non-small cell lung cancer—the pathologist’s point of view

Author

Frédérique Penault-Llorca and Nina Radosevic-Robin

Subjects
0301 basic medicine, Pathology, medicine.medical_specialty, business.industry, medicine.medical_treatment, Cell, non-small cell lung cancer (NSCLC), Immunotherapy, Pembrolizumab, Mini-Review, medicine.disease, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, medicine, ROS1, Personalized medicine, Non small cell, business, Lung cancer
Abstract

In non-small cell lung cancer (NSCLC), the pathologist has contributed to the development of personalized medicine from the determination of the right histological type to EGFR and ALK/ROS1 molecular screening for targeted therapies. With the development of immunotherapies, pathologists intervene forefront with programmed death-ligand 1 (PD-L1) immunohistochemical testing, companion test for pembrolizumab monotherapy, first line and complementary test to the other programmed cell death-1 (PD-1) PD-L1 inhibitors. Recently, tumor mutational burden has emerged as a promising tool to evaluate sensitivity to immunotherapy (IO). The pathologist has a crucial role in the setting of tumor mutational burden (TMB) testing for the selection and the preparation of the sample for high throughput molecular analysis, and in the first steps of the next-generation sequencing (NGS) workflow.

Published
2018

152. Prevalence of NTRK1/3 fusions in mismatch repair-deficient (dMMR)/microsatellite instable (MSI) tumors of patients with metastatic colorectal cancer (mCRC)

Author

Frédérique Penault-Llorca, Romain Cohen, Anne Cayre, Thierry André, Raphael Colle, Pierre Bourgoin, Nina Radosevic-Robin, and Magali Svrcek

Subjects
Cancer Research, biology, Colorectal cancer, Kinase, business.industry, Cell, medicine.disease, Tropomyosin, digestive system diseases, medicine.anatomical_structure, Oncology, Trk receptor, medicine, Cancer research, biology.protein, DNA mismatch repair, Receptor, business, neoplasms, Neurotrophin
Abstract

e15537 Background: Inhibitors of tropomyosin receptor kinase (TRK) have shown promising activity against neurotrophic TRK ( NTRK) fusion-driven cancers, regardless of tumor histotype or cell of origin. NTRK gene fusions are observed in less than 1% of colorectal cancers (CRCs). CRCs harboring wild-type BRAF and KRAS and MisMatch Repair deficiency (dMMR)/MicroSatellite Instability (MSI) due to MLH1 hypermethylation have been associated with NTRK fusions in small cohorts of non-metastatic tumors. We aimed at evaluating the incidence of NTRK fusions among dMMR/MSI metastatic CRCs (mCRC) for which there is a need for innovative therapies, as well as the associated clinical characteristics of these patients (pts) carrying NTRK fusion-positive tumors. Methods: Tumor samples of dMMR/MSI mCRC pts, paired primary and metastasis or primary alone, were obtained from a French multicenter retrospective cohort and from a single-center cohort of patients treated by immune checkpoint inhibitors (ICI) (Saint-Antoine Hospital, Paris). Clinico-pathological data including KRAS and BRAFV600E status, MMR proteins and MLH1 methylation status were available for all pts. All samples were screened for TRK expression by immunohistochemistry (IHC) using a pan-TRK antibody (clone EPR17341, Abcam; positivity: 1% of labeled tumor cells)) and for NTRK1 and NTRK3 gene rearrangements, by fluorescent in situ hybridation (FISH). A threshold of 15% nuclei positive for a break apart signal was considered positive for gene rearrangement. Results: A total of 158 pts with dMMR/MSI mCRCs (paired samples: n=39; primary only: n=119) were screened. Tumor samples of 10 patients (6.3%) harbored NTRK fusion genes by FISH ( NTRK1=8; NTRK3=2). Only four of these 10 patients had TRK immunoreactivity. One patient showed a discordance between metastasis harboring NTRK1 fusion (+) and primary tumor being negative. Eight tumors were sporadic with MLH1 hypermethylation. The remaining 2 cases were related to a MMR gene germline mutation (Lynch syndrome) with concurrent loss of MSH2 and MSH6 expression and isolated loss of MSH6 respectively. One Lynch-related tumor was KRAS mutated, one sporadic MLH1-negative tumor was BRAF V600E mutated. Four patients out of 91 treated by ICI had tumors with NTRK fusions. Three have shown radiological response according to iRECIST criteria (two complete responses, one partial response with 25 to 54 months of follow up) and one had primary resistance to ICI. Conclusions: Frequency of NTRK1/3 fusions is 6.3% in our dMMR/MSI mCRCs population. These fusions are not restricted to sporadic cases. The diagnostic accuracy of pan-TRK IHC is low. Optimal testing algorithms for theragnostics remain to be defined in this setting.

Published
2021

153. Clinical and molecular practice of European thoracic pathology laboratories during the COVID-19 pandemic. The past and the near future

Author

John R. Gosney, G. Troncone, W. Dietmaier, A. De Muret, P. Brest, S.R.Y. Cajal, E. Long-Mira, G. Gorkiewicz, H. Wolff, Lina Carvalho, J. Stojsic, A. Hofman, Izidor Kern, L. Chalabreysse, A. Dema, Cristian Ortiz-Villalón, R. Schiappa, Lukas Bubendorf, S. Garcia, L. Gibault, L. de Leval, M.-C. Copin, Aurélie Cazes, Hans-Ulrich Schildhaus, E. Shaw, M. Antoine, Véronique Hofman, A. Stenzinger, M. Garcia-Martos, M. Evert, V. Nakache, E. Chamorey, S. Savic-Prince, P. Boström, P. Brousset, M. Sajin, S. Lassalle, H. Begueret, Wim Timens, Mark Kriegsmann, Mauro Papotti, Peter Schirmacher, M.-P. Chenard, M. Barberis, V. Thomas de Montpreville, J. Meilleroux, P. Delongova, M. Ilié, C. Bonnetaud, C. Werlein, Keith M. Kerr, J.-F. Côté, A. Mamilos, A. Lupo, Patrick Pauwels, Frédérique Penault-Llorca, I. Serre, N. Poté, C.-H. Marquette, Paul Hofman, J.-C. Sabourin, J.-P. Berthet, Giuseppe Pelosi, A. Foulet, D. Damotte, D. Sizaret, Fabien Forest, Erik Thunnissen, A. Panizo, L. Panico, O. Pop, G. Cathomas, M. Kossai, I. Salmon, F. Calabrese, F. Bibeau, Aurelie Fabre, R. Matěj, J. Benzaquen, Danny Jonigk, Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), FHU OncoAge - Pathologies liées à l’âge [CHU Nice] (OncoAge), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Pharmacologie Moléculaire et Cellulaire [UNIV Côte d'Azur] (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Université Côte d'Azur (UCA), Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), European Institute of Oncology IRCCS [Milan, Italy] (EIO), CHU Bordeaux [Bordeaux], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Université de Caen Normandie (UNICAEN), Normandie Université (NU), Turku University Hospital (TYKS), Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), University Hospital Basel [Basel], University of Coimbra [Portugal] (UC), Kantonsspital Baselland [Bruderholz] (KSBL), Physiopathologie et Epidémiologie des Maladies Respiratoires (PHERE (UMR_S_1152 / U1152)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Groupement Hospitalier Est [Bron], Hospices Civils de Lyon (HCL), CHU Strasbourg, CHU Lille, Université de Lille, Institut Mutualiste de Montsouris (IMM), 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), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), University of Lausanne (UNIL), University Hospital Ostrava, Centre chirurgical Marie Lannelongue, CHU Trousseau [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Victor Babeş University of Medicine and Pharmacy (UMFT), University of Regensburg, University College Dublin [Dublin] (UCD), Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Centre Hospitalier Le Mans (CH Le Mans), Hôpital Nord AP‐MM Marseille, France (AP‐MM Marseille), Aix Marseille Université (AMU), Hospital General Universitario 'Gregorio Marañón' [Madrid], 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), University of Graz, Hannover Medical School [Hannover] (MHH), Royal Liverpool University Hospital, University of Liverpool-Royal Liverpool and Broadgreen University Hospital NHS Trust, University Clinic Golnik, Aberdeen Royal Infirmary, Aberdeen, Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Heidelberg University Hospital [Heidelberg], Charles University [Prague] (CU), Karolinska University Hospital [Stockholm], Monaldi-Cotugno-CTO, Complejo Hospitalario de Navarra, Università degli studi di Torino (UNITO), University of Antwerp (UA), University of Milan, University of Oradea, Romania, AP-HP - Hôpital Bichat - Claude Bernard [Paris], Vall d'Hebron University Hospital [Barcelona], Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Rouen, Université libre de Bruxelles (ULB), University of Medicine and Pharmacy 'Carol Davila' Bucharest (UMPCD), University Hospital [Essen, Germany], Hôpital Gui de Chauliac, Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), University Hospital Southampton NHS Foundation Trust, University of Belgrade [Serbia], Institute of Zoology [Serbia], University of Amsterdam [Amsterdam] (UvA), University of Groningen [Groningen], Università degli studi di Napoli Federico II, Finnish Institute of Occupational Health of Helsinki, University of Padova Medical School, Université Nice Sophia Antipolis (1965 - 2019) (UNS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Pharmacologie Moléculaire et Cellulaire [UNIV Côte d'Azur] (UPMC)-Université Côte d'Azur (UCA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Université de Lausanne = University of Lausanne (UNIL), Centre Chirurgical Marie Lannelongue (CCML), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Karl-Franzens-Universität Graz, Università degli studi di Torino = University of Turin (UNITO), Università degli Studi di Milano = University of Milan (UNIMI), University of Oradea, Hôpital Gui de Chauliac [CHU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), University of Naples Federico II = Università degli studi di Napoli Federico II, Università degli Studi di Padova = University of Padua (Unipd), Institut Català de la Salut, [Hofman P, Ilié M, Nakache V] Laboratory of Clinical and Experimental Pathology, FHU OncoAge, BB-0033-00025, Louis Pasteur Hospital, IRCAN, Université Côte d'Azur, Nice, France. [Brest P] Team 4, IRCAN, INSERM, CNRS, Centre Antoine-Lacassagne, Université Côte d'Azur, Nice, France. [Chamorey E, Schiappa R] Epidemiology and Biostatistics Unit, Centre Antoine-Lacassagne, Université Côte d'Azur, Nice, France. [Cajal SRY] Servei d’Anatomia Patològica, Vall d'Hebron Hospital Universitari, Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), COLO, Mouniati, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)-Institut de Pharmacologie Moléculaire et Cellulaire [UNIV Côte d'Azur] (UPMC), Karl-Franzens-Universität [Graz, Autriche], Hofman, P., Ilie, M., Chamorey, E., Brest, P., Schiappa, R., Nakache, V., Antoine, M., Barberis, M., Begueret, H., Bibeau, F., Bonnetaud, C., Bostrom, P., Brousset, P., Bubendorf, L., Carvalho, L., Cathomas, G., Cazes, A., Chalabreysse, L., Chenard, M. -P., Copin, M. -C., Cote, J. -F., Damotte, D., de Leval, L., Delongova, P., Thomas de Montpreville, V., de Muret, A., Dema, A., Dietmaier, W., Evert, M., Fabre, A., Forest, F., Foulet, A., Garcia, S., Garcia-Martos, M., Gibault, L., Gorkiewicz, G., Jonigk, D., Gosney, J., Hofman, A., Kern, I., Kerr, K., Kossai, M., Kriegsmann, M., Lassalle, S., Long-Mira, E., Lupo, A., Mamilos, A., Matej, R., Meilleroux, J., Ortiz-Villalon, C., Panico, L., Panizo, A., Papotti, M., Pauwels, P., Pelosi, G., Penault-Llorca, F., Pop, O., Pote, N., Cajal, S. R. Y., Sabourin, J. -C., Salmon, I., Sajin, M., Savic-Prince, S., Schildhaus, H. -U., Schirmacher, P., Serre, I., Shaw, E., Sizaret, D., Stenzinger, A., Stojsic, J., Thunnissen, E., Timens, W., Troncone, G., Werlein, C., Wolff, H., Berthet, J. -P., Benzaquen, J., Marquette, C. -H., Hofman, V., and Calabrese, F.

Subjects
Cancer Research, Pathology, [SDV]Life Sciences [q-bio], Medizin, Disease Outbreaks, varnost, Biosafety, 0302 clinical medicine, Surveys and Questionnaires, Pandemic, virosis::infecciones por virus ARN::infecciones por Nidovirales::infecciones por Coronaviridae::infecciones por Coronavirus [ENFERMEDADES], Medicine, Pathology, Molecular, COVID-19, activity, biosafety, lung cancer, pathology, biološka varnost, Health Occupations::Medicine::Pathology::Pathology, Clinical [DISCIPLINES AND OCCUPATIONS], Original Research, Biological Specimen Banks, 0303 health sciences, Pathology, Clinical, Molecular pathology, Virus Diseases::RNA Virus Infections::Nidovirales Infections::Coronaviridae Infections::Coronavirus Infections [DISEASES], Workload, Clinical Laboratory Services, Containment of Biohazards, Biobank, 3. Good health, [SDV] Life Sciences [q-bio], Europe, covid-19, Oncology, 030220 oncology & carcinogenesis, Thoracic diseases, COVID-19 (Malaltia) - Europa, Laboratoris anatòmics, localizaciones geográficas::Europa (continente) [DENOMINACIONES GEOGRÁFICAS], safety, medicine.medical_specialty, 2019-20 coronavirus outbreak, Coronavirus disease 2019 (COVID-19), lung neoplasms, pljučni rak, Geographic Locations::Europe [GEOGRAPHICALS], Specimen Handling, 03 medical and health sciences, Thoracic Diseases, udc:616.9, Humans, Pandemics, 030304 developmental biology, SARS-CoV-2, business.industry, pljučne novotvorbe, profesiones sanitarias::medicina::anatomía patológica::patología clínica [DISCIPLINAS Y OCUPACIONES], patologija, Human medicine, business, Biological Specimen Banks/organization & administration, Biological Specimen Banks/statistics & numerical data, COVID-19/epidemiology, COVID-19/prevention & control, COVID-19/virology, Clinical Laboratory Services/statistics & numerical data, Clinical Laboratory Services/trends, Containment of Biohazards/statistics & numerical data, Europe/epidemiology, Forecasting, Pathology, Clinical/methods, Pathology, Clinical/statistics & numerical data, Pathology, Clinical/trends, Pathology, Molecular/methods, Pathology, Molecular/statistics & numerical data, Pathology, Molecular/trends, SARS-CoV-2/isolation & purification, SARS-CoV-2/physiology, Specimen Handling/methods, Specimen Handling/statistics & numerical data, Thoracic Diseases/diagnosis, Thoracic Diseases/therapy
Abstract

Background This study evaluated the consequences in Europe of the COVID-19 outbreak on pathology laboratories orientated toward the diagnosis of thoracic diseases. Materials and methods A survey was sent to 71 pathology laboratories from 21 European countries. The questionnaire requested information concerning the organization of biosafety, the clinical and molecular pathology, the biobanking, the workload, the associated research into COVID-19, and the organization of education and training during the COVID-19 crisis, from 15 March to 31 May 2020, compared with the same period in 2019. Results Questionnaires were returned from 53/71 (75%) laboratories from 18 European countries. The biosafety procedures were heterogeneous. The workload in clinical and molecular pathology decreased dramatically by 31% (range, 3%-55%) and 26% (range, 7%-62%), respectively. According to the professional category, between 28% and 41% of the staff members were not present in the laboratories but did teleworking. A total of 70% of the laboratories developed virtual meetings for the training of residents and junior pathologists. During the period of study, none of the staff members with confirmed COVID-19 became infected as a result of handling samples. Conclusions The COVID-19 pandemic has had a strong impact on most of the European pathology laboratories included in this study. Urgent implementation of several changes to the organization of most of these laboratories, notably to better harmonize biosafety procedures, was noted at the onset of the pandemic and maintained in the event of a new wave of infection occurring in Europe., Highlights • Biosafety measures used in the first wave of the COVID-19 crisis were heterogeneous in 53 European pathology laboratories. • A dramatic decrease of the workload in pathology laboratories was noted. • No case of healthcare workers contaminated with SARS-CoV-2 associated with samples handling was identified.

Published
2021

154. Standardized evaluation of tumor-infiltrating lymphocytes in breast cancer: results of the ring studies of the international immuno-oncology biomarker working group

Author

Shahinaz Bedri, Karen Willard-Gallo, Sunil R. Lakhani, Stefan Michiels, Jan Budczies, Nina Radosevic-Robin, Zuzana Kos, Michael Untch, S Rim Kim, Giuseppe Viale, Barbara Ingold Heppner, Bruno Valentin Sinn, Stephen B. Fox, Roberto Salgado, Nicolas Sirtaine, Peter Sinn, Toralf Reimer, Sandra Demaria, Stephan Wienert, Anita Bane, Sandra A O'Toole, David L. Rimm, Zsuzsanna Bago-Horvath, Carsten Denkert, Matthias Christgen, Ewa Chmielik, Dongxia Gao, Frédérique Penault-Llorca, Giuseppe Floris, Sibylle Loibl, Sherene Loi, Gunter von Minckwitz, Audrey Poterie, Stuart J. Schnitt, Hans Kreipe, Koen Van de Vijver, Sunil V. Badve, Roland de Wind, Jane E. Brock, Cecile Colpaert, Gert Van den Eynden, Peter A. Fasching, Giancarlo Pruneri, and Frederick Klauschen

Subjects
0301 basic medicine, Oncology, Pathology, medicine.medical_specialty, Intraclass correlation, Concordance, Breast Neoplasms, Pathology and Forensic Medicine, Surgical pathology, 03 medical and health sciences, Lymphocytes, Tumor-Infiltrating, 0302 clinical medicine, Breast cancer, Internal medicine, Image Interpretation, Computer-Assisted, medicine, Humans, Pathology, Clinical, Clinical pathology, business.industry, medicine.disease, Confidence interval, Clinical trial, 030104 developmental biology, 030220 oncology & carcinogenesis, Biomarker (medicine), Female, business
Abstract

Multiple independent studies have shown that tumor-infiltrating lymphocytes (TIL) are prognostic in breast cancer with potential relevance for response to immune-checkpoint inhibitor therapy. Although many groups are currently evaluating TIL, there is no standardized system for diagnostic applications. This study reports the results of two ring studies investigating TIL conducted by the International Working Group on Immuno-oncology Biomarkers. The study aim was to determine the intraclass correlation coefficient (ICC) for evaluation of TIL by different pathologists. A total of 120 slides were evaluated by a large group of pathologists with a web-based system in ring study 1 and a more advanced software-system in ring study 2 that included an integrated feedback with standardized reference images. The predefined aim for successful ring studies 1 and 2 was an ICC above 0.7 (lower limit of 95% confidence interval (CI)). In ring study 1 the prespecified endpoint was not reached (ICC: 0.70; 95% CI: 0.62-0.78). On the basis of an analysis of sources of variation, we developed a more advanced digital image evaluation system for ring study 2, which improved the ICC to 0.89 (95% CI: 0.85-0.92). The Fleiss' kappa value for

Published
2016

155. Combination of phosphotidylinositol-3-kinase targeting with cetuximab and irradiation: A preclinical study on an orthotopic xenograft model of head and neck cancer

Author

Gérard Milano, Alexandre Bozec, Mathieu Gautier, Hedi Ben Yahia, Nina Radosevic-Robin, Serge Marcie, Emmanuel Chamorey, Frédérique Penault-Llorca, and Nathalie Ebran

Subjects
0301 basic medicine, Oncology, MAPK/ERK pathway, medicine.medical_specialty, Buparlisib, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Growth factor receptor, Internal medicine, medicine, neoplasms, Protein kinase B, PI3K/AKT/mTOR pathway, Cetuximab, business.industry, Head and neck cancer, medicine.disease, Head and neck squamous-cell carcinoma, digestive system diseases, 3. Good health, 030104 developmental biology, Otorhinolaryngology, chemistry, 030220 oncology & carcinogenesis, business, medicine.drug
Abstract

Background The purpose of this study was to investigate the effects of combining the phosphotidylinositol-3-kinase (PI3K) inhibitor buparlisib (BKM)120 with the anti-epidermal growth factor receptor (EGFR) agent cetuximab and radiotherapy (RT) on an orthotopic model of head and neck squamous cell carcinoma (HNSCC). Methods We evaluated the antitumor efficacy of BKM120, cetuximab, and RT, administered alone or in combination, using the human PIK3CA-mutated HNSCC cell line, CAL33, injected into the floor of the mouth of nude mice. Results Compared with control, the BKM120-cetuximab and the BKM120-cetuximab-RT combinations led to the highest tumor inhibition (p < .001). The highest inhibitory effect of treatments on cell proliferation, mitogen-activated protein kinase (MAPK) and PI3K/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathways were found with the BKM120-cetuximab association. The association of BKM120 and cetuximab with RT inhibited RT-induced activation of the MAPK pathway. Conclusion These results can serve as a preclinical rationale for innovative treatments combining PI3K inhibition with anti-EGFR therapies and irradiation in patients with HNSCC. © 2016 Wiley Periodicals, Inc. Head Neck, 2016

Published
2016

156. H3K4 acetylation, H3K9 acetylation and H3K27 methylation in breast tumor molecular subtypes

Author

Marjolaine Ngollo, Dominique Bernard-Gallon, Yves-Jean Bignon, Seher Karsli-Ceppioglu, André Lebert, Aslihan Dagdemir, Gaëlle Judes, Frédérique Penault-Llorca, and Maureen Echegut

Subjects
0301 basic medicine, Cancer Research, Tumor suppressor gene, Gene Expression, Receptors, Cytoplasmic and Nuclear, Breast Neoplasms, Biology, Methylation, Epigenesis, Genetic, Histones, 03 medical and health sciences, Histone H3, Breast cancer, Genetics, medicine, Humans, Promoter Regions, Genetic, skin and connective tissue diseases, EZH2, Acetylation, Promoter, Chromatin Assembly and Disassembly, medicine.disease, Gene Expression Regulation, Neoplastic, 030104 developmental biology, Histone, Nuclear receptor coactivator 3, Cancer research, biology.protein, Female, Protein Processing, Post-Translational
Abstract

Aim: Here, we investigated how the St Gallen breast molecular subtypes displayed distinct histone H3 profiles. Patients & methods: 192 breast tumors divided into five St Gallen molecular subtypes (luminal A, luminal B HER2-, luminal B HER2+, HER2+ and basal-like) were evaluated for their histone H3 modifications on gene promoters. Results: ANOVA analysis allowed to identify specific H3 signatures according to three groups of genes: hormonal receptor genes (ERS1, ERS2, PGR), genes modifying histones (EZH2, P300, SRC3) and tumor suppressor gene (BRCA1). A similar profile inside high-risk cancers (luminal B [HER2+], HER2+ and basal-like) compared with low-risk cancers including luminal A and luminal B (HER2-) were demonstrated. Conclusion: The H3 modifications might contribute to clarify the differences between breast cancer subtypes.

Published
2016

157. Routine molecular profiling of patients with advanced non-small-cell lung cancer: results of a 1-year nationwide programme of the French Cooperative Thoracic Intergroup (IFCT)

Author

Alexandra Langlais, P. Missy, Franck Morin, Antoinette Lemoine, Sylvie Lantuejoul, Quân Tran, Didier Debieuvre, Jean-Philippe Merlio, Julien Mazieres, Jean-Christophe Sabourin, L'Houcine Ouafik, Bernard Milleron, Jacques Cadranel, Jean Mosser, Hervé Lena, R. Lamy, Clarisse Audigier-Valette, Pierre-Paul Bringuier, Virginie Westeel, Isabelle Monnet, Benjamin Besse, Fabrice Barlesi, Isabelle Rouquette, Fabienne Escande, Jean-Charles Soria, Frédérique Penault-Llorca, Remi Veillon, Gérard Zalcman, Michèle Beau-Faller, Marc G. Denis, Hélène Blons, and Jean-Louis Pujol

Subjects
0301 basic medicine, Oncology, medicine.medical_specialty, business.industry, General Medicine, Gene rearrangement, medicine.disease, medicine.disease_cause, Bioinformatics, 3. Good health, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, 030220 oncology & carcinogenesis, Internal medicine, medicine, Carcinoma, Adenocarcinoma, Anaplastic lymphoma kinase, KRAS, Young adult, Lung cancer, business, Prospective cohort study
Abstract

Background: The molecular profiling of patients with advanced non-small-cell lung cancer (NSCLC) for known oncogenic drivers is recommended during routine care. Nationally, however, the feasibility and effects on outcomes of this policy are unknown. We aimed to assess the characteristics, molecular profiles, and clinical outcomes of patients who were screened during a 1-year period by a nationwide programme funded by the French National Cancer Institute. Methods This study included patients with advanced NSCLC, who were routinely screened for EGFR mutations, ALK rearrangements, as well as HER2 (ERBB2), KRAS, BRAF, and PIK3CA mutations by 28 certified regional genetics centres in France. Patients were assessed consecutively during a 1-year period from April, 2012, to April, 2013. We measured the frequency of molecular alterations in the six routinely screened genes, the turnaround time in obtaining molecular results, and patients' clinical outcomes. This study is registered with ClinicalTrials.gov, number NCT01700582. Findings 18 679 molecular analyses of 17 664 patients with NSCLC were done (of patients with known data, median age was 64·5 years [range 18–98], 65% were men, 81% were smokers or former smokers, and 76% had adenocarcinoma). The median interval between the initiation of analysis and provision of the written report was 11 days (IQR 7–16). A genetic alteration was recorded in about 50% of the analyses; EGFR mutations were reported in 1947 (11%) of 17 706 analyses for which data were available, HER2 mutations in 98 (1%) of 11 723, KRAS mutations in 4894 (29%) of 17 001, BRAF mutations in 262 (2%) of 13 906, and PIK3CA mutations in 252 (2%) of 10 678; ALK rearrangements were reported in 388 (5%) of 8134 analyses. The median duration of follow-up at the time of analysis was 24·9 months (95% CI 24·8–25·0). The presence of a genetic alteration affected first-line treatment for 4176 (51%) of 8147 patients and was associated with a significant improvement in the proportion of patients achieving an overall response in first-line treatment (37% [95% CI 34·7–38·2] for presence of a genetic alteration vs 33% [29·5–35·6] for absence of a genetic alteration; p=0·03) and in second-line treatment (17% [15·0–18·8] vs 9% [6·7–11·9]; p

Published
2016

158. Abstract P1-08-06: SToRM: A prospective clinical trial of 1502 metastatic breast cancer (mBC) patients with detail of clinical presentation, molecular subtype, treatment modalities, prognosis and GWAS genotyping

Author

Ellen Blanc, N Quenel-Tueux, Thierry Petit, Sophie Abadie-Lacourtoisie, Monica Arnedos, David G. Cox, J.P. Jacquin, Frédérique Penault-Llorca, Emilie Lavergne, Olivier Tredan, P-E Heudel, Isabelle Moullet, H. Orfeuvre, Thomas Bachelot, Gilles Romieu, Loic Chaigneau, Maria Rios, C. Roemer-Becuwe, Christelle Jouannaud, and J-M Ferrero

Subjects
Oncology, Cancer Research, medicine.medical_specialty, business.industry, Cancer, Bone metastasis, Retrospective cohort study, medicine.disease, Metastatic breast cancer, Surgery, Clinical trial, Breast cancer, Trastuzumab, Internal medicine, Epidemiology, medicine, business, medicine.drug
Abstract

Background: Due to better molecular classification and new treatment options, epidemiology and prognosis of mBC is rapidly changing. Clinical data extracted from randomized studies are only relevant to specific subpopulations and retrospective studies are prone to selection bias. SToRM is a prospective clinical trial that aims to create a cohort of 1500 mBC patients, with the ultimate goal of identifying germ line polymorphisms associated with prognosis of breast cancer (BC) and response to treatment in the metastatic phase. Material and methods: Any newly (within 1 year) diagnosed mBC patients were eligible. Whole blood samples were drawn and germline DNA extracted for genetic analysis. Extensive epidemiologic data, disease history from primary diagnosis to metastatic spread, pathological characteristics and ER, PR and HER2 status were collected. Patients are prospectively followed until death. Genotyping using the HumanCoreExome chipset from Illumina is currently underway and will be completed in early summer 2015. Results: 1502 patients were included from March 2012 to May 2014 from 71 French institutions. Median age at metastatic relapse was 60 years (range 26-93). Median time from primary diagnosis to metastatic relapse was 30 months (range 0-473) with 24% of patients already metastatic at initial diagnosis. 78% of patients were ER+, 18% were HER2+ and only 16% were triple negative. Molecular subtype classification derived from pathological data following St Gallen consensus recommendations is presented below: n (%)Luminal A like261 (22.2%)Luminal B like HER2 negative476 (40.5%)Luminal B like HER2 positive134 (11.4%)HER2 positive non Luminal (ER-)111 (9.5%)Triple negative193 (16.4%)Missing data327 64% of the patients had received previous adjuvant treatment, among which 81% received adjuvant chemotherapy and 9% trastuzumab. At metastatic relapse, loco-regional progression, liver, lung and bone metastasis were documented in 301 (20%), 494 (33%), 410 (27%) and 1017 (68%) patients respectively. 313 patients (21%) had bone only metastatic disease. First line treatment included: chemotherapy (71%), endocrine therapy (50%) and anti-HER2 treatments (17%). Survival data will be presented at the meeting. Conclusion: Despite a theoretically better prognosis and widespread use of adjuvant hormonal treatment, ER+/HER2- breast cancer still account for more than 60% of mBC. The proportion of patients with HER2+ disease (18%) and triple negative disease (16%) is consistent with percentages observed in early BC populations. In comparison with a cohort of "cured", localized cancer, such as the SIGNAL/PHARE study, GWAS analysis will allow for the identification of genetic polymorphisms correlated with treatment resistance. Fundamentally, such variants will provide insight into the molecular mechanisms responsible for host-genetic influence on BC progression. From a clinical perspective, genetic variants that predispose to metastatic disease can serve as stratification variables in future clinical trials, particularly as the development of new treatment options for resistant BC is needed. Citation Format: Bachelot T, Lavergne E, Romieu G, Rios M, Heudel P-E, Roemer-Becuwe C, Jouannaud C, Tredan O, Chaigneau L, Arnedos M, Orfeuvre H, Petit T, Quenel-Tueux N, Jacquin J-P, Ferrero J-M, Moullet I, Abadie-Lacourtoisie S, Penault-Llorca F, Blanc E, Cox D. SToRM: A prospective clinical trial of 1502 metastatic breast cancer (mBC) patients with detail of clinical presentation, molecular subtype, treatment modalities, prognosis and GWAS genotyping. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-08-06.

Published
2016

159. Stratégie de testing moléculaire des carcinomes pulmonaires

Author

Anne Cayre, L. Perrot, Frédérique Penault-Llorca, and Lucie Tixier

Subjects
0301 basic medicine, Oncology, medicine.medical_specialty, medicine.diagnostic_test, business.industry, medicine.disease, medicine.disease_cause, Pathology and Forensic Medicine, Clinical trial, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, 030220 oncology & carcinogenesis, Cytology, Internal medicine, Biopsy, medicine, ROS1, Adenocarcinoma, Immunohistochemistry, KRAS, business, Lung cancer
Abstract

Nowadays, the analysis of theranostic molecular markers is central in the management of lung cancer. As those tumors are diagnosed in two third of the cases at an advanced stage, molecular screening is frequently performed on "small samples". The screening strategy starts by an accurate histopathological characterization, including on biopsies or cytological specimens. WHO 2015 provided a new classification for small biopsy and cytology, defining categories such as non-small cell carcinoma (NSCC), favor adenocarcinoma (TTF1 positive), or favor squamous cell carcinoma (p40 positive). Only the NSCC tumors, non-squamous, are eligible to molecular testing. A strategy aiming at tissue sparing for the small biopsies has to be organized. Tests corresponding to available drugs are prioritized. Blank slides will be prepared for immunohistochemistry and in situ hybridization based tests such as ALK. DNA will then be extracted for the other tests, EGFR mutation screening first associated or not to KRAS. Then, the emerging biomarkers (HER2, ROS1, RET, BRAF…) as well as potentially other markers in case of clinical trials, can been tested. The spread of next generation sequencing technologies, with a very sensitive all-in-one approach will allow the identification of minority clones. Eventually, the development of liquid biopsies will provide the opportunity to monitor the apparition of resistance clones during treatment. This non-invasive approach allows patients with a contraindication to perform biopsy or with non-relevant biopsies to access to molecular screening.

Published
2016

160. Multicentric neoadjuvant pilot Phase II study of cetuximab combined with docetaxel in operable triple negative breast cancer

Author

N. Chalabi, K.E. Benmammar, V. Servent, Sharif Kullab, Xavier Durando, I. van Praagh, Anne Cayre, Fabrice Kwiatkowski, Y-J Bignon, Nina Radosevic-Robin, M.M. Dauplat, Catherine Abrial, J.P. Jacquin, J-M Nabholtz, Frédérique Penault-Llorca, Ph. Chollet, Marie-Ange Mouret-Reynier, and M.R.K. Bahadoor

Subjects
0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, Chemotherapy, Cetuximab, business.industry, medicine.medical_treatment, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Docetaxel, 030220 oncology & carcinogenesis, Internal medicine, medicine, Clinical endpoint, Panitumumab, Combined Modality Therapy, business, Neoadjuvant therapy, Triple-negative breast cancer, medicine.drug
Abstract

Systemic therapy for triple negative breast cancer (TNBC) is mostly based upon chemotherapy. Epithelial Growth Factor Receptor (EGFR) is overexpressed in around 50% of TNBC and may play a role in its pathogenesis. Consequently, we performed a multicentric pilot Phase II neoadjuvant trial of cetuximab (anti-EGFR antibody) combined with docetaxel for patients with operable, Stage II-III TNBC. Therapy consisted of weekly cetuximab (first infusion: 400 mg/m(2), then 250 mg/m(2)) combined with six cycles of docetaxel (T: 100 mg/m(2)) q.3 weeks. Subsequently, all patients underwent surgery. The primary endpoint was pathological complete response (pCR) while clinical response, toxicity and ancillary studies were secondary endpoints. Paraffin-embedded and frozen tumor samples were systematically collected in order to identify predictive biomarkers of efficacy and resistance. From a total of 35 accrued patients, 25 were assessable for pathologic response. The pCR rate was 24% [95% CI: 7.3-40.7]. Complete clinical response rate (cCR) was observed in 22% of cases. Conservative surgery was performed in 75% of patients. Toxicity, mostly cutaneous and hematologic, was manageable. The pre-therapy ratio between CD8+ and FOXP3+ tumor-infiltrating lymphocytes equal or higher than 2.75 was predictive of pCR: 43% versus 0%, p = 0.047. Cetuximab in combination with docetaxel displays a modest activity, but acceptable toxicity as neoadjuvant therapy of operable TNBC. Similarly to previous observations using panitumumab, another anti-EGFR antibody, the immune component of the tumor microenvironment may play an important role in predicting TNBC response to the neoadjuvant therapy.

Published
2015

161. LBA11 IMpassion031: Results from a phase III study of neoadjuvant (neoadj) atezolizumab + chemotherapy in early triple-negative breast cancer (TNBC)

Author

Cristiano Ferrario, Shigehira Saji, Luciana Molinero, Kevin Punie, A. Nguyen Duc, Melinda L. Telli, Hong Zhang, S.Y. Chui, Carlos H. Barrios, Mario Liste-Hermoso, Kyung Hwa Jung, Nadia Harbeck, H. Iwata, Joohyuk Sohn, A. Koehler, Vidya Maiya, Elizabeth A. Mittendorf, Roberto Hegg, Sheetal Patel, and Frédérique Penault-Llorca

Subjects
Oncology, Chemotherapy, medicine.medical_specialty, Atezolizumab, business.industry, medicine.medical_treatment, Internal medicine, medicine, Hematology, business, Triple-negative breast cancer
Published
2020

163. 604TiP ON-TRK: A non-interventional study of larotrectinib in patients with TRK fusion cancer

Author

J.C-H. Yang, Paolo G. Casali, John A. Reeves, A. Drilon, G. Castro, Ulrik Lassen, Marc Mardoche Fellous, Alberto S. Pappo, Erin R. Rudzinski, Frédérique Penault-Llorca, Gilles Vassal, Hendrik Nogai, Jonathan C. Trent, F. Lopez-Rios, Serge Leyvraz, Ghazaleh Tabatabai, Edward S. Kim, and Marcia S. Brose

Subjects
Oncology, medicine.medical_specialty, business.industry, Cancer, Hematology, Tropomyosin receptor kinase A, medicine.disease, Internal medicine, Trk receptor, Non interventional, Medicine, In patient, business
Published
2020

164. 28P Europe-side external quality assessment (EQA) of RNA based testing of ER, PR, HER2 and Ki67 in invasive breast cancer

Author

Fulvia Ferrazzi, E. Guerini Rocco, Matthias Ruebner, Anne Cayre, M. W. Beckmann, T. Caniego Casa, Peter A. Fasching, Thomas Mairinger, Hanna Huebner, Ramona Erber, G. Viale, Robert Stöhr, Lina Khoury, J. Palacios Calvo, A. Hartmann, C Denkert, Paul Jank, M. Zentgraf, Frédérique Penault-Llorca, and J. Fischer

Subjects
Oncology, medicine.medical_specialty, Breast cancer, business.industry, Internal medicine, External quality assessment, Medicine, RNA, Hematology, business, medicine.disease
Published
2020

165. Breaking down the Contradictory Roles of Histone Deacetylase SIRT1 in Human Breast Cancer

Author

Yves-Jean Bignon, Dominique Bernard-Gallon, Khaldoun Rifaï, Frédérique Penault-Llorca, Mouhamed Idrissou, Département d'Oncogénétique, Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER-UNICANCER, UNICANCER, Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), and RIFAI, khaldoun

Subjects
0301 basic medicine, Cancer Research, deacetylation, tumor suppressor, [SDV.CAN]Life Sciences [q-bio]/Cancer, Review, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, medicine.disease_cause, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, lcsh:RC254-282, Metastasis, 03 medical and health sciences, Breast cancer, breast cancer, SIRT1, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, SIRT1 modulators, Regulation of gene expression, biology, business.industry, tumor promoter, Cancer, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, epigenetic silencing, 3. Good health, 030104 developmental biology, Histone, Oncology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Cancer research, biology.protein, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Histone deacetylase, Carcinogenesis, business, Deacetylase activity
Abstract

International audience; Breast cancer (BC) is the most common type of cancer in women worldwide; it is a multifactorial genetic disease. Acetylation and deacetylation are major post-translational protein modifications that regulate gene expression and the activity of a myriad of oncoproteins. Aberrant deacetylase activity can promote or suppress tumorigenesis and cancer metastasis in different types of human cancers, including breast cancer. Sirtuin-1 (SIRT1) is a class-III histone deacetylase (HDAC) that deacetylates both histone and non-histone targets. The often-described ‘regulator of regulators’ is deeply implicated in apoptosis, gene regulation, genome maintenance, DNA repair, aging, and cancer development. However, despite the accumulated studies over the past decade, the role of SIRT1 in human breast cancer remains a subject of debate and controversy. The ambiguity surrounding the implications of SIRT1 in breast tumorigenesis stems from the discrepancy between studies, which have shown both tumor-suppressive and promoting functions of SIRT1. Furthermore, studies have shown that SIRT1 deficiency promotes or suppresses tumors in breast cancer, making it an attractive therapeutic target in cancer treatment. This review provides a comprehensive examination of the various implications of SIRT1 in breast cancer development and metastasis. We will also discuss the mechanisms underlying the conflicting roles of SIRT1, as well as its selective modulators, in breast carcinogenesis.

Published
2018

166. Impact of chemotherapy-induced menopause in women of childbearing age with non-metastatic breast cancer – Preliminary results from the MENOCOR study

Author

Aude-Marie Savoye, Emilie Thivat, Angeline Ginzac, Marie-Ange Mouret-Reynier, Xavier Durando, Frédérique Penault-Llorca, Catherine Abrial, Olivier Collard, Fabrice Kwiatkowski, Joyce Dohou, Judith Passildas, 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), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Institut de Cancérologie de la Loire Lucien Neuwirth, Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Institut Jean Godinot [Reims], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Mollecular Oncology Laboratory, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), and Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)

Subjects
0301 basic medicine, Adult, Cancer Research, medicine.medical_specialty, Adolescent, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Menstruation, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Breast cancer, Quality of life, Internal medicine, Surveys and Questionnaires, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, Prospective Studies, 10. No inequality, Ovarian reserve, Prospective cohort study, ComputingMilieux_MISCELLANEOUS, business.industry, Middle Aged, Interim analysis, medicine.disease, Prognosis, humanities, Hormones, 3. Good health, Menopause, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Quality of Life, Amenorrhea, Female, medicine.symptom, business, Follow-Up Studies
Abstract

Background Young patients with breast cancer treated with chemotherapy can experience ovarian failure, which can lead to chemotherapy-induced menopause (CIM) impacting the quality of life (QoL). A prospective study was set out to evaluate the impact of CIM on QoL in women of childbearing age with non-metastatic breast cancer, and this article reports results of the interim analysis conducted to evaluate feasibility and to see preliminary results. Patients and Methods A total of 58 women (age, 18-46 years) with newly diagnosed breast cancer and treated with chemotherapy were eligible. QoL was assessed by self-administered questionnaires (Quality of Life Questionnaire-Core 30 [QLQ-C30], Quality of Life Questionnaire-Breast 23 [QLQ-BR23], and Kupperman index) and hormonal variations (anti-Mullerian hormone [AMH], follicle-stimulating hormone, and estradiol) were explored. We compared patients with ≥ 12 months amenorrhea (CIM) (n = 41) to patients with Results A good inclusion rate (approximately 4/month) and sufficient data enabled us to perform this analysis. QLQ-C30 failed to show any difference between CIM and non-CIM patients (P = .5). In contrast, at 6 months post-chemotherapy, CIM patients tended to have lower QoL as shown by QLQ-BR23 (P = .16) and more severe climacteric symptoms (P = .01). Regarding hormonal variations, AMH pre-treatment level was higher in non-CIM patients (P = .0032). We also noted that CIM patients were older (P = .00013), had shorter menstruation cycle (P = .082), and experienced faster amenorrhea (P = .088). Conclusions The study is technically feasible, and our preliminary results underline that age in association with pre-treatment AMH level could be helpful to predict ovarian function. QLQ-BR23 seemed to be stronger, more precise, and appropriate to evaluate QoL changes in patients with breast cancer than the QLQ-C30.

Published
2018

167. Immunological signature meta-analysis across lung cancer cohorts within the NanoString Clinical Transcriptional Atlas Group (CTAG) associated with patient outcome and history

Author

Diane Damotte, M. Cumberbatch, P Morel, Sarah Warren, Karen Leroy, M. Duruisseaux, A. Brindel, M. Bhagat, Frédérique Penault-Llorca, J. Lopez, J. Reeves, SuFey Ong, Nina Radosevic-Robin, and François Goldwasser

Subjects
Oncology, medicine.medical_specialty, business.industry, Tumor biology, Hematology, Gene signature, medicine.disease, Internal medicine, Meta-analysis, T cell subset, Overall survival, Medicine, Progression-free survival, business, Lung cancer, Objective response, health care economics and organizations
Abstract

Background With the approval of anti-PD1 blocking antibodies in a growing number of indications, understanding the mechanisms responsible for potentiating response to these agents has been a critical avenue of research. However, most studies rely on the use of single cohorts and are relatively limited in their scope, thus limited their utility. Methods We created a consortium of investigators who share clinical and accompanying transcriptional data collected on the NanoString® nCounter® platform from patients treated with single agent immunotherapy to facilitate biomarker research. In this study, we apply a meta-analysis to a combined cohort of 4 lung cancer studies (n = 150) to identify transcriptional correlates of response to identify patients who are likely to experience clinical benefit. Results RNA was profiled with the NanoString IO360 and IO360 beta gene expression panels, and 43 signatures that describe facets of the immune response, tumor biology, and the tumor microenvironment were calculated. Included in these signatures is the Tumor Inflammation Signature (TIS), an investigational 18 gene signature of a suppressed adaptive immune response which enriches for clinical response to pembrolizumab. These signatures, as well as genes of interest identified in a given cohort, were compared to objective response, overall survival, or progression free survival across the cohorts. We confirm previously reported association of TIS with patient outcome and identify immune cell subsets that are also associated with response. In addition, we examine differences between patients with distinct mutational backgrounds, smoking histories, or histological classifications, as well as differences attributable to biopsy location. Conclusion This multi-cohort study allows for the development of multi-variate predictors of response to anti-PD1 monotherapy using a single research assay to transcriptionally profile the tumors. We can generate robust predictions from real-world cohorts, which may lead to the development of improved diagnostic assays to guide treatment decisions. Legal entity responsible for the study NanoString Technologies. Funding NanoString Technologies. Disclosure N. Radosevic-Robin: Research grant / Funding (institution): NanoString Technologies. J. Reeves: Full / Part-time employment: NanoString Technologies. K. Leroy: Research grant / Funding (self): NanoString Technologies. M. Duruisseaux: Research grant / Funding (self): NanoString Technologies. P. Morel: Full / Part-time employment: NanoString Technologies. M. Bhagat: Research grant / Funding (institution): NanoString Technologies. F. Penault-Llorca: Advisory / Consultancy, Research grant / Funding (institution): NanoString Technologies. D. Damotte: Research grant / Funding (institution): NanoString Technologies. F. Goldwasser: Research grant / Funding (institution): NanoString Technologies. A. Brindel: Research grant / Funding (institution): NanoString Technologies. M. Cumberbatch: Research grant / Funding (institution): NanoString Technologies. S. Ong: Full / Part-time employment: NanoString Technologies. J. Lopez: Research grant / Funding (institution): NanoString Technologies. S. Warren: Full / Part-time employment: NanoString Technologies.

Published
2019

168. Exciting History of Tip60 and Its Companions in Carcinogenesis Across the Heterochromatin Landscapes

Author

Marine Daures, Dominique Bernard-Gallon, Yves-Jean Bignon, Frédérique Penault-Llorca, Khaldoun Rifaï, Mouhamed Idrissou, Département d'Oncogénétique, Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER-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]), UNICANCER, and Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, Heterochromatin, Carcinogenesis, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, medicine.disease_cause, Biochemistry, Polyploidy, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Evolutionary biology, 030220 oncology & carcinogenesis, Genetics, medicine, Molecular Medicine, Humans, Molecular Biology, ComputingMilieux_MISCELLANEOUS, Biotechnology
Abstract

International audience

Published
2018

169. A new metabolic gene signature in prostate cancer regulated by JMJD3 and EZH2

Author

Dominique Bernard-Gallon, Khaldoun Rifaï, Frédérique Penault-Llorca, Laurent Guy, Mouhamed Idrissou, Gaëlle Judes, Yves-Jean Bignon, Marine Daures, 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]), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), and UNICANCER

Subjects
0301 basic medicine, JMJD3, [SDV.CAN]Life Sciences [q-bio]/Cancer, macromolecular substances, 03 medical and health sciences, Prostate cancer, 0302 clinical medicine, gene panel, Histone methylation, LNCaP, medicine, PTEN, Epigenetics, EZH2, epidrugs, Regulation of gene expression, biology, Gene signature, medicine.disease, prostate cancer, 3. Good health, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, biology.protein, Cancer research, Research Paper
Abstract

International audience; Histone methylation is essential for gene expression control. Trimethylated lysine 27 of histone 3 (H3K27me3) is controlled by the balance between the activities of JMJD3 demethylase and EZH2 methyltransferase. This epigenetic mark has been shown to be deregulated in prostate cancer, and evidence shows H3K27me3 enrichment on gene promoters in prostate cancer. To study the impact of this enrichment, a transcriptomic analysis with TaqMan Low Density Array (TLDA) of several genes was studied on prostate biopsies divided into three clinical grades: normal (n = 23) and two tumor groups that differed in their aggressiveness (Gleason score ≤ 7 (n = 20) and >7 (n = 19)). ANOVA demonstrated that expression of the gene set was upregulated in tumors and correlated with Gleason score, thus discriminating between the three clinical groups. Six genes involved in key cellular processes stood out: JMJD3, EZH2, MGMT, TRA2A, U2AF1 and RPS6KA2. Chromatin immunoprecipitation demonstrated collocation of EZH2 and JMJD3 on gene promoters that was dependent on disease stage. Gene set expression was also evaluated on prostate cancer cell lines (DU 145, PC-3 and LNCaP) treated with an inhibitor of JMJD3 (GSK-J4) or EZH2 (DZNeP) to study their involvement in gene regulation. Results showed a difference in GSK-J4 sensitivity under PTEN status of cell lines and an opposite gene expression profile according to androgen status of cells. In summary, our data describe the impacts of JMJD3 and EZH2 on a new gene signature involved in prostate cancer that may help identify diagnostic and therapeutic targets in prostate cancer.

Published
2018

170. [PD-L1 testing in non-small cell lung carcinoma: Guidelines from the PATTERN group of thoracic pathologists]

Author

Sylvie, Lantuejoul, Julien, Adam, Nicolas, Girard, Mickael, Duruisseaux, Audrey, Mansuet-Lupo, Aurélie, Cazes, Isabelle, Rouquette, Laure, Gibault, Stéphane, Garcia, Martine, Antoine, Jean Michael, Vignaud, Françoise, Galateau-Sallé, Christine, Sagan, Cécile, Badoual, Frédérique, Penault-Llorca, Diane, Damotte, Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Pathology, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Normandie Université (NU), Service de Pathologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôtel-Dieu, Pathologie vasculaire et endocrinologie rénale - Chaire de médecine expérimentale (INSERM U36), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), 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 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), Interactions cellulaires tumorales et leur environnement et réponse aux agents anti-cancéreux, Université Pierre et Marie Curie - Paris 6 (UPMC), Laboratoire d'Anatomie Pathologique [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), Anatomy-Pathology Hôpital Nord Laënnec, Hôpital Guillaume-et-René-Laennec [Saint-Herblain], Service d'anatomo-pathologie [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), 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]), Service de chirurgie thoracique et d'anatomopathologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Hôtel Dieu, Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, and 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)

Subjects
PD-L1, Lung Neoplasms, Organoplatinum Compounds, Quality Assurance, Health Care, Recommandations, [SDV.CAN]Life Sciences [q-bio]/Cancer, Guidelines, B7-H1 Antigen, Specimen Handling, Antineoplastic Agents, Immunological, Carcinoma, Non-Small-Cell Lung, Antineoplastic Combined Chemotherapy Protocols, Biomarkers, Tumor, Humans, Molecular Targeted Therapy, Randomized Controlled Trials as Topic, Cancer, Patient Selection, Immunohistochimie, Immunohistochemistry, Neoplasm Proteins, Poumon, Clinical Trials, Phase III as Topic, Reagent Kits, Diagnostic, Lung cancer, Algorithms
Abstract

International audience; Lung cancer is the leading cause of cancer death in France with low response rates to conventional chemotherapy. Nevertheless, new therapies have emerged recently, among which PD1 immune checkpoint inhibitors (ICI), such as nivolumab (OPDIVO®, Bristol-Myers Squibb) and pembrolizumab (KEYTRUDA®, Merck & Co), or PD-L1 ICI, such as atezolizumab (TECENTRIQ®, Genentech), durvalumab (IMFINZI®, Astra-Zeneca), and avelumab (BAVENCIO®, EMD Serono). The prescription of pembrolizumab for advanced stage non-small cell lung carcinoma (NSCLC) patients requires the demonstration of PD-L1 expression by tumor cells by immunohistochemistry (IHC) (minimum of 50% of positive tumor cells is required for first-line setting, and of 1% for second-line and beyond) and PD-L1 assay is now considered as a companion diagnostic tool for this drug. Numerous standardized PD-L1 assays performed on dedicated platforms have been validated in clinical trials, each antibody being associated to one specific PD1 or PD-L1 inhibitor. However, not all pathologists have access to the dedicated platforms and the high cost of these assays is still a limitation to their implementation; in addition, the small size of the NSCLC tumor samples does not allow to perform at the same time multiple assays for multiple drugs. The use of laboratory-developed tests seems feasible but their validation must guarantee the same sensitivities and specificities as standardized tests. In this context, the French group of thoracic pathologists PATTERN has teamed up with thoracic oncologists to provide recommendations on the indication, the critical technical steps and the interpretation of the PD-L1 IHC test to help pathologists to implement quickly and in the best conditions this new theranostic test.

Published
2018

171. SIRT1 in Colorectal Cancer: A Friend or Foe?

Author

Marine Daures, Yves-Jean Bignon, Frédérique Penault-Llorca, Khaldoun Rifaï, Mouhamed Idrissou, Dominique Bernard-Gallon, 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), Département d'Oncogénétique, Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER-UNICANCER, UNICANCER, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])

Subjects
0301 basic medicine, Senescence, DNA damage, Colorectal cancer, Cell, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biochemistry, 03 medical and health sciences, 0302 clinical medicine, Sirtuin 1, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Genetics, medicine, Humans, Molecular Biology, business.industry, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Colorectal carcinogenesis, medicine.disease, 3. Good health, 030104 developmental biology, medicine.anatomical_structure, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Apoptosis, 030220 oncology & carcinogenesis, Cancer research, Molecular Medicine, Disease Susceptibility, Colorectal Neoplasms, business, Biotechnology
Abstract

International audience; It has been well established that SIRT1 plays a key role in the regulation of various crucialbiological processes such as apoptosis, DNA damage response, cell senescence andmetabolism. However, its role in Colorectal carcinogenesis is still subject to debate.In this study, we uncover a double role of SIRT1 in colorectal carcinoma

Published
2018

172. SIRT1-dependent epigenetic regulation of H3 and H4 histone acetylation in human breast cancer

Author

Marine Daures, Yves-Jean Bignon, Frédérique Penault-Llorca, Khaldoun Rifaï, Dominique Bernard-Gallon, Mouhamed Idrissou, Gaëlle Judes, Imagerie Moléculaire et Stratégies Théranostiques - Clermont Auvergne (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Département d'Oncogénétique, CRLCC Jean Perrin, Institut National de la Recherche Agronomique (INRA)-Réseau National Alimentation Cancer Recherche (réseau NACRe)-Centre Jean Perrin (CJP-EA 4233), 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]), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER-UNICANCER, UNICANCER-UNICANCER-Institut National de la Recherche Agronomique (INRA)-Réseau National Alimentation Cancer Recherche (réseau NACRe), UNICANCER, Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Recherche Agronomique (INRA)-Réseau National Alimentation Cancer Recherche (réseau NACRe)-Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), and COLO, Mouniati

Subjects
0301 basic medicine, [SDV.CAN]Life Sciences [q-bio]/Cancer, medicine.disease_cause, 03 medical and health sciences, Breast cancer, breast cancer, SIRT1, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, Epigenetics, Regulation of gene expression, biology, epigenetics, histone marks, EZH2, Cancer, medicine.disease, 3. Good health, 030104 developmental biology, Histone, Oncology, Cancer research, biology.protein, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Histone deacetylase, epigenetic modulation, Carcinogenesis, Research Paper
Abstract

International audience; Breast cancer is the most frequently diagnosed malignancy in women worldwide. It is well established that the complexity of carcinogenesis involves profound epigenetic deregulations that contribute to the tumorigenesis process. Deregulated H3 and H4 acetylated histone marks are amongst those alterations. Sirtuin-1 (SIRT1) is a class-III histone deacetylase deeply involved in apoptosis, genomic stability, gene expression regulation and breast tumorigenesis. However, the underlying molecular mechanism by which SIRT1 regulates H3 and H4 acetylated marks, and consequently cancer-related gene expression in breast cancer, remains uncharacterized. In this study, we elucidated SIRT1 epigenetic role and analyzed the link between the latter and histones H3 and H4 epigenetic marks in all 5 molecular subtypes of breast cancer. Using a cohort of 135 human breast tumors and their matched normal tissues, as well as 5 human-derived cell lines, we identified H3k4ac as a new prime target of SIRT1 in breast cancer. We also uncovered an inverse correlation between SIRT1 and the 3 epigenetic marks H3k4ac, H3k9ac and H4k16ac expression patterns. We showed that SIRT1 modulates the acetylation patterns of histones H3 and H4 in breast cancer. Moreover, SIRT1 regulates its H3 acetylated targets in a subtype-specific manner. Furthermore, SIRT1 siRNA-mediated knockdown increases histone acetylation levels at 6 breast cancer-related gene promoters: AR, BRCA1, ERS1, ERS2, EZH2 and EP300. In summary, this report characterizes for the first time the epigenetic behavior of SIRT1 in human breast carcinoma. These novel findings point to a potential use of SIRT1 as an epigenetic therapeutic target in breast cancer.

Published
2018

173. High rate of PIK3CA mutations but no TP53 mutations in low-grade adenosquamous carcinoma of the breast

Author

Anne Vincent-Salomon, Caterina Marchiò, Laurent Arnould, Ivan Bièche, Isabelle Treilleux, Frédérique Penault-Llorca, Marick Laé, Emanuelle Menet, Guillaume Bataillon, Roman Rouzier, Laetitia Fuhrmann, Mathieu Capovilla, Elodie Girard, Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad), Oncogénèse et progression tumorale, Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), 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]), CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Breakthrough Breast Cancer Centre, London Institute of Cancer, Genetique Moleculaire des Cancers d'Origine Epitheliale, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie [Paris], Département de Pathologie, Institut Curie [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Adult, 0301 basic medicine, Mutation rate, Histology, Class I Phosphatidylinositol 3-Kinases, Adenosquamous carcinoma, Metaplastic carcinoma, Triple Negative Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, medicine.disease_cause, metaplastic carcinoma, Pathology and Forensic Medicine, Carcinoma, Adenosquamous, 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, Breast cancer, breast cancer, androgen receptor, medicine, Humans, Missense mutation, low-grade adenosquamous carcinoma, PIK3CA mutations, 2734, Aged, Retrospective Studies, Aged, 80 and over, Sanger sequencing, Mutation, General Medicine, Middle Aged, medicine.disease, 3. Good health, Androgen receptor, 030104 developmental biology, 030220 oncology & carcinogenesis, Cancer research, symbols, Female, Tumor Suppressor Protein p53
Abstract

Aims Low-grade adenosquamous carcinoma of the breast (LGASC) is a rare variant of metaplastic carcinoma characterised by a favourable outcome and histologically composed of glandular and squamous elements in a spindle cell background typically associated with a lymphocytic stromal reaction. Because of its rarity, the immunophenotypic and genetic profile of LGASC has not been sufficiently characterised. The aim of this study was to gain insights into the molecular and phenotypic characteristics of LGASC. Methods and results We reviewed the clinical and morphological features and detailed the immunohistochemical characteristics of a retrospective series of 13 LGASCs. Targeted sequencing of 50 genes was performed in 10 of 13 cases. Identified mutations were further assessed by Sanger sequencing in a validation series of 11 additional cases. All tumours showed a triple-negative immunophenotype, expressed 'basal' keratins, showed variable levels of epidermal growth factor receptor expression, and did not express androgen receptor. Sequencing analysis of the screening set of LGASCs revealed a high rate (seven of 10 cases) of PIK3CA mutations, whereas no TP53 mutations were found. All PIK3CA mutations were missense mutations located either in exon 20 (n = 6) or in exon 9 (n = 1). The global PIK3CA mutation rate, including the validation series, was 52% (11 of 21 cases). No disease recurrences were observed. [Correction added on 11 June 2018, after first online publication: The percentage of mutation rate was corrected to 52%] CONCLUSIONS: Our results indicate that LGASC of the breast is a low-grade triple-negative breast cancer that harbours a basal-like phenotype with no androgen receptor expression, and shows a high rate of PIK3CA mutations but no TP53 mutations.

Published
2018

174. Le statut télomérique dans le cancer bronchopulmonaire : un nouveau biomarqueur du pronostic et de la résistance à l’immunothérapie

Author

Gaëlle Jeannin, Eve Faugeras, Lauren Véronèse, Anne Cayre, Lise Thibonnier, Patrick Merle, Jean-Louis Kemeny, P. Vago, Frédérique Penault-Llorca, A. Tchirkov, Jacques-Olivier Bay, Henri Janicot, and Sébastien Bailly

Subjects
Anatomy
Abstract

Introduction/objectifs Le cancer du poumon est la premiere cause de mortalite en France et dans le monde. Le cancer bronchique non a petites cellules (CBNPC) est le sous-type histologique le plus frequent. Malgre les progres therapeutiques recents avec notamment l’introduction d’immunotherapie, le CBNPC est souvent diagnostique a stade avance et son pronostic est pejoratif. La dysfonction des telomeres est une etape cle du processus tumoral et l’etude du statut telomerique dans le CBNPC pourrait apporter les nouveaux biomarqueurs pour mieux evaluer le pronostic et la reponse au traitement. Nous avons recherche une correlation entre le statut telomerique et la survie dans le CBNPC metastatique. Patients et methodes Les acides nucleiques (ADN et ARN) ont ete extraits a partir de 89 biopsies tumorales. Le statut telomerique a ete evalue par la longueur des telomeres, l’expression de TERT (telomerase) et des genes du complexe Shelterin impliques dans la regulation de la maintenance des telomeres (TRF1, TRF2, POT1, TPP1, RAP1 et TIN2) par PCR quantitative. Resultats Des telomeres courts et une surexpression de TERT etaient associes a la survie globale (SG) plus courte (p = 0,0053 et p = 0,05, respectivement). Une forte expression de TRF2 (p = 0,025) et une faible expression de RAP1 et TIN2 (p = 0,0037 et p = 0,017, respectivement) etait egalement correlee a la SG reduite. De facon tres interessante, un raccourcissement des telomeres influencait negativement la SG dans le sous-groupe de patients ayant recu une immunotherapie (p = 0,0037). Conclusion A notre connaissance, il s’agit de la premiere etude analysant le statut telomerique dans le CBNPC metastatique. Nous avons demontre que la dysfonction telomerique etait associee au mauvais pronostic et a la resistance au traitement. Ainsi, la determination de ces parametres pourrait permettre d’ajuster les therapies proposees aux patients et represente une voie d’espoir pour le developpement de nouveaux traitements cibles.

Published
2019

175. The Epigenetic Landscape of Promoter Genome-wide Analysis in Breast Cancer

Author

Dominique Bernard-Gallon, Aslihan Dagdemir, Seher Karsli-Ceppioglu, Yves-Jean Bignon, André Lebert, Gaëlle Judes, Frédérique Penault-Llorca, Polytech'Clermont-Ferrand, Université Blaise Pascal - Clermont-Ferrand 2 (UBP), 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]), Département d'Oncogénétique, UNICANCER-UNICANCER-Institut National de la Recherche Agronomique (INRA)-Réseau National Alimentation Cancer Recherche (réseau NACRe), Institut Pascal (IP), SIGMA Clermont (SIGMA Clermont)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), UNICANCER-UNICANCER, LEBERT, André, Laboratoire de Pharmacognosie / Biotechnologies (UMR484), Université d'Auvergne - Clermont-Ferrand I (UdA), Karsli-Ceppioglu, Seher, Dagdemir, Aslihan, Judes, Gaelle, Lebert, Andre, Penault-Llorca, Frederique, Bignon, Yves-Jean, Bernard-Gallon, Dominique, SIGMA Clermont (SIGMA Clermont)-Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Centre Jean Perrin, CRLCC Jean Perrin, Imagerie Moléculaire et Stratégies Théranostiques - Clermont Auvergne (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), and Institut National de la Recherche Agronomique (INRA)-Réseau National Alimentation Cancer Recherche (réseau NACRe)-Centre Jean Perrin (CJP-EA 4233)

Subjects
0301 basic medicine, Oncology, Disease, medicine.disease_cause, Epigenesis, Genetic, SUBTYPES, Histones, chemistry.chemical_compound, PROGNOSTIC-FACTORS, PRIMARY THERAPY, Gene Regulatory Networks, Promoter Regions, Genetic, skin and connective tissue diseases, ComputingMilieux_MISCELLANEOUS, Epigenomics, Regulation of gene expression, Multidisciplinary, METHYLATION, INTERNATIONAL EXPERT CONSENSUS, ASSOCIATION, 3. Good health, RUNX1, Medicine, Female, medicine.medical_specialty, ACETYLATION, Science, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Article, 03 medical and health sciences, Breast cancer, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, medicine, Humans, Epigenetics, Gene, medicine.disease, 030104 developmental biology, chemistry, CELLS, Cancer research, TRIMETHYLATION, Carcinogenesis, Protein Processing, Post-Translational, HISTONE MODIFICATIONS
Abstract

Breast cancer is a heterogeneous disease due to its clinico-pathological features and response to therapy. The classification of breast tumors based on their hormone receptor status and pathologic features. Post-translational histone modifications come into prominence for regulation of gene expression in cancer pathogenesis. Here, we analyzed dysregulation of H3K9ac and H3K27me3-enriched subtype-specific genes using ChIP-on-chip assay in breast cancer tumors and matched normal tissue samples. Breast cancer tumors were classified according to St Gallen Consensus 2013. Our results indicated that the promoter regions of genes modified by H3K9ac epi-mark are commonly associated with tumors with HER2-positive and TNBC subtype. H3K27me3-enriched genes were comprised of Luminal A and B1 subtypes. We constructed a network structure to elicit epigenetically regulated genes related with breast cancer progression. The central genes of the network (RUNX1, PAX3, GATA4 and DLX5) were subjected for epigenetically dysregulation in association with different breast cancer subtypes. Our study submits epigenetic mechanisms are crucial to elicit subtype-specific regulation in breast cancer and ChIP-on-chip assay provides a better understanding for breast tumorigenesis and new approaches for prevention and treatment.

Published
2017

176. EZH2 Histone Methyltransferase and JMJD3 Histone Demethylase Implications in Prostate Cancer

Author

Yves-Jean Bignon, Amani Ben Jemia, Khaldoun Rifaï, Mouhamed Idrissou, Laurent Guy, Frédérique Penault-Llorca, Gaëlle Judes, Dominique Bernard-Gallon, Marine Daures, Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, 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), Département d'Oncogénétique, Institut National de la Recherche Agronomique (INRA)-Réseau National Alimentation Cancer Recherche (réseau NACRe)-Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER-UNICANCER, Rhodia Opérations, RHODIA, Centre Jean Perrin, CRLCC Jean Perrin, Imagerie Moléculaire et Stratégies Théranostiques - Clermont Auvergne (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Institut National de la Recherche Agronomique (INRA)-Réseau National Alimentation Cancer Recherche (réseau NACRe)-Centre Jean Perrin (CJP-EA 4233), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), and UNICANCER-UNICANCER-Institut National de la Recherche Agronomique (INRA)-Réseau National Alimentation Cancer Recherche (réseau NACRe)

Subjects
0301 basic medicine, Epigenomics, Male, Jumonji Domain-Containing Histone Demethylases, [SDV]Life Sciences [q-bio], [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Adenocarcinoma, Biochemistry, Methylation, Histones, 03 medical and health sciences, Genetics, Humans, Enhancer of Zeste Homolog 2 Protein, Cancer epigenetics, Promoter Regions, Genetic, Molecular Biology, ComputingMilieux_MISCELLANEOUS, Histone deacetylase 5, Histone deacetylase 2, HDAC11, HDAC10, EZH2, Prostatic Neoplasms, 3. Good health, 030104 developmental biology, Histone methyltransferase, Cancer research, biology.protein, Molecular Medicine, JARID1B, Biotechnology
Abstract

International audience

Published
2017

177. Programmed Death-Ligand 1 Immunohistochemistry Testing: A Review of Analytical Assays and Clinical Implementation in Non–Small-Cell Lung Cancer

Author

Fernando Lopez-Rios, Frédérique Penault-Llorca, Andrew Wotherspoon, Keith Kerr, John W. Longshore, Julien Adam, Giuseppe Viale, Manfred Dietel, Noriko Motoi, John R Gosney, Ming-Sound Tsao, Birgit Guldhammer Skov, Kenneth Joel Bloom, Reinhard Büttner, Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, 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), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])

Subjects
0301 basic medicine, Oncology, Male, Cancer Research, medicine.medical_specialty, Pathology, Lung Neoplasms, Concordance, [SDV.CAN]Life Sciences [q-bio]/Cancer, Pembrolizumab, Antibodies, Monoclonal, Humanized, Risk Assessment, B7-H1 Antigen, Disease-Free Survival, 03 medical and health sciences, 0302 clinical medicine, Atezolizumab, Internal medicine, Carcinoma, Non-Small-Cell Lung, medicine, Humans, Molecular Targeted Therapy, Lung cancer, Survival rate, business.industry, Biopsy, Needle, Antibodies, Monoclonal, medicine.disease, Prognosis, Immunohistochemistry, 3. Good health, Clinical trial, Gene Expression Regulation, Neoplastic, Survival Rate, 030104 developmental biology, Nivolumab, Treatment Outcome, Editorial, 030220 oncology & carcinogenesis, Female, business
Abstract

Purpose Three programmed death-1/programmed death-ligand 1 (PD-L1) inhibitors are currently approved for treatment of non–small-cell lung cancer (NSCLC). Treatment with pembrolizumab in NSCLC requires PD-L1 immunohistochemistry (IHC) testing. Nivolumab and atezolizumab are approved without PD-L1 testing, though US Food and Drug Administration-cleared complementary PD-L1 tests are available for both. PD-L1 IHC assays used to assess PD-L1 expression in patients treated with programmed death-1/PD-L1 inhibitors in clinical trials include PD-L1 IHC 28-8 pharmDx (28-8), PD-L1 IHC 22C3 pharmDx (22C3), Ventana PD-L1 SP142 (SP142), and Ventana PD-L1 SP263 (SP263). Differences in antibodies and IHC platforms have raised questions about comparability among these assays and their diagnostic use. This review provides practical information to help physicians and pathologists understand analytical features and comparability of various PD-L1 IHC assays and their diagnostic use. Methods We reviewed and summarized published or otherwise reported studies (January 2016 to January 2017) on clinical trial and laboratory-developed PD-L1 IHC assays (LDAs). Studies assessing the effect of diagnostic methods on PD-L1 expression levels were analyzed to address practical issues related to tissue samples used for testing. Results High concordance and interobserver reproducibility were observed with the 28-8, 22C3, and SP263 clinical trial assays for PD-L1 expression on tumor cell membranes, whereas lower PD-L1 expression was detected with SP142. Immune-cell PD-L1 expression was variable and interobserver concordance was poor. Inter- and intratumoral heterogeneity had variable effects on PD-L1 expression. Concordance among LDAs was variable. Conclusion High concordance among 28-8, 22C3, and SP263 when assessing PD-L1 expression on tumor cell membranes suggests possible interchangeability of their clinical use for NSCLC but not for assessment of PD-L1 expression on immune cells. Development of LDAs requires stringent standardization before their recommendation for routine clinical use.

Published
2017

178. A non-inferiority randomized phase III trial of standard immunotherapy by checkpoint inhibitors vs. reduced dose intensity in responding patients with metastatic cancer: the MOIO protocol study

Author

Gwenaelle Gravis, Patricia Marino, Daniel Olive, Frederique Penault-LLorca, Jean-Pierre Delord, Clotilde Simon, Assia Lamrani-Ghaouti, Renaud Sabatier, Joseph Ciccolini, and Jean-Marie Boher

Subjects
Metastatic cancer, Immunotherapy, Checkpoint inhibitors, Health Economics, Quality of life, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background Immunotherapy (IO) has become a standard of care for treating various types of metastatic cancers and has significantly improved clinical outcome. With the exception of metastatic melanoma in complete response for which treatment can be stopped at 6 months, these treatments are currently administered until either disease progression for some IO, 2 years for others, or unacceptable toxicity. However, a growing number of studies are reporting maintenance of response despite discontinuation of therapy. There is currently no evidence of a dose effect of IO in pharmacokinetic studies. Maintaining efficacy despite a reduction in treatment intensity by decreasing the frequency of administration in patients with highly selected metastatic cancer, is the hypothesis evaluated in the MOIO study. Method/design This non-inferiority, randomized phase III study aims to compare the standard regimen to a 3 monthly regimen of variousIO drugs in adult patients with metastatic cancer in partial (PR) or complete response (CR) after 6 months of standard IO dosing (except melanoma in CR). This is a French national study conducted in 36 centers. The main objective is to demonstrate that the efficacy of a three-monthly administration is not unacceptably less efficacious than a standard administration. Secondary objectives are cost-effectiveness, quality of life (QOL), anxiety, fear of relapse, response rate, overall survival and toxicity. After 6 months of standard IO, patients with partial or complete response will be randomized 1:1 between standard IO or a reduced intensity dose of IO, administered every 3 months. The randomization will be stratified on therapy line,, tumor type, IO type and response status. The primary endpoint is the hazard ratio of progression-free survival. With a planned study duration of 6 years, including 36 months enrolment time, 646 patients are planned to demonstrate with a statistical level of evidence of 5% that the reduced IO regimen is non-inferior to the standard IO regimen, with a relative non-inferiority margin set at 1.3. Discussion Should the hypothesis of non-inferiority with an IO reduced dose intensity be validated, alternate scheduling could preserve efficacy while being cost-effective and allowing a reduction of the toxicity, with an increase in patient’s QOL. Trial registration NCT05078047.

Published
2023
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179. Combination of mTOR and EGFR targeting in an orthotopic xenograft model of head and neck cancer

Author

Gérard Milano, Marco Merlano, Cristiana Lo Nigro, Anne Sudaka, Martino Monteverde, Nina Radosevic-Robin, Alexandre Bozec, Frédérique Penault-Llorca, Nicolas Toussan, Nathalie Ebran, and Marie-Christine Etienne-Grimaldi

Subjects
0301 basic medicine, Oncology, medicine.medical_specialty, Cetuximab, business.industry, medicine.disease, Head and neck squamous-cell carcinoma, Temsirolimus, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Otorhinolaryngology, Tumor progression, 030220 oncology & carcinogenesis, Internal medicine, Sirolimus, medicine, Cancer research, business, Protein kinase B, PI3K/AKT/mTOR pathway, medicine.drug, EGFR inhibitors
Abstract

Objectives/Hypothesis Recent preclinical and clinical studies on head and neck squamous cell carcinoma (HNSCC) revealed synergistic effects when combining anti-EGFR agents with conventional chemotherapeutic drugs. Activation of the PI3-kinase/AKT/mTOR signaling pathway has been identified as an important mechanism implicated in tumor progression and resistance to EGFR inhibitors. The aim of this study was to investigate the effects of combining the mTOR inhibitor temsirolimus (Tem) with the anti-EGFR agent cetuximab (Cet) and conventional chemotherapeutic drugs (cisplatin and fluorouracil (C/F)) on an orthotopic model of HNSCC. Study Design Preclinical in vivo study. Methods We evaluated the anti-tumor efficacy (measured tumor volume) of Tem, Cet, and C/F, administered alone or in combination. Investigations were performed using a human HNSCC cell line, CAL33, injected into the mouth floor of nude mice. Results As compared with the control, the combination of Tem and Cet led to the highest tumor inhibition and induced almost complete tumor growth arrest (P = 0.001). Tem significantly enhanced the impact of the Cet-C/F combination on tumor growth (P < 0.001). The highest inhibitory effects of treatments on cell proliferation (Ki67 labeling), MAPK (pP42/44 labeling), and PI3K/AKT/mTOR (pS6R labeling) signaling pathways were found with the Tem-Cet association. Conclusion In this orthotopic HNSCC model, the combination of Tem with Cet produced synergistic effects on tumor growth. These results were corroborated by a strong inhibition of both MAPK and PI3K-mTOR signaling pathways. Level of Evidence N/A. Laryngoscope, 126:E156–E163, 2016

Published
2015

180. Facteurs pronostiques des carcinomes lobulaires infiltrants du sein : à propos de 940 cas

Author

R. Villet, C. Belichard, Monique Cohen, M.-P. Chauvet, G. Houvenaeghel, François Dravet, Anthony Gonçalves, S. Giard, C. Tunon de Lara, Marc Martino, J.-R. Garbay, H. Charitansky, E. Chéreau Ewald, Camille Jauffret, Frédérique Penault-Llorca, Emile Daraï, J-M Classe, Charles Coutant, Delphine Hudry, Eric Lambaudie, P. Gimbergues, C. Faure, and Pierre Azuar

Subjects
Gynecology, medicine.medical_specialty, Reproductive Medicine, business.industry, medicine, Obstetrics and Gynecology, General Medicine, business
Abstract

Resume Objectifs L’objectif etait d’evaluer les facteurs pronostiques des carcinomes lobulaires infiltrants (CLI) T1 et T2 du sein et les facteurs predictifs de l’atteinte ganglionnaire axillaire. Methodes Etude retrospective multicentrique, menee de 1999 a 2008, parmi 13 centres francais. Les donnees concernant les patientes traitees d’un cancer du sein T1 ou T2 par une chirurgie premiere ont ete recueillies. Une mastectomie partielle ou totale etait realisee avec un curage axillaire systematique durant la periode de validation ou en cas d’envahissement des ganglions sentinelles. Parmi ces 8100 patients, 940 cas de CLI ont ete extraits. Apres analyse univariee identifiant les facteurs pronostiques significatifs, une regression logistique de Cox a ete appliquee. L’analyse a permis de determiner les facteurs pronostiques de survie sans recidive (SSR) et de survie globale (SG). Les differents facteurs correles a une atteinte des ganglions lymphatiques ont ete recherches en analyse univarie, puis multivarie, afin de determiner les facteurs predictifs d’envahissement ganglionnaire axillaire. Resultats L’âge median etait de 60 ans (27–89). La majorite des patientes presentaient une tumeur d’une taille superieure a 10 mm (n = 676 : 72 %), avec une minorite de lesions de haut grade SBR (n = 38 : 4 %) et une majorite de statut hormonal positif (n = 880 : 93,6 %). La duree mediane de suivi etait de 59 mois (1–131). Les facteurs significativement associes a une diminution de la SSR etaient le grade SBR 3 (hazard ratio [HR] : 3,85, IC 1,21–12,21), la taille tumorale superieure a 2 cm (HR : 2,85, IC : 1,43–5,68) et le statut ganglionnaire macrometastatique (HR : 3,11, IC : 1,47–6,58). L’analyse multivariee mettait en evidence un impact significatif sur la SG de l’âge de moins de 50 ans (HR : 5,2, IC : 1,39–19,49), du grade SBR 3 (HR : 5,03, IC : 1,19–21,25), de la taille tumorale superieure a 2 cm (HR : 2,53, IC : 1,13–5,69). Il n’a pas ete mis en evidence de correlation significative entre la prescription de chimiotherapie et la SSR (odds ratio [OR] 0,8, IC : 0,35–1,80) ou la SG (OR : 0,72, IC : 0,28–1,82). La SSR n’etait pas differente entre les pN0 (aucune invasion axillaire), les pNi+ (cellules tumorales isolees) ou les pNmic (micrometastase). Il n’y avait pas de difference entre un ou plus d’un ganglion lymphatique macromatastatique (pN1). Les SSR etaient statistiquement differentes entre les pN1 et les autres statuts ganglionnaires (pN0, pNi+ ou pNmic). Les facteurs associes a l’atteinte ganglionnaire en analyse multivariee etaient : l’âge entre 51 et 65 ans (OR : 2,1, IC 1,45–3,04), l’âge inferieur a 50 ans (OR 3,2, IC : 2,05–5,03), la taille tumorale superieure a 2 cm (OR 4,4, IC : 3,2–6,14), le grade SBR 2 (OR 1,9, IC : 1,30–2,90) et le grade SBR 3 (OR 3,5, IC : 1,61–7,75). Conclusion L’analyse de cette serie de 940 CLI de stade T1 et T2 apporte plusieurs informations : les facteurs associes a l’atteinte des ganglions lymphatiques axillaires sont l’âge de moins de 65 ans, la taille de la tumeur de plus de 20 mm et un grade SBR 2 ou 3. Les memes facteurs sont significativement correles aux taux de SSR et de SG. L’envahissement macrometastatique des ganglions axillaires a un impact significatif sur la SSR et la SG, contrairement aux pNi+ et aux pNmic, qui semblent avoir le meme pronostic que les pN0.

Published
2015

181. Combined evaluation of LC3B puncta and HMGB1 expression predicts residual risk of relapse after adjuvant chemotherapy in breast cancer

Author

Laurent Arnould, Sylvain Ladoire, David Enot, Laura Senovilla, Marie Laure Poillot, Aicha Goubar, Patrick Arveux, Laurence Zitvogel, Suzette Delaloge, C. Dalban, François Ghiringhelli, Frédérique Penault-Llorca, Nicole Prada, Fabrice Andre, Guido Kroemer, Vichnou Poirier-Colame, Clara Locher, Pierre Fumoleau, Marc Spielmann, and Kariman Chaba

Subjects
Oncology, medicine.medical_specialty, Anthracycline, medicine.medical_treatment, Breast Neoplasms, Biology, Breast cancer, Recurrence, Risk Factors, Internal medicine, Autophagy, Biomarkers, Tumor, medicine, Humans, HMGB1 Protein, Molecular Biology, Chemotherapy, Hazard ratio, Cell Biology, medicine.disease, Confidence interval, Gene Expression Regulation, Neoplastic, Chemotherapy, Adjuvant, Immunology, Cohort, Cancer cell, Immunohistochemistry, Female, Clinical Research Paper, Microtubule-Associated Proteins
Abstract

In spite of adjuvant chemotherapy, a significant fraction of patients with localized breast cancer (BC) relapse after optimal treatment. We determined the occurrence of cytoplasmic MAP1LC3B/LC3B (microtubule-associated protein 1 light chain 3B)-positive puncta, as well as the presence of nuclear HMGB1 (high mobility group box 1) in cancer cells within surgical BC specimens by immunohistochemistry, first in a test cohort (152 patients) and then in a validation cohort of localized BC patients who all received adjuvant anthracycline-based chemotherapy (1646 patients). Cytoplasmic LC3B(+) puncta inversely correlated with the intensity of SQSTM1 staining, suggesting that a high percentage cells of LC3B(+) puncta reflects increased autophagic flux. After setting optimal thresholds in the test cohort, cytoplasmic LC3B(+) puncta and nuclear HMGB1 were scored as positive in 27.2% and 28.6% of the tumors, respectively, in the validation cohort, while 8.7% were considered as double positive. LC3B(+) puncta or HMGB1 expression alone did not constitute independent prognostic factors for metastasis-free survival (MFS) in multivariate analyses. However, the combined positivity for LC3B(+) puncta and nuclear HMGB1 constituted an independent prognostic factor significantly associated with prolonged MFS (hazard ratio: 0.49 95% confidence interval [0.26-0.89]; P = 0.02), and improved breast cancer specific survival (hazard ratio: 0.21 95% confidence interval [0.05-0.85]; P = 0.029). Subgroup analyses revealed that within patients with poor-prognosis BC, HMGB1(+) LC3B(+) double-positive tumors had a better prognosis than BC that lacked one or both of these markers. Altogether, these results suggest that the combined positivity for LC3B(+) puncta and nuclear HMGB1 is a positive predictor for longer BC survival.

Published
2015

182. Can pathologic complete response (pCR) be used as a surrogate marker of survival after neoadjuvant therapy for breast cancer?

Author

N. Chalabi, Jean-Marc Nabholtz, Sharif Kullab, Xavier Durando, Kheir-Eddine Benmammar, Marie-Ange Mouret-Reynier, Nina Radosevic-Robin, Philippe Chollet, Catherine Abrial, Mohun Bahadoor, Qian Wang-Lopez, and Frédérique Penault-Llorca

Subjects
Oncology, medicine.medical_specialty, Pathology, Receptor, ErbB-2, medicine.medical_treatment, Breast Neoplasms, Breast cancer, In vivo, Internal medicine, Evaluation methods, Biomarkers, Tumor, Humans, Medicine, Breast, Pathological, Neoadjuvant therapy, Complete response, business.industry, Surrogate endpoint, Hematology, Prognosis, medicine.disease, Neoadjuvant Therapy, Treatment Outcome, Immunohistochemistry, Female, business
Abstract

Breast cancer is heterogeneous in clinical, morphological, immunohistochemical and biological features, as reflected by several different prognostic subgroups. Neoadjuvant approaches are currently used for the "in vivo" efficacy assessment of treatments. Pathological complete response (pCR) has been reported as a reliable predictive factor of survival in that setting. However, pCR remains a subject of controversy in terms of definition and its evaluation methods. In addition, its predictive value for patient outcome in various breast cancer biological subtypes has been under debate. In this review, we will present the existing definitions of pCR, the impact of its evaluation methods on its rate and the assessment of its predictive value for patient outcome in the molecular subtypes of breast cancer (luminal A and B, Triple Negative and HER2-positive).

Published
2015

183. Prospective Clinical Utility Study of the Use of the 21-Gene Assay in Adjuvant Clinical Decision Making in Women With Estrogen Receptor-Positive Early Invasive Breast Cancer: Results From the SWITCH Study

Author

Frédérique Penault-Llorca, Roman Rouzier, Xavier Pivot, Christophe Pomel, Jean-Louis Misset, Philippe Rouanet, Rémy Largillier, Herve L. Naman, Joseph Gligorov, Dominique Spaeth, Anne de Roquancourt, J.-L. Sautière, William Jacot, Michel-Avella, Amandine, Sorbonne Université (SU), Alliance Pour la Recherche En Cancérologie [CHU Tenon] (APREC), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-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), Ingénierie et biologie cellulaire et tissulaire (IBCT (ex IFR133)), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), Institut du Cancer de Montpellier (ICM), Université de Montpellier (UM), 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 Azuréen de Cancérologie [Mougins, France], Oncologie médicale [Polyclinique de Gentilly, Nancy], Polyclinique de Gentilly, Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Diderot - Paris 7 (UPD7), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Risques cliniques et sécurité en santé des femmes et en santé périnatale (RISCQ), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Institut Curie [Paris], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), 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), and Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC)-Université de Franche-Comté (UFC)

Subjects
Adult, Oncology, Cancer Research, medicine.medical_specialty, medicine.drug_class, medicine.medical_treatment, Estrogen receptor, Breast Neoplasms, Disease, Breast cancer, Internal medicine, Breast Cancer, medicine, Humans, Chemotherapy, Prospective Studies, Estrogen receptor-positive, Prospective cohort study, Adjuvant, Aged, Gynecology, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, medicine.diagnostic_test, business.industry, Early breast cancer, Middle Aged, medicine.disease, 3. Good health, Receptors, Estrogen, Chemotherapy, Adjuvant, Estrogen, Biological Assay, Female, Neoplasm Recurrence, Local, Oncotype DX, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Background. The 21-gene Oncotype DX Recurrence Score assay is a validated assay to help decide the appropriate treatment for estrogen receptor-positive (ER+), early-stage breast cancer (EBC) in the adjuvant setting. The choice of adjuvant treatments might vary considerably in different countries according to various treatment guidelines. This prospective multicenter study is the first to assess the impact of the Oncotype DX assay in the French clinical setting. Methods. A total of 100 patients with ER+, human epidermal growth factor receptor 2-negative EBC, and node-negative (pN0) disease or micrometastases in up to 3 lymph nodes (pN1mi) were enrolled. Treatment recommendations, physicians’ confidence before and after knowing the Recurrence Score value, and physicians’ perception of the assay were recorded. Results. Of the 100 patients, 95 were evaluable (83 pN0, 12 pN1mi). Treatment recommendations changed in 37% of patients, predominantly from chemoendocrine to endocrine treatment alone. The proportion of patients recommended chemotherapy decreased from 52% pretest to 25% post-test. Of patients originally recommended chemotherapy, 61% were recommended endocrine treatment alone after receiving the Recurrence Score result. For both pN0 and pN1mi patients, post-test recommendations appeared to follow the Recurrence Score result for low and high values. Physicians’ confidence improved significantly. Conclusion. These are the first prospective data on the impact of the Oncotype DX assay on adjuvant treatment decisions in France. Using the assay was associated with a significant change in treatment decisions and an overall reduction in chemotherapy use. These data are consistent with those presented from European and non-European studies. Implications for Practice: This study shows that in estrogen receptor-positive, human epidermal growth factor receptor 2-negative early breast cancer (either node-negative or with micrometastases in up to 3 lymph nodes), Oncotype DX testing is associated with a treatment recommendation change in more than a third of patients (primarily from chemoendocrine treatment to endocrine treatment alone but also in the opposite direction) and an overall reduction in chemotherapy use. These results are consistent with those from other decision impact studies worldwide and further emphasize the role of Oncotype DX testing in management of early breast cancer, as reflected in international treatment guidelines.

Published
2015

184. Salpingectomie prophylactique ou annexectomie prophylactique dans la prévention du cancer de l’ovaire ?

Author

Gautier Chene, Frédérique Penault-Llorca, Jacques Dauplat, François Golfier, Karine Le Bail-Carval, Gery Lamblin, P. Chabert, Georges Mellier, and Liane Deligdisch

Subjects
Gynecology, medicine.medical_specialty, education.field_of_study, endocrine system diseases, business.industry, medicine.medical_treatment, Population, BRCA mutation, Oophorectomy, General Medicine, medicine.disease, female genital diseases and pregnancy complications, Bilateral Salpingectomy, Serous fluid, medicine.anatomical_structure, Salpingectomy, medicine, Ovarian cancer, education, business, Fallopian tube
Abstract

A recent hypothesis has stated that many ovarian cancers (especially high-grade serous histotype) could arise from the distal part of the fallopian tube. On one hand we know that risk-reducing salpingo-oophorectomy is the most effective prevention for ovarian cancer among BRCA mutation carriers. On the other, oophorectomy increases the relative risk for cardiovascular, osteoporotic psychosexual and cognitive dysfunctions in premenopausal women. This raises the question whether bilateral salpingectomy could be an effective strategy in the prevention of ovarian cancer in case of hereditary predisposition and in the general population. Here we discuss origin of ovarian cancer in the light of the latest molecular studies and the relative risks and benefits of a strategy of exclusive salpingectomy in comparison with the classical adnexectomy.

Published
2015

185. The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014

Author

Andrea L. Richardson, Sandra Demaria, Carsten Denkert, Kimberly H. Allison, Frederick L. Baehner, Helen Bailey, Frédérique Penault-Llorca, Nicolas Sirtaine, Stephan Wienert, G. Van den Eynden, Carmen Criscitiello, Giancarlo Pruneri, Karen Willard-Gallo, E. A. Perez, William Fraser Symmans, Torsten O. Nielsen, Christos Sotiriou, Michail Ignatiadis, David L. Rimm, Frederick Klauschen, Jorge S. Reis-Filho, E. A. Thompson, Sherene Loi, Sunil S. Badve, Roberto Salgado, Jane E. Brock, Zuzana Kos, Sylvia Adams, Joseph A. Sparano, Giuseppe Viale, Giuseppe Floris, and Sibylle Loibl

Subjects
Oncology, medicine.medical_specialty, Lymphocytic infiltration, Tumor-infiltrating lymphocytes, business.industry, H&E stain, Breast Neoplasms, hemic and immune systems, chemical and pharmacologic phenomena, Hematology, medicine.disease, 3. Good health, Clinical trial, Lymphocytes, Tumor-Infiltrating, Breast cancer, Internal medicine, Clinical validity, Humans, Biomarker (medicine), Medicine, Female, Clinical significance, Human medicine, business
Abstract

Evidence is strengthening for the morphological evaluation of tumor infiltrating lymphocytes (TILs) in breast cancer. Herein, the concepts for TILs assessment are laid out by pathologists to facilitate their wider evaluation and consistent interpretation. The goal of this article is to promote the evaluation of TILs as a biomarker in research, clinical trial settings and day-to-day practice. Background The morphological evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer (BC) is gaining momentum as evidence strengthens for the clinical relevance of this immunological biomarker. Accumulating evidence suggests that the extent of lymphocytic infiltration in tumor tissue can be assessed as a major parameter by evaluation of hematoxylin and eosin (H&E)-stained tumor sections. TILs have been shown to provide prognostic and potentially predictive value, particularly in triple-negative and human epidermal growth factor receptor 2-overexpressing BC. Design A standardized methodology for evaluating TILs is now needed as a prerequisite for integrating this parameter in standard histopathological practice, in a research setting as well as in clinical trials. This article reviews current data on the clinical validity and utility of TILs in BC in an effort to foster better knowledge and insight in this rapidly evolving field, and to develop a standardized methodology for visual assessment on H&E sections, acknowledging the future potential of molecular/multiplexed approaches. Conclusions The methodology provided is sufficiently detailed to offer a uniformly applied, pragmatic starting point and improve consistency and reproducibility in the measurement of TILs for future studies. ispartof: Annals Of Oncology vol:26 issue:2 pages:259-271 ispartof: location:England status: published

Published
2015

186. Mini-P-gp and P-gp Co-Expression in Brown Trout Erythrocytes: A Prospective Blood Biomarker of Aquatic Pollution

Author

François Desmolles, Bruno Combourieu, Mahchid Bamdad, Christian Amblard, Frédérique Penault-Llorca, Emeline Valton, Laboratoire Microorganismes : Génome et Environnement (LMGE), Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Synthèse et étude de systèmes à intêret biologique (SEESIB), Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Laboratoire Biochimie Médicale (UMR 384), Institut National de la Santé et de la Recherche Médicale (INSERM), BRICHEUX, Genevieve, Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), and Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Clinical Biochemistry, [SDV.MP.PRO] Life Sciences [q-bio]/Microbiology and Parasitology/Protistology, 010501 environmental sciences, [SDV.MP.PRO]Life Sciences [q-bio]/Microbiology and Parasitology/Protistology, 01 natural sciences, Article, Microbiology, 03 medical and health sciences, chemistry.chemical_compound, Brown trout, brown trout, [SDV.EE.SANT] Life Sciences [q-bio]/Ecology, environment/Health, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0105 earth and related environmental sciences, [SDV.EE.SANT]Life Sciences [q-bio]/Ecology, environment/Health, Pollutant, lcsh:R5-920, 0303 health sciences, biology, river pollution, Pesticide, biology.organism_classification, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, In vitro, [SDV.TOX] Life Sciences [q-bio]/Toxicology, Multiple drug resistance, Biomarker, Trout, chemistry, [SDV.TOX]Life Sciences [q-bio]/Toxicology, Environmental chemistry, erythrocytes, mini-P-gp, P-gp, [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, blood biomarker, lcsh:Medicine (General), Xenobiotic
Abstract

In aquatic organisms, such as fish, blood is continually exposed to aquatic contaminants. Multidrug Resistance (MDR) proteins are ubiquitous detoxification membrane pumps, which recognize various xenobiotics. Moreover, their expression is induced by a large class of drugs and pollutants. We have highlighted the co-expression of a mini P-gp of 75 kDa and a P-gp of 140 kDa in the primary culture of brown trout erythrocytes and in the erythrocytes of wild brown trout collected from three rivers in the Auvergne region of France. In vitro experiments showed that benzo[a]pyrene, a highly toxic pollutant model, induced the co-expression of mini-P-gp and P-gp in trout erythrocytes in a dose-dependent manner and relay type response. Similarly, in the erythrocytes of wild brown trout collected from rivers contaminated by a mixture of PAH and other multi-residues of pesticides, mini-P-gp and P-gp were able to modulate their expression, according to the nature of the pollutants. The differential and complementary responses of mini-P-gp and P-gp in trout erythrocytes suggest the existence in blood cells of a real protective network against xenobiotics/drugs. This property could be exploited to develop a blood biomarker of river pollution.

Published
2015

187. Morphological and immunohistochemical pattern of tubo-ovarian dysplasia and serous tubal intraepithelial carcinoma

Author

Nicole Lagarde, Gautier Chene, Ines Raoelfils, Jacques Dauplat, Anne Cayre, and Frédérique Penault-Llorca

Subjects
Pathology, medicine.medical_specialty, Ovariectomy, Stem cell marker, medicine.disease_cause, Aldehyde Dehydrogenase 1 Family, Histones, Salpingectomy, Biomarkers, Tumor, medicine, Fallopian Tube Neoplasms, Humans, Neoplastic transformation, Ovarian Diseases, Fallopian Tubes, business.industry, Ovary, Retinal Dehydrogenase, Obstetrics and Gynecology, Serous Tubal Intraepithelial Carcinoma, Fallopian Tube Diseases, medicine.disease, female genital diseases and pregnancy complications, Isoenzymes, Serous fluid, Cell Transformation, Neoplastic, Ki-67 Antigen, Proto-Oncogene Proteins c-bcl-2, Reproductive Medicine, Dysplasia, Disease Progression, Immunohistochemistry, Female, Tumor Suppressor Protein p53, Ovarian cancer, business, Carcinogenesis, Carcinoma in Situ
Abstract

A B S T R A C T Objective: Histopathological examination of material from prophylactic salpingo-oophorectomies performed in patients at genetic risk of ovarian cancer can reveal abnormalities interpreted as possible pre-cancerous ‘‘ovarian dysplasia’’ and tubal precursors lesions. We sought to study the morphological features and immunohistochemical expression patterns of neoplasia-associated markers in prophylactically removed ovaries and fallopian tubes (pBSO) in comparison with a group of serous tubal intraepithelial carcinoma (STIC) and non-cancerous controls. Study design: Morphological features and immunohistochemical expression patterns of Ki-67 (for proliferation biomarker), p53 (key pathway of mullerian serous tumorogenesis), Bcl2 (anti-apoptotic), gH2AX (a double-strand breaks marker) and ALDH1 (a stem cell marker significantly associated with early-stage ovarian cancer) were blindly evaluated by two pathologists in 111 pBSO, 12 STICs and 116 non-cancerous salpingo-oophorectomies (control group) (nBSO). Results: Morphological ovarian and tubal dysplasia scores were significantly higher in the pBSO than in controls (respectively, 8.8 vs 3.12, p < 0.0001, for ovaries and 6.54 vs 1.58, p < 0.0001 for tubes). Increased gH2AX expression was observed in the pBSO and STICs compared with the controls whereas expression patterns of Ki67, p53 and bcl2 were low to moderate in the pBSO group. STICs overexpressed Ki67 and p53 while bcl2 expression was low; Interestingly, ALDH1 expression was low in non dysplastic epithelium, high in dysplasia and constantly low in STICs. Conclusion: The morphological and immunohistochemical profile of tubo-ovarian dysplasia and STICs might be consistent with progression toward neoplastic transformation in the Serous Carcinogenesis Sequence. These changes may be pre-malignant and could represent an important phase in early neoplasia. ALDH1 activation in pBSO samples and its extinction in STICs should be considered as a target for prevention.

Published
2014

188. Epigenetic mechanisms of breast cancer: an update of the current knowledge

Author

Gaëlle Judes, Yves-Jean Bignon, Dominique Bernard-Gallon, Marjolaine Ngollo, Seher Karsli-Ceppioglu, Aslihan Dagdemir, Amaury Pajon, and Frédérique Penault-Llorca

Subjects
Regulation of gene expression, Cancer Research, EZH2, Antineoplastic Agents, Breast Neoplasms, DNA Methylation, Biology, medicine.disease_cause, medicine.disease, Epigenesis, Genetic, Gene Expression Regulation, Neoplastic, Histone Deacetylase Inhibitors, Histones, Breast cancer, DNA methylation, Genetics, medicine, Cancer research, Humans, Female, Epigenetics, Cancer epigenetics, skin and connective tissue diseases, Carcinogenesis, Epigenetic therapy
Abstract

Epigenetic alterations are heritable changes in gene expression that occur without causing any change in DNA sequence. They are important key factors for cancer development and prognosis. Breast cancer is induced by the accumulation of altered gene regulation. Besides genetic mutations, epigenetics mechanisms have an important role in breast cancer tumorigenesis. Investigations related with aberrant epigenetic regulations in breast cancer focus on initiating molecular mechanisms in cancer development, identification of new biomarkers to predict breast cancer aggressiveness and the potential of epigenetic therapy. In this review, we will summarize the recent knowledge about the role of epigenetic alterations related with DNA methylation and histone modification in breast cancer. In addition, altered regulation of breast cancer specific genes and the potential of epigenetic therapy will be discussed according to epigenetic mechanisms.

Published
2014

189. Les lésions glandulaires du col utérin : cas no 7

Author

Frédérique Penault-Llorca and Mojgan Devouassoux-Shisheboran

Subjects
0301 basic medicine, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, business.industry, 030220 oncology & carcinogenesis, Medicine, business, Pathology and Forensic Medicine
Published
2016

190. Les lésions glandulaires du col utérin : cas no 8

Author

Frédérique Penault-Llorca and Mojgan Devouassoux-Shisheboran

Subjects
0301 basic medicine, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, business.industry, 030220 oncology & carcinogenesis, Medicine, business, Pathology and Forensic Medicine
Published
2016

191. The JMJD3 Histone Demethylase and the EZH2 Histone Methyltransferase in Prostate Cancer

Author

Laurent Guy, Marine Daures, Dominique Bernard-Gallon, Yves-Jean Bignon, Gaëlle Judes, Marjolaine Ngollo, Jean-Louis Kemeny, Frédérique Penault-Llorca, and Khaldoun Rifaï

Subjects
Male, 0301 basic medicine, Jumonji Domain-Containing Histone Demethylases, Receptors, Retinoic Acid, Gene Expression, Adenocarcinoma, Biochemistry, 03 medical and health sciences, 0302 clinical medicine, Cell Line, Tumor, Biomarkers, Tumor, Genetics, Humans, Enhancer of Zeste Homolog 2 Protein, Cancer epigenetics, Promoter Regions, Genetic, Molecular Biology, Histone deacetylase 5, biology, HDAC11, Histone deacetylase 2, EZH2, Polycomb Repressive Complex 2, Prostatic Neoplasms, 030104 developmental biology, 030220 oncology & carcinogenesis, Histone methyltransferase, biology.protein, Cancer research, Molecular Medicine, Demethylase, Neoplasm Grading, JARID1B, Biotechnology
Published
2016

192. TIP60 Histone Acetyltransferase in Adipose Tissue: Possible Linkages with Breast Cancer Development?

Author

Gaëlle Judes, Lucas Dubois, Yves-Jean Bignon, Marine Daures, Khaldoun Rifaï, Mouhamed Idrissou, Dominique Bernard-Gallon, Frédérique Penault-Llorca, Département d'Oncogénétique, Institut National de la Recherche Agronomique (INRA)-Réseau National Alimentation Cancer Recherche (réseau NACRe)-Centre Jean Perrin (CJP-EA 4233), Centre Jean Perrin, CRLCC Jean Perrin, Imagerie Moléculaire et Stratégies Théranostiques - Clermont Auvergne (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER-UNICANCER-Institut National de la Recherche Agronomique (INRA)-Réseau National Alimentation Cancer Recherche (réseau NACRe), 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]), Institut National de la Recherche Agronomique (INRA)-Réseau National Alimentation Cancer Recherche (réseau NACRe)-Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER-UNICANCER, and Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, Adipose tissue, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biochemistry, Models, Biological, Lysine Acetyltransferase 5, Histones, 03 medical and health sciences, Breast cancer, Genetics, medicine, Humans, Molecular Biology, ComputingMilieux_MISCELLANEOUS, Adipogenesis, biology, Histone acetyltransferase, medicine.disease, 3. Good health, 030104 developmental biology, Adipose Tissue, biology.protein, Cancer research, Molecular Medicine, Female, Biotechnology, Signal Transduction
Abstract

International audience

Published
2017

193. Prospective, multicenter French study evaluating the clinical impact of the Breast Cancer Intrinsic Subtype-Prosigna® Test in the management of early-stage breast cancers

Author

Sonia Zilberman, Qianyi Li, Coraline Dubot, Céline Callens, David Gentien, Nadeem Ghali, Benoit Albaud, Anne Cayre, Marie-Ange Mouret-Reynier, Delphine Hequet, Cyrille Huchon, Florence Lerebours, Anne Vincent Salomon, Frédérique Penault-Llorca, Aurélie Roulot, Paul Cottu, John Hornberger, Helene Berseneff, Jean-Marc Guinebretière, Rémy Salmon, P Morel, Roman Rouzier, Cyril Foa, Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Curie [Paris], Plateforme de génomique [Institut Curie], 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]), Département de Recherche Translationnelle, Laboratory of Solid Tumors Genetics, Nice University Hospital, Departement de chirurgie [Institut Curie], Genetique Moleculaire des Cancers d'Origine Epitheliale, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Etude Métabolique des Molécules Marquées, Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'anatomo-cytopathologie, CRLCC René Huguenin, Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Oncology, Campus Biomedico University, Université Paris Descartes - Paris 5 (UPD5)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département de recherche translationnelle, Institut Curie/ Departement de chirurgie/ 26 rue d'Ulm/ 75005 Paris, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie [Paris], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Curie, Plate-forme de génomique, Imagerie Moléculaire et Stratégies Théranostiques - Clermont Auvergne (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Jean Perrin, CRLCC Jean Perrin, and CHU Tenon [APHP]

Subjects
Questionnaires, 0301 basic medicine, Oncology, Medical Doctors, Adjuvant Chemotherapy, Health Care Providers, Emotions, Cancer Treatment, lcsh:Medicine, Social Sciences, Anxiety, Systemic therapy, 0302 clinical medicine, Quality of life, Breast Tumors, Medicine and Health Sciences, Psychology, Medical Personnel, Prospective Studies, Stage (cooking), lcsh:Science, Prospective cohort study, Multidisciplinary, Pharmaceutics, Middle Aged, 3. Good health, Professions, Exact test, Treatment Outcome, Research Design, Chemotherapy, Adjuvant, 030220 oncology & carcinogenesis, Female, France, medicine.symptom, Research Article, Clinical Oncology, medicine.medical_specialty, Health Planning Guidelines, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Research and Analysis Methods, Cancer Chemotherapy, 03 medical and health sciences, Breast cancer, Drug Therapy, Physicians, Internal medicine, Breast Cancer, medicine, Adjuvant therapy, Chemotherapy, Humans, Immunohistochemistry Techniques, Neoplasm Staging, Survey Research, business.industry, lcsh:R, Cancers and Neoplasms, Biology and Life Sciences, medicine.disease, Health Care, Histochemistry and Cytochemistry Techniques, 030104 developmental biology, People and Places, Quality of Life, Immunologic Techniques, lcsh:Q, Population Groupings, Clinical Medicine, Neoplasm Recurrence, Local, business
Abstract

Purpose The Prosigna® breast cancer prognostic gene signature assay identifies a gene-expression profile that permits the classification of tumors into subtypes and gives a score for the risk of recurrence (ROR) at 10 years. The primary objective of this multicenter study was to evaluate the impact of Prosigna’s assay information on physicians’ adjuvant treatment decisions in patients with early-stage breast cancer. Secondary objectives were to assess confidence of practitioners in their therapeutic recommendations before and after the added information provided by the Prosigna assay; and to evaluate the emotional state of patients before and after the Prosigna test results. Methods Consecutive patients with invasive early-stage breast cancer were enrolled in a prospective, observational, multicenter study carried out in 8 hospitals in France. The Prosigna test was carried out on surgical specimens using the nCounter® Analysis System located at the Institut Curie. Both before and after receiving the Prosigna test results, physicians completed treatment confidence questionnaires and patients completed questionnaires concerning their state of anxiety, the difficulties felt in face of the therapy and quality of life. Information was also collected at 6 months regarding the physicians’ opinion on the test results and the patients’ degree of anxiety, difficulties with therapy and quality of life. Results Between March 2015 and January 2016, 8 study centers in France consecutively enrolled 210 postmenopausal women with estrogen receptor (ER) positive, human epidermal growth hormone-2 (HER-2) negative, and node negative tumors, either stage 1 or stage 2. Intrinsic tumor subtypes as assessed by the Prosigna test were 114 (58.2%) Luminal A, 79 (40.3%) Luminal B, 1 (0.5%) HER-2 enriched (HER-2E), and 2 (1.0%) basal-like. Before receiving the Prosigna test results, physicians categorized tumor subtypes based on immunohistochemistry (IHC) as Luminal A in 126 (64%) patients and Luminal B in 70 (36%) patients, an overall discordance rate of 25%. The availability of Prosigna assay results was significantly associated with the likelihood of change in treatment recommendations, with 34 patients (18%) having their treatment plan changed from Adjuvant Chemotherapy to No Adjuvant Chemotherapy or vice versa (p

Published
2017

194. Development and validation of a high-performance liquid chromatography method for the quantitation of intracellular PARP inhibitor Olaparib in cancer cells

Author

Robin Dufour, Emmanuelle Mounetou, Mahchid Bamdad, Pierre Daumar, Clémence Dubois, Frédérique Penault-Llorca, Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), 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]), Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), and Daumar, Pierre

Subjects
0301 basic medicine, Bioanalysis, [CHIM.ANAL] Chemical Sciences/Analytical chemistry, [SDV.SP.MED] Life Sciences [q-bio]/Pharmaceutical sciences/Medication, [CHIM.THER] Chemical Sciences/Medicinal Chemistry, Clinical Biochemistry, Pharmaceutical Science, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, bioanalytical method validation, Poly(ADP-ribose) Polymerase Inhibitors, High-performance liquid chromatography, Sensitivity and Specificity, Piperazines, Analytical Chemistry, Olaparib, 03 medical and health sciences, chemistry.chemical_compound, [SDV.SP.MED]Life Sciences [q-bio]/Pharmaceutical sciences/Medication, Chromatography detector, [CHIM.ANAL]Chemical Sciences/Analytical chemistry, Limit of Detection, Cell Line, Tumor, Drug Discovery, Protein precipitation, Humans, Sample preparation, PARP inhibitors, Spectroscopy, ComputingMilieux_MISCELLANEOUS, Chromatography, High Pressure Liquid, Detection limit, Chromatography, intracellular drug concentration, Reproducibility of Results, 3. Good health, HPLC-UV-DAD, 030104 developmental biology, chemistry, PARP inhibitor, Phthalazines
Abstract

International audience; Olaparib is a potent PARP inhibitor in clinical use for cancer therapy. A bioanalytical assay was developed and validated for quantitation of intracellular level of olaparib in cells exposed to the drug. The assay involves an optimized and straightforward sample pretreatment with acetonitrile for olaparib solubilization, cell lysis and protein precipitation, and a high performance liquid chromatography (HPLC) method with ultraviolet detection. Several parameters in both the sample preparation and the detection steps were investigated. Optimal chromatographic conditions were achieved with a 5 μL injection on a Nova-Pak® C18 column (150 × 3.9 mm, 4 μm) using a mobile phase consisting of acetonitrile and ultra-pure water in gradient mode, at a constant 1.2 mL/min flow rate, at 35 °C. Detection was carried out at 254 nm and a diode array detector was used to insure purity of the olaparib peak. The method was validated according to Food and Drug Administration guidelines. Linearity, accuracy and precisions were satisfactory over the concentration range of 200–2000 ng/mL. Limits of detection and quantification for olaparib were 50 ng/mL and 200 ng/mL, respectively. Good stability was showed in three relevant analytical conditions. Finally, the validated analytical method was successfully used to estimate the intracellular level of olaparib in SUM1315 breast cancer cells. A significant difference was observed in intracellular drug level after 1 and 3 h incubations. This method permitting measurement of drug level in tumor cells would allow dosage optimization and improvement of treatment response predictions.

Published
2017

195. miR-10b, miR-26a, miR-146a And miR-153 Expression in Triple Negative Vs Non Triple Negative Breast Cancer: Potential Biomarkers

Author

Yves-Jean Bignon, Insaf Fkih M’hamed, Mounir Trimeche, Frédérique Penault-Llorca, Maud Privat, Abderraouf Kenani, Equipe de recherche sur les traitements individualisés des cancers (ERTICa), Université d'Auvergne - Clermont-Ferrand I (UdA), Imagerie Moléculaire et Stratégies Théranostiques - Clermont Auvergne (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Département de Pathologie, CHU Sousse, Centre Jean Perrin, CRLCC Jean Perrin, Département d'Oncogénétique, Institut National de la Recherche Agronomique (INRA)-Réseau National Alimentation Cancer Recherche (réseau NACRe)-Centre Jean Perrin (CJP-EA 4233), Mécanismes moléculaires et pathologies, Unité 05/UR/09-09-Faculté de Médecine de Monastir [Tunisie], 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), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Institut National de la Recherche Agronomique (INRA)-Réseau National Alimentation Cancer Recherche (réseau NACRe)-Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER-UNICANCER, Faculté de Médecine de Monastir [Tunisie]-Unité 05/UR/09-09, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), and UNICANCER-UNICANCER-Institut National de la Recherche Agronomique (INRA)-Réseau National Alimentation Cancer Recherche (réseau NACRe)

Subjects
0301 basic medicine, Oncology, Adult, Cancer Research, medicine.medical_specialty, LNM, Breast Neoplasms, Triple Negative Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Pathology and Forensic Medicine, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Gene expression, microRNA, medicine, Biomarkers, Tumor, Humans, skin and connective tissue diseases, Lymph node, Gene, Triple-negative breast cancer, Aged, Aged, 80 and over, Cancer, General Medicine, Middle Aged, medicine.disease, Human triple negative breast cancer, 3. Good health, MicroRNAs, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Lymphatic Metastasis, Immunohistochemistry, Triple-Negative Breast Carcinoma, Biomarkers
Abstract

International audience; MicroRNAs (miRNAs) are small non-coding RNAs composed of 18-25 nucleotides that can post-transcriptionally regulate gene expression and have key regulatory roles in cancer, acting as both oncogenes and tumor suppressors. About 1000 genes in humans encode miRNAs, which account for approximately 3% of the human genome, and up to 30% of human protein coding genes may be regulated by miRNAs. The objective of this article is to evaluate the expression profile of four miRNAs previously implicated in triple negative breast cancer: miR-10b, miR-26a, miR-146a and miR-153, and to determine their possible interaction in triple negative and non triple negative breast cancer based on clinical outcome and the expression of BRCA1. 24 triple-negative and 13 non triple negative breast cancer cases, were studied by q-RT-PCR and immunohistochemistry to determine the expression of the four studied miRNAs and the BRCA1 protein, respectively. We observed that the BRCA1 protein was absent in 62.5% of the triple negative cases. Besides, the miR-146a and miR-26a were over expressed in triple negative breast cancer. These two miRNAs, miR-10b and miR-153 were significantly associated to lymph node metastases occurrence in triple negative breast carcinoma. All the analyzed microRNAs were not associated with the expression of BRCA1 in our conditions. Our work provides evidence that miR-146a, miR-26a, miR-10b and miR-153 could be defined as biomarkers in triple negative breast cancer to predict lymph node metastases (LNM).

Published
2017

196. Pathology of Breast Cancer

Author

Nina Radosevic-Robin and Frédérique Penault-Llorca

Subjects
Oncology, medicine.medical_specialty, Pathology, Surgical margin, business.industry, medicine.medical_treatment, Cancer, Pathology Report, medicine.disease, Malignancy, Breast cancer, Internal medicine, Epidemiology of cancer, medicine, Stage (cooking), business, Neoadjuvant therapy
Abstract

The pathologist is involved at various steps in the management of patients with breast cancer, beginning with the confirmation of malignancy and ending with the establishment of prognostic and predictive markers. A close collaboration between surgeons and pathologists is mandatory for proper diagnostics of breast cancer, especially during frozen section analysis, gross tumour examination and evaluation of response to neoadjuvant therapy. The pathology report must contain the histological characteristics of the tumour, the classical prognostic and theranostic markers (stage, receptor profile) as well as the surgical margin status. More recently, prognostic parameters obtained by gene expression analysis may complete the report.

Published
2017

197. Assessing tumor infiltrating lymphocytes in solid tumors: a practical review for pathologists and proposal for a standardized method from the International Immuno-Oncology Biomarkers Working Group: Part 1: Assessing the host immune response, TILs in invasive breast carcinoma and ductal carcinoma in situ, metastatic tumor deposits and areas for further research

Author

Melinda E. Sanders, Jorge S. Reis-Filho, Maria Vittoria Dieci, Prudence A. Russell, Stephen B. Fox, Baljit Singh, Fabrice Andre, Torsten O. Nielsen, Laura Comerma, Carmen Criscitiello, Bibhusal Thapa, Magali Lacroix-Triki, Stephan Wienert, Shona Hendry, Yves Allory, Gelareh Farshid, Peter H. Watson, Jiping Zha, Fraser Symmans, Fabien Gaire, Brad H. Nelson, Denis Larsimont, Stuart J. Schnitt, Stefan J. Scherer, Justin M. Balko, Paula I. Gonzalez-Ericsson, Stefan Michiels, Andrea L. Richardson, Maria Urbanowicz, Zuzana Kos, Amy C. Y. Lo, Shahinaz Bedri, Hugo M. Horlings, Stephen J Luen, Matthias Preusser, Cecile Colpaert, E. A. Thompson, Koen Van de Vijver, Douglas B. Johnson, Mark van de Vijver, Monica V. Estrada, Peter Savas, Roland de Wind, Giuseppe Floris, Johannes A. Hainfellner, Soonmyung Paik, Konstanty Korski, Paolo Nuciforo, Roberto Salgado, Andrea Vingiani, Seong-Rim Kim, Sibylle Loibl, Ewa Chmielik, Giuseppe Viale, Sunil R. Lakhani, Nadine Tung, Joseph A. Sparano, Nicole Burchardi, Christos Sotiriou, Fred R. Hirsch, Thomas John, Carsten Denkert, Karen Willard-Gallo, Hartmut Koeppen, Kimberly H. Allison, Iva Brcic, Robert H. Pierce, Sandra A O'Toole, Jennifer M. Giltnane, Susan Fineberg, Giuseppe Curigliano, Leena Gandhi, Thomas Gevaert, Stephen M. Hewitt, Sandra Demaria, Jonathan Juco, Marlon Rebelatto, Jane E. Brock, Sherene Loi, Giancarlo Pruneri, Keith Steele, Michail Ignatiadis, David L. Rimm, Yihong Wang, Veerle Bossuyt, Frederick Klauschen, Federico Rojo, Ashok Srinivasan, Frédérique Penault-Llorca, Andre L. Moreira, Nicolas Sirtaine, Benjamin sss Solomon, Nils Ternès, Sunil Badve, Cinzia Solinas, Kenneth Emancipator, Michael Christie, Gert Van den Eynden, Tomohagu Sugie, and Sylvia Adams

Subjects
lymphocytes, 0301 basic medicine, Oncology, Pathology, Colorectal cancer, medicine.medical_treatment, COLORECTAL-CANCER, 0302 clinical medicine, PROGNOSTIC-SIGNIFICANCE, Medicine and Health Sciences, NODE MELANOMA METASTASES, hemic and immune systems, Neoplasms, Second Primary, SPATIAL HETEROGENEITY, 3. Good health, 030220 oncology & carcinogenesis, Biomarker (medicine), immunotherapy, Anatomy, medicine.medical_specialty, CELL LUNG-CANCER, chemical and pharmacologic phenomena, Breast Neoplasms, MEDULLARY CARCINOMA, Article, Pathology and Forensic Medicine, 03 medical and health sciences, Breast cancer, Lymphocytes, Tumor-Infiltrating, Internal medicine, medicine, Carcinoma, Biomarkers, Tumor, cancer, Animals, Humans, REGULATORY T-CELLS, Tumor-infiltrating lymphocytes, business.industry, biomarkers, Cancer, Immunotherapy, tumor-infiltrating, Ductal carcinoma, medicine.disease, PD-1 BLOCKADE, pathology, 2734, Pathologists, ESTROGEN-RECEPTOR, 030104 developmental biology, Carcinoma, Intraductal, Noninfiltrating, TERTIARY LYMPHOID STRUCTURES, business
Abstract

Assessment of tumor-infiltrating lymphocytes (TILs) in histopathologic specimens can provide important prognostic information in diverse solid tumor types, and may also be of value in predicting response to treatments. However, implementation as a routine clinical biomarker has not yet been achieved. As successful use of immune checkpoint inhibitors and other forms of immunotherapy become a clinical reality, the need for widely applicable, accessible, and reliable immunooncology biomarkers is clear. In part 1 of this review we briefly discuss the host immune response to tumors and different approaches to TIL assessment. We propose a standardized methodology to assess TILs in solid tumors on hematoxylin and eosin sections, in both primary and metastatic settings, based on the International Immuno-Oncology Biomarker Working Group guidelines for TIL assessment in invasive breast carcinoma. A review of the literature regarding the value of TIL assessment in different solid tumor types follows in part 2. The method we propose is reproducible, affordable, easily applied, and has demonstrated prognostic and predictive significance in invasive breast carcinoma. This standardized methodology may be used as a reference against which other methods are compared, and should be evaluated for clinical validity and utility. Standardization of TIL assessment will help to improve consistency and reproducibility in this field, enrich both the quality and quantity of comparable evidence, and help to thoroughly evaluate the utility of TILs assessment in this era of immunotherapy.

Published
2017

198. 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

199. Assessing Tumor-Infiltrating Lymphocytes in Solid Tumors: A Practical Review for Pathologists and Proposal for a Standardized Method from the International Immuno-Oncology Biomarkers Working Group: Part 2: TILs in Melanoma, Gastrointestinal Tract Carcinomas, Non-Small Cell Lung Carcinoma and Mesothelioma, Endometrial and Ovarian Carcinomas, Squamous Cell Carcinoma of the Head and Neck, Genitourinary Carcinomas, and Primary Brain Tumors

Author

Monica V. Estrada, Nadine Tung, Veerle Bossuyt, Sunil R. Lakhani, Amy C. Y. Lo, Prudence A. Russell, Fabrice Andre, Michail Ignatiadis, Cinzia Solinas, Johannes A. Hainfellner, Karen Willard-Gallo, David L. Rimm, Yihong Wang, Kenneth Emancipator, Torsten O. Nielsen, Giuseppe Viale, Andrea Vingiani, Maria Urbanowicz, Shona Hendry, Ewa Chmielik, Nicole Burchardi, Fraser Symmans, Jiping Zha, Peter Savas, Denis Larsimont, Giancarlo Pruneri, Michael Christie, Thomas John, Stephan Wienert, Peter H. Watson, Seong Rim Kim, Benjamin Solomon, Stefan Michiels, Andrea L. Richardson, E. A. Thompson, Koen Van de Vijver, Sherene Loi, Susan Fineberg, Robert H. Pierce, Frédérique Penault-Llorca, Nils Ternès, Keith Steele, Stephen B. Fox, Baljit Singh, Jane E. Brock, Hugo M. Horlings, Bibhusal Thapa, Magali Lacroix-Triki, Frederick Klauschen, Laura Comerma, Stephen J Luen, Maria Vittoria Dieci, Ashok Srinivasan, Gert Van den Eynden, Marlon Rebelatto, Justin M. Balko, Paula I. Gonzalez-Ericsson, Melinda E. Sanders, Fabien Gaire, Gelareh Farshid, Jorge S. Reis-Filho, Federico Rojo, Mark van de Vijver, Stuart J. Schnitt, Yves Allory, Stephen M. Hewitt, Stefan J. Scherer, Matthias Preusser, Hartmut Koeppen, Kimberly H. Allison, Roland de Wind, Soonmyung Paik, Konstanty Korski, Douglas B. Johnson, Tomohagu Sugie, Sylvia Adams, Giuseppe Floris, Sibylle Loibl, Cecile Colpaert, Joseph A. Sparano, Giuseppe Curigliano, Nicolas Sirtaine, Paolo Nuciforo, Roberto Salgado, Sandra A O'Toole, Sunil S. Badve, Jonathan Juco, Iva Brcic, Leena Gandhi, Thomas Gevaert, Andre L. Moreira, Carmen Criscitiello, Shahinaz Bedri, Jennifer M. Giltnane, Christos Sotiriou, Sandra Demaria, Fred R. Hirsch, Carsten Denkert, Brad H. Nelson, and Zuzana Kos

Subjects
lymphocytes, 0301 basic medicine, Oncology, Mesothelioma, Lung Neoplasms, Skin Neoplasms, medicine.medical_treatment, Biopsy, 0302 clinical medicine, Carcinoma, Non-Small-Cell Lung, Pathology, Medicine, Melanoma, Gastrointestinal Neoplasms, Ovarian Neoplasms, Brain Neoplasms, Immunohistochemistry, 3. Good health, Phenotype, Head and Neck Neoplasms, 030220 oncology & carcinogenesis, Carcinoma, Squamous Cell, Biomarker (medicine), Female, immunotherapy, Anatomy, medicine.medical_specialty, Article, Pathology and Forensic Medicine, 03 medical and health sciences, Lymphocytes, Tumor-Infiltrating, Predictive Value of Tests, Internal medicine, Carcinoma, Biomarkers, Tumor, cancer, Humans, business.industry, Genitourinary system, Tumor-infiltrating lymphocytes, Squamous Cell Carcinoma of Head and Neck, biomarkers, Cancer, Immunotherapy, tumor-infiltrating, medicine.disease, pathology, 2734, Endometrial Neoplasms, 030104 developmental biology, business, Urogenital Neoplasms
Abstract

Assessment of the immune response to tumors is growing in importance as the prognostic implications of this response are increasingly recognized, and as immunotherapies are evaluated and implemented in different tumor types. However, many different approaches can be used to assess and describe the immune response, which limits efforts at implementation as a routine clinical biomarker. In part 1 of this review, we have proposed a standardized methodology to assess tumor infiltrating lymphocytes (TILs) in solid tumors, based on the International Immuno-Oncology Biomarkers Working Group guidelines for invasive breast carcinoma. In part 2 of this review, we discuss the available evidence for the prognostic and predictive value of TILs in common solid tumors, including carcinomas of the lung, gastrointestinal tract, genitourinary system, gynecological system, and head and neck, as well as primary brain tumors, mesothelioma and melanoma. The particularities and different emphases in TIL assessment in different tumor types are discussed. The standardized methodology we propose can be adapted to different tumor types and may be used as a standard against which other approaches can be compared. Standardization of TIL assessment will help clinicians, researchers and pathologists to conclusively evaluate the utility of this simple biomarker in the current era of immunotherapy.

Published
2017

200. Combined cetuximab and trastuzumab are superior to gemcitabine in the treatment of human pancreatic carcinoma xenografts

Author

Caroline Bascoul-Mollevi, Alexandre Ho-Pun-Cheung, Bruno Robert, Frédérique Penault-Llorca, Christelle Larbouret, Isabelle Navarro-Teulon, Jean-Pierre Mach, David Azria, André Pèlegrin, Sébastien Morisseau, Le Ster, Yves, 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), CRLC Val d'Aurelle-Paul Lamarque, CRLCC Val d'Aurelle - Paul Lamarque, Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Département de biochimie, Université de Lausanne = University of Lausanne (UNIL), 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), and Université de Lausanne (UNIL)

Subjects
Pancreatic disease, Receptor, ErbB-2, Cetuximab, Deoxycytidine, MESH: Antibodies, Monoclonal, Mice, 0302 clinical medicine, Trastuzumab, Antineoplastic Combined Chemotherapy Protocols, MESH: Animals, Epidermal growth factor receptor, 0303 health sciences, biology, gemcitabine, Antibodies, Monoclonal, Hematology, Immunohistochemistry, 3. Good health, ErbB Receptors, MESH: Antineoplastic Combined Chemotherapy Protocols, Oncology, MESH: Receptor, erbB-2, 030220 oncology & carcinogenesis, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, CA19-9, monoclonal antibodies, MESH: Pancreatic Neoplasms, medicine.drug, MESH: Xenograft Model Antitumor Assays, MESH: Cell Line, Tumor, [SDV.IMM] Life Sciences [q-bio]/Immunology, EGFR, Blotting, Western, HER2, pancreatic carcinoma, Mice, Nude, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH: Receptor, Epidermal Growth Factor, Antibodies, Monoclonal, Humanized, Article, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cell Line, Tumor, Pancreatic cancer, medicine, MESH: Mice, Nude, Animals, Humans, MESH: Blotting, Western, MESH: Mice, 030304 developmental biology, MESH: Humans, business.industry, MESH: Deoxycytidine, Cancer, MESH: Immunohistochemistry, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, medicine.disease, Xenograft Model Antitumor Assays, Gemcitabine, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Pancreatic Neoplasms, MESH: Antibodies, Monoclonal, Humanized, Cancer research, biology.protein, business, MESH: Female
Abstract

International audience; BACKGROUND: Pancreatic carcinoma remains a treatment-refractory cancer with a poor prognosis. Here, we compared anti-epidermal growth factor receptor (EGFR) and anti-HER2 monoclonal antibodies (2mAbs) injections with standard gemcitabine treatment on human pancreatic carcinoma xenografts. MATERIALS AND METHODS: Nude mice, bearing human pancreatic carcinoma xenografts, were treated with either combined anti-EGFR (cetuximab) and anti-HER2 (trastuzumab) or gemcitabine, and tumor growth was observed. RESULTS AND CONCLUSION: In first-line therapy, mice survival was significantly longer in the 2mAbs group compared with gemcitabine (P < 0.0001 for BxPC-3, P = 0.0679 for MiaPaCa-2 and P = 0.0019 for Capan-1) and with controls (P < 0.0001). In second-line therapy, tumor regressions were observed after replacing gemcitabine by 2mAbs treatment, resulting in significantly longer animal survival compared with mice receiving continuous gemcitabine injections (P = 0.008 for BxPC-3, P = 0.05 for MiaPaCa-2 and P < 0.001 for Capan-1). Therapeutic benefit of 2mAbs was observed despite K-Ras mutation. Interestingly, concerning the mechanism of action, coinjection of F(ab')(2) fragments from 2mAbs induced significant tumor growth inhibition, compared with controls (P = 0.001), indicating that the 2mAbs had an Fc fragment-independent direct action on tumor cells. This preclinical study demonstrated a significant improvement of survival and tumor regression in mice treated with anti-EGFR/anti-HER2 2mAbs in first- and second-line treatments, compared with gemcitabine, independently of the K-Ras status.

Published
2017

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