Author: "Yves Humblet" / Topic: colorectal cancer - Searchworks@Jio Institute Digital Library Search Results

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76 results on '"Yves Humblet"'

1. Lymph node ratio and surgical quality are strong prognostic factors of rectal cancer: results from a single referral centre

Author: Alex Kartheuser, Etienne Danse, Daniel Léonard, A Medina Benites, M. Van den Eynde, Yves Humblet, N. Abbes Orabi, Anne Jouret-Mourin, Daphné Debetancourt, A. van Maanen, C. Remue, JC De Schoutheete, Ch Sempoux, F. Maddalena, A Dragean, and Pierre Scalliet
Subjects: Male, Oncology, medicine.medical_specialty, Multivariate analysis, Databases, Factual, Colorectal cancer, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Humans, Medicine, Mesentery, Elective surgery, Lymph node, Digestive System Surgical Procedures, Aged, Neoplasm Staging, Quality of Health Care, Retrospective Studies, Rectal Neoplasms, business.industry, Rectum, Gastroenterology, Middle Aged, Prognosis, medicine.disease, Survival Analysis, Total mesorectal excision, Acs nsqip, medicine.anatomical_structure, Elective Surgical Procedures, 030220 oncology & carcinogenesis, Referral centre, Lymph Node Excision, Female, 030211 gastroenterology & hepatology, Lymph Nodes, Lymph, business
Abstract: AIM Nodal stage is a strong prognostic factor of oncological outcome of rectal cancer. To compensate for the variation in total number of harvested nodes, calculation of the lymph node ratio (LNR) has been advocated. The aim of the study was to compare the impact, on the long-term oncological outcome, of the LNR with other predictive factors, including the quality of total mesorectal excision (TME) and the state of the circumferential resection margin. METHOD Consecutive patients having elective surgery for nonmetastatic rectal cancer were extracted from a prospectively maintained database. Retrospective uni- and multivariate analyses were performed based on patient-, surgical- and tumour-related factors. The prognostic value of the LNR on overall survival (OS) and on overall recurrence-free survival (ORFS) was assessed and a cut-off value was determined. RESULTS From 1998 to 2013, out of 456 patients, 357 with nonmetastatic disease were operated on for rectal cancer. Neoadjuvant radiochemotherapy was administered to 66.7% of the patients. The mean number of lymph nodes retrieved was 12.8 ± 8.78 per surgical specimen. A lower lymph node yield was obtained in patients who received neoadjuvant chemoradiotherapy (11.8 vs 14.2; P = 0.014). The 5-year ORFS was 71.8% and the 5-year OS was 80.1%. Multivariate analysis confirmed LNR, the quality of TME and age to be independent prognostic factors of OS. LNR, age and perineural infiltration were independently associated with ORFS. Low- and high-risk patients could be discriminated using an LNR cut-off value of 0.2. CONCLUSION LNR is an independent prognostic factor of OS and ORFS. In line with the principles of optimal surgical management, the quality of TME and lymph node yield are essential technical requirements.
Published: 2016
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2. Evolution of Metastases in Space and Time under Immune Selection

Author: Gabriela Bindea, Lucie Lafontaine, Yves Humblet, Anne Jouret-Mourin, Najeeb Syed, Catherine Hubert, Alex Kartheuser, Mihaela Angelova, Daniela Bruni, Jérôme Galon, Michele Ceccarelli, Davide Bedognetti, Marc Van den Eynde, Bénédicte Buttard, Bernhard Mlecnik, Angela Vasaturo, Francesco M. Marincola, Erwan Morgand, Tessa Fredriksen, Angelova, Mihaela, Mlecnik, Bernhard, Vasaturo, Angela, Bindea, Gabriela, Fredriksen, Tessa, Lafontaine, Lucie, Buttard, Bénédicte, Morgand, Erwan, Bruni, Daniela, Jouret-Mourin, Anne, Hubert, Catherine, Kartheuser, Alex, Humblet, Yve, Ceccarelli, Michele, Syed, Najeeb, Marincola, Francesco M., Bedognetti, Davide, Van den Eynde, Marc, and Galon, Jérôme
Subjects: 0301 basic medicine, Genetics and Molecular Biology (all), recurrence, Colorectal cancer, CD3, medicine.medical_treatment, immunoscore, Somatic evolution in cancer, Biochemistry, General Biochemistry, Genetics and Molecular Biology, Metastasis, immunoediting, 03 medical and health sciences, clonal, 0302 clinical medicine, Immune system, Lymphocytes, Tumor-Infiltrating, Leukemic Infiltration, Neoplasms, medicine, Tumor Microenvironment, Humans, Neoplasm Metastasis, Models, Statistical, biology, Cancer, T cell, Immunotherapy, medicine.disease, microenvironment, Tumor Burden, 030104 developmental biology, Immunoediting, 030220 oncology & carcinogenesis, Cancer research, biology.protein, metastasi, immunotherapy, heterogeneity, mutation
Abstract: We examined how the immune microenvironment molds tumor evolution at different metastatic organs in a longitudinal dataset of colorectal cancer. Through multiplexed analyses, we showed that clonal evolution patterns during metastatic progression depend on the immune contexture at the metastatic site. Genetic evidence of neoantigen depletion was observed in the sites with high Immunoscore and spatial proximity between Ki67+ tumor cells and CD3+ cells. The immunoedited tumor clones were eliminated and did not recur, while progressing clones were immune privileged, despite the presence of tumor-infiltrating lymphocytes. Characterization of immune-privileged metastases revealed tumor-intrinsic and tumor-extrinsic mechanisms of escape. The lowest recurrence risk was associated with high Immunoscore, occurrence of immunoediting, and low tumor burden. We propose a parallel selection model of metastatic progression, where branched evolution could be traced back to immune-escaping clones. The findings could inform the understanding of cancer dissemination and the development of immunotherapeutics.
Published: 2018

3. Pathological responses after angiogenesis or EGFR inhibitors in metastatic colorectal cancer depend on the chemotherapy backbone

Author: Catherine Hubert, Javier Carrasco, M. Van den Eynde, Anne Jouret-Mourin, J-L Canon, Etienne Danse, J-F Gigot, B. Navez, X Chapaux, Marco Gizzi, Christine Sempoux, Géraldine Pairet, P. Lefesvre, Yves Humblet, N Tinton, and Valérie Lannoy
Subjects: Oncology, Adult, Male, Cancer Research, medicine.medical_specialty, Disease free survival, Organoplatinum Compounds, Angiogenesis, Colorectal cancer, medicine.medical_treatment, colorectal cancer, Antineoplastic Agents, Irinotecan, Disease-Free Survival, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, Pathological, EGFR inhibitors, Aged, Retrospective Studies, Aged, 80 and over, Chemotherapy, Neovascularization, Pathologic, business.industry, Retrospective cohort study, surgical resection, Middle Aged, medicine.disease, targeted therapy, ErbB Receptors, Oxaliplatin, Camptothecin, Female, business, Translational Therapeutics, Colorectal Neoplasms, pathological response, liver metastases, medicine.drug
Abstract: Background: Optimal preoperative treatment before colorectal cancer metastases (CRCM) resection remains unclear. This study evaluated pathological responses (pR) in CRCM resected after chemotherapy alone or combined with angiogenesis or epidermal growth factor receptor (EGFR) inhibitors. Methods: Pathological response was retrospectively evaluated on 264 resected metastases from 99 patients. The proportion of responding metastases after different preoperative treatments was reported and compared. Patient's progression-free survival (PFS) and overall survival (OS) were compared based on pR. Results: The combination of anti-angiogenics with oxaliplatin-based chemotherapy resulted in more pR than when they were combined with irinotecan-based chemotherapy (80% vs 50% P
Published: 2015

4. Combined BRAF, EGFR, and MEK Inhibition in Patients With BRAFV600E-Mutant Colorectal Cancer

Author: Gary Middleton, A. Scott Jung, Fatima Rangwala, Kei Muro, Takayuki Yoshino, Salvatore Siena, Ryan B. Corcoran, Eric Van Cutsem, Savina Jaeger, Michael S. Gordon, Thierry André, Jan C. Brase, Josep Tabernero, Autumn J. McRee, Yves Humblet, Filip de Vos, Jan H.M. Schellens, Peter J. O'Dwyer, Antoine Hollebecque, Johanna C. Bendell, Chloe E. Atreya, Severine Bettinger, Rona Yaeger, and Bijoyesh Mookerjee
Subjects: 0301 basic medicine, MAPK/ERK pathway, Neuroblastoma RAS viral oncogene homolog, Male, Proto-Oncogene Proteins B-raf, endocrine system diseases, Colorectal cancer, Pyridones, MAP Kinase Signaling System, Oncology and Carcinogenesis, Drug Resistance, Pyrimidinones, medicine.disease_cause, Article, 03 medical and health sciences, 0302 clinical medicine, Oximes, Antineoplastic Combined Chemotherapy Protocols, medicine, Panitumumab, Humans, Protein Kinase Inhibitors, neoplasms, Cancer, Trametinib, Mitogen-Activated Protein Kinase Kinases, business.industry, Melanoma, Imidazoles, Dabrafenib, medicine.disease, digestive system diseases, Colo-Rectal Cancer, ErbB Receptors, 030104 developmental biology, Good Health and Well Being, Oncology, Drug Resistance, Neoplasm, 030220 oncology & carcinogenesis, Mutation, Cancer research, Neoplasm, Female, KRAS, business, Digestive Diseases, Colorectal Neoplasms, medicine.drug
Abstract: Although BRAF inhibitor monotherapy yields response rates >50% in BRAFV600-mutant melanoma, only approximately 5% of patients with BRAFV600E colorectal cancer respond. Preclinical studies suggest that the lack of efficacy in BRAFV600E colorectal cancer is due to adaptive feedback reactivation of MAPK signaling, often mediated by EGFR. This clinical trial evaluated BRAF and EGFR inhibition with dabrafenib (D) + panitumumab (P) ± MEK inhibition with trametinib (T) to achieve greater MAPK suppression and improved efficacy in 142 patients with BRAFV600E colorectal cancer. Confirmed response rates for D+P, D+T+P, and T+P were 10%, 21%, and 0%, respectively. Pharmacodynamic analysis of paired pretreatment and on-treatment biopsies found that efficacy of D+T+P correlated with increased MAPK suppression. Serial cell-free DNA analysis revealed additional correlates of response and emergence of KRAS and NRAS mutations on disease progression. Thus, targeting adaptive feedback pathways in BRAFV600E colorectal cancer can improve efficacy, but MAPK reactivation remains an important primary and acquired resistance mechanism. Significance: This trial demonstrates that combined BRAF + EGFR + MEK inhibition is tolerable, with promising activity in patients with BRAFV600E colorectal cancer. Our findings highlight the MAPK pathway as a critical target in BRAFV600E colorectal cancer and the need to optimize strategies inhibiting this pathway to overcome both primary and acquired resistance. Cancer Discov; 8(4); 428–43. ©2018 AACR. See related commentary by Janku, p. 389. See related article by Hazar-Rethinam et al., p. 417. This article is highlighted in the In This Issue feature, p. 371
Published: 2018

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

Author: Jean-François Emile, Catherine Julié, Karine Le Malicot, Come Lepage, Josep Tabernero, Enrico Mini, Gunnar Folprecht, Jean-Luc Van Laethem, Stéphanie Dimet, Camille Boulagnon-Rombi, Marc-Antoine Allard, Frédérique Penault-Llorca, Jaafar Bennouna, Pierre Laurent-Puig, Julien Taieb, Josef Thaler, Richard Greil, Johannes Gaenzer, Wolfgang Eisterer, Joerg Tschmelitsch, Felix Keil, Hellmut Samonigg, August Zabernigg, Franz Schmid, Günther Steger, Robert Steinacher, Johannes Andel, Björn Jagdt, Alois Lang, Michael Fridrik, Reinhold Függer, Friedrich Hofbauer, Ewald Woell, Dietmar Geissler, Alfred Lenauer, Manfred Prager, Geert D'Haens, Gauthier Demolin, Joseph Kerger, Guido Deboever, Gilbert Ghillebert, Marc Polus, Eric Van Cutsem, Hassan Rezaie Kalantari, Thierry Delaunoit, Jean Charles Goeminne, Marc Peeters, Philippe Vergauwe, Ghislain Houbiers, Yves Humblet, Jos Janssens, Dirk Schrijvers, Erik Vanderstraeten, Jan Vermorken, Daniel Van Daele, Michel Ferrante, Frederic Forget, Alain Hendlisz, Mette Yilmaz, Svend Erik Nielsen, Lene Vestermark, Jim Larsen, Mohamed-Ayman Zawadi, Olivier Bouche, Laurent Mineur, Jaafar Bennouna-Louridi, Louis Marie Dourthe, Marc Ychou, Eveline Boucher, Denis Pezet, Francoise Desseigne, Michel Ducreux, Patrick Texereau, Laurent Miglianico, Philippe Rougier, Serge Fratte, Charles-Briac Levache, Yacine Merrouche, Stephen Ellis, Christophe Locher, Jean-Francois Ramee, Claire Garnier, Frederic Viret, Bruno Chauffert, Isabelle Cojean-Zelek, Pierre Michel, Cedric Lecaille, Christian Borel, Jean-Francois Seitz, Denis Smith, Catherine Lombard-Bohas, Thierry Andre, Jean-Marc Gornet, Francine Fein, Marie-Aude Coulon-Sfairi, Marie-Christine Kaminsky, Jean-Paul Lagasse, Dominique Luet, Pierre-Luc Etienne, Mohamed Gasmi, Andre Vanoli, Suzanne Nguyen, Thomas Aparicio, Hervé Perrier, Noel Stremsdoerfer, Philippe Laplaige, Dominique Arsene, Dominique Auby, Laurent Bedenne, Romain Coriat, Bernard Denis, Patrick Geoffroy, Gilles Piot, Yves Becouarn, Gilbert Bordes, Gael Deplanque, Olivier Dupuis, Frederic Fruge, Rosine Guimbaud, Thierry Lecomte, Gérard Lledo, Iradej Sobhani, Amani Asnacios, Ahmed Azzedine, Christophe Desauw, Marie-Pierre Galais, Dany Gargot, You-Heng Lam, Abakar Abakar-Mahamat, Jean-Francois Berdah, Sylviane Catteau, Marie-Christine Clavero-Fabri, Jean-Francois Codoul, Jean-Louis Legoux, Denis Goldfain, Pierre Guichard, Denis Pere Verge, Jocelyne Provencal, Bruno Vedrenne, Catherine Brezault-Bonnet, Denis Cleau, Jean-Paul Desir, David Fallik, Bruno Garcia, Marie-Hélène Gaspard, Dominique Genet, Johannes Hartwig, Yves Krummel, Tamara Matysiak Budnik, Vanessa Palascak-Juif, Harizo Randrianarivelo, Yves Rinaldi, Albert Aleba, Ariane Darut-Jouve, Aimery de Gramont, Herve Hamon, Frederic Wendehenne, Axel Matzdorff, Michael Konrad Stahl, Wolfgang Schepp, Martin Burk, Lothar Mueller, Michael Geissler, Luisa Mantovani-Loeffler, Thomas Hoehler, Walter Asperger, Hendrik Kroening, Ludwig Fischer von Weikersthal, Stefan Fuxius, Matthias Groschek, Johannes Meiler, Tanja Trarbach, Jacqueline Rauh, Nicolas Ziegenhagen, Albrecht Kretzschmar, Ullrich Graeven, Arnd Nusch, Goetz von Wichert, Ralf-Dieter Hofheinz, Gerhard Kleber, Karl-Heinz Schmidt, Ursula Vehling-Kaiser, Claudia Baum, Jochen Schuette, Georg Martin Haag, Wilhelm Holtkamp, Jochen Potenberg, Tobias Reiber, Georg Schliesser, Hans-Joachim Schmoll, Wolfgang Schneider-Kappus, Wolfgang Abenhardt, Claudio Denzlinger, Jan Henning, Bartscht Marxsen, Hans Guenter Derigs, Helmut Lambertz, Ingulf Becker-Boost, Karel Caca, Christian Constantin, Thomas Decker, Henning Eschenburg, Sigrun Gabius, Holger Hebart, Albrecht Hoffmeister, Heinz-August Horst, Stephan Kremers, Malte Leithaeuser, Sebastian Mueller, Siegfried Wagner, Severin Daum, Frank Schlegel, Martina Stauch, Volker Heinemann, Evaristo Maiello, Luciano Latini, Alberto Zaniboni, Dino Amadori, Giuseppe Aprile, Sandro Barni, Rodolfo Mattioli, Andrea Martoni, Rodolfo Passalacqua, Mario Nicolini, Enzo Pasquini, Carla Rabbi, Enrico Aitini, Alberto Ravaioli, Carlo Barone, Guido Biasco, Stefano Tamberi, Angelo Gambi, Claudio Verusio, Marina Marzola, Giorgio Lelli, Corrado Boni, Stefano Cascinu, Paolo Bidoli, Massimo Vaghi, Giorgio Cruciani, Francesco Di Costanzo, Alberto Sobrero, Roberto Petrioli, Massimo Aglietta, Oscar Alabiso, Federico Capuzzo, Alfredo Falcone, Domenico Cristi Corsi, Roberto Labianca, Stefania Salvagni, Silvana Chiara, Libero Ciuffreda, Francesco Ferraù, Francesco Giuliani, Sara Lonardi, Nicola Gebbia, Giovanni Mantovani, Evaristo Sanches, Juan Carlos Mellidez, Pedro Santos, Joao Freire, Cristina Sarmento, Luis Costa, Antonio Moreira Pinto, Sergio Barroso, Jorge Espirito Santo, Fátima Guedes, Amélia Monteiro, Anabela Sa, Irene Furtado, Ramon Salazar, Enrique Aranda Aguilar, Fernando Rivera Herrero, Javier Sastre Valera, Manuel Valladares Ayerbes, Jaime Feliu Batlle, Silvia Gil, Albert Abad Esteve, Carlos Garcia-Giron, Guillermo Lopez Vivanco, Antonia Salud Salvia, Vicente Alonso Orduña, Ruth Vera Garcia, Javier Gallego, Bartomeu Massuti Sureda, Jordi Remon, Maria Jose Safont Aguilera, Luis Cirera Nogueras, Bernado Queralt Merino, Cristina Gravalos Castro, Purificacion Martinez de Prado, Carlos Pijaume Pericay, Manuel Constenla Figueiras, Inmaculada Guasch Jordan, Maria Jose Gome Reina, Amelia Lopez-Ladron Garcia, Antonio Arrivi Garcia-Ramos, Andres Cervantes, Carlos Fernandez Martos, Eugenio Marcuello Gaspar, Ines Cabezas Montero, Pilar Escudero Emperador, Ana Leon Carbonero, Manuel Gallen Castillo, Teresa Garcia Garcia, Jose Garcia Lopez, Encarnacion Gonzalez Flores, Monica Guillot Morales, Marta Llanos Muñoz, Ana López Martín, Joan Maurel, Juan Carlos Camara, Rosario Dueñas Garcia, Mercedes Salgado, Isabel Hernandez Busquier, Teresa Checa Ruiz, Adelaida Lacasta Muñoa, Miquel Nogue Aliguer, Amalia Velasco Ortiz de Taranco, Miguel Mendez Ureña, Ferran Losa Gaspa, Jose Juan Ponce, Carlos Bosch Roig, Pedro Valero Jimenez, Antonio Galan Brotons, Santiago Albiol Rodriguez, Jose Ales Martinez, Liliana Canosa Ruiz, Margarita Centelles Ruiz, John Bridgewater, Rob Glynne-Jones, Saad Tahir, Tamas Hickish, Jim Cassidy, Leslie Samuel, UE 1373 Fourrages Environnement Ruminants Lusignan, Institut National de la Recherche Agronomique ( INRA ) -Physiologie Animale et Systèmes d'Elevage ( PHASE ) -Environnement et Agronomie ( E.A. ) -Biologie et Amélioration des Plantes ( BAP ) -Fourrages Environnement Ruminants Lusignan ( FERLUS ), Service de pathologie [CHU Ambroise Paré], Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Ambroise Paré, Service de Biostatistique, Fédération Francophone de la Cancérologie Digestive, FFCD, Lipides - Nutrition - Cancer [Dijon - U1231] ( LNC ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service d'hépato-gastroentérologie et cancérologie digestive (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Vall d'Hebron University Hospital [Barcelona], Dpt of Internal Medicine, Section of Immunoallergology and Respiratory [Florence] Diseases, University of Florence, Carl Gustav Carus University Hospital, Erasme Hospital, Brussels, Centre Hepato-Biliaire, AP-HP Hôpital Paul Brousse, Modèles de Cellules Souches Malignes et Thérapeutiques, Université Paris-Sud - Paris 11 ( UP11 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris-Sud - Paris 11 ( UP11 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Imagerie Moléculaire et Stratégies Théranostiques - Clermont Auvergne ( IMoST ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Clermont Auvergne ( UCA ), Institut de cancérologie de l'Ouest - Nantes ( ICO Nantes ), CRLCC Paul Papin-CRLCC René Gauducheau, Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers ( CRCINA ), Université d'Angers ( UA ) -Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche en Santé de l'Université de Nantes ( IRS-UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), Université de Nantes ( UN ), Médecine Personnalisée, Pharmacogénomique, Optimisation Thérapeutique ( MEPPOT - U1147 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Klinikum Wels Grieskirchen, Oncology department [Salzburg], Salzburger Landesklinikum - Uniklinikum Salzburg ( SALK ), Institute of Chemical Reaction Engineering, Hamburg University of Technology, Alfred-Wegener-Institut, Helmholtz-Zentrum für Polar- und Meeresforschung ( AWI ), Department of Medical Oncology, Medical University Vienna, Department of Internal Medicine, Hospital of Steyr, Department Internal Medicine 3, Centre for Hematology and Medical Oncology, General Hospital Linz, Department Medicine LKH, Institut für Festköperfirschung, Institut des Sciences Moléculaires de Marseille ( ISM2 ), Centre National de la Recherche Scientifique ( CNRS ) -Ecole Centrale de Marseille ( ECM ) -Aix Marseille Université ( AMU ), University Hospitals Leuven [Leuven], Katholieke Universiteit Leuven ( KU Leuven ), Pharmacology and Toxicology, Ahvaz Jundishapur University of Medical Sciences, Institut de Biologie Computationnelle ( IBC ), Centre de Coopération Internationale en Recherche Agronomique pour le Développement ( CIRAD ) -Institut National de la Recherche Agronomique ( INRA ) -Institut National de Recherche en Informatique et en Automatique ( Inria ) -Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut des Sciences Moléculaires ( ISM ), Université Montesquieu - Bordeaux 4-Université Sciences et Technologies - Bordeaux 1-École Nationale Supérieure de Chimie et de Physique de Bordeaux (ENSCPB)-Centre National de la Recherche Scientifique ( CNRS ), Faculty of Veterinary Medicine, Ghent University [Belgium] ( UGENT ), Medical Oncology, Antwerp University Hospital [Edegem], Recombinaison et Expression Génétique, Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre Hospitalier de L'Ardenne (Libramont), Department of Cardiology [Sivas, Turkey], Cumhuriyet University [Sivas, Turkey], Department of Earth Sciences, Durham University, Department of Oncology, Rigshospitalet [Copenhagen], Odense Hospital, CP Kelco ApS, Centre Hospitalier Universitaire de Reims ( CHU Reims ), Institut de Recherche en Cancérologie de Montpellier ( IRCM - U1194 Inserm - UM ), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ), Université du Québec à Montréal ( UQAM ), Université Panthéon-Sorbonne ( UP1 ), École nationale supérieure d'architecture de Nantes ( ENSA Nantes ), Department of Hepatogastroenterology and Oncology, Hopital Ambroise Pare, 9, Avenue Charles de Gaulle, 92104, Boulogne Cedex, France., Hôpital Ambroise Paré, CH Belfort-Montbéliard, Polyclinique Francheville, Institut de Cancérologie de la Loire Lucien Neuwirth, Centre Hospitalier Universitaire de Saint-Etienne ( CHU de Saint-Etienne ), Centre Hospitalier de Meaux, Service d'hématologie, Clinique Catherine de Sienne, Unité de recherche sur les Biopolymères, Interactions Assemblages ( BIA ), Institut National de la Recherche Agronomique ( INRA ), Université de la Méditerranée - Aix-Marseille 2, Centre hospitalier universitaire d'Amiens ( CHU Amiens-Picardie ), CHU Amiens-Picardie, Pôle oncologie médicale, Hôpital des Diaconesses, Génétique du cancer et des maladies neuropsychiatriques ( GMFC ), Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université de Bretagne Occidentale - École de sages-femmes ( UBO UFR MSS ESF ), Université de Brest ( UBO ) -Centre Hospitalier Régional Universitaire de Brest ( CHRU Brest ), Service d'oncologie digestive et hépato-gastro-entérologie [Hôpital de la Timone - APHM], Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ), Service d'Oncologie Médicale [Centre hospitalier Lyon Sud - HCL], Centre Hospitalier Lyon Sud [CHU - HCL] ( CHLS ), Hospices Civils de Lyon ( HCL ) -Hospices Civils de Lyon ( HCL ), Service d'Oncologie Médicale [CHU Saint -Antoine], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Saint-Antoine [APHP], Centre de Recherche Saint-Antoine ( CR Saint-Antoine ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ), Hôpital Saint-Louis, Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Diderot - Paris 7 ( UPD7 ), Service Gastro-Entérologie, CHU Besançon, Université de Franche-Comté ( UFC ) -Université de Franche-Comté ( UFC ), Centre Alexis Vautrin ( CAV ), Ecophysiologie Végétale, Agronomie et Nutritions ( EVA ), Université de Caen Normandie ( UNICAEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Institut National de la Recherche Agronomique ( INRA ), Image et ville ( IV ), Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique ( CNRS ), Département informatique ( INFO ), Université européenne de Bretagne ( UEB ) -Télécom Bretagne-Institut Mines-Télécom [Paris], Service de Gastro-entérologie [Avicenne], Université Paris 13 ( UP13 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Avicenne, Agence de l'Environnement et de la Maîtrise de l'Energie - ADEME, Service d'hépato-gastroentérologie, CHU Caen-Hôpital côte de nacre, Département de Médecine, Centre hospitalier de Libourne, Service d'Hépato-Gastro-Entérologie (CHU de Dijon), Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Fondation FondaMental, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor, Variabilité de réponse aux psychotropes ( VariaPsy - U1144 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Diderot - Paris 7 ( UPD7 ), Département d'oncologie digestive, Institut Bergonié - CRLCC Bordeaux, Hôpital St Joseph, Service de Gynécologie et d'Obstétrique ( CHU Lyon ), Hospices Civils de Lyon ( HCL ), Gastro - Entérologie et Nutrition, CHU Toulouse [Toulouse]-Hôpital de Rangueil, CHU Toulouse [Toulouse], Génétique, Immunothérapie, Chimie et Cancer ( GICC ), Université de Tours-Centre National de la Recherche Scientifique ( CNRS ), Université Montpellier 1 ( UM1 ), Service de gastro-entérologie - Hôpital Henri Mondor, Laboratoire Matière et Systèmes Complexes ( Laboratoire MSC ), Université Paris Diderot - Paris 7 ( UPD7 ) -UFR de Physique, France, Amériques, Espagne – Sociétés, pouvoirs, acteurs ( FRAMESPA ), Université Toulouse - Jean Jaurès ( UT2J ) -Centre National de la Recherche Scientifique ( CNRS ), Regional Hospital of Orleans, Histoire, Archéologie et littératures des Mondes chrétiens et musulmans médiévaux ( CIHAM ), École normale supérieure - Lyon ( ENS Lyon ) -Université Lumière - Lyon 2 ( UL2 ) -École des hautes études en sciences sociales ( EHESS ) -Université Jean Moulin - Lyon III ( UJML ) -Université d'Avignon et des Pays de Vaucluse ( UAPV ) -Centre National de la Recherche Scientifique ( CNRS ), Neurobiologie des signaux intercellulaires ( NSI ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Centre National de la Recherche Scientifique ( CNRS ), Dept Med Genet, Hôpital Erasme (Bruxelles), Polyclinique de Limoges - site François Chénieux [Limoges], Clinique Médicale B, CHU Strasbourg, Service de gastro-entérologie, Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Hôpital Jean Minjoz, Hôpital Européen [Fondation Ambroise Paré - Marseille], Asklepios Klinikum Uckermark GmbH, DESY, Notkestr 85, D-22607 Hamburg, Germany, NASA Ames Research Center ( ARC ), Department of Chemistry, Center for Structural Biology, Vanderbilt University [Nashville], Biostatistique et Processus Spatiaux ( BIOSP ), Institute of Ecology [Jena], Friedrich-Schiller-Universität Jena, University of Rostock [Germany], Universität Stuttgart [Stuttgart], Oneonta, Zentrum für Innere Medizin, Klinikum Schwäbisch Gmünd/Stauferklinik, Physiopathologie du stress pancréatique, Institut Armand Frappier ( INRS-IAF ), Institut National de la Recherche Scientifique [Québec] ( INRS ) -Réseau International des Instituts Pasteur ( RIIP ) -Institut Armand Frappier, Institut de Mathématiques de Marseille ( I2M ), Aix Marseille Université ( AMU ) -Ecole Centrale de Marseille ( ECM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre des Sciences du Goût et de l'Alimentation [Dijon] ( CSGA ), Institut National de la Recherche Agronomique ( INRA ) -Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique ( CNRS ), Department of Computer Science [Freiburg], University of Freiburg [Freiburg], Institut für Mathematik [Berlin], Technische Universität Berlin ( TUB ), Department of Information Engineering, Computer Science and Mathematics, Università degli Studi dell'Aquila [L'Aquila] ( UNIVAQ.IT ), Department of Animal Sciences, North Carolina Agricultural and Technical State University, FEEM, Romagna Cancer Registry, IRST, Luigi Pierantoni Hospital, Observatoire sociologique du changement ( OSC ), Sciences Po-Centre National de la Recherche Scientifique ( CNRS ), Dipartimento di Chimica, Fisica e Ambiente, Università degli Studi di Udine - University of Udine [Italie], Department of Nuclear Medicine, PET/CT Centre, Centre de Psychiatrie et Neurosciences ( CPN - U894 ), Clinica di Oncologia Medica, AO Ospedali Riuniti, Università Politecnica delle Marche [Ancona] ( UNIVPM ), Universidade Nova de Lisboa ( UNINOVA ), Ottawa Hospital Research Institute [Ottawa] ( OHRI ), Oncologia Medica, Ospedali Riuniti, Ospedale 'San Vincenzo', NIPE, CIPES, European Synchrotron Radiation Facility ( ESRF ), Departamento de Engenharia Informática, Faculdade de Engenharia [Porto] ( FEUP ), Universidade do Porto [Porto]-Universidade do Porto [Porto], 3Decide, Unité de recherche Amélioration, Génétique et Physiologie Forestières ( UAGPF ), Universidade Federal de Campina Grande [Campina Grande] ( UFCG ), Instituto de Engenharia de Sistemas e Computadores ( INESC ), Departamento de Ciências Biológicas, Universidade Regional do Cariri ( URCA Brasil ), Department of Biochemistry and Molecular Biology [Barcelona, Spain], Universitat de Barcelona ( UB ), Associated Unit to Consejo Superior de Investigaciones Científicas - CSIC [Barcelona, Spain], University of Barcelona-Institute of Biomedicine - IBUB [Barcelona, Spain], IRCELYON-Caractérisation et remédiation des polluants dans l'air et l'eau ( CARE ), Institut de recherches sur la catalyse et l'environnement de Lyon ( IRCELYON ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique ( CNRS ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique ( CNRS ), Laboratoire d'analyse et d'architecture des systèmes [Toulouse] ( LAAS ), Centre National de la Recherche Scientifique ( CNRS ) -Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National des Sciences Appliquées - Toulouse ( INSA Toulouse ), Institut National des Sciences Appliquées ( INSA ) -Institut National des Sciences Appliquées ( INSA ) -Institut National Polytechnique [Toulouse] ( INP ), Institut Charles Gerhardt Montpellier - Institut de Chimie Moléculaire et des Matériaux de Montpellier ( ICGM ICMMM ), Université Montpellier 1 ( UM1 ) -Université Montpellier 2 - Sciences et Techniques ( UM2 ) -Ecole Nationale Supérieure de Chimie de Montpellier ( ENSCM ) -Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Instituto de Ciencia de Materiales de Madrid [Madrid] ( ICMM ), Interactions, Corpus, Apprentissages, Représentations ( ICAR ), École normale supérieure - Lyon ( ENS Lyon ) -Université Lumière - Lyon 2 ( UL2 ) -INRP-Ecole Normale Supérieure Lettres et Sciences Humaines-Centre National de la Recherche Scientifique ( CNRS ), Institut d'Investigacions Biomèdiques August Pi i Sunyer ( IDIBAPS ), North Region Cancer Registry of Portugal, UMR 5805 Environnements et Paléoenvironnements Océaniques et Continentaux ( EPOC ), Observatoire aquitain des sciences de l'univers ( OASU ), Université Sciences et Technologies - Bordeaux 1-Institut national des sciences de l'Univers ( INSU - CNRS ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Sciences et Technologies - Bordeaux 1-Institut national des sciences de l'Univers ( INSU - CNRS ) -Centre National de la Recherche Scientifique ( CNRS ) -École pratique des hautes études ( EPHE ) -Centre National de la Recherche Scientifique ( CNRS ), Department of Paediatrics and Intensive Care, Hospital Universitari Sant Joan de Deu, Laboratoire de Psychologie Sociale ( LPS ), Aix Marseille Université ( AMU ), Universitat de València ( UV ), Instituto de Cienca de Materiales de Madrid [Madrid] ( ICMM ), Biology, New Mexico State University, New Mexico State University, Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ), Centre de recherche sur les Ions, les MAtériaux et la Photonique ( CIMAP - UMR 6252 ), Centre National de la Recherche Scientifique ( CNRS ) -Ecole Nationale Supérieure d'Ingénieurs de Caen ( ENSICAEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université de Caen Normandie ( UNICAEN ), Normandie Université ( NU ), Institut d'Electronique et de Télécommunications de Rennes ( IETR ), Université de Nantes ( UN ) -Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National des Sciences Appliquées - Rennes ( INSA Rennes ) -CentraleSupélec-Centre National de la Recherche Scientifique ( CNRS ), Computer Science Department - Carnegie Mellon University, University of Pittsburgh, Laboratoire de Sciences Actuarielle et Financière ( SAF ), Université de Lyon-Université de Lyon, Instituto de Oncologia Corachan ( IDOC ), Laboratoire d'informatique de l'école normale supérieure ( LIENS ), École normale supérieure - Paris ( ENS Paris ) -Centre National de la Recherche Scientifique ( CNRS ), Experimental Quantum Optics and Photonics Group, University of Strathclyde, Institut de recherches Asiatiques ( IrAsia ), Aix Marseille Université ( AMU ) -Centre National de la Recherche Scientifique ( CNRS ), Centre Européen de Réalité Virtuelle ( CERV ), École Nationale d'Ingénieurs de Brest ( ENIB ), Sol Agro et hydrosystème Spatialisation ( SAS ), Institut National de la Recherche Agronomique ( INRA ) -AGROCAMPUS OUEST, Grenoble Institut des Neurosciences ( GIN ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -CHU Grenoble-Université Joseph Fourier - Grenoble 1 ( UJF ), Centre de recherche cerveau et cognition ( CERCO ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Laboratoire Géomatériaux et Environnement ( LGE ), Université Paris-Est Marne-la-Vallée ( UPEM ), Hôpital Ambroise Paré [AP-HP], Université Paris-Saclay, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Ambroise Paré [AP-HP], Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Centre hépato-biliaire (CHB), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Université de Nantes (UN), Médecine Personnalisée, Pharmacogénomique, Optimisation Thérapeutique (MEPPOT - U1147), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Salzburger Landesklinikum - Uniklinikum Salzburg (SALK), Alfred-Wegener-Institut, Helmholtz-Zentrum für Polar- und Meeresforschung (AWI), Institut des Sciences Moléculaires de Marseille (ISM2), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-École Centrale de Marseille (ECM)-Institut de Chimie du CNRS (INC), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Institut de Biologie Computationnelle (IBC), Université de Montpellier (UM)-Institut National de la Recherche Agronomique (INRA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS), Institut des Sciences Moléculaires (ISM), Université Montesquieu - Bordeaux 4-Université Sciences et Technologies - Bordeaux 1-École Nationale Supérieure de Chimie et de Physique de Bordeaux (ENSCPB)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Universiteit Gent = Ghent University [Belgium] (UGENT), Antwerp University Hospital [Edegem] (UZA), Hillerød Hospital, Copenhagen University Hospital-Copenhagen University Hospital, Centre Hospitalier Universitaire de Reims (CHU Reims), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université du Québec à Montréal = University of Québec in Montréal (UQAM), Université Paris 1 Panthéon-Sorbonne (UP1), École nationale supérieure d'architecture de Nantes (ENSA Nantes), Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Unité de recherche sur les Biopolymères, Interactions Assemblages (BIA), Institut National de la Recherche Agronomique (INRA), Génétique du cancer et des maladies neuropsychiatriques (GMFC), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bretagne Occidentale - École de sages-femmes (UBO UFR MSS ESF), Université de Brest (UBO)-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Centre Alexis Vautrin (CAV), Ecophysiologie Végétale, Agronomie et Nutritions (EVA), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Recherche Agronomique (INRA), Image et ville (IV), Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS), Département informatique (INFO), Université européenne de Bretagne - European University of Brittany (UEB)-Télécom Bretagne-Institut Mines-Télécom [Paris] (IMT), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris 13 (UP13)-Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Agence de l'Environnement et de la Maîtrise de l'Energie (ADEME), Service d'Hépato-Gastro-Enterologie et Nutrition [CHU Caen], Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Centre Hospitalier Libourne, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Fondation FondaMental [Créteil], Variabilité de réponse aux Psychotropes (VariaPsy - U1144), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Bergonié [Bordeaux], UNICANCER-UNICANCER, Service de Gynécologie et d'Obstétrique (CHU Lyon), Hospices Civils de Lyon (HCL), Génétique, immunothérapie, chimie et cancer (GICC), UMR 7292 CNRS [2012-2017] (GICC UMR 7292 CNRS), Université de Tours-Centre National de la Recherche Scientifique (CNRS), Université Montpellier 1 (UM1), Service de gastro-entérologie [Henri Mondor AP-HP, Créteil], Hôpital Henri Mondor-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Matière et Systèmes Complexes (MSC (UMR_7057)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Hôpital privé Toulon Hyères : Sainte Marguerite, Clinique des Quatre Pavillons, Lormont, France, Neurobiologie des signaux intercellulaires (NSI), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB)-Faculté de Médecine [Bruxelles] (ULB), NASA Ames Research Center (ARC), Biostatistique et Processus Spatiaux (BioSP), Friedrich-Schiller-Universität = Friedrich Schiller University Jena [Jena, Germany], University of Rostock, State University of New York at Oneonta (SUNY Oneonta), State University of New York (SUNY), Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Armand Frappier (INRS-IAF), Réseau International des Instituts Pasteur (RIIP)-Institut National de la Recherche Scientifique [Québec] (INRS), Institut de Mathématiques de Marseille (I2M), Aix Marseille Université (AMU)-École Centrale de Marseille (ECM)-Centre National de la Recherche Scientifique (CNRS), Klinikum Deggendorf, Technische Universität Berlin (TU), Università degli Studi dell'Aquila (UNIVAQ), North Carolina A&T State University, University of North Carolina System (UNC)-University of North Carolina System (UNC), Observatoire sociologique du changement (OSC), Sciences Po (Sciences Po)-Centre National de la Recherche Scientifique (CNRS), Institut de psychiatrie et neurosciences (U894 / UMS 1266), Università Politecnica delle Marche [Ancona] (UNIVPM), Universidade Nova de Lisboa = NOVA University Lisbon (NOVA), Ottawa Hospital Research Institute [Ottawa] (OHRI), European Synchrotron Radiation Facility (ESRF), Departamento de Engenharia Informática [Porto], Faculdade de Engenharia da Universidade do Porto (FEUP), Universidade do Porto-Universidade do Porto, Universidade Federal de Campina Grande [Campina Grande] (UFCG), Instituto de Engenharia de Sistemas e Computadores (INESC), Universidade Regional do Cariri (URCA Brasil), Universitat de Barcelona (UB), IRCELYON-Catalytic and Atmospheric Reactivity for the Environment (CARE), Institut de recherches sur la catalyse et l'environnement de Lyon (IRCELYON), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Laboratoire d'analyse et d'architecture des systèmes (LAAS), Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse 1 Capitole (UT1), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées, Institut Charles Gerhardt Montpellier - Institut de Chimie Moléculaire et des Matériaux de Montpellier (ICGM ICMMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut de Chimie du CNRS (INC), Instituto de Ciencia de Materiales de Madrid (ICMM), Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), Interactions, Corpus, Apprentissages, Représentations (ICAR), École normale supérieure - Lyon (ENS Lyon)-Université Lumière - Lyon 2 (UL2)-INRP-Ecole Normale Supérieure Lettres et Sciences Humaines (ENS LSH)-Centre National de la Recherche Scientifique (CNRS), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), UMR 5805 Environnements et Paléoenvironnements Océaniques et Continentaux (EPOC), Observatoire aquitain des sciences de l'univers (OASU), Université Sciences et Technologies - Bordeaux 1-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Sciences et Technologies - Bordeaux 1-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Hospital Universitario de Valme, Anenida de Bellavista s/n, Sevilla 41014, Spain, Hospital Son Llatzer, Universitat de València (UV), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Hospital Universitari Son Espases, University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE)-Pennsylvania Commonwealth System of Higher Education (PCSHE), Instituto de Oncologia Corachan (IDOC), Laboratoire d'informatique de l'école normale supérieure (LIENS), École normale supérieure - Paris (ENS Paris), Institut de recherches Asiatiques (IrAsia), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Centre Européen de Réalité Virtuelle (CERV), École Nationale d'Ingénieurs de Brest (ENIB), Sol Agro et hydrosystème Spatialisation (SAS), Institut National de la Recherche Agronomique (INRA)-AGROCAMPUS OUEST, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de recherche cerveau et cognition (CERCO), Institut des sciences du cerveau de Toulouse. (ISCT), Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Géomatériaux et Environnement (LGE), Université Paris-Est Marne-la-Vallée (UPEM), Fédération Francophone de Cancérologie Digestive (FFCD), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Aix Marseille Université (AMU)-École Centrale de Marseille (ECM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Service d'Oncologie Médicale [CHU Saint-Antoine], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Institut National de la Recherche Agronomique (INRA)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Avicenne [AP-HP], Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor, Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP), Department of Information Engineering, Computer Science and Mathematics = Dipartimento di Ingegneria e Scienze dell'Informazione e Matematica [L'Aquila] (DISIM), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut Charles Gerhardt Montpellier - Institut de Chimie Moléculaire et des Matériaux de Montpellier (ICGM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Département d'informatique - ENS Paris (DI-ENS), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-École Centrale de Marseille (ECM)-Aix Marseille Université (AMU), Institute of Biomedicine - IBUB [Barcelona, Spain]-University of Barcelona, Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche en Informatique et en Automatique (Inria)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche en Informatique et en Automatique (Inria)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), AGROCAMPUS OUEST, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut National de la Recherche Agronomique (INRA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure de Chimie et de Physique de Bordeaux (ENSCPB)-Université Sciences et Technologies - Bordeaux 1-Université Montesquieu - Bordeaux 4-Institut de Chimie du CNRS (INC), AGROCAMPUS OUEST-Institut National de la Recherche Agronomique (INRA), Institut National de la Recherche Agronomique (INRA)-Physiologie Animale et Systèmes d'Elevage (PHASE), Institut National de la Recherche Agronomique (INRA)-Environnement et Agronomie (E.A.)-Biologie et Amélioration des Plantes (BAP)-Fourrages Environnement Ruminants Lusignan (FERLUS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Ambroise Paré, University of Florence (UNIFI), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Imagerie Moléculaire et Stratégies Théranostiques - Clermont Auvergne (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Institut de cancérologie de l'Ouest - Nantes (ICO Nantes), Université Montesquieu - Bordeaux 4-Université Sciences et Technologies - Bordeaux 1-École Nationale Supérieure de Chimie et de Physique de Bordeaux (ENSCPB)-Centre National de la Recherche Scientifique (CNRS), Ghent University [Belgium] (UGENT), CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université du Québec à Montréal (UQAM), Université Panthéon-Sorbonne (UP1), Centre hospitalier universitaire d'Amiens (CHU Amiens-Picardie), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Saint-Antoine [APHP], Centre de Recherche Saint-Antoine (CR Saint-Antoine), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Université de Franche-Comté (UFC)-Université de Franche-Comté (UFC), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris 13 (UP13)-Hôpital Avicenne, Optimisation Thérapeutique en Neuropsychopharmacologie (VariaPsy - U1144), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC), Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Hôpital Jean Minjoz, Biostatistique et Processus Spatiaux (BIOSP), Centre des Sciences du Goût et de l'Alimentation [Dijon] (CSGA), Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique (CNRS), Technische Universität Berlin (TUB), Università degli Studi dell'Aquila [L'Aquila] (UNIVAQ.IT), Universidade Nova de Lisboa (NOVA), Faculdade de Engenharia [Porto] (FEUP), Unité de recherche Amélioration, Génétique et Physiologie Forestières (UAGPF), IRCELYON-Caractérisation et remédiation des polluants dans l'air et l'eau (CARE), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse 1 Capitole (UT1)-Université Toulouse - Jean Jaurès (UT2J), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Consejo Superior de Investigaciones Científicas [Spain] (CSIC), École normale supérieure - Lyon (ENS Lyon)-Université Lumière - Lyon 2 (UL2)-INRP-Ecole Normale Supérieure Lettres et Sciences Humaines-Centre National de la Recherche Scientifique (CNRS), Université Sciences et Technologies - Bordeaux 1-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Sciences et Technologies - Bordeaux 1-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-École pratique des hautes études (EPHE)-Centre National de la Recherche Scientifique (CNRS), École normale supérieure - Paris (ENS Paris)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut des sciences du cerveau de Toulouse. (ISCT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse - Jean Jaurès (UT2J)-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-Institut National de la Santé et de la Recherche Médicale (INSERM), Emile, J, Julie, C, Le Malicot, K, Lepage, C, Tabernero, J, Mini, E, Folprecht, G, Van Laethem, J, Dimet, S, Boulagnon-Rombi, C, Allard, M, Penault-Llorca, F, Bennouna, J, Laurent-Puig, P, Taieb, J, Bidoli, P, Emile, J. -F., Julie, C., Le Malicot, K., Lepage, C., Tabernero, J., Mini, E., Folprecht, G., Van Laethem, J. -L., Dimet, S., Boulagnon-Rombi, C., Allard, M. -A., Penault-Llorca, F., Bennouna, J., Laurent-Puig, P., Taieb, J., Thaler, J., Greil, R., Gaenzer, J., Eisterer, W., Tschmelitsch, J., Keil, F., Samonigg, H., Zabernigg, A., Schmid, F., Steger, G., Steinacher, R., Andel, J., Jagdt, B., Lang, A., Fridrik, M., Fugger, R., Hofbauer, F., Woell, E., Geissler, D., Lenauer, A., Prager, M., D'Haens, G., Demolin, G., Kerger, J., Deboever, G., Ghillebert, G., Polus, M., Van Cutsem, E., Kalantari, H. R., Delaunoit, T., Goeminne, J. C., Peeters, M., Vergauwe, P., Houbiers, G., Humblet, Y., Janssens, J., Schrijvers, D., Vanderstraeten, E., Vermorken, J., Van Daele, D., Ferrante, M., Forget, F., Hendlisz, A., Yilmaz, M., Nielsen, S. E., Vestermark, L., Larsen, J., Zawadi, M. -A., Bouche, O., Mineur, L., Bennouna-Louridi, J., Dourthe, L. M., Ychou, M., Boucher, E., Pezet, D., Desseigne, F., Ducreux, M., Texereau, P., Miglianico, L., Rougier, P., Fratte, S., Levache, C. -B., Merrouche, Y., Ellis, S., Locher, C., Ramee, J. -F., Garnier, C., Viret, F., Chauffert, B., Cojean-Zelek, I., Michel, P., Lecaille, C., Borel, C., Seitz, J. -F., Smith, D., Lombard-Bohas, C., Andre, T., Gornet, J. -M., Fein, F., Coulon-Sfairi, M. -A., Kaminsky, M. -C., Lagasse, J. -P., Luet, D., Etienne, P. -L., Gasmi, M., Vanoli, A., Nguyen, S., Aparicio, T., Perrier, H., Stremsdoerfer, N., Laplaige, P., Arsene, D., Auby, D., Bedenne, L., Coriat, R., Denis, B., Geoffroy, P., Piot, G., Becouarn, Y., Bordes, G., Deplanque, G., Dupuis, O., Fruge, F., Guimbaud, R., Lecomte, T., Lledo, G., Sobhani, I., Asnacios, A., Azzedine, A., Desauw, C., Galais, M. -P., Gargot, D., Lam, Y. -H., Abakar-Mahamat, A., Berdah, J. -F., Catteau, S., Clavero-Fabri, M. -C., Codoul, J. -F., Legoux, J. -L., Goldfain, D., Guichard, P., Verge, D. P., Provencal, J., Vedrenne, B., Brezault-Bonnet, C., Cleau, D., Desir, J. -P., Fallik, D., Garcia, B., Gaspard, M. -H., Genet, D., Hartwig, J., Krummel, Y., Budnik, T. M., Palascak-Juif, V., Randrianarivelo, H., Rinaldi, Y., Aleba, A., Darut-Jouve, A., de Gramont, A., Hamon, H., Wendehenne, F., Matzdorff, A., Stahl, M. K., Schepp, W., Burk, M., Mueller, L., Geissler, M., Mantovani-Loeffler, L., Hoehler, T., Asperger, W., Kroening, H., von Weikersthal, L. F., Fuxius, S., Groschek, M., Meiler, J., Trarbach, T., Rauh, J., Ziegenhagen, N., Kretzschmar, A., Graeven, U., Nusch, A., von Wichert, G., Hofheinz, R. -D., Kleber, G., Schmidt, K. -H., Vehling-Kaiser, U., Baum, C., Schuette, J., Haag, G. M., Holtkamp, W., Potenberg, J., Reiber, T., Schliesser, G., Schmoll, H. -J., Schneider-Kappus, W., Abenhardt, W., Denzlinger, C., Henning, J., Marxsen, B., Derigs, H. G., Lambertz, H., Becker-Boost, I., Caca, K., Constantin, C., Decker, T., Eschenburg, H., Gabius, S., Hebart, H., Hoffmeister, A., Horst, H. -A., Kremers, S., Leithaeuser, M., Mueller, S., Wagner, S., Daum, S., Schlegel, F., Stauch, M., Heinemann, V., Maiello, E., Latini, L., Zaniboni, A., Amadori, D., Aprile, G., Barni, S., Mattioli, R., Martoni, A., Passalacqua, R., Nicolini, M., Pasquini, E., Rabbi, C., Aitini, E., Ravaioli, A., Barone, C., Biasco, G., Tamberi, S., Gambi, A., Verusio, C., Marzola, M., Lelli, G., Boni, C., Cascinu, S., Bidoli, P., Vaghi, M., Cruciani, G., Di Costanzo, F., Sobrero, A., Petrioli, R., Aglietta, M., Alabiso, O., Capuzzo, F., Falcone, A., Corsi, D. C., Labianca, R., Salvagni, S., Chiara, S., Ciuffreda, L., Ferrau, F., Giuliani, F., Lonardi, S., Gebbia, N., Mantovani, G., Sanches, E., Mellidez, J. C., Santos, P., Freire, J., Sarmento, C., Costa, L., Pinto, A. M., Barroso, S., Santo, J. E., Guedes, F., Monteiro, A., Sa, A., Furtado, I., Salazar, R., Aguilar, E. A., Herrero, F. R., Valera, J. S., Ayerbes, M. V., Batlle, J. F., Gil, S., Esteve, A. A., Garcia-Giron, C., Vivanco, G. L., Salvia, A. S., Orduna, V. A., Garcia, R. V., Gallego, J., Sureda, B. M., Remon, J., Safont Aguilera, M. J., Nogueras, L. C., Merino, B. Q., Castro, C. G., de Prado, P. M., Pericay, C. P., Figueiras, M. C., Jordan, I. G., Gome Reina, M. J., Garcia, A. L. -L., Garcia-Ramos, A. A., Cervantes, A., Martos, C. F., Gaspar, E. M., Montero, I. C., Emperador, P. E., Carbonero, A. L., Castillo, M. G., Garcia, T. G., Lopez, J. G., Flores, E. G., Morales, M. G., Munoz, M. L., Martin, A. L., Maurel, J., Camara, J. C., Garcia, R. D., Salgado, M., Busquier, I. H., Ruiz, T. C., Munoa, A. L., Aliguer, M. N., de Taranco, A. V. O., Urena, M. M., Gaspa, F. L., Ponce, J. J., Roig, C. B., Jimenez, P. V., Brotons, A. G., Rodriguez, S. A., Martinez, J. A., Ruiz, L. C., Ruiz, M. C., Bridgewater, J., Glynne-Jones, R., Tahir, S., Hickish, T., Cassidy, J., and Samuel, L.
Subjects: 0301 basic medicine, Oncology, Male, Cancer Research, Organoplatinum Compounds, Colorectal cancer, medicine.medical_treatment, Medizin, Leucovorin, Prospective cohort study, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 0302 clinical medicine, FOLFOX, Organoplatinum Compounds/therapeutic use, Antineoplastic Combined Chemotherapy Protocols, tudy, Lymphocytes, Prospective Studies, Leucovorin/therapeutic use, Middle Aged, Prognosis, 3. Good health, Colorectal carcinoma, Fluorouracil, 030220 oncology & carcinogenesis, Predictive value of tests, Colonic Neoplasms, Biomarker (medicine), Lymphocytes/pathology, Female, Adjuvant, medicine.drug, Adult, medicine.medical_specialty, [SDV.CAN]Life Sciences [q-bio]/Cancer, Fluorouracil/therapeutic use, Biomarkers, Tumor/analysis, 03 medical and health sciences, Lymphocytes, Tumor-Infiltrating, Predictive Value of Tests, Biomarker, Immune response, Internal medicine, medicine, Biomarkers, Tumor, Humans, Survival analysis, Aged, business.industry, medicine.disease, Survival Analysis, Surgery, 030104 developmental biology, Prospective cohort&nbsp, Multivariate Analysis, Colonic Neoplasms/diagnosis, Antineoplastic Combined Chemotherapy Protocols/therapeutic use, business
Abstract: IF 6.029; International audience; BackgroundThe prognostic value of lymphocyte infiltration (LI) of colorectal carcinoma (CC) has been demonstrated by several groups. However, no validated test is currently available for clinical practice. We previously described an automated and reproducible method for testing LI and aimed to validate it for clinical use.Patients and methodsAccording to National Institutes of Health criteria, we designed a prospective validation of this biomarker in patients included in the PETACC8 phase III study. Primary objective was to compare percentage of patients alive and without recurrence at 2 years in patients with high versus low LI (#NCT02364024). Associations of LI with patient recurrence and survival were analysed, and multivariable models were adjusted for treatment and relevant factors. Automated testing of LI was performed on virtual slides without access to clinical data.ResultsAmong the 1220 CC patients enrolled, LI was high, low and not evaluable in 241 (19.8%), 790 (64.8%) and 189 (15.5%), respectively. Primary objective was met with a 2-year recurrence rate of 14.4% versus 21.1% in patients with high and low LI, respectively (p = 0.02). Patients with high LI also had better disease free survival (DFS) and overall survival (OS). Tumour stage, grade, RAS status and BRAF status were with LI the only prognostic markers in multivariable analysis for OS. Subgroup analyses revealed that high LI had better DFS and OS in mismatch repair (MMR) proficient patients, and in patients without RAS mutation, but not in MMR deficient and RAS mutated patients.ConclusionAlthough this is the first validation with high level of evidence (IIB) of the prognostic value of a LI test in colon cancers, it still needs to be confirmed in independent series of colon cancer patients.
Published: 2017
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6. Final results from PRIME: randomized phase III study of panitumumab with FOLFOX4 for first-line treatment of metastatic colorectal cancer

Author: Salvatore Siena, Yves Humblet, Jim Cassidy, Jacek Jassem, György Bodoky, Ying Tian, Mark Rother, Maria Blasinska-Morawiec, Mario Edmundo Barugel, Roger Sidhu, Josep Tabernero, Ilona Kocáková, Fernando Rivera, Paul Ruff, Martin Šmakal, David Cunningham, Ronald Burkes, Jean-Yves Douillard, F. Xu, Kelly S. Oliner, and Jean-Luc Canon
Subjects: Adult, Male, Oncology, medicine.medical_specialty, Organoplatinum Compounds, Colorectal cancer, Leucovorin, medicine.disease_cause, law.invention, Randomized controlled trial, FOLFOX, law, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Clinical endpoint, Humans, Panitumumab, Progression-free survival, Neoplasm Metastasis, Aged, Aged, 80 and over, business.industry, Hazard ratio, Antibodies, Monoclonal, Hematology, Middle Aged, medicine.disease, digestive system diseases, Genes, ras, Quality of Life, Female, Fluorouracil, KRAS, Colorectal Neoplasms, business, medicine.drug
Abstract: Background: The Panitumumab Randomized trial In combination with chemotherapy for Metastatic colorectal cancer to determine Efficacy (PRIME) demonstrated that panitumumab-FOLFOX4 significantly improved progression-free survival (PFS) versus FOLFOX4 as first-line treatment of wild-type (WT) KRAS metastatic colorectal cancer (mCRC), the primary end point of the study. Patients and methods: Patients were randomized 1:1 to panitumumab 6.0 mg/kg every 2 weeks + FOLFOX4 (arm 1) or FOLFOX4 (arm 2). This prespecified final descriptive analysis of efficacy and safety was planned for 30 months after the last patient was enrolled. Results: A total of 1183 patients were randomized. Median PFS for WT KRAS mCRC was 10.0 months [95% confidence interval (CI) 9.3-11.4 months] for arm 1 and 8.6months (95% CI 7.5-9.5 months) for arm 2; hazard ratio (HR) = 0.80; 95% CI 0.67-0.95; P = 0.01. Median overall survival (OS) forWT KRAS mCRC was 23.9 months (95%CI 20.3-27.7 months) for arm 1 and 19.7 months (95% CI 17.6-22.7 months) for arm 2; HR = 0.88; 95% CI 0.73-1.06; P=0.17 (68%OS events). An exploratory analysis of updated survival (>80%OS events) was carried out which demonstrated improvement in OS; HR = 0.83; 95%CI 0.70-0.98; P=0.03 forWT KRASmCRC. The adverse event profile was consistent with the primary analysis. Conclusions: In WT KRAS mCRC, PFS was improved, objective response was higher, and there was a trend toward improved OS with panitumumab-FOLFOX4, with significant improvement in OS observed in an updated analysis of survival in patients with WT KRAS mCRC treated with panitumumab + FOLFOX4 versus FOLFOX4 alone (P = 0.03). These data support a positive benefit-risk profile for panitumumab-FOLFOX4 for patients with previously untreated WT KRAS mCRC. KRAS testing is critical to select appropriate patients for treatment with panitumumab. © The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.
Published: 2014
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7. Panitumumab–FOLFOX4 Treatment and RAS Mutations in Colorectal Cancer

Author: Maria Blasinska-Morawiec, Richard Thomas Williams, György Bodoky, Fernando Rivera, Ronald Burkes, Jeffrey Wiezorek, Paul Ruff, Josep Tabernero, Martin Šmakal, Yves Humblet, Mario Edmundo Barugel, Salvatore Siena, Scott D. Patterson, David Cunningham, Mark Rother, Ilona Kocáková, Jacek Jassem, Roger Sidhu, Alan Rong, Jean-Luc Canon, Jean-Yves Douillard, Kelly S. Oliner, UCL - SSS/IREC/MIRO - Pôle d'imagerie moléculaire, radiothérapie et oncologie, and UCL - (SLuc) Unité d'oncologie médicale
Subjects: Proto-Oncogene Proteins B-raf, Neuroblastoma RAS viral oncogene homolog, Oncology, Pathology, medicine.medical_specialty, Organoplatinum Compounds, Colorectal cancer, Leucovorin, medicine.disease_cause, Disease-Free Survival, GTP Phosphohydrolases, Proto-Oncogene Proteins p21(ras), Exon, Proto-Oncogene Proteins, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, Panitumumab, Neoplasm Metastasis, FOLFOXIRI, business.industry, Hazard ratio, Antibodies, Monoclonal, Membrane Proteins, General Medicine, medicine.disease, digestive system diseases, ErbB Receptors, Genes, ras, Mutation, ras Proteins, Receptor, Epidermal Growth Factor, Fluorouracil, KRAS, Colorectal Neoplasms, business, medicine.drug
Abstract: Patients with metastatic colorectal cancer that harbors KRAS mutations in exon 2 do not benefit from anti-epidermal growth factor receptor (EGFR) therapy. Other activating RAS mutations may also be negative predictive biomarkers for anti-EGFR therapy.In this prospective-retrospective analysis, we assessed the efficacy and safety of panitumumab plus oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) as compared with FOLFOX4 alone, according to RAS (KRAS or NRAS) or BRAF mutation status. A total of 639 patients who had metastatic colorectal cancer without KRAS mutations in exon 2 had results for at least one of the following: KRAS exon 3 or 4; NRAS exon 2, 3, or 4; or BRAF exon 15. The overall rate of ascertainment of RAS status was 90%.Among 512 patients without RAS mutations, progression-free survival was 10.1 months with panitumumab-FOLFOX4 versus 7.9 months with FOLFOX4 alone (hazard ratio for progression or death with combination therapy, 0.72; 95% confidence interval [CI], 0.58 to 0.90; P=0.004). Overall survival was 26.0 months in the panitumumab-FOLFOX4 group versus 20.2 months in the FOLFOX4-alone group (hazard ratio for death, 0.78; 95% CI, 0.62 to 0.99; P=0.04). A total of 108 patients (17%) with nonmutated KRAS exon 2 had other RAS mutations. These mutations were associated with inferior progression-free survival and overall survival with panitumumab-FOLFOX4 treatment, which was consistent with the findings in patients with KRAS mutations in exon 2. BRAF mutations were a negative prognostic factor. No new safety signals were identified.Additional RAS mutations predicted a lack of response in patients who received panitumumab-FOLFOX4. In patients who had metastatic colorectal cancer without RAS mutations, improvements in overall survival were observed with panitumumab-FOLFOX4 therapy. (Funded by Amgen and others; PRIME ClinicalTrials.gov number, NCT00364013.).
Published: 2013
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8. Regorafenib induced severe toxic hepatitis: characterization and discussion

Author: Yves Humblet, Nicolas Lanthier, Astrid De Cuyper, Anne-France Dekairelle, Anne Sacré, Marc Van den Eynde, Achim Weber, Daniela Leggenhager, Jean-Luc Gala, Selda Aydin, Hélène Dano, and Christine Sempoux
Subjects: 0301 basic medicine, Toxic hepatitis, Male, Pathology, medicine.medical_specialty, Side effect, Colorectal cancer, Pyridines, medicine.medical_treatment, Antineoplastic Agents, Gene mutation, Gastroenterology, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Belgium, Regorafenib, Internal medicine, Medicine, Cytochrome P-450 CYP3A, Humans, Glucuronosyltransferase, Neoplasm Metastasis, Adverse effect, Promoter Regions, Genetic, Aged, Retrospective Studies, Chemotherapy, Hepatology, business.industry, Phenylurea Compounds, medicine.disease, Irinotecan, 030104 developmental biology, chemistry, Liver, 030220 oncology & carcinogenesis, UDP-Glucuronosyltransferase 1A9, Female, medicine.symptom, Chemical and Drug Induced Liver Injury, business, Colorectal Neoplasms, medicine.drug
Abstract: BACKGROUND Regorafenib is the first small-molecule multikinase inhibitor which showed survival benefits in pretreated metastatic colorectal cancer (mCRC) patients. Beside classical adverse events of this drug class, hepatotoxicity has been described as a frequent side effect. MATERIAL AND METHODS Patients with refractory mCRC treated with regorafenib in our institution were reviewed. Severe treatment-related liver toxicity was investigated. Clinical history, liver histology and genetic assessment (sequence analysis) of cytochrome P 3A4 (CYP3A4) and uridine diphosphate-glucuronosyltransferase 1A9 (UGT1A9) involved in regorafenib metabolization were here reported for patients with severe hepatotoxicity. RESULTS Among the 93 reviewed patients, 3 presented severe and icteric toxic hepatitis which was fatal for 1 patient. Histopathological liver lesions were different depending on the onset of hepatotoxicity (acute or subacute): acinar zone 3 necrosis in case of acute symptoms and portal tract inflammation with porto-central bridging and fibrosis in the delayed presentation. None patients had CYP3A4 gene mutations. Similar polymorphisms in UGT1A9 gene promoter region (UGT1A9 variant -118T9>10 (rs3832043)) were found in both patients who presented acute hepatitis. Moreover, it appears retrospectively that both of them already experienced significant toxicity under irinotecan-based chemotherapy. CONCLUSION This is the first report of severe hepatotoxicity with available liver histology and genetic assessment of enzymes involved in regorafenib metabolization. This report also reminds the importance of a close liver tests monitoring during regorafenib treatment. This article is protected by copyright. All rights reserved.
Published: 2016

9. Randomized, Phase III Trial of Panitumumab With Infusional Fluorouracil, Leucovorin, and Oxaliplatin (FOLFOX4) Versus FOLFOX4 Alone As First-Line Treatment in Patients With Previously Untreated Metastatic Colorectal Cancer: The PRIME Study

Author: Ronald Burkes, Fernando Rivera, Josep Tabernero, Mario Edmundo Barugel, Martin Šmakal, David Cunningham, György Bodoky, Maria Blasinska-Morawiec, Jean-Luc Canon, Mark Rother, Yves Humblet, Jean-Yves Douillard, Ilona Kocáková, Jennifer Gansert, Paul Ruff, Jim Cassidy, Jacek Jassem, Michael S. Wolf, Salvatore Siena, and Kelly S. Oliner
Subjects: Male, Oncology, Cancer Research, Organoplatinum Compounds, Colorectal cancer, medicine.medical_treatment, Leucovorin, Kaplan-Meier Estimate, medicine.disease_cause, Antineoplastic Combined Chemotherapy Protocols, Clinical endpoint, Medicine, Prospective Studies, Infusions, Intravenous, Aged, 80 and over, Panitumumab, Hazard ratio, Antibodies, Monoclonal, Middle Aged, ErbB Receptors, Gene Expression Regulation, Neoplastic, Treatment Outcome, Chemotherapy, Adjuvant, Fluorouracil, Female, KRAS, Colorectal Neoplasms, medicine.drug, Adult, medicine.medical_specialty, Disease-Free Survival, Drug Administration Schedule, Proto-Oncogene Proteins p21(ras), Predictive Value of Tests, Proto-Oncogene Proteins, Internal medicine, Biomarkers, Tumor, Humans, Aged, Neoplasm Staging, Chemotherapy, business.industry, medicine.disease, Oxaliplatin, Mutation, ras Proteins, business
Abstract: Purpose Panitumumab, a fully human anti–epidermal growth factor receptor (EGFR) monoclonal antibody that improves progression-free survival (PFS), is approved as monotherapy for patients with chemotherapy-refractory metastatic colorectal cancer (mCRC). The Panitumumab Randomized Trial in Combination With Chemotherapy for Metastatic Colorectal Cancer to Determine Efficacy (PRIME) was designed to evaluate the efficacy and safety of panitumumab plus infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as initial treatment for mCRC. Patients and Methods In this multicenter, phase III trial, patients with no prior chemotherapy for mCRC, Eastern Cooperative Oncology Group performance status of 0 to 2, and available tissue for biomarker testing were randomly assigned 1:1 to receive panitumumab-FOLFOX4 versus FOLFOX4. The primary end point was PFS; overall survival (OS) was a secondary end point. Results were prospectively analyzed on an intent-to-treat basis by tumor KRAS status. Results KRAS results were available for 93% of the 1,183 patients randomly assigned. In the wild-type (WT) KRAS stratum, panitumumab-FOLFOX4 significantly improved PFS compared with FOLFOX4 (median PFS, 9.6 v 8.0 months, respectively; hazard ratio [HR], 0.80; 95% CI, 0.66 to 0.97; P = .02). A nonsignificant increase in OS was also observed for panitumumab-FOLFOX4 versus FOLFOX4 (median OS, 23.9 v 19.7 months, respectively; HR, 0.83; 95% CI, 0.67 to 1.02; P = .072). In the mutant KRAS stratum, PFS was significantly reduced in the panitumumab-FOLFOX4 arm versus the FOLFOX4 arm (HR, 1.29; 95% CI, 1.04 to 1.62; P = .02), and median OS was 15.5 months versus 19.3 months, respectively (HR, 1.24; 95% CI, 0.98 to 1.57; P = .068). Adverse event rates were generally comparable across arms with the exception of toxicities known to be associated with anti-EGFR therapy. Conclusion This study demonstrated that panitumumab-FOLFOX4 was well tolerated and significantly improved PFS in patients with WT KRAS tumors and underscores the importance of KRAS testing for patients with mCRC.
Published: 2010
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10. Effect of oral magnesium supplementation on the kinetics of magnesium wasting induced by EGFR targeted antibody therapy for colorectal carcinoma (MAGNET trial)

Author: Yves Humblet, Wim Demey, K. Kargar Samani, Marc Ferrante, H. Rezaei Kalantari, J.-L. Van Laethem, Hubert Piessevaux, Sabine Tejpar, Guido Deboever, Anne Demols, Stéphanie Laurent, Alain Bols, T. Rondou, Jozef Janssens, Marc Polus, and E Monsaert
Subjects: medicine.medical_specialty, Magnesium supplementation, Magnesium, Colorectal cancer, business.industry, Kinetics, chemistry.chemical_element, Hematology, medicine.disease, Gastroenterology, Oncology, chemistry, Internal medicine, medicine, medicine.symptom, business, Antibody therapy, Wasting
Published: 2018
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11. Prevalence and clinical relevance of pathological hepatic changes occurring after neoadjuvant chemotherapy for colorectal liver metastases

Author: Yves Humblet, Jean-François Gigot, Catherine Hubert, Jean-Pascal Machiels, Antonino Ceratti, Caroline Fervaille, Christine Sempoux, Francis Zech, and Yves Horsmans
Subjects: Adult, Male, medicine.medical_specialty, Adolescent, Colorectal cancer, medicine.medical_treatment, Gastroenterology, Young Adult, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, Hepatectomy, Humans, Medicine, Clinical significance, Neoadjuvant therapy, Aged, Aged, 80 and over, Chemotherapy, business.industry, Liver Neoplasms, Cancer, Retrospective cohort study, Perioperative, Middle Aged, medicine.disease, Neoadjuvant Therapy, Surgery, Liver, Female, Colorectal Neoplasms, business
Abstract: BACKGROUND: Hepatotoxicity from neoadjuvant chemotherapy before liver resection for colorectal metastases (CRLM) has been recently reported. The purpose of the present study was to evaluate the prevalence and the clinical relevance of this phenomenon. It was a retrospective study conducted at an academic secondary referral hospital. METHODS: One hundred patients suffering from CRLM and having undergone the resection of at least 1 liver segment (114 hepatectomies; 100 first, 13 second, 1 third) were enrolled. The surgical specimens were reviewed using standardized criteria for diagnosis and grading of pathological liver changes. Their impact on perioperative bleeding, transfusion, morbidity, and mortality rates after liver resection was studied. RESULTS: Sinusoidal congestion was the single hepatotoxic lesion significantly more frequently encountered in patients having received neoadjuvant chemotherapy (P = .0014), even in patients having received chemotherapy more than 6 months before liver resection, but was not related to the type of chemotherapy. Despite a significant increase in perioperative blood losses, the presence of sinusoidal lesions, even severe, had no clinically significant effect on postoperative mortality, morbidity, and transfusion rates. CONCLUSION: Neoadjuvant chemotherapy before operation for CRLM is significantly associated to sinusoidal congestion, irrespective of the type of chemotherapy but without any significant impact on postoperative clinical outcome. Sinusoidal lesions may persist more than 6 months after the end of chemotherapy.
Published: 2010
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12. Drug Insight: panitumumab, a human EGFR-targeted monoclonal antibody with promising clinical activity in colorectal cancer

Author: Max Mano and Yves Humblet
Subjects: Oncology, medicine.medical_specialty, Colorectal cancer, medicine.medical_treatment, Antineoplastic Agents, Disease, law.invention, Randomized controlled trial, law, Internal medicine, medicine, Humans, Panitumumab, Stage (cooking), Adverse effect, Clinical Trials as Topic, Chemotherapy, business.industry, Antibodies, Monoclonal, General Medicine, medicine.disease, ErbB Receptors, Clinical trial, Treatment Outcome, Immunology, Drug Therapy, Combination, Colorectal Neoplasms, business, Biomarkers, medicine.drug
Abstract: Colorectal cancer (CRC) is the second leading cause of cancer-related mortality in Western countries. Despite the progress achieved with the introduction of new cytotoxic agents, CRC recurrence rates for patients with resected stage II and/or stage III disease remain higher than 20%. Furthermore, for patients diagnosed with metastatic CRC, the median survival time remains below 2 years and cure is often an elusive goal. These data highlight the need for more-effective systemic therapies. The EGFR is frequently overexpressed in CRC and has been associated with the malignant phenotype. Numerous clinical trials are now investigating the role of EGFR-targeted agents in CRC and have produced some encouraging results. Panitumumab is a fully human IgG(2) monoclonal antibody that in a randomized phase III trial was shown to increase efficacy when added to best supportive care in patients with chemotherapy-refractory metastatic CRC. In phase I-III trials, panitumumab was safe and well tolerated, with most of its adverse effects related to some form of skin toxic effect. Early studies assessing the safety and efficacy of panitumumab alongside chemotherapy have also yielded promising results, and this combination is now being investigated in the first-line and second-line settings in randomized clinical trials.
Published: 2008
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13. Radiological imaging markers predicting clinical outcome in patients with metastatic colorectal carcinoma treated with regorafenib : post hoc analysis of the CORRECT phase III trial (RadioCORRECT study)

Author: Thibault Mazard, Antonella Verrioli, Alessandro Pastorino, Daniela Redaelli, Joleen M. Hubbard, Katia Bencardino, Axel Grothey, Olivier Bouché, Hans Prenen, Yves Humblet, Konstantinos Papadimitriou, Antoine Adenis, Sophie Deguelte-Lardiere, Angelo Vanzulli, Luca Porcu, Alfredo Falcone, Marc Peeters, Andrea Sartore-Bianchi, Carlo Barone, Hajer Jarraya, Chiara Cremolini, Silvia Ghezzi, Giulia Carlo-Stella, Guillem Argiles, Josep Tabernero, Marc Ychou, Laurent Mineur, Riccardo Ricotta, Valter Torri, Marc Van den Eynde, Alessio Amatu, Alberto Sobrero, Salvatore Siena, Eric Van Cutsem, C. Funaioli, Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université Lille Nord de France (COMUE)-UNICANCER, Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Universitaire de Reims (CHU Reims), Institut Sainte Catherine [Avignon], UCL - SSS/IREC/MIRO - Pôle d'imagerie moléculaire, radiothérapie et oncologie, UCL - (SLuc) Unité d'oncologie médicale, UCL - (SLuc) Centre du cancer, and Université de Lille-UNICANCER
Subjects: Oncology, Target lesion, Cancer Research, medicine.medical_specialty, Radiological Predictive Factors, Colorectal cancer, CELL LUNG-CANCER, Cavitation, Metastatic Colorectal Cancer, Regorafenib, BEVACIZUMAB, [SDV.CAN]Life Sciences [q-bio]/Cancer, Placebo, THERAPY, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, PROPOSAL, Internal medicine, Post-hoc analysis, Medicine, CRITERIA, COMPUTED-TOMOGRAPHY, 030304 developmental biology, Original Research, 0303 health sciences, Univariate analysis, Lung, Science & Technology, business.industry, PULMONARY HEMORRHAGE, TUMOR CAVITATION, medicine.disease, RESPONSE EVALUATION, 3. Good health, medicine.anatomical_structure, chemistry, RECIST, 030220 oncology & carcinogenesis, Cohort, Radiology, business, Life Sciences & Biomedicine, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: OBJECTIVE: To identify imaging markers predicting clinical outcomes to regorafenib in metastatic colorectal carcinoma (mCRC). METHODS: The RadioCORRECT study is a post hoc analysis of a cohort of patients with mCRC treated within the phase III placebo-controlled CORRECT trial of regorafenib. Baseline and week 8 contrast-enhanced CT were used to assess response by RECIST 1.1, changes in the sum of target lesion diameters (ΔSTL), lung metastases cavitation and liver metastases density. Primary and secondary objectives were to develop ex novo univariable and multivariable models to predict overall survival (OS) and progression-free survival (PFS), respectively. RESULTS: 202 patients were enrolled, 134 (66.3%) treated with regorafenib and 68 (33.7%) with placebo. In the univariate analysis, PFS predictors were lung metastases cavitation at baseline (HR 0.50, 95% CI 0.27 to 0.92, p=0.03) and at week 8 (HR 0.58, 95% CI 0.36 to 0.93, p=0.02). Baseline cavitation (HR 0.23, 95% CI 0.08 to 0.66, p=0.007), RECIST 1.1 (HR 0.23, 95% CI 0.14 to 0.4, p
Published: 2016
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14. COST-EFFECTIVENESS OF CETUXIMAB IN COMBINATION WITH IRINOTECAN COMPARED WITH CURRENT CARE IN METASTATIC COLORECTAL CANCER AFTER FAILURE ON IRINOTECAN – A BELGIAN ANALYSIS

Author: Harry Bleiberg, J.-L. Van Laethem, Lieven Annemans, E. Van Cutsem, and Yves Humblet
Subjects: Male, Oncology, medicine.medical_specialty, Cost effectiveness, Colorectal cancer, Cost-Benefit Analysis, medicine.medical_treatment, Cetuximab, Antineoplastic Agents, Antibodies, Monoclonal, Humanized, Irinotecan, Drug Costs, Metastasis, Belgium, Internal medicine, Humans, Medicine, Epidermal growth factor receptor, neoplasms, health care economics and organizations, Retrospective Studies, Chemotherapy, biology, business.industry, Antibodies, Monoclonal, Cancer, General Medicine, Middle Aged, medicine.disease, digestive system diseases, Surgery, Survival Rate, biology.protein, Camptothecin, Female, Colorectal Neoplasms, business, medicine.drug
Abstract: This analysis compared the cost-effectiveness in Belgium of cetuximab plus irinotecan with current current care in the treatment of epidermal growth factor receptor (EGFR)-expressing metastatic colorectal cancer (CRC) that has failed irinotecan-containing therapy. Treatment outcomes and medical resource use data for patients receiving cetuximab plus irinotecan from the BOND study were compared with those from a matched group of patients (current care) (n = 66). Two scenarios were considered in which cetuximab was discontinued either at 6 weeks or at 12 weeks if there was no tumour response at those time points. Cost-effectiveness was expressed in Euros as the additional cost per additional life year gained (LYG) (referred to as the incremental cost-effectiveness ratio (ICER)). For the 6-week rule, the ICERs were is an element of 17000 compared with current care. For the 12-week rule, the ICER was:is an element of 40000 /LYG. Sensitivity analyses revealed that, in the worst case, considering all assumptions against the cetuximab combination, the maximum ICER is:is an element of 30000 or is an element of 59000. In conclusion, cetuximab plus irinotecan for patients with metastatic CRC, after failure on irinotecan-containing chemotherapy, is rather cost-effective compared with current care in both scenarios tested.
Published: 2007
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15. Association of progression-free survival with patient-reported outcomes and survival: results from a randomised phase 3 trial of panitumumab

Author: Emilio Bajetta, D Comandini, R Amado, Salvatore Siena, T. Salek, M Woolley, G. Van Hazel, Pierfranco Conte, Yves Humblet, E. Van Cutsem, Marc Peeters, G Devercelli, Michael Wolf, György Bodoky, UCL - MD/MINT - Département de médecine interne, and UCL - (SLuc) Unité d'oncologie médicale
Subjects: Oncology, Cancer Research, medicine.medical_specialty, Colorectal cancer, Severity of Illness Index, Drug Administration Schedule, law.invention, disease progression, Quality of life, Randomized controlled trial, law, Internal medicine, Clinical Studies, Severity of illness, medicine, Humans, Panitumumab, Progression-free survival, Neoplasm Metastasis, improvement, Survival analysis, progression free survival, Colorectal Neoplasms - drug therapy, pathology, business.industry, Antibodies, Monoclonal - immunology, therapeutic use, Antibodies, Monoclonal, medicine.disease, symptom, Survival Analysis, Surgery, ErbB Receptors, patient reported outcome, Treatment Outcome, quality of life, patient-reported outcomes, panitumumab, Drug Resistance, Neoplasm, Disease Progression, Quality of Life, Self-Examination, Receptor, Epidermal Growth Factor, Colorectal Neoplasms, business, Progressive disease, medicine.drug
Abstract: In a randomised phase 3 trial, panitumumab significantly improved progression-free survival (PFS) in patients with refractory metastatic colorectal cancer (mCRC). This analysis characterises the association of PFS with CRC symptoms, health-related quality of life (HRQoL), and overall survival (OS). CRC symptoms (NCCN/FACT CRC symptom index, FCSI) and HRQoL (EQ-5D) were assessed for 207 panitumumab patients and 184 best supportive care (BSC) patients who had at least one post-baseline patient-reported outcome (PRO) assessment. Patients alive at week 8 were included in the PRO and OS analyses and categorised by their week 8 progression status as follows: no progressive disease (no PD; best response of at least stable disease) vs progressive disease (PD). Standard imputation methods were used to assign missing values. Significantly more patients were progression free at weeks 8–24 with panitumumab vs BSC. After excluding responders, a significant difference in PFS remained favouring panitumumab (HR=0.63, 95% CI=0.52–0.77; P
Published: 2007
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16. Phase II Trial of Cetuximab in Combination With Fluorouracil, Leucovorin, and Oxaliplatin in the First-Line Treatment of Metastatic Colorectal Cancer

Author: Josep Tabernero, Patrick Soulié, Yves Humblet, Eric Van Cutsem, Fortunato Ciardiello, Giampaolo Tortora, O. Kisker, Esther Casado, Jean-Luc Van Laethem, Aimery de Gramont, Javier Sastre Valera, Thierry André, Eduardo Díaz-Rubio, Chris Verslype, Andrés Cervantes, Tabernero, J, Van Cutsem, E, Díaz Rubio, E, Cervantes, A, Humblet, Y, André, T, Van Laethem, Jl, Soulié, P, Casado, E, Verslype, C, Sastre Valera, J, Tortora, Giampaolo, Ciardiello, F, Kisker, O, and de Gramont, A.
Subjects: Adult, Male, Cancer Research, medicine.medical_specialty, Organoplatinum Compounds, medicine.drug_class, Colorectal cancer, medicine.medical_treatment, Transplantation, Heterologous, Leucovorin, Phases of clinical research, Antibodies, Monoclonal, Humanized, Antimetabolite, Gastroenterology, Mice, Clinical trial, colon cancer, cetuximab, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Animals, Humans, Neoplasm Metastasis, Aged, Mice, Inbred BALB C, Chemotherapy, Cetuximab, business.industry, Antibodies, Monoclonal, Middle Aged, medicine.disease, digestive system diseases, Surgery, Oxaliplatin, Transplantation, Oncology, Fluorouracil, Patient Compliance, Female, Colorectal Neoplasms, business, Neoplasm Transplantation, medicine.drug
Abstract: Purpose This phase II study investigated the efficacy and safety of cetuximab combined with standard oxaliplatin-based chemotherapy (infusional fluorouracil, leucovorin, and oxaliplatin [FOLFOX-4]) in the first-line treatment of epidermal growth factor receptor–expressing metastatic colorectal cancer (mCRC). Patients and Methods The activity of cetuximab plus oxaliplatin was investigated in colon cancer cell lines and xenograft models. In the clinical study, patients with mCRC received on day 1 of a 14 day cycle, cetuximab (initial dose 400 mg/m2 during week 1, then 250 mg/m2 weekly) followed by FOLFOX-4 (oxaliplatin 85 mg/m2 on day 1; leucovorin 200 mg/m2 on days 1 and 2, followed by fluorouracil 400 mg/m2 bolus then 600 mg/m2 intravenous infusion during 22 hours on days 1 and 2). Results The preclinical studies confirmed the supra-additive activity of cetuximab to oxaliplatin. In the clinical study, 43 patients were included, with a median age of 65 years (range, 43 to 78 years). Response rates (RRs) were 79% (unconfirmed) and 72% (confirmed), with 95% disease control. Median progression-free survival (mPFS) and median duration of response were 12.3 and 10.8 months, respectively. Ten patients (23%) underwent resection with curative intent of previously unresectable metastases. After a median follow-up of 30.5 months, median overall survival (mOS) was 30.0 months. Cetuximab did not increase the characteristic toxicity of FOLFOX-4 and was generally well tolerated. Conclusion Cetuximab in combination with FOLFOX-4 is a highly active first-line treatment for mCRC, showing encouraging RR, mPFS, and mOS values. The treatment resulted in a high resectability rate, which could potentially result in an improved cure rate. This combination is under phase III development.
Published: 2007
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17. Phase I/II study of preoperative cetuximab, capecitabine, and external beam radiotherapy in patients with rectal cancer

Author: Yves Humblet, Joseph Kerger, Christine Sempoux, Stéphanie Laurent, Marc Peeters, Pierre Scalliet, C. Kirkove, Lionel Duck, Karin Haustermans, Alex Kartheuser, J-C. Coche, Blanche M. De Coster, J-P. Machiels, Ma Bonny, B. Honhon, E. Van Cutsem, J.F. Daisne, J-L Canon, Sarah Roels, and Selda Aydin
Subjects: Adult, Male, medicine.medical_specialty, Colorectal cancer, medicine.medical_treatment, Cetuximab, Antibodies, Monoclonal, Humanized, Deoxycytidine, Preoperative care, Gastroenterology, Capecitabine, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, External beam radiotherapy, Aged, Rectal Neoplasms, business.industry, Antibodies, Monoclonal, Hematology, Middle Aged, medicine.disease, Combined Modality Therapy, Surgery, Pulmonary embolism, Radiation therapy, Oncology, Fluorouracil, Female, Radiotherapy, Conformal, business, medicine.drug
Abstract: BACKGROUND: To assess the safety and preliminary efficacy of concurrent radiotherapy, capecitabine, and cetuximab in the preoperative treatment of patients with rectal cancer. PATIENTS AND METHODS: Forty patients with rectal cancer (T3-T4, and/or N+, endorectal ultrasound) received preoperative radiotherapy (1.8 Gy, 5 days/week for 5 weeks, total dose 45 Gy, three-dimensional conformal technique) in combination with cetuximab [initial dose 400 mg/m(2) intravenous given 1 week before the beginning of radiation followed by 250 mg/m(2)/week for 5 weeks] and capecitabine for the duration of radiotherapy (650 mg/m(2) orally twice daily, first dose level; 825 mg/m(2) twice daily, second dose level). RESULTS: Four and six patients were treated at the first and second dose level of capecitabine, respectively. No dose-limiting toxicity occurred. Thirty additional patients were treated with capecitabine at 825 mg/m(2) twice daily. The most frequent grade 1/2 side-effects were acneiform rash (87%), diarrhea (65%), and fatigue (57%). Grade 3 diarrhea was found in 15%. Three grade 4 toxic effects were recorded: one myocardial infarction, one pulmonary embolism, and one pulmonary infection with sepsis. Two patients (5%) had a pathological complete response. CONCLUSIONS: Preoperative radiotherapy in combination with capecitabine and cetuximab is feasible with some patients achieving pathological downstaging.
Published: 2007
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18. Analysis of circulating DNA and protein biomarkers to predict the clinical activity of regorafenib and assess prognosis in patients with metastatic colorectal cancer: a retrospective, exploratory analysis of the CORRECT trial

Author: Axel Grothey, Salvatore Siena, Eric Van Cutsem, Andrea Wagner, Takayuki Yoshino, D. Laurent, Laurent Mineur, Michael Jeffers, Richard M. Goldberg, Olivier Bouché, Marc Ychou, Alfredo Falcone, Antoine Adenis, Josep Tabernero, Alberto Sobrero, Yves Humblet, Heinz-Josef Lenz, Michael Teufel, Daniel J. Sargent, Carlo Barone, Vall d'Hebron University Hospital [Barcelona], University of Southern California (USC), Università degli Studi di Milano = University of Milan (UNIMI), Istituto di ricovero e cura a carattere scientifico Azienda Ospedaliera Universitaria 'San Martino' (IRCCS AOU San Martino), Azienda Ospedaliera Universitaria Pisana, Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut du Cancer de Montpellier (ICM), Université Catholique de Louvain = Catholic University of Louvain (UCL), Centre Hospitalier Universitaire de Reims (CHU Reims), Institut Sainte Catherine [Avignon], Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université de Lille-UNICANCER, Ohio State University [Columbus] (OSU), Mayo Clinic [Rochester], Bayer Pharma AG [Berlin], Bayer HealthCare Pharmaceuticals Inc [Whippany], University Hospitals Leuven [Leuven], Università degli Studi di Milano [Milano] (UNIMI), and Université Lille Nord de France (COMUE)-UNICANCER
Subjects: Male, Oncology, Time Factors, Pyridines, Colorectal cancer, DNA Mutational Analysis, Kaplan-Meier Estimate, medicine.disease_cause, Bioinformatics, Phosphatidylinositol 3-Kinases, chemistry.chemical_compound, 0302 clinical medicine, Medicine (all), Genotype, Precision Medicine, Randomized Controlled Trials as Topic, 0303 health sciences, DNA, Neoplasm, Receptor, TIE-1, Middle Aged, 3. Good health, Phenotype, Treatment Outcome, Real-time polymerase chain reaction, 030220 oncology & carcinogenesis, Disease Progression, Adenocarcinoma, Biomarker (medicine), Female, KRAS, Colorectal Neoplasms, Proto-Oncogene Proteins B-raf, medicine.medical_specialty, Class I Phosphatidylinositol 3-Kinases, Antineoplastic Agents, Real-Time Polymerase Chain Reaction, Article, Disease-Free Survival, Proto-Oncogene Proteins p21(ras), 03 medical and health sciences, Predictive Value of Tests, Proto-Oncogene Proteins, Internal medicine, Regorafenib, Biomarkers, Tumor, medicine, Humans, Genetic Predisposition to Disease, Aged, Proportional Hazards Models, Retrospective Studies, 030304 developmental biology, business.industry, Patient Selection, Phenylurea Compounds, medicine.disease, Clinical Trials, Phase III as Topic, chemistry, ras Proteins, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Summary Background Tumour mutational status is an important determinant of the response of metastatic colorectal cancer to targeted treatments. However, the genotype of the tissue obtained at the time of diagnosis might not accurately represent tumour genotype after multiple lines of treatment. This retrospective exploratory analysis investigated the clinical activity of regorafenib in biomarker subgroups of the CORRECT study population defined by tumour mutational status or plasma protein levels. Methods We used BEAMing technology to identify KRAS, PIK3CA , and BRAF mutations in DNA obtained from the plasma of 503 patients with metastatic colorectal cancer who enrolled in the CORRECT trial. We quantified total human genomic DNA isolated from plasma samples for 503 patients using a modified version of human long interspersed nuclear element-1 (LINE-1) quantitive real-time PCR. We also measured the concentration of 15 proteins of interest—angiopoietin 2, interleukin 6, interleukin 8, placental growth factor, soluble TIE-1, soluble VEGFR1, VEGF-A, VEGF-C, VEGF-D, VEGF-A isoform 121, bone morphogenetic protein 7, macrophage colony-stimulating factor, stromal cell-derived factor-1, tissue inhibitor of metalloproteinase 2, and von Willebrand factor—in plasma samples from 611 patients. We did correlative analyses of overall survival and progression-free survival in patient subgroups based on mutational status, circulating DNA concentration, and protein concentrations. The CORRECT trial was registered with ClinicalTrials.gov, number NCT01103323. Findings Tumour-associated mutations were readily detected with BEAMing of plasma DNA, with KRAS mutations identified in 349 (69%) of 503 patients, PIK3CA mutations in 84 (17%) of 503 patients, and BRAF mutations in 17 (3%) of 502 patients. We did not do correlative analysis based on BRAF genotype because of the low mutational frequency detected for this gene. Some of the most prevalent individual hot-spot mutations we identified included: KRAS ( KRAS G12D, 116 [28%] of 413 mutations; G12V, 72 [17%]; and G13D, 67 [16%]) and PIK3CA ( PIK3CA E542K, 27 [30%] of 89 mutations; E545K, 37 [42%]; and H1047R, 12 [14%]). 41 (48%) of 86 patients who had received anti-EGFR therapy and whose archival tumour tissue DNA was KRAS wild-type in BEAMing analysis were identified as having KRAS mutations in BEAMing analysis of fresh plasma DNA. Correlative analyses suggest a clinical benefit favouring regorafenib across patient subgroups defined by KRAS and PIK3CA mutational status (progression-free survival with regorafenib vs placebo: hazard ratio [HR] 0·52, 95% CI 0·35–0·76 for KRAS wild-type; HR 0·51, 95% CI 0·40–0·65 for KRAS mutant [ KRAS wild type vs mutant, p interaction =0·74]; HR 0·50, 95% CI 0·40–0·63 for PIK3CA wild-type; HR 0·54, 95% CI 0·32–0·89 for PIK3CA mutant [ PIK3CA wild-type vs mutant, p interaction =0·85]) or circulating DNA concentration (progression-free survival with regorafenib vs placebo: HR 0·53, 95% CI 0·40–0·71, for low circulating DNA concentrations; HR 0·52, 95% CI 0·40–0·70, for high circulating DNA concentrations; low vs high circulating DNA, p interaction =0·601). With the exception of von Willebrand factor, assessed with the median cutoff method, plasma protein concentrations were also not associated with regorafenib activity in terms of progression-free survival. In univariable analyses, the only plasma protein that was associated with overall survival was TIE-1, high concentrations of which were associated with longer overall survival compared with low TIE-1 concentrations. This association was not significant in multivariable analyses. Interpretation BEAMing of circulating DNA could be a viable approach for non-invasive analysis of tumour genotype in real time and for the identification of potentially clinically relevant mutations that are not detected in archival tissue. Additionally, the results show that regorafenib seems to be consistently associated with a clinical benefit in a range of patient subgroups based on mutational status and protein biomarker concentrations. Funding Bayer HealthCare Pharmaceuticals.
Published: 2015
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19. Cetuximab Monotherapy and Cetuximab plus Irinotecan in Irinotecan-Refractory Metastatic Colorectal Cancer

Author: Ian Chau, Andreas Harstrick, David Khayat, David Cunningham, Chris Verslype, M. Mueser, Salvatore Siena, Eric Van Cutsem, D. Bets, Harry Bleiberg, Armando Santoro, and Yves Humblet
Subjects: Oncology, medicine.medical_specialty, Cetuximab, business.industry, Colorectal cancer, Matuzumab, General Medicine, medicine.disease, digestive system diseases, Irinotecan, Regimen, Internal medicine, medicine, FOLFIRI, FOLFIRI Regimen, Panitumumab, business, neoplasms, medicine.drug
Abstract: background The epidermal growth factor receptor (EGFR), which participates in signaling pathways that are deregulated in cancer cells, commonly appears on colorectal-cancer cells. Cetuximab is a monoclonal antibody that specifically blocks the EGFR. We compared the efficacy of cetuximab in combination with irinotecan with that of cetuximab alone in metastatic colorectal cancer that was refractory to treatment with irinotecan. methods We randomly assigned 329 patients whose disease had progressed during or within three months after treatment with an irinotecan-based regimen to receive either cetuximab and irinotecan (at the same dose and schedule as in a prestudy regimen [218 patients]) or cetuximab monotherapy (111 patients). In cases of disease progression, the addition of irinotecan to cetuximab monotherapy was permitted. The patients were evaluated radiologically for tumor response and were also evaluated for the time to tumor progression, survival, and side effects of treatment. results The rate of response in the combination-therapy group was significantly higher than that in the monotherapy group (22.9 percent [95 percent confidence interval, 17.5 to 29.1 percent] vs. 10.8 percent [95 percent confidence interval, 5.7 to 18.1 percent], P=0.007). The median time to progression was significantly greater in the combination-therapy group (4.1 vs. 1.5 months, P
Published: 2004
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20. Panitumumab as a radiosensitizing agent in KRAS wild-type locally advanced rectal cancer

Author: Thierry Delaunoit, Karin Haustermans, Anne Jouret-Mourin, Javier Carrasco, Nicolas Meert, Anne Moxhon, Yves Humblet, Feby Ingriani Mardjuadi, Marc Van den Eynde, Jean-François Daisne, Jean-Charles Coche, Christine Sempoux, Pierre Scalliet, Jean-Charles Goeminne, Jean-Pascal Machiels, Jean-Luc Canon, Peter Vuylsteke, UCL - SSS/IREC/MIRO - Pôle d'imagerie moléculaire, radiothérapie et oncologie, UCL - SSS/IREC/GAEN - Pôle d'Hépato-gastro-entérologie, UCL - (SLuc) Service d'anatomie pathologique, UCL - (SLuc) Unité d'oncologie médicale, UCL - (SLuc) Service de radiothérapie oncologique, and UCL - (SLuc) Centre du cancer
Subjects: Neuroblastoma RAS viral oncogene homolog, Oncology, Male, Cancer Research, medicine.medical_specialty, Radiosensitizer, Radiation-Sensitizing Agents, Colorectal cancer, Enzyme-Linked Immunosorbent Assay, medicine.disease_cause, Ligands, Proto-Oncogene Proteins p21(ras), Internal medicine, Neoplasms, medicine, Clinical endpoint, Panitumumab, Humans, Pharmacology (medical), Aged, Radiotherapy, business.industry, Rectal Neoplasms, Antibodies, Monoclonal, Middle Aged, medicine.disease, ErbB Receptors, Gene Expression Regulation, Neoplastic, Regimen, Concomitant, Female, KRAS, business, medicine.drug
Abstract: Our goal was to optimize the radiosensitizing potential of anti-epidermal growth factor receptor (EGFR) monoclonal antibodies, when given concomitantly with preoperative radiotherapy in KRAS wild-type locally advanced rectal cancer (LARC). Based on pre-clinical studies conducted by our group, we designed a phase II trial in which panitumumab (6 mg/kg/q2 weeks) was combined with preoperative radiotherapy (45 Gy in 25 fractions) to treat cT3-4/N + KRAS wild-type LARC. The primary endpoint was complete pathologic response (pCR) (H0 = 5 %, H1 = 17 %, α = 0.05, β = 0.2). From 19 enrolled patients, 17 (89 %) were evaluable for pathology assessment. Although no pCR was observed, seven patients (41 %) had grade 3 Dworak pathological tumor regression. The regimen was safe and was associated with 95 % of sphincter-preservation rate. No NRAS, BRAF, or PI3KCA mutation was found in this study, but one patient (5 %) showed loss of PTEN expression. The quantification of plasma EGFR ligands during treatment showed significant upregulation of plasma TGF-α and EGF following panitumumab administration (p
Published: 2014

21. Mutational analysis of biomarker samples from the CORRECT study: Correlating mutation status with clinical response to regorafenib

Author: Richard M. Goldberg, Axel Grothey, Takayuki Yoshino, Salvatore Siena, Yves Humblet, Marc Ychou, Eric Van Cutsem, Michael Jeffers, Olivier Bouché, Antoine Adenis, Dirk Laurent, Andrea Wagner, Laurent Mineur, Heinz-Josef Lenz, Alfredo Falcone, Daniel J. Sargent, Carlo Barone, Alberto Sobrero, Josep Tabernero, and Frank Cihon
Subjects: Oncology, Cancer Research, medicine.medical_specialty, Mutation, business.industry, Colorectal cancer, Concordance, medicine.disease_cause, medicine.disease, Placebo, digestive system diseases, Mutational analysis, chemistry.chemical_compound, chemistry, Internal medicine, Regorafenib, medicine, Cancer research, Biomarker (medicine), KRAS, business, neoplasms
Abstract: 381 Background: In the CORRECT Ph3 trial, regorafenib demonstrated significant improvement in OS and PFS vs. placebo in subjects with metastatic colorectal cancer (mCRC) who had progressed on standard therapies. An exploratory biomarker substudy was conducted on samples collected from subjects enrolled in CORRECT. Methods: DNA was isolated from archival tumor tissue and fresh baseline plasma samples that were available from 239 (31%) and 503 (66%) subjects enrolled in CORRECT, respectively. Mutations in KRAS, PIK3CA and BRAF were evaluated via BEAMing technology. Results: Mutations were readily detected in DNA isolated from both tumor and plasma samples: KRAS: 59/69%; PIK3CA: 12/17% and BRAF: 1.5/3.4%. The frequency of KRAS mutation detected in tumor samples via BEAMing (59%) was identical to the frequency determined from pre-existing “historical” KRAS mutation data that was available from 96% of the subjects enrolled in the study. Concordance among the mutations detected via BEAMing in tumor vs. plasma was 76% (KRAS), 88% (PIK3CA), and 97% (BRAF). A subset of CRC which was found to be KRAS-wildtype in DNA from archival tumor, but KRAS-mutant in DNA from fresh plasma was identified and may represent subjects whose KRAS mutational status had changed during prior therapy. Correlative subgroup analyses demonstrated that regorafenib mediated a trend for clinical benefit vs. placebo in both KRAS wildtype and mutant subgroups identified by plasma BEAMing (OS: KRAS WT, HR: 0.67, 95% CI: 0.41–1.08; KRAS mutant, HR: 0.81, 95% CI: 0.61–1.09; interaction p=0.561). Similar results were noted for PIK3CA WT/mutant subgroups (OS: WT, HR: 0.75, 95% CI: 0.57–0.99; mutant, HR: 0.84, 95% CI: 0.47–1.50; interaction p=0.723). BRAF was not analysed due to the small number of BRAF-mutant samples. Conclusions: The mutational analysis of DNA isolated from fresh plasma is feasible and robust using the BEAMing platform and may better represent the mutational status of the tumor(s) that a mCRC patient harbors at the time of enrollment than does the mutational analysis of archival primary tumor tissue. Regorafenib was associated with clinical benefit (vs. placebo) in all mutational subgroups evaluated. Clinical trial information: NCT01103323.
Published: 2013

22. Massively parallel tumor multigene sequencing to evaluate response to panitumumab in a randomized phase III study of metastatic colorectal cancer

Author: Jean-Luc Van Laethem, Kelly S. Oliner, Jeffrey Wiezorek, Salvatore Siena, Marc Peeters, Eric Van Cutsem, Scott D. Patterson, Jing Huang, Yves Humblet, David Reese, Alexander N. Parker, Thierry André, UCL - SSS/IREC/MIRO - Pôle d'imagerie moléculaire, radiothérapie et oncologie, and UCL - (SLuc) Unité d'oncologie médicale
Subjects: Neuroblastoma RAS viral oncogene homolog, Oncology, Cancer Research, Mutation rate, medicine.medical_specialty, Colorectal cancer, Antineoplastic Agents, Bioinformatics, medicine.disease_cause, Mutation Rate, Internal medicine, medicine, Biomarkers, Tumor, Panitumumab, PTEN, Humans, Neoplasm Metastasis, neoplasms, Mutation, biology, business.industry, Antibodies, Monoclonal, High-Throughput Nucleotide Sequencing, medicine.disease, Prognosis, ErbB Receptors, Genes, ras, Treatment Outcome, Tumor Markers, Biological, biology.protein, KRAS, Receptor, Epidermal Growth Factor, Human medicine, Antibody, business, Colorectal Neoplasms, medicine.drug, Multilocus Sequence Typing
Abstract: Purpose: To investigate whether EGF receptor (EGFR) pathway mutations predicted response to monotherapy with panitumumab, an anti-EGFR monoclonal antibody, in a randomized phase III study of metastatic colorectal cancer. Experimental Design: Using massively parallel multigene sequencing, we analyzed 320 samples for 9 genes, with multigene sequence data from 288 (90%) samples. Results: Mutation rates were: KRAS (45%), NRAS (5%), BRAF (7%), PIK3CA (9%), PTEN (6%), TP53 (60%), EGFR (1%), AKT1 ( Conclusions: These results show the feasibility and potential clinical use of next-generation sequencing for evaluating predictive biomarkers. Clin Cancer Res; 19(7); 1902–12. ©2012 AACR.
Published: 2013

23. Characteristics of patients (pts) with metastatic colorectal cancer (mCRC) treated with regorafenib (REG) who had progression-free survival (PFS) >4 months (m): Subgroup analysis of the phase 3 CORRECT trial

Author: L. Huang, J. Tabernero, H-J. Lenz, Takayuki Yoshino, Richard M. Goldberg, O. Bouche, Yves Humblet, L. Mineur, Andrea Wagner, A. Falcone, A. Grothey, E. Van Cutsem, and Antoine Adenis
Subjects: 0301 basic medicine, Oncology, medicine.medical_specialty, Colorectal cancer, business.industry, Subgroup analysis, Hematology, medicine.disease, 03 medical and health sciences, chemistry.chemical_compound, 030104 developmental biology, 0302 clinical medicine, chemistry, 030220 oncology & carcinogenesis, Regorafenib, Internal medicine, medicine, Progression-free survival, business
Published: 2016
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24. Efficacy and circulating tumor DNA (ctDNA) analysis of the BRAF inhibitor dabrafenib (D), MEK inhibitor trametinib (T), and anti-EGFR antibody panitumumab (P) in patients (pts) with BRAF V600E–mutated (BRAFm) metastatic colorectal cancer (mCRC)

Author: Rona Yaeger, Elena Elez, Gary Middleton, Autumn J. McRee, Salvatore Siena, E. Van Cutsem, Chloe E. Atreya, Johanna C. Bendell, Savina Jaeger, Michael S. Gordon, K. Muro, J.H.M. Schellens, Michel Ducreux, Takayuki Yoshino, T. Andre, Fatima Rangwala, Ryan B. Corcoran, Yves Humblet, Roger Sidhu, and Matthew Squires
Subjects: 0301 basic medicine, Trametinib, Oncology, medicine.medical_specialty, BRAF inhibitor, Colorectal cancer, business.industry, MEK inhibitor, Dabrafenib, Hematology, medicine.disease, BRAF V600E, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, 030220 oncology & carcinogenesis, Internal medicine, medicine, Cancer research, Panitumumab, In patient, business, medicine.drug
Published: 2016
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25. Preoperative staging with magnetic resonance imaging (MRI) and endorectal ultra-sonography (ERUS) for locally advanced rectal cancer (LARC) after chemoradiotherapy (CRT): Accuracy with histopathologic findings

Author: Etienne Danse, Christophe Remue, Marc Van den Eynde, Marie-Armelle Denis, Daniel Léonard, Aline Van Maanen, Alex Kartheuser, Pierre Scalliet, Cristina Dragean, Pamela Baldin, Yves Humblet, Anne Jouret-Mourin, and Nathalie Kouinche
Subjects: Cancer Research, medicine.medical_specialty, medicine.diagnostic_test, Colorectal cancer, business.industry, Locally advanced, Magnetic resonance imaging, medicine.disease, Total mesorectal excision, 03 medical and health sciences, 0302 clinical medicine, Preoperative staging, Oncology, 030220 oncology & carcinogenesis, Ultra sonography, medicine, 030211 gastroenterology & hepatology, Radiology, business, Chemoradiotherapy
Abstract: 3618Background: Pre-operative CRT followed by total mesorectal excision (TME) is nowadays the standard for LARC (cT3-T4N0 or cTxN+). TME could be avoided for patients with pathologic complete respo...
Published: 2016
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26. Successful long-term management of a patient with late-stage metastatic colorectal cancer treated with panitumumab

Author: Christine Sempoux, Emmanuel Coche, Liliane Marot, Emmanuel Seront, Yves Humblet, and Jean-Luc Gala
Subjects: Adult, Diarrhea, Male, medicine.medical_specialty, Colorectal cancer, Leucovorin, Antineoplastic Agents, Adenocarcinoma, medicine.disease_cause, Gastroenterology, Carcinoembryonic antigen, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Panitumumab, Humans, Radiology, Nuclear Medicine and imaging, Neoplasm Staging, Folliculitis, Clinical Trials as Topic, Cetuximab, biology, business.industry, Cancer, Antibodies, Monoclonal, General Medicine, Exanthema, Middle Aged, medicine.disease, Surgery, Irinotecan, Oncology, Lymphatic Metastasis, FOLFIRI, biology.protein, Camptothecin, KRAS, Fluorouracil, Neoplasm Recurrence, Local, business, Colorectal Neoplasms, Tomography, X-Ray Computed, medicine.drug
Abstract: Introduction: Recent approval and introduction into clinical practice of epidermal growth factor receptor inhibitors such as the chimeric monoclonal antibody cetuximab and the fully human monoclonal antibody panitumumab have provided new treatment options for chemotherapy-refractory patients. Here, we report a case of a 47-year-old man with metastatic, chemotherapy-refractory colorectal cancer who achieved long-term partial remission during panitumumab therapy. Case presentation: A 41-year-old male patient presented with a 24-hour history of abdominal pain and fever. A computed tomography (CT) scan revealed a voluminous and perforated abscess with a suspected tumour lesion in the sigmoid colon. The patient underwent sigmoidectomy and was diagnosed with a poorly differentiated necrotic carcinoma of the sigmoid colon with invasion in 13 of 19 tested lymph nodes. A colonoscopy revealed multiple tubular adenomas and a positron emission tomography CT scan showed multiple and bilateral hyperfixating lumbar-aortic lymph nodes leading to a final tumour classification of T4 N2 M1. Carcinoembryonic antigen (CEA) was elevated. The patient achieved a partial response following six cycles of FOLFIRI (irinotecan, 5-fluorouracil, leucovorin), then progressed and was enrolled in a trial where he received treatment with FOLFOX4 (oxaliplatin, leucovorin and 5-fluorouracil) with or without a vascular endothelial growth factor inhibitor (PTK787/ZK 222584 [valatinib]). Eight months later he progressed again and was included in a panitumumab (6 mg/kg every 2 weeks) monotherapy trial. A partial response was noted after 8 weeks of therapy along with a rapid CEA reduction and decrease in lymph node size. The patient is continuing panitumumab treatment and is still in partial remission after 65 months' treatment. He has non-mutated KRAS and no human-anti-human antibodies have been detected. During treatment the patient has on occasion experienced grade 1-2 diarrhoea as well as folliculitis and acne-like rash up to grade 3 in severity. Cutaneous toxicity was managed with a combination dose interruption/reduction and the use of topical agents. No eye or nail toxicities occurred. Conclusion: This case shows that long-term responses are possible during panitumumab therapy and that this agent may be an effective long-term treatment option for selected patients with metastatic colorectal cancer. The associated skin toxicities can be successfully managed. (C) 2010 Elsevier Ltd. All rights reserved.
Published: 2010

27. Clinical usefulness of EGFR gene copy number as a predictive marker in colorectal cancer patients treated with cetuximab: a fluorescent in situ hybridization study

Author: Steffen Fieuws, Jean-Luc Van Laethem, Eric Van Cutsem, Maria Debiec-Rychter, Wendy De Roock, Sabine Tejpar, Yves Humblet, Hubert Piessevaux, Marc Peeters, Gert De Hertogh, Nicola Personeni, An Capoen, Jef De Schutter, Bart Biesmans, UCL - MD/MINT - Département de médecine interne, UCL - (SLuc) Unité d'oncologie médicale, and UCL - (SLuc) Service de gastro-entérologie
Subjects: Oncology, Adult, Genetic Markers, Male, Cancer Research, medicine.medical_specialty, Colorectal cancer, Gene Dosage, Cetuximab, medicine.disease_cause, Antibodies, Monoclonal, Humanized, Gene dosage, Disease-Free Survival, Internal medicine, medicine, Humans, Epidermal growth factor receptor, In Situ Hybridization, Fluorescence, Aged, Aged, 80 and over, Predictive marker, medicine.diagnostic_test, biology, business.industry, Cancer, Antibodies, Monoclonal, Genes, erbB-1, Middle Aged, medicine.disease, Prognosis, Immunology, biology.protein, Female, KRAS, business, Colorectal Neoplasms, Fluorescence in situ hybridization, medicine.drug
Abstract: Purpose: To evaluate the usefulness and the pitfalls inherent to the assessment of the epidermal growth factor receptor (EGFR) gene copy number (GCN) by fluorescence in situ hybridization (FISH) for outcome prediction to cetuximab in metastatic colorectal cancer. The value of testing KRAS mutation status, in addition to EGFR GCN, was also explored. Experimental Design: FISH analysis of 87 metastatic colorectal cancer patients treated with cetuximab was done, recording individual GCN per cell and using different samples per tumor. Performances of published cutoff points and different summaries of EGFR GCN distribution were assessed for response prediction. Results: In our data set, two published cutoff points performed less well than in their training set, yielding positive predictive values and negative predictive values between 40.0% and 48.3% and between 81.0% and 86.5%, respectively. Among summaries of GCN distribution explored, mean and right-tailed distribution of GCN yielded the highest performances. A mean EGFR GCN ≥2.83 provided an area under the curve of 0.71. Important heterogeneity of repeated measures of mean EGFR GCN was observed within tumors (intraclass correlation, 0.61; within-class SD, 0.40), leading to potential misclassifications of FISH status in 7 of 18 (38.8%) patients if a cutoff point were used. In multivariable analysis, EGFR GCN testing provided significant information independent of the KRAS status to predict response (P = 0.016) and overall survival (P = 0.005). Conclusions: We confirm the association between increased EGFR GCN and outcome after cetuximab. However, because of reproducibility concerns, any decision making based on published cutoff points is not warranted.
Published: 2008

28. KRAS wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximab

Author: Marc Peeters, J. De Schutter, Sabine Tejpar, Nicola Personeni, G. De Hertogh, Hubert Piessevaux, J.-L. Van Laethem, E. Van Cutsem, Bart Biesmans, M. Janssens, W. De Roock, and Yves Humblet
Subjects: Oncology, Male, Pathology, Colorectal cancer, Cetuximab, medicine.disease_cause, growth-factor receptor, Metastasis, antibody, cetuximab, Antineoplastic Combined Chemotherapy Protocols, irinotecan, Antibodies, Monoclonal, Hematology, Middle Aged, KRAS Mutation Analysis, Survival Rate, Female, KRAS, Colorectal Neoplasms, medicine.drug, medicine.medical_specialty, colorectal cancer, Antineoplastic Agents, Antibodies, Monoclonal, Humanized, Irinotecan, survival, Sensitivity and Specificity, Disease-Free Survival, Proto-Oncogene Proteins p21(ras), Internal medicine, Proto-Oncogene Proteins, expression, medicine, Humans, neoplasms, Proportional Hazards Models, Retrospective Studies, business.industry, Proportional hazards model, k-ras mutation, kras, Cancer, medicine.disease, digestive system diseases, Logistic Models, egfr, Mutation, ras Proteins, Camptothecin, business, Tomography, X-Ray Computed, phase-ii
Abstract: Background: KRAS mutation status is a candidate marker for predicting survival in patients with metastatic colorectal cancer (mCRC) treated with cetuximab (CTX). Patients and methods: We studied the KRAS mutation status of 113 patients with irinotecan refractory mCRC treated with CTX in clinical trials. A predictive model for objective response (OR), progression-free survival (PFS) and overall survival (OS) was constructed using logistic and Cox regression. Results: OR was seen in 27 of 66 KRAS wild-type (WT) patients versus 0 of 42 in KRAS mutants. Median OS was significantly better in KRAS WT versus mutants (43.0 versus 27.3 weeks; P = 0.020). Decrease in tumor sizes was significantly larger at all time points in WT patients. KRAS WT patients with an initial relative decrease of tumor size > 9.66% at week 6 had a significantly better median OS compared with all other patients (74.9 versus 30.6 weeks; P = 0.0000025). Within KRAS WT patients OS was significantly better in patients with an initial decrease compared with those without [median OS: 74.9 versus 30.6 weeks (P = 0.00000012)]. Conclusions: KRAS WT status is associated to survival benefit in CTX treated mCRC. This benefit is even more pronounced in those patients with early radiological response. These characteristics may be exploited for response prediction.
Published: 2007

29. An open-label, single-arm study assessing safety and efficacy of panitumumab in patients with metastatic colorectal cancer refractory to standard chemotherapy

Author: Yves Humblet, Salvatore Siena, Bart Neyns, Juan Maurel, R Amado, D Kotasek, N Hogan, Emilio Bajetta, S Spadafora, Marc Peeters, E. Van Cutsem, Werner Scheithauer, J-L Canon, and Armando Santoro
Subjects: Oncology, Adult, Male, medicine.medical_specialty, Colorectal cancer, Phases of clinical research, Adenocarcinoma, Disease-Free Survival, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Clinical endpoint, Panitumumab, Humans, Adverse effect, Survival analysis, Aged, Aged, 80 and over, Salvage Therapy, business.industry, Cancer, Antibodies, Monoclonal, Hematology, Middle Aged, medicine.disease, Chemotherapy regimen, Survival Analysis, Surgery, Neoplasm Proteins, ErbB Receptors, Drug Resistance, Neoplasm, Disease Progression, Female, Drug Eruptions, Immunotherapy, business, Colorectal Neoplasms, medicine.drug
Abstract: Background: A phase 3 study demonstrated that panitumumab, a human monoclonal anti-epidermal growth factor receptor antibody, significantly prolonged progression-free survival versus best supportive care (BSC) in patients with chemorefractory metastatic colorectal cancer. Patients and methods: This open-label extension study evaluated panitumumab monotherapy in BSC patients with radiographically documented disease progression in the phase 3 study. Patients received panitumurnab 6 mg/kg every 2 weeks. The primary end point was safety; efficacy was also evaluated. Results: One hundred and seventy-six patients were randomly assigned to the BSC arm of the phase 3 study received >= 1 panitumumab dose in this extension study. Panitumumab was well tolerated. The most frequent treatment-related adverse events were skin toxic effects. Three (2%) patients had a grade 4 treatment-related adverse event. There were no infusion reactions. One (0.6%) patient had a complete response; 19 (11%) patients had a partial response; and 58 (33%) patients had stable disease. Median progression-free survival time was 9.4 [95% confidence interval (Cl): 8.0-13.4) weeks. Median overall survival time was 6.3 (95% Cl: 5.1-6.8) months. Anti-panitumumab antibodies were detected in 3 (4.2%) of 71 patients with a post-baseline sample. Conclusions: These findings are comparable to those from the phase 3 study and support panitumumab monotherapy for chemorefractory colorectal cancer.
Published: 2007

30. Cavitation of lung metastases induced by regorafenib is associated with radiological response in metastatic colorectal cancer: data from the phase III correct study

Author: A. Grothey, D. Redaelli, Federica Tosi, Alberto Sobrero, O. Bouche, Antoine Adenis, L. Mineur, M. Maiolani, Silvia Ghezzi, D. Galbiati, A. Verrioli, Lisa Pietrogiovanna, Riccardo Ricotta, Chiara Cremolini, Yves Humblet, Luca Porcu, Guillem Argiles, C. Barone, and Marc Ychou
Subjects: Oncology, medicine.medical_specialty, Lung, Colorectal cancer, business.industry, Hematology, medicine.disease, chemistry.chemical_compound, medicine.anatomical_structure, chemistry, Regorafenib, Internal medicine, Radiological weapon, medicine, business
Published: 2015
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31. Subgroup analysis of patients with metastatic colorectal cancer (mCRC) treated with regorafenib (REG) in the CORRECT trial who had progression-free survival (PFS) longer than 4 months

Author: H. J. Lenz, E. Van Cutsem, Alfredo Falcone, Richard M. Goldberg, Antoine Adenis, L. Mineur, S. Siena, Marc Ychou, Takayuki Yoshino, Carlo Barone, O. Bouche, Andrea Wagner, Lei Xu, Alberto Sobrero, J. Tabernero, A. Grothey, and Yves Humblet
Subjects: Oncology, medicine.medical_specialty, business.industry, Colorectal cancer, Hematology, medicine.disease, chemistry.chemical_compound, chemistry, Internal medicine, Regorafenib, medicine, Progression-free survival, business
Published: 2015
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32. 2015 Cavitation of lung metastases induced by regorafenib in patients with colorectal carcinoma: Data from the phase III CORRECT study

Author: Antonella Verrioli, Riccardo Ricotta, C. Cremolini, Alessio Amatu, S. Siena, Yves Humblet, Andrea Sartore-Bianchi, M. Ychou, Angelo Vanzulli, Luca Porcu, Silvia Ghezzi, O. Bouchet, Guillem Argiles, C. Barone, Monika Peeters, A. Grothey, Alberto Sobrero, Antoine Adenis, L. Mineur, and E. Van Cutsem
Subjects: Oncology, Cancer Research, medicine.medical_specialty, Lung, Colorectal cancer, business.industry, medicine.disease, chemistry.chemical_compound, medicine.anatomical_structure, chemistry, Internal medicine, Regorafenib, medicine, In patient, business
Published: 2015
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33. 2154 Metastatic colorectal cancer has heterogeneous immune microenvironment and mutational expression

Author: M. Van den Evnde, Christine Sempoux, Gabriela Bindea, Lucie Lafontaine, Christophe Remue, Florence Marliot, Yves Humblet, Nacilla Haicheur, Jérôme Galon, Catherine Hubert, Alex Kartheuser, Daniel Léonard, J-P. Machiels, Daphné Debetancourt, Jean-François Gigot, Tessa Fredriksen, Javier Carrasco, Anne Jouret-Mourin, Bernhard Mlecnik, and Franck Pages
Subjects: Oncology, Cancer Research, medicine.medical_specialty, Expression (architecture), Colorectal cancer, business.industry, Immune microenvironment, Internal medicine, medicine, medicine.disease, business
Published: 2015
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34. Phase III trial comparing 4-day chronomodulated therapy versus 2-day conventional delivery of fluorouracil, leucovorin, and oxaliplatin as first-line chemotherapy of metastatic colorectal cancer: the European Organisation for Research and Treatment of Cancer Chronotherapy Group

Author: Jean-Luc Canon, Antoine Adenis, Marco Tampellini, Francis Lévi, Giovanni Lo Re, Yves Humblet, Thierry Gorlia, Marie Ange Lentz, Georg A. Bjarnason, Carlo Garufi, Rune Smaaland, Sylvie Giacchetti, Dominique Genet, Christian Focan, Bruno Coudert, Nicole Anciaux, Carlos Carvalho, Johannes Schueller, Benoit Baron, and Stefano Iacobelli
Subjects: Adult, Male, Oncology, Cancer Research, medicine.medical_specialty, Organoplatinum Compounds, Colorectal cancer, medicine.medical_treatment, Leucovorin, Disease-Free Survival, Metastasis, Predictive Value of Tests, Risk Factors, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, Biomarkers, Tumor, medicine, Humans, Aged, Neoplasm Staging, Proportional Hazards Models, Chronotherapy, business.industry, Cancer, Middle Aged, Prognosis, medicine.disease, Survival Analysis, Chronotherapy (treatment scheduling), Surgery, Oxaliplatin, Europe, Drug Chronotherapy, Treatment Outcome, Tolerability, Fluorouracil, Female, Colorectal Neoplasms, business, Follow-Up Studies, medicine.drug
Abstract: Purpose In two previous randomized trials, the adjustment of chemotherapy delivery to circadian rhythms improved tolerability and anticancer activity compared with constant-rate infusion during 5 days in patients with metastatic colorectal cancer. Patients and Methods For this multicenter randomized trial, it was hypothesized that a chronomodulated infusion of fluorouracil, leucovorin, and oxaliplatin for 4 days (chronoFLO4) would improve survival by 10% compared with conventional 2-day delivery of the same drugs (FOLFOX2). Patients were treated every 2 weeks with intrapatient dose escalation. Results Baseline characteristics were similar in both arms for the 564 patients (36 institutions, 10 countries). Median survival was 19.6 months (95% confidence limit [CL] = 18.2, 21.2) with chronoFLO4 and 18.7 months with FOLFOX2 (95% CL = 17.7, 21.0; P = .55). The main dose-limiting toxicities were diarrhea for chronoFLO4 and neutropenia for FOLFOX2. The analysis of survival predictors showed that sex was the single most important factor (P = .001). In women, the risk of an earlier death with chronoFLO4 was increased by 38% compared with FOLFOX2, with median survival times of 16.3 and 19.1 months (P = .03), respectively. In men, the risk of death was decreased by 25% with chronoFLO4 compared with FOLFOX2, with median survival times of 21.4 and 18.3 months (P = .02), respectively. Conclusion Both regimens achieved similar median survival times more than 18 months with an acceptable toxicity. The chronomodulated schedule produced a survival advantage over FOLFOX in men. The strong sex dependency of optimal scheduling of fluorouracil, leucovorin, and oxaliplatin calls for translational investigations of determinants related to the patient's molecular clock.
Published: 2006

35. Evaluation of KRAS, NRAS, and BRAF Mutations in Prime: Panitumumab with FOLFOX4 as First-Line Treatment in Metastatic Colorectal Cancer (MCRC)

Author: Mario Edmundo Barugel, Fernando Rivera, Richard Thomas Williams, Salvatore Siena, Scott D. Patterson, Josep Tabernero, Yves Humblet, Ilona Kocáková, David Cunningham, Jean-Yves Douillard, Jeffrey Wiezorek, Kelly S. Oliner, Paul Ruff, Jacek Jassem, György Bodoky, Martin Šmakal, Ronald Burkes, Maria Blasinska Morawiec, Roger Sidhu, and Alan Rong
Subjects: Neuroblastoma RAS viral oncogene homolog, Oncology, medicine.medical_specialty, Colorectal cancer, business.industry, Hematology, medicine.disease, medicine.disease_cause, Prime (order theory), First line treatment, Internal medicine, Cancer research, medicine, Panitumumab, KRAS, business, medicine.drug
Published: 2013
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36. Phase III double-blind placebo-controlled study of farnesyl transferase inhibitor R115777 in patients with refractory advanced colorectal cancer

Author: Thierry André, Y.C. Park, Yves Humblet, Sheela Rao, G. Kourteva, Werner Scheithauer, A. de Gramont, P.A. Palmer, Martin Šmakal, Timothy Iveson, R. Belly, J. Dostalova, David Cunningham, Juan Jose Perez-Ruixo, and Árpád Illés
Subjects: Adult, Male, Cancer Research, medicine.medical_specialty, Colorectal cancer, medicine.medical_treatment, Placebo-controlled study, Antineoplastic Agents, Quinolones, Placebo, Gastroenterology, Placebos, Refractory, Double-Blind Method, Internal medicine, Clinical endpoint, Medicine, Farnesyltranstransferase, Humans, Progression-free survival, Survival rate, Aged, Chemotherapy, Alkyl and Aryl Transferases, business.industry, Middle Aged, medicine.disease, Survival Rate, Oncology, Female, business, Colorectal Neoplasms
Abstract: Purpose To determine whether R115777 improves survival in patients with refractory advanced colorectal cancer (CRC) in a multicenter, double-blind, prospective randomized study. Patients and Methods Three hundred sixty-eight patients were randomly assigned to R115777 (300 mg twice daily) orally for 21 days every 28 days or placebo in a 2:1 ratio. All patients received best supportive care. The primary end point was overall survival; secondary end points were progression free survival, tumor response, toxicity, and quality of life. Results The two treatment groups were well balanced for baseline demographics, including previous chemotherapy for advanced CRC. The median overall survival for R115777 was 174 days (95% CI, 157 to 198 days), and 185 days (95% CI, 158 to 238 days) for those patients receiving placebo (P = .376). One patient achieved a partial response in the R115777 arm. Stable disease (> 3 months) was observed in 24.3% patients in the R115777 group compared to 12.8% in the placebo arm. This did not translate into a statistically significant increase in progression-free survival. Overall, treatment was well tolerated. There was an increased incidence of reversible myelosuppression (neutropenia, thrombocytopenia), rash, and grade 1 to 2 diarrhea in the R115777 arm. There was no statistically significant difference in quality of life between arms. Conclusion Single agent R115777 , given at this dose and schedule, has an acceptable toxicity profile, but does not improve overall survival compared to best supportive care alone in refractory advanced CRC.
Published: 2004

37. Cetuximab: an IgG(1) monoclonal antibody for the treatment of epidermal growth factor receptor-expressing tumours

Author: Yves Humblet
Subjects: Oncology, Male, medicine.medical_specialty, Lung Neoplasms, medicine.drug_class, Colorectal cancer, Cetuximab, Gene Expression, Monoclonal antibody, Antibodies, Monoclonal, Humanized, Irinotecan, Drug Administration Schedule, Mice, Internal medicine, Carcinoma, Non-Small-Cell Lung, Antineoplastic Combined Chemotherapy Protocols, medicine, Carcinoma, Animals, Humans, Pharmacology (medical), Epidermal growth factor receptor, neoplasms, Pharmacology, biology, business.industry, Antibodies, Monoclonal, General Medicine, Genes, erbB-1, medicine.disease, digestive system diseases, ErbB Receptors, Head and Neck Neoplasms, Immunoglobulin G, Monoclonal, biology.protein, Camptothecin, Female, Antibody, Drug Screening Assays, Antitumor, business, Colorectal Neoplasms, medicine.drug
Abstract: The epidermal growth factor receptor (EGFR) plays an essential role in normal cell growth and differentiation and in the survival of healthy and cancerous cells. EGFR expression is a common feature of non-haematological malignancies and is associated with poor clinical prognosis. Cetuximab is an IgG(1) monoclonal antibody that blocks EGFR activation. It has efficacy alone, and in combination with irinotecan, in the treatment of metastatic colorectal cancer that has progressed on irinotecan-containing therapy. It has been approved for use in combination with irinotecan in both Switzerland and the US and as monotherapy in the US. Cetuximab also has efficacy in cancers of the head and neck and non-small cell lung cancer. Cetuximab is well-tolerated and does not exacerbate the side effects of co-administered cytotoxic chemotherapy.
Published: 2004

38. O-0023 Phase 3 Correct Trial of Regorafenib in Metastatic Colorectal Cancer (mCRC)

Author: Salvatore Siena, Eric Van Cutsem, Alberto Sobrero, D. Laurent, Axel Grothey, Heinz Joseph Lenz, Yves Humblet, Richard M. Goldberg, Marc Ychou, Josep Tabernero, Daniel J. Sargent, Frank Cihon, Alfredo Falcone, Carlo Barone, Michael Jeffers, Takayuki Yoshino, Andrea Wagner, Laurent Mineur, Olivier Bouché, and Antoine Adenis
Subjects: Oncology, medicine.medical_specialty, business.industry, Colorectal cancer, Proportional hazards model, Hazard ratio, Hematology, medicine.disease, Placebo, medicine.disease_cause, Interim analysis, chemistry.chemical_compound, chemistry, Internal medicine, Regorafenib, Clinical endpoint, Medicine, KRAS, business
Abstract: Introduction Regorafenib (REG) is an oral multi-kinase inhibitor. The CORRECT trial was conducted to evaluate REG in patients (pts) with mCRC who had progressed after all approved standard therapies. Methods Enrollment criteria included documented mCRC and progression during or ≤3 months after last standard therapy. Pts were randomized 2:1 to receive best supportive care plus either REG (160 mg od po, 3 wks on/1 wk off) or placebo (PL). The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), overall response rate, disease control rate, safety and quality of life (QoL). Efficacy analyses across prespecified subgroups were evaluated using univariate Cox regression. Mutations in KRAS, BRAF and PIK3CA genes were determined both from plasma DNA and from available biopsy samples using BEAMing technology. Historical KRAS status was collected from patient record. Results 760 pts were randomized (REG: 505; PL: 255). The OS primary endpoint was met at a preplanned interim analysis. OS and PFS were significantly improved in REG arm compared to PL arm. Hazard ratio (HR) for OS was 0.77 (95% CI 0.64-0.94, 1-sided p = 0.0052); median OS 6.4 vs 5.0 mos. HR for PFS was 0.49 (95% CI 0.42-0.58, 1-sided p Conclusion REG demonstrated statistically significant improvement in OS and PFS over PL, as well as comparable efficacy benefits across pt subgroups analyzed. Table 1 .
Published: 2012
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39. Randomized phase II studies comparing pathological responses observed on colorectal cancer metastases resected after preoperative treatment combining bevacizumab or cetuximab with FOLFOX or FOLFIRI

Author: Jean-Luc Re Canon, Jean-Charles Goeminne, Javier Carrasco, Lionel D'Hondt, Christine Sempoux, Thierry Delaunoit, Anne Jouret-Mourin, Jean-Pascal Machiels, Géraldine Pairet, Daniel Van Daele, Gauthier Demolin, Marie-Laure Castella, Gabriella Beniuga, Jean-Charles Coche, Ghislain Houbiers, Aline Van Maanen, Yves Humblet, and Marc Van den Eynde
Subjects: Oncology, Cancer Research, medicine.medical_specialty, Cetuximab, Bevacizumab, Colorectal cancer, business.industry, medicine.disease, digestive system diseases, Oxaliplatin, Irinotecan, FOLFOX, Internal medicine, medicine, FOLFIRI, business, medicine.drug, EGFR inhibitors
Abstract: TPS795 Background: Even if the use of targeted therapies combined with chemotherapy has demonstrated increase response rate and survival benefit in non resectable metastatic colorectal cancer (mCRC), the administration of these combinations in frontline resectable disease is source of debate and optimal association is still unclear. Based on a retrospective analysis, we previously reported thatthe chemotherapy partner combined with VEGF or EGFR inhibitors influenced pathological responses (pR) on the resected colorectal cancer metastases (CRCM) with a significant advantage for oxaliplatin with anti-VEGF or irinotecan with anti-EGFR combinations. We aimed to design 2 parallel studies (BEV-ONCO, CET-ONCO) to prospectively precise optimal combination between oxaliplatin and irinotecan with bevacizumab or cetuximab before CRCM resection. Methods: The 2 studies are open label randomized multi-centric trials and concern mCRC patients with resectable disease in whom a preoperative treatment is considered. The primary objective is to assess the CRCM pR rate according the Tumor Regression Grade classification (Rubbia-Brandt) after allocated preoperative treatment (bevacizumab combined with FOLFOX vs. FOLFIRI without consideration of RAS/BRAF for BEV-ONCO trial (EUDRACT 2012-005376-34) and cetuximab associated with FOLFOX or FOLFIRI only for RAS/BRAF wild type tumor for CET-ONCO trial (EUDRACT 2012-005249-19)). According investigator’s choice, patient will received 3 to 6 treatment cycles before CRCM resection. Patient’s survival, safety, surgical complications and treatment associated liver-toxicity are secondary end-points. Up to 60 patients (30 per treatment group) will be randomised in each study (power: 80%, type I error of 5% to detect a difference in proportion of pR rate between FOLFOX or FOLFIRI association of 0.40). Formal comparison will not be done across studies. Translational research projects are ongoing (CRCM immune response, tumour specific genetic rearrangements as new specific biomarkers). Clinical trial information: NCT01858649 (BEV-ONCO); NCT01858662 (CET-ONCO). Clinical trial information: NCT01858649 (BEVONCO) NCT01858662 (CETONCO).
Published: 2015
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40. B Cells (Cd20+) Associated to Tumor Infiltrating Cytotoxic T-Cells Observed on Resected Liver Colorectal Metastases (Lcm) are Prognostic

Author: J-P. Machiels, Catherine Hubert, Daphné Debetancourt, Nacilla Haicheur, Yves Humblet, Jérôme Galon, M. Van den Eynde, F. Marliot, Franck Pages, Christine Sempoux, Jean-François Gigot, Bernhard Mlecnik, and Anne Jouret-Mourin
Subjects: Oncology, CD20, medicine.medical_specialty, biology, Colorectal cancer, business.industry, Hazard ratio, Hematology, medicine.disease, Primary tumor, Metastasis, Internal medicine, medicine, biology.protein, Cytotoxic T cell, Immunohistochemistry, business, CD8
Abstract: Aim: Colorectal cancer infiltrating cytotoxic T-cells (CD8+ cells) are a strong prognostic factor for survival after primary tumor and metastases resection. The impact of B cells for prognosis is less characterized. Methods: Metastatic colorectal patients (pts) engaged for curative liver surgery with available FFPE blocks for all resected LCM, were included. The density of CD8+ and CD20+ cells in the metastasis (CT) and the invasive margin (IM) for all LCM was determined by whole-slide immunohistochemistry and quantified with dedicated image analysis software. The mean value of the 3 most infiltrated areas (0.8 mm2) was calculated. The densities of CD8 and CD20 (CT and IM regions) were classified into Hi or Lo according to cut-off values (minimal p-value approach). The total number of Hi densities was calculated to determine the immunoscore (IS) 0-2 Hi (low IS) or 3-4 Hi (high IS). For pts with multiple LCM, all LCM were quantified. The mean value of all densities, the least and the most infiltrated LCM/pt were analyzed. Cumulative DFS/OS analyses were performed using the Kaplan-Meier estimator. The hazard ratio (HR) for OS/DFS comparing (IS0-2 vs 3-4) was determined using univariate Cox regression and the significance by log-rank tests. Results: 294 LCM from 88 patients (M/F 1.1, mean 3.3/pt, synchr/metachr 5.8) were included. For the least infiltrated metastasis: a high IS is prognostic for DFS and OS. Independently of CD8 cells, a high CD20 density associated concomitantly with both regions (CT/IM) is prognostic for OS (HR: 0.36; p = 0.00004) but not for DFS (HR 0.58, p = 0.1). LCM/patient IS Survival HR Logrank (IS0-2 vs 3-4; 95%IC) p-value Mean of all CD8-CD20 DFS 0.44 (0.22-0.91) 0.5 OS 0.29 (0.09-1.00) 0.03 Less of all CD8-CD20 DFS 0.31 (0.18-0.53) 0.0005 OS 0.25 (0.12-0.51) 0.00003 Most of all CD8-CD20 DFS 0.92 (0.53-1.56) 0.7 OS 0.95 (0.42-2.12) 0.9 Conclusions: B cells (CD20+) associated with cytotoxic T cells (CD8+) in both tumor regions (CT/IM) of the least infiltrated LCM/pt are highly prognostic after curative resection. These results confirm the important role of tumor regions and of B-cells (CD20+) for the tumor immune response. Disclosure: All authors have declared no conflicts of interest.
Published: 2014
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41. AXE Beam: Neo-Adjuvant Triplet Versus Doublet Therapy with Radiation and Total Mesorectal Excision for Locally Advanced Rectal Cancer – A Randomized Phase II Study at the End of Recruitment

Author: Philippe Vergauwe, J. Decaestecker, G. Chiritescu, Xavier Sagaert, J.F. Daisne, J. Arts, Len Verbeke, Kristoffel R. Dumon, M. Verstraete, Karin Haustermans, J.-L. Van Laethem, André D'Hoore, Marc Polus, E. Van Cutsem, Annelies Debucquoy, Yves Humblet, and F. Mardjuadi
Subjects: medicine.medical_specialty, business.industry, Colorectal cancer, Locally advanced, Phases of clinical research, Hematology, Neo adjuvant, medicine.disease, Total mesorectal excision, Surgery, Pharmaceutical Adjuvants, Oncology, Rectal carcinoma, medicine, business
Published: 2014
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42. Restricted overexpression of p53 immunohistochemistry (p53IHC RO) as prognostic after colorectal cancer (CRC) resection

Author: Karin Dahan, Roger Detry, Yves Humblet, Aline Van Maanen, Christophe Remue, Christine Sempoux, Ha Molinh Le, Alex Kartheuser, Daniel Léonard, Christine Nyiraneza, Marc Van den Eynde, and Anne Jouret-Mourin
Subjects: Oncology, Cancer Research, medicine.medical_specialty, business.industry, Colorectal cancer, medicine.disease, MLH1, digestive system diseases, MSH6, symbols.namesake, MSH2, Internal medicine, Cohort, medicine, PMS2, symbols, Immunohistochemistry, business, neoplasms, Fisher's exact test
Abstract: e14602 Background: p53IHC RO was previously described as a distinct pattern from the negative or diffuse p53 IHC expression. p53IHC RO is characterized by a limited number of homogenously scattered strongly positive CRC cells and is associated with some clinico-pathologic CRC feature. The prognostic impact of p53IHC RO remains unknown. Methods: p53 and MMR (MLH1, MSH2, MSH6 and PMS2) proteins IHC expression were performed on CRC primary tumors from an unselected cohort of patients who underwent surgery at the Cliniques St-Luc between 1995 and 2000. p53 IHC results were defined as negative, diffuse or restricted expression. Clinico-pathologic CRC characteristics and patients follow-up were available for this analysis. Comparisons of numerical and categorical clinico-pathological data were evaluated respectively by ANOVA and Fisher exact tests between p53 expression groups. Progression-Free Survival (PFS) and Overall Survival (OS) analyses were performed using Kaplan-Meier method and compared with the log-r...
Published: 2014
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43. Comprehensive Kras and Nras Mutation Analysis: Predictive Biomarkers in a Phase 3 Panitumumab Monotherapy Study of Metastatic Colorectal Cancer (Mcrc)

Author: Scott D. Patterson, Salvatore Siena, Eric Van Cutsem, Yves Humblet, Ying Tian, Thierry André, Roger Sidhu, Kelly S. Oliner, Jean-Luc Van Laethem, and Marc Peeters
Subjects: Neuroblastoma RAS viral oncogene homolog, Oncology, medicine.medical_specialty, business.industry, Colorectal cancer, Hematology, medicine.disease_cause, medicine.disease, Internal medicine, Mutation testing, Medicine, Panitumumab, KRAS, business, Predictive biomarker, medicine.drug
Published: 2013
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44. Population Pharmacokinetics Analysis of Regorafenib and Its Active Metabolites From the Phase III Correct Study of Metastatic Colorectal Cancer

Author: Andrea Wagner, Alberto Sobrero, Stefanie Reif, Carlo Barone, Marc Ychou, Laurent Mineur, D. Laurent, Zuzana Jirakova Trnkova, Josep Tabernero, Frank Cihon, Heinz Joseph Lenz, Konstanze Diefenbach, Olivier Bouché, Yves Humblet, Axel Grothey, Salvatore Siena, Eric Van Cutsem, Antoine Adenis, Takayuki Yoshino, Alfredo Falcone, and Jean Smeets
Subjects: Oncology, medicine.medical_specialty, Colorectal cancer, business.industry, Geographic population, Hematology, medicine.disease, chemistry.chemical_compound, chemistry, Pharmacokinetics, Internal medicine, Regorafenib, medicine, business, Active metabolite
Published: 2013
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45. Comprehensive analysis of KRAS and NRAS mutations as predictive biomarkers for single agent panitumumab (pmab) response in a randomized, phase III metastatic colorectal cancer (mCRC) study (20020408)

Author: Jean-Luc Van Laethem, Ying Tian, Thierry André, Salvatore Siena, Kelly S. Oliner, Eric Van Cutsem, Yves Humblet, Scott D. Patterson, Roger Sidhu, and Marc Peeters
Subjects: Neuroblastoma RAS viral oncogene homolog, Oncology, Cancer Research, medicine.medical_specialty, business.industry, Colorectal cancer, Bioinformatics, medicine.disease, medicine.disease_cause, digestive system diseases, Exon, Internal medicine, medicine, Panitumumab, Single agent, Biomarker Analysis, KRAS, business, neoplasms, Predictive biomarker, medicine.drug
Abstract: 3617 Background: An exploratory biomarker analysis of the randomized, phase 3 monotherapy 20020408 study of pmab vs best supportive care (BSC) demonstrated that mutations in KRAS exon 3 and NRAS exons 2 and 3 appeared to be predictive of pmab response (Peeters et al, 2013). We expanded these results to determine whether mutations in exon 4 of the KRAS and NRAS genes are predictive for pmab treatment and to determine the treatment effect in the overall wild-type (WT) KRAS and NRAS population. Methods: Using a combination of Next Generation Sequencing, Sanger Sequencing, and WAVE-based SURVEYOR Scan Kits from Transgenomic, archival patient tumors were examined for mutations in KRAS and NRAS exon 4. These data were combined with previously presented data from KRAS and NRAS exon 2 and 3 analyses for evaluation of the comprehensive WT KRAS and NRAS subgroup. Results: 9/243 (3.7%) and 2/243 (0.8%) patient tumors with WT KRAS exon 2 status harbored a mutation in KRAS or NRAS exon 4, respectively. One tumor had mutations in both KRAS and NRAS exon 4. In the pmab arm, patients with WT KRAS and WT NRAS tumor status had an objective response rate (ORR) of 15% (11/72) whereas patients with mutant (MT) KRAS or MT NRAS tumor status had an ORR of 1% (1/95; 1 patient with MT KRAS exon 4 had a partial response). There were no responses in the BSC arm regardless of the tumor status. In this analysis set, the treatment hazard ratio (HR; pmab:BSC) for progression-free survival (PFS) in the WT KRAS and WT NRAS subgroup was 0.38 (95% CI: 0.27 - 0.56), and in the MT KRAS or MT NRAS subgroup was 0.98 (95% CI: 0.73 - 1.31). The original WT KRAS exon 2 subgroup PFS HR was 0.45 (95% CI: 0.34 - 0.59) (Amado et al, 2007). Conclusions: This exploratory analysis suggests that mutations in KRAS and NRAS exon 4 occur in a small, but meaningful percentage of patients with mCRC. Extending previous findings from this study in patients with MT KRAS and/or MT NRAS exon 2 and/or 3 tumors, patients with MT KRAS and/or MT NRAS exon 4 tumors do not appear to benefit from pmab therapy. Clinical trial information: NCT00113763.
Published: 2013
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46. Analysis of KRAS/NRAS and BRAF mutations in the phase III PRIME study of panitumumab (pmab) plus FOLFOX versus FOLFOX as first-line treatment (tx) for metastatic colorectal cancer (mCRC)

Author: Jacek Jassem, Paul Ruff, Salvatore Siena, Scott D. Patterson, Jean-Yves Douillard, Richard Thomas Williams, Jeffrey Wiezorek, Fernando Rivera, Roger Sidhu, David Cunningham, Alan Rong, Josep Tabernero, Kelly S. Oliner, Yves Humblet, György Bodoky, Ilona Kocáková, Ronald Burkes, Maria Blasinska-Morawiec, Martin Šmakal, and Mario Edmundo Barugel
Subjects: Oncology, Neuroblastoma RAS viral oncogene homolog, Cancer Research, medicine.medical_specialty, business.industry, Colorectal cancer, medicine.disease, Bioinformatics, medicine.disease_cause, digestive system diseases, First line treatment, FOLFOX, Internal medicine, Medicine, Panitumumab, KRAS, business, medicine.drug
Abstract: 3511 Background: Analysis of a phase III pmab monotherapy study indicated that KRAS and NRAS mutations beyond KRAS exon 2 may be predictive of pmab efficacy (Peeters et al, 2013). Methods: The primary objective of this prospectively defined retrospective analysis of PRIME was to assess the effect of pmab + FOLFOX vs FOLFOX on overall survival (OS) in pts with mCRC based on RAS (KRAS or NRAS) or BRAF mutation status. "Gold standard" bidirectional Sanger sequencing and WAVE-based SURVEYOR Scan Kits from Transgenomic (conducted independently) were used to detect mutations in KRAS exon 3, exon 4; NRAS exon 2, exon 3, exon 4; and BRAF exon 15. Results: RAS ascertainment rate was 90%. Tx HRs for pts with WT RAS were 0.78 (95% CI, 0.62 - 0.99; p = 0.04) for OS (median gain of 5.8 months in the pmab arm) and 0.72 (95% CI, 0.58 - 0.90; p = < 0.01) for PFS. Tx HRs for WT KRAS exon 2/mutant (MT) other RAS were 1.29 (95% CI, 0.79 - 2.10; p = 0.31) for OS and 1.28 (95% CI, 0.79 - 2.07; p = 0.32) for PFS. Tx HRs for pts with WT or MT BRAF were inconsistent with a predictive biomarker (Table). Prognostic effects of the tested biomarkers will be presented. Conclusions: A statistically significant OS benefit was observed in pts with WT RAS mCRC treated with pmab + FOLFOX vs FOLFOX. Pmab is unlikely to benefit pts with any RAS mutations. In this analysis, BRAF mutation had no predictive value. Clinical trial information: NCT00364013. [Table: see text]
Published: 2013
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47. Time profile of adverse events (AEs) from regorafenib (REG) treatment for metastatic colorectal cancer (mCRC) in the phase III CORRECT study

Author: Salvatore Siena, Eric Van Cutsem, Carlo Barone, Alberto Sobrero, D. Laurent, Olivier Bouché, Alfredo Falcone, Lisa Cupit, Antoine Adenis, Andrea Wagner, Laurent Mineur, Takayuki Yoshino, Heinz-Josef Lenz, Yves Humblet, Frank Cihon, Axel Grothey, Daniel J. Sargent, Richard M. Goldberg, Guillem Argiles, and Marc Ychou
Subjects: Oncology, Cancer Research, medicine.medical_specialty, Colorectal cancer, business.industry, medicine.disease, Placebo, Surgery, Multikinase inhibitor, chemistry.chemical_compound, chemistry, Regorafenib, Internal medicine, medicine, Overall survival, In patient, Adverse effect, business, Time profile
Abstract: 3637 Background: In the CORRECT phase III trial, the multikinase inhibitor REG demonstrated significant improvement in overall survival and progression-free survival vs placebo (P) in patients with mCRC whose disease had progressed on other standard therapies. The most frequent grade 3 AEs were hand–foot skin reaction (HFSR), fatigue, diarrhea, hypertension, and rash. We examined when these AEs first occurred and what impact they had on REG dosing. Methods: Adults with mCRC progressing after all standard therapies were randomized to receive REG 160 mg (n=505) or P (n=255) orally once daily for the first 3 weeks of each 4-week cycle. AEs were managed with dose modifications (reduction and interruption) according to the protocol. Results: The safety population comprised 753 pts (REG n=500, P n=253). The mean ± SD treatment duration was 12.1 ± 9.7 weeks for REG and 7.8 ± 5.2 weeks for P. Treatment-emergent AEs occurred in 99.6% of REG pts and 96.8% of P pts. AEs occurring in ≥10% more REG than P pts were fatigue, HFSR, anorexia, diarrhea, weight loss, voice changes, hypertension, rash/desquamation, oral mucositis, fever, hyperbilirubinemia, and low platelet count. The incidence of grade ≥3 HFSR, fatigue, hypertension, and rash/desquamation typically peaked in cycle 1 and tapered to a relatively stable lower incidence over later cycles, while the incidence of diarrhea remained relatively constant throughout the study; median time to first occurrence and worst grade of these AEs is shown in the table. AEs led to dose modifications in 66.6% of REG pts and 22.5% of P pts. Conclusions: The most common AEs in the REG group typically occurred early during treatment. Close early monitoring of AEs and proper management by dose modification is recommended. Clinical trial information: NCT01103323. [Table: see text]
Published: 2013
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48. Analysis of plasma protein biomarkers from the CORRECT phase III study of regorafenib for metastatic colorectal cancer

Author: Richard M. Goldberg, Andrea Wagner, Marc Ychou, Michael Jeffers, Laurent Mineur, Olivier Bouché, Josep Tabernero, Frank Cihon, Antoine Adenis, D. Laurent, Takayuki Yoshino, Yves Humblet, Heinz-Josef Lenz, Axel Grothey, Alberto Sobrero, Alfredo Falcone, Carlo Barone, Salvatore Siena, Eric Van Cutsem, and Daniel J. Sargent
Subjects: Oncology, Cancer Research, medicine.medical_specialty, business.industry, Colorectal cancer, medicine.disease, Blood proteins, Multikinase inhibitor, chemistry.chemical_compound, chemistry, Internal medicine, Regorafenib, Overall survival, Medicine, business
Abstract: 3514 Background: In the CORRECT phase III trial, the multikinase inhibitor regorafenib (REG) demonstrated significant improvement in overall survival (OS) and progression-free survival (PFS) vs placebo (Pla) in patients with metastatic colorectal cancer (mCRC) whose disease had progressed on other standard therapies. An exploratory biomarker subanalysis was conducted to identify protein biomarkers with potential predictive or prognostic value. Methods: Fifteen proteins of interest, many of which are involved in angiogenesis, were quantified by multiplex immunoassay or ELISA in baseline plasma samples collected at study entry from 80% (611/760) of patients. Potential predictive and prognostic effects were evaluated. Results: The biomarker subpopulation was representative of the overall study population in terms of OS and PFS. Using OS as the clinical endpoint, Tie-1 was the only protein whose level demonstrated significant correlation with efficacy (low protein group: REG/Pla, HR 0.87; high protein group, HR 0.56; interaction, p=0.035). Using PFS as the clinical endpoint, von Willebrand factor (VWF) was the only protein whose level demonstrated significant correlation with efficacy (low protein group: REG/Pla, HR 0.39; high protein group, HR 0.60; interaction, p=0.02). Following correction for multiple testing, neither Tie-1 nor VWF data retained statistical significance. Baseline levels of IL-8 and placental growth factor (PlGF) were found to have prognostic value for OS (IL-8: high/low protein levels, HR 3.48, p
Published: 2013
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49. Phase 3 Correct Trial of Regorafenib in Metastatic Colorectal Cancer (MCRC): Overall Survival Update

Author: Alberto Sobrero, A. Falcone, H. J. Lenz, Richard M. Goldberg, Andrea Wagner, Antoine Adenis, L. Mineur, J. Tabernero, E. Van Cutsem, Frank Cihon, A. Grothey, Yves Humblet, S. Siena, Lisa Cupit, M. Ychou, Daniel J. Sargent, Carlo Barone, D. Laurent, Takayuki Yoshino, and O. Bouche
Subjects: medicine.medical_specialty, Colorectal cancer, business.industry, Hazard ratio, Hematology, medicine.disease, Interim analysis, chemistry.chemical_compound, Oncology, chemistry, Internal medicine, Regorafenib, Clinical endpoint, medicine, Overall survival, Data monitoring committee, business, Clin oncol
Abstract: Background The CORRECT trial was conducted to evaluate the oral multikinase inhibitor regorafenib (REG) in patients (pts) with mCRC whose disease had progressed after all approved standard therapies. This trial met its primary endpoint at a pre-planned interim analysis, the results of which were presented previously (J Clin Oncol 30, 2012 [suppl; abstr 3502]). The updated overall survival (OS) data are reported here. Methods Enrollment criteria included documented mCRC and progression during or ≤3 months after last standard therapy. Pts were randomized 2:1 to receive best supportive care plus either REG (160 mg od po) or placebo (PL) on a 3 weeks on/1 week off schedule. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), overall response rate, and disease control rate. Safety and quality of life were also evaluated. Results From May 2010 to March 2011, 760 pts were randomized (REG: 505; PL: 255). Baseline characteristics were balanced between the two arms. A descriptive updated analysis of OS was performed, based on a database cutoff of Nov 13, 2011 with 566 total events (97% of events originally required). In this analysis, the hazard ratio (HR, REG/PL) for OS was 0.79 (95% CI, 0.66-0.94, 1-sided p = 0.0038). Median OS was 6.4 months (95% CI, 5.8-7.0) in the REG arm vs 5.0 months (95% CI, 4.4-5.9) in the PL arm. OS rate at 6 and 12 months was 52.2% and 24.1% in the REG arm vs 43.1% and 17% in the PL arm, respectively. These data serve as an update to previously reported OS data from the earlier interim analysis based on 432 (74%) events, which showed a HR for OS of 0.77 (95% CI, 0.64-0.94, 1-sided p = 0.0052). Pts in the REG arm received an average of 78.9% of the planned dose, and pts in PL arm 90.2% of the planned dose. The mean treatment duration was 12.1 ± 9.7 wks (REG) and 7.8 ± 5.2 wks (PL), respectively. Incidence of treatment-emergent, REG-related adverse events was similar in subgroups by age, sex, renal function and hepatic function, whereas the incidence was higher in Asian pts (98.6%) compared with Caucasian pts (92.3%), and higher in pts with a baseline ECOG score of 0 (97.0%) compared with pts with ECOG score of 1 (88.6%). Conclusions This updated OS analysis demonstrated the robustness and consistency of the OS benefit of REG treatment over PL in pts with previously treated mCRC. Disclosure E. Van Cutsem: Received research funding from Bayer A. Grothey: Mayo Clinic received research funding and honoraria for my consulting activity from Bayer, Genentech, Sanofi, Bayer, Daiichi, Imclone. Onyx and BMS A. Sobrero: Advisory board member and has spoken at symposia for: Roche, Merck, Bayer, Amgen, Sanofi S. Siena: Advisory board member for Amgen, AstraZeneca, Bayer, Genentech, Merck-Serono, Roche, Sanofi A. Falcone: Received honoraria from Bayer for speaking, consultancy and sitting on advisory boards. Also received research support from Bayer M. Ychou: Received honoraria from Bayer for sitting on advisory board Y. Humblet: Has received honoraria from Bayer to act as consultant. Has also received research funding from Bayer O. Bouche: Received honoraria from Roche, Merck-Sereno, Amgen L. Mineur: No conflicts of interest to declare C. Barone: Received honoraria for lecturing and advisory boards from Bayer, Merck, Roche, Novartis. Received honoraria for lecturing from GlaxoSmithKline, Amgen A. Adenis: Received honoraria from Bayer (conference and research funding) J. Tabernero: No conflicts of interest to declare T. Yoshino: Received consulting fee from Takeda; honoraria from Chugai, Takeda, Yakult, Bristol-Meyers Squibb and Merck-Serono; research funding from Daiichi Sankyo, Taiho, Bayer and Imclone H-J. Lenz: No conflicts of interest to declare R. Goldberg: Research support to hip State University from Sanofi, Bayer, Myriad, Jennerex. Consulting (unpaid) for Bayer, Sanofi. Payment for a Data Safety Monitoring Board, Lilly D. Sargent: Consulting fees from the CORRECT steering committee of F. Cihon: Employee of Bayer (sponsor of the study) L. Cupit: Employee of Bayer (sponsor of the study) A. Wagner: Employee of Bayer (sponsor of the study) D. Laurent: Employee of Bayer (sponsor of the study) All other authors have declared no conflicts of interest.
Published: 2012
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50. Phase III CORRECT trial of regorafenib in metastatic colorectal cancer (mCRC)

Author: Alfredo Falcone, Heinz-Josef Lenz, D. Laurent, Salvatore Siena, Olivier Bouché, Eric Van Cutsem, Takayuki Yoshino, Axel Grothey, Josep Tabernero, Frank Cihon, Antoine Adenis, Alberto Sobrero, Andrea Wagner, Laurent Mineur, Richard M. Goldberg, Marc Ychou, Daniel J. Sargent, Carlo Barone, and Yves Humblet
Subjects: Oncology, Cancer Research, medicine.medical_specialty, Colorectal cancer, business.industry, medicine.disease, Surgery, chemistry.chemical_compound, chemistry, Internal medicine, Regorafenib, medicine, In patient, business
Abstract: 3502 Background: Regorafenib (REG) is an oral multi-kinase inhibitor. The CORRECT trial was conducted to evaluate REG in patients (pts) with mCRC who had progressed after all approved standard therapies. Methods: Enrollment criteria included documented mCRC and progression during or ≤3 months after last standard therapy. Pts were randomized 2:1 to receive best supportive care plus either REG (160 mg od po, 3 wks on/1 wk off) or placebo (PL). The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), overall response rate, disease control rate, safety and quality of life (QoL). Efficacy analyses across prespecified subgroups were evaluated using univariate Cox regression. Results: 760 pts were randomized (REG: 505; PL: 255). The OS primary endpoint was met at a preplanned interim analysis. OS and PFS were significantly improved in REG arm compared to PL arm: hazard ratio (HR) for OS 0.77 (95% CI 0.64-0.94, 1-sided p=0.0052), median OS 6.4 vs 5.0 mos; HR for PFS 0.49 (95% CI 0.42-0.58, 1-sided p
Published: 2012
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