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1. Prospective Evaluation of First-Line Erlotinib in Advanced Non-Small Cell Lung Cancer (NSCLC) Carrying an Activating EGFR Mutation: A Multicenter Academic Phase II Study in Caucasian Patients (FIELT).

Author: Jacques De Grève, Jan Van Meerbeeck, Johan F Vansteenkiste, Lore Decoster, Anne-Pascale Meert, Peter Vuylsteke, Christian Focan, Jean-Luc Canon, Yves Humblet, Guy Berchem, Benoit Colinet, Danny Galdermans, Lionel Bosquée, Joanna Vermeij, Alex Dewaele, Caroline Geers, Denis Schallier, and Erik Teugels
Subjects: Medicine, Science
Abstract: INTRODUCTION:Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibition is the preferred first-line treatment of advanced adenocarcinoma of the lung that harbors EGFR activating tyrosine kinase domain mutations. Most data available pertain to Asian populations in which such mutations are more prevalent. We report on the long-term results of first-line treatment with erlotinib in Caucasian patients with advanced adenocarcinoma of the lung that have a somatic EGFR mutation in their tumor. METHODS:Multicenter academic prospective phase II study with erlotinib in patients with an activating EGFR tyrosine kinase (TK) domain somatic mutation (any exon encoding the kinase domain) in the tumor and no prior treatment for their advanced disease. RESULTS:Phenotypic preselecting of 229 patients led to a high EGFR mutation detection rate of 24% of which 46 patients were included in the phase II study. With a progression free survival (PFS) of 81% at three months the study met its primary endpoint for presumed superiority over chemotherapy. With an overall median PFS of 11 months and a median overall survival (OS) of 23 months, the results compare favorably with results obtained in randomized studies using TKI in first line in EGFR mutation positive adenocarcinoma of the lung. CONCLUSION:The present study reinforces the use of EGFR tyrosine kinase inhibition (TKI) as a first line treatment of choice for advanced adenocarcinoma of the lung carrying an activating EGFR mutation. The mutation rate in preselected Caucasian patients is higher than previously reported. Issues relevant for clinical practice are discussed. TRIAL REGISTRATION:ClinicalTrials.gov NCT00339586.
Published: 2016
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2. Supplementary Material from Combined BRAF, EGFR, and MEK Inhibition in Patients with BRAFV600E-Mutant Colorectal Cancer

Author: Eric Van Cutsem, Fatima Rangwala, Bijoyesh Mookerjee, Severine Bettinger, Savina Jaeger, Jan C. Brase, A. Scott Jung, Filip De Vos, Yves Humblet, Peter J. O'Dwyer, Rona Yaeger, Josep Tabernero, Michael S. Gordon, Kei Muro, Gary Middleton, Salvatore Siena, Autumn J. McRee, Antoine Hollebecque, Johanna C. Bendell, Takayuki Yoshino, Jan H.M. Schellens, Chloe E. Atreya, Thierry André, and Ryan B. Corcoran
Abstract: Supplementary Material
Published: 2023
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3. Supplementary Figure Legend, Tables 1 - 3 from Massively Parallel Tumor Multigene Sequencing to Evaluate Response to Panitumumab in a Randomized Phase III Study of Metastatic Colorectal Cancer

Author: Scott D. Patterson, David Reese, Jeffrey Wiezorek, Thierry André, Jean-Luc Van Laethem, Yves Humblet, Jing Huang, Eric Van Cutsem, Salvatore Siena, Alex Parker, Kelly S. Oliner, and Marc Peeters
Abstract: PDF file - 109K, PCR Primer Sequences; Baseline Demographic and Clinical Characteristics for Patients With and Without Available Multigene Information; Mutations Identified In Available Patient Tumor Specimens
Published: 2023
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4. Data from Massively Parallel Tumor Multigene Sequencing to Evaluate Response to Panitumumab in a Randomized Phase III Study of Metastatic Colorectal Cancer

Author: Scott D. Patterson, David Reese, Jeffrey Wiezorek, Thierry André, Jean-Luc Van Laethem, Yves Humblet, Jing Huang, Eric Van Cutsem, Salvatore Siena, Alex Parker, Kelly S. Oliner, and Marc Peeters
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 (CTNNB1 (2%). In the randomized study and open-label extension, 22 of 138 (16%) wild-type KRAS (codons 12/13/61) patients versus 0 of 103 mutant KRAS (codons 12/13) patients had objective responses. Of 6 mutant KRAS (codon 61) patients, 1 with a Q61H mutation achieved partial response during the extension. Among wild-type KRAS (codons 12/13/61) patients, 0 of 9 patients with NRAS mutations, 0 of 13 with BRAF mutations, 2 of 10 with PIK3CA mutations, 1 of 9 with PTEN mutations, and 1 of 2 with CTNNB1 mutations responded to panitumumab. No patients responded to best supportive care alone. Panitumumab treatment was associated with longer progression-free survival (PFS) among wild-type KRAS (codons 12/13/61) patients [HR, 0.39; 95% confidence interval (CI), 0.28–0.56]. Among wild-type KRAS patients, a treatment effect for PFS favoring panitumumab occurred in patients with wild-type NRAS (HR, 0.39; 95% CI, 0.27–0.56) and wild-type BRAF (HR, 0.37; 95% CI, 0.24–0.55) but not mutant NRAS (HR, 1.94; 95% CI, 0.44–8.44).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: 2023
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5. Supplementary Tables S1-S4 from 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: Sabine Tejpar, Eric Van Cutsem, Yves Humblet, Marc Peeters, Jean-Luc Van Laethem, Maria Debiec-Rychter, An Capoen, Wendy De Roock, Bart Biesmans, Jef De Schutter, Gert De Hertogh, Hubert Piessevaux, Steffen Fieuws, and Nicola Personeni
Abstract: Supplementary Tables S1-S4 from Clinical Usefulness of EGFR Gene Copy Number as a Predictive Marker in Colorectal Cancer Patients Treated with Cetuximab: A Fluorescent In situ Hybridization Study
Published: 2023
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6. Supplementary Figure 1 from Massively Parallel Tumor Multigene Sequencing to Evaluate Response to Panitumumab in a Randomized Phase III Study of Metastatic Colorectal Cancer

Author: Scott D. Patterson, David Reese, Jeffrey Wiezorek, Thierry André, Jean-Luc Van Laethem, Yves Humblet, Jing Huang, Eric Van Cutsem, Salvatore Siena, Alex Parker, Kelly S. Oliner, and Marc Peeters
Abstract: PDF file - 57K, Summary of tumor response and tumor genotype among patients who received treatment with panitumuab plus BSC or BSC alone in either the randomized phase 3 study or the extension and who had multigene sequencing information available. For all patients enrolled, tumor response was based on investigator assessment. BSC, best supportive care.
Published: 2023
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7. Data from 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: Sabine Tejpar, Eric Van Cutsem, Yves Humblet, Marc Peeters, Jean-Luc Van Laethem, Maria Debiec-Rychter, An Capoen, Wendy De Roock, Bart Biesmans, Jef De Schutter, Gert De Hertogh, Hubert Piessevaux, Steffen Fieuws, and Nicola Personeni
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: 2023
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8. Phenotypic variation of an ALK-positive large-cell neuroendocrine lung carcinoma with carcinoid morphology during treatment with ALK inhibitors

Author: Yves Humblet, Louis Libbrecht, Delphine Hoton, UCL - SSS/IREC/MIRO - Pôle d'imagerie moléculaire, radiothérapie et oncologie, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Service d'anatomie pathologique, UCL - (SLuc) Unité d'oncologie médicale, and UCL - (SLuc) Centre du cancer
Subjects: 0301 basic medicine, Pathology, medicine.medical_specialty, Histology, ALK rearrangement, Biology, Pathology and Forensic Medicine, Lesion, 03 medical and health sciences, 0302 clinical medicine, Carcinoma neuroendocrine, medicine, Carcinoma, Anaplastic lymphoma kinase, Lung neoplams, Lymph node, Lung, medicine.diagnostic_test, Carcinoid tumor, Large cell, General Medicine, medicine.disease, Phenotype, 030104 developmental biology, medicine.anatomical_structure, Fine-needle aspiration, 030220 oncology & carcinogenesis, medicine.symptom
Abstract: Rearrangement of the ALK gene and overexpression of ALK seems to occur very rarely in neuroendocrine lung tumors, with only 3 cases of atypical carcinoid and 1 large cell neuroendocrine carcinoma (LCNEC) reported in detail until now.1,2,3,4 Here, we report a case of an ALK-positive neuroendocrine lung tumor showing a variable phenotype during the course of treatment. A pulmonary lesion with mediastinal adenopathies was detected in a 69-year-old, non-smoking female of Turkish origin during work-up for back pain. A very small amount of tumoral tissue was obtained through fine needle aspiration of a lymph node and stainings performed on paraffin-embedded tissue showed a very limited amount of tumoral tissue with a well-differentiated cytological aspect with regular nuclei. This article is protected by copyright. All rights reserved.
Published: 2017
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9. 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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10. 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

11. 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

12. Prognostic value of KRAS mutations in stage III colon cancer: post hoc analysis of the PETACC8 phase III trial dataset

Author: Josef Thaler, Richard Greil, Johannes Gaenzer, Wolfgang Eisterer, Joerg Tschmelitsch, Hellmut Samonigg, August Zabernigg, Franz Schmid, Günther Steger, Robert Steinacher, Johannes Andel, Alois Lang, Reinhold Függer, Friedrich Hofbauer, Ewald Woell, Dietmar Geissler, Alfred Lenauer, Manfred Prager, Jean-Luc Van Laethem, Eric Van Cutsem, Geert D'Haens, Gauthier Demolin, Joseph Kerger, Guido Deboever, Gilbert Ghillebert, Marc Polus, Hassan RezaieKalantari, 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, Marc Ychou, Ayman Zawadi, Mohamed-Ayman Zawadi, Olivier Bouche, Laurent Mineur, Jaafar Bennouna-Louridi, Louis Marie Dourthe, Eveline Boucher, Julien Taieb, 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 MatysiakBudnik, 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, Gunnar Folprecht, 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 GuenterDerigs, 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, Roberto Labianca, Giuseppe Colucci, Dino Amadori, Enrico Mini, Alfredo Falcone, Corrado Boni, Evaristo Maiello, Luciano Latini, Alberto Zaniboni, 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, Stefano Cascinu, Paolo Bidoli, Massimo Vaghi, Giorgio Cruciani, Francesco Di Costanzo, Alberto Sobrero, Roberto Petrioli, Massimo Aglietta, Oscar Alabiso, Federico Capuzzo, Domenico Cristi Corsi, Stefania Salvagni, Silvana Chiara, 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, Josep Tabernero, Ramon Salazar, Enrique Aranda Aguilar, Fernando Rivera Herrero, Javier Sastre Valera, Manuel ValladaresAyerbes, Jaime FeliuBatlle, Silvia Gil, 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 CireraNogueras, BernadoQueralt Merino, Cristina Gravalos Castro, Purificacion Martinez de Prado, Carlos PijaumePericay, Manuel ConstenlaFigueiras, InmaculadaGuasch Jordan, Maria Jose GomeReina, Amelia Lopez-Ladron Garcia, Antonio Arrivi Garcia-Ramos, Andres Cervantes, Carlos Fernandez Martos, Eugenio MarcuelloGaspar, Ines Cabezas Montero, Pilar Escudero Emperador, Ana Leon Carbonero, Manuel Gallen Castillo, Teresa Garcia Garcia, Jose Garcia Lopez, Encarnacion Gonzalez Flores, Monica GuillotMorales, Marta LlanosMuñoz, Ana López Martín, Joan Maurel, Juan Carlos Camara, Rosario Dueñas Garcia, Mercedes Salgado, Isabel HernandezBusquier, Teresa Checa Ruiz, Adelaida LacastaMuñoa, MiquelNogue Aliguer, Amalia Velasco Ortiz de Taranco, Miguel Mendez Ureña, Ferran Losa Gaspa, Jose Juan Ponce, Carlos Bosch Roig, Pedro Valero Jimenez, Antonio GalanBrotons, Santiago AlbiolRodriguez, Jose Ales Martinez, Liliana Canosa Ruiz, Margarita CentellesRuiz, John Bridgewater, Rob Glynne-Jones, Saad Tahir, Tamas Hickish, Jim Cassidy, and Leslie Samuel
Subjects: Oncology, Hematology
Published: 2015
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13. 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

14. 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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15. 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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16. 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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17. 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

18. Human equilibrative nucleoside transporter 1 (hENT1) expression is a potential predictive tool for response to gemcitabine in patients with advanced cholangiocarcinoma

Author: Jean-François Gigot, Hubert Piessevaux, L Verbrugghe, Ivan Borbath, Raymond Lai, Christine Sempoux, and Yves Humblet
Subjects: Adult, Male, Oncology, Antimetabolites, Antineoplastic, Cancer Research, Pathology, medicine.medical_specialty, medicine.medical_treatment, Population, Equilibrative nucleoside transporter 1, Deoxycytidine, Disease-Free Survival, Cholangiocarcinoma, Equilibrative Nucleoside Transporter 1, Predictive Value of Tests, Internal medicine, Pancreatic cancer, medicine, Humans, Progression-free survival, education, Aged, Retrospective Studies, Aged, 80 and over, Cisplatin, education.field_of_study, Chemotherapy, biology, business.industry, Retrospective cohort study, Middle Aged, medicine.disease, Gemcitabine, Treatment Outcome, Bile Duct Neoplasms, biology.protein, Female, business, medicine.drug
Abstract: BACKGROUND: Cholangiocarcinoma (CC) is a rare cancer of the liver. Surgery offers the only chance for cure. When surgery is unfeasible, chemotherapy is the backbone of treatment. The combined administration of cisplatin and gemcitabine is considered standard of care. Human equilibrative nucleoside transporter 1 (hENT1) is the major transporter responsible for gemcitabine uptake into cells. hENT1 expression is associated with an increased survival for patients receiving gemcitabine after pancreatic cancer surgery, suggesting that hENT1 is predictive of response to gemcitabine. AIM: To determine whether there is a correlation between the expression of hENT1 and disease outcome in CC. METHODS: A retrospective study on 43 patients treated at our centre with a locally advanced or metastatic CC, who received first line treatment with gemcitabine, was performed. RESULTS: For the whole population, median Progression Free Survival (PFS) and overall survival (OS) were 4.0 (95% Confidence Interval 2.7-5.3 months) and 10.0 months (95%CI 6.8-13.2 months), respectively. From the 26 samples available for hENT1 staining, 18 (69%) and 8 (31%) patients had high and low hENT1 immunostaining, respectively. The median PFS were 2.0 versus 6.0 months for low versus high staining respectively (p = 0.012). The median OS were 5.0 versus 11.0 months for low versus high staining, respectively (p = 0.036). On multivariate analysis, hENT1 expression was the single independent predictive factor associated with prolonged PFS (HR 0.35, p = 0.023) and OS (HR 0.41, p = 0.046). CONCLUSION: In this study we show the potential of hENT1 expression as a predictor of outcome in CC treated with gemcitabine. Larger studies are necessary to confirm these promising results.
Published: 2012
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19. 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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20. 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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21. 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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22. Amphiregulin and Epiregulin mRNA Expression in Primary Tumors Predicts Outcome in Metastatic Colorectal Cancer Treated With Cetuximab

Author: Robin Van Oirbeek, Pierre Laurent-Puig, Jo Vandesompele, Steffen Fieuws, Eric Van Cutsem, Jean-Luc Van Laethem, Hubert Piessevaux, Marc Peeters, Yves Humblet, Sabine Tejpar, Gert De Hertogh, Wendy De Roock, Bart Jacobs, Jef De Schutter, Bart Biesmans, and Frédérique Penault-Llorca
Subjects: Oncology, EGF Family of Proteins, Cancer Research, medicine.medical_specialty, Cetuximab, Gene Expression, Antineoplastic Agents, Antibodies, Monoclonal, Humanized, Irinotecan, Ligands, medicine.disease_cause, Amphiregulin, Epiregulin, Cohort Studies, Proto-Oncogene Proteins p21(ras), Proto-Oncogene Proteins, Internal medicine, Humans, Medicine, RNA, Messenger, Survival analysis, Glycoproteins, Epidermal Growth Factor, business.industry, Hazard ratio, Antibodies, Monoclonal, Prognosis, Survival Analysis, ErbB Receptors, KRAS Mutation Analysis, Endocrinology, Response Evaluation Criteria in Solid Tumors, ras Proteins, Intercellular Signaling Peptides and Proteins, Camptothecin, KRAS, Colorectal Neoplasms, business, medicine.drug
Abstract: Purpose To study the power of the epidermal growth factor receptor (EGFR) epiregulin (EREG) and amphiregulin (AREG) ligands' expression in primary tumors to predict the outcome in patients with chemorefractory metastatic colorectal cancer (cmCRC) treated with the combination of cetuximab and irinotecan. Patients and Methods Gene expression measurements and KRAS mutation analysis were performed on archival formalin-fixed paraffin-embedded primary tumors of 220 cmCRC patients. Response was measured using RECIST (Response Evaluation Criteria in Solid Tumors) criteria. The relation between ligand expression levels and outcome was evaluated using logistic regression for response and Cox regression for survival data. Receiver operating characteristics analysis was performed for response and survival data. CIs for the performance indices were obtained with a nonparametric bootstrap procedure. Findings were externally validated on a series of 67 samples treated in a similar setting. Results In KRAS wild type (WT) patients, there was a significant association between log-transformed ligand expression and response for EREG (odds ratio for objective response, 1.90; 95% CI, 1.27 to 2.83; P = .0005; concordance index [c-index], 0.681) and for AREG (odds ratio for objective response, 1.862; 95% CI, 1.22 to 2.72; P = .0017; c-index, 0.673). In a Cox regression model, dichotomized ligand expression was significantly associated with progression-free survival (PFS) and overall survival (OS). EREG PFS hazard ratio (HR) was 0.41 (95% CI, 0.274 to 0.609; P < .001; time-dependent c-index [Cτ index], 0.640), and AREG PFS HR was 0.43 (95% CI, 0.29 to 0.64; P < .001; Cτ index, 0.627). EREG OS HR was 0.42 (95% CI, 0.28 to 0.63; P < .0001; Cτ index, 0.639), and AREG OS HR was 0.40 (95% CI, 0.27 to 0.64; P < .0001; Cτ index, 0.625). There was no predictive power of ligand expression in patients with KRAS mutation. Conclusion Expression of EGFR ligands in primary tumors significantly predicts outcome in KRAS WT cmCRC treated with cetuximab and irinotecan.
Published: 2009
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23. An open-label study of vandetanib with pemetrexed in patients with previously treated non-small-cell lung cancer

Author: Tsveta Milenkova, L. Nogova, Yves Humblet, A. Godwood, R. De Boer, K. Ruffert, Juergen Wolf, Johan Vansteenkiste, R. Smith, UCL - MD/MINT - Département de médecine interne, and UCL - (SLuc) Unité d'oncologie médicale
Subjects: Male, vandetanib, medicine.medical_specialty, Guanine, Lung Neoplasms, EGFR, Pemetrexed, advanced NSCLC, Vandetanib, Gastroenterology, chemistry.chemical_compound, Glutamates, Piperidines, Carcinoma, Non-Small-Cell Lung, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, Humans, Medicine, pemetrexed, Lung cancer, Adverse effect, Aged, business.industry, Cancer, Hematology, Middle Aged, medicine.disease, Rash, Surgery, Oncology, Tolerability, chemistry, Antifolate, Quinazolines, Female, Angiogenesis, medicine.symptom, business, medicine.drug
Abstract: Background: Vandetanib (ZACTIMA (TM); ZD6474) is a once-daily, oral inhibitor of vascular endothelial growth factor receptor and epidermal growth factor receptor signaling. The safety and tolerability of vandetanib plus pemetrexed was assessed in patients with advanced non-small-cell lung cancer (NSCLC). Patients and methods: Patients with previously treated NSCLC (stage IIIB/IV) received once-daily oral vandetanib (100 or 300 mg) with pemetrexed (500 mg/m(2) i.v. infusion every 21 days). Results: Patients received vandetanib 100 mg + pemetrexed (n = 10) or vandetanib 300 mg + pemetrexed (n = 11). The protocol definition of a tolerable dose [vandetanib-related dose-limiting toxicity (DLT) in less than 2 patients] was met in both dose cohorts, with one DLT reported in each: asymptomatic QTc prolongation (> 100 ms increase from baseline, but absolute QTc < 500 ms) in the 100 mg cohort and interstitial lung disease, which resolved after steroid therapy, in the 300 mg cohort. The most common adverse events were rash, anorexia, fatigue and diarrhea (all n = 10). Conclusion: Vandetanib and pemetrexed in combination were generally well tolerated in patients with advanced NSCLC.
Published: 2009
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24. 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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25. Prospective Evaluation of First-Line Erlotinib in Advanced Non-Small Cell Lung Cancer (NSCLC) Carrying an Activating EGFR Mutation: A Multicenter Academic Phase II Study in Caucasian Patients (FIELT)

Author: Jean-Luc Canon, Guy Berchem, Christian Focan, Joanna Vermeij, D. Galdermans, Jacques De Greve, Benoit Colinet, Lionel Bosquée, Yves Humblet, Lore Decoster, Erik Teugels, Alex Dewaele, Denis Schallier, Anne-Pascale Meert, Jan P. van Meerbeeck, Peter Vuylsteke, Caroline Geers, Johan Vansteenkiste, Rosell, Rafael, Clinical sciences, Laboratory of Molecular and Medical Oncology, and Department of Embryology and Genetics
Subjects: 0301 basic medicine, Oncology, Male, DNA Mutational Analysis, Cancer Treatment, Gene Identification and Analysis, Psychologie appliquée, non-small cell lung cancer (NSCLC), lcsh:Medicine, PACLITAXEL, Lung and Intrathoracic Tumors, Database and Informatics Methods, PLUS GEMCITABINE, 0302 clinical medicine, Adenocarcinomas, Carcinoma, Non-Small-Cell Lung, Medicine and Health Sciences, Epidermal growth factor receptor, Prospective Studies, Erlotinib Hydrochloride, lcsh:Science, Aged, 80 and over, Multidisciplinary, biology, Adenocarcinoma of the Lung, Pharmaceutics, CHEMOTHERAPY, Middle Aged, Sciences bio-médicales et agricoles, OPEN-LABEL, FACTOR RECEPTOR MUTATIONS, ErbB Receptors, Treatment Outcome, 030220 oncology & carcinogenesis, SURVIVAL, Adenocarcinoma, TRIAL, Female, Erlotinib, Tyrosine kinase, Biologie, Engineering sciences. Technology, medicine.drug, Research Article, Clinical Oncology, Adult, medicine.medical_specialty, European Continental Ancestry Group, Research and Analysis Methods, Carcinomas, White People, GEFITINIB, 03 medical and health sciences, Gefitinib, Drug Therapy, Internal medicine, TYROSINE KINASE INHIBITORS, medicine, Adenocarcinoma of the lung, Genetics, Chemotherapy, Humans, Mutation Detection, Aged, business.industry, lcsh:R, Biology and Life Sciences, Cancers and Neoplasms, ADENOCARCINOMA, medicine.disease, Survival Analysis, Non-Small Cell Lung Cancer, respiratory tract diseases, 030104 developmental biology, Biological Databases, Mutation, Mutation Databases, Cancer research, biology.protein, lcsh:Q, Receptor, Epidermal Growth Factor, Clinical Medicine, business
Abstract: INTRODUCTION: Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibition is the preferred first-line treatment of advanced adenocarcinoma of the lung that harbors EGFR activating tyrosine kinase domain mutations. Most data available pertain to Asian populations in which such mutations are more prevalent. We report on the long-term results of first-line treatment with erlotinib in Caucasian patients with advanced adenocarcinoma of the lung that have a somatic EGFR mutation in their tumor., SCOPUS: ar.j, info:eu-repo/semantics/published
Published: 2016

26. Afatinib beyond progression in patients with non-small-cell lung cancer following chemotherapy, erlotinib/gefitinib and afatinib: phase III randomized LUX-Lung 5 trial

Author: M. Schuler, J.C.-H. Yang, K. Park, J.-H. Kim, J. Bennouna, Y.-M. Chen, C. Chouaid, F. De Marinis, J.-F. Feng, F. Grossi, D.-W. Kim, X. Liu, S. Lu, J. Strausz, Y. Vinnyk, R. Wiewrodt, C. Zhou, B. Wang, V.K. Chand, D. Planchard, SaiHong Ignatius Ou, David Planchard, Keunchil Park, Martin Schuler, James Yang, Vikram Chand, Klaus Rohr, Claudia Bagnes, Claudio Marcelo Martin, Gonzalo Recondo, Juan Jose Zarba, Cesar Blajman, Martín Richardet, Sue-Anne McLachlan, Phillip Parente, Craig Underhill, Catherine Crombie, Paul Mainwaring, Richard Greil, Yves Humblet, Frédérique Bustin, Luciano Carestia, Danny Galdermans, Marc Lambrechts, Laetitia Delval, Piet Vercauter, Caicun Zhou, Jin Wang, Cheng Huang, Xiaoyan Lin, Yilong Wu, Xiaoqing Liu, Ying Cheng, Shukui Qin, Jifeng Feng, Jianjin Huang, Yiping Zhang, Shun Lu, Manuela Zereu, Bernardo Garicochea, Cyntia Albuquerque Zadra, Henrik Riska, Tuomo Alanko, Jacques Cadranel, Christos Chouaid, Gérard Zalcman, Denis Moro Sibilot, Maurice Perol, Jaafar Bennouna, Pierre Fournel, Radj Gervais, Maciej Rotarski, Bruno Coudert, Michael Thomas, Thomas Wehler, Martin Faehling, Ulrich Keilholz, Eckart Laack, Joachim von Pawel, Rudolf Huber, Nicolas Dickgreber, Rainer Wiewrodt, Zsuzsanna Mark, Sandor Tehenes, Janos Strausz, Veronika Sarosi, Kumar Prabhash, Minish Jain, Srinivasan Venkatesan, Lalit Sharma, Hemant Dadhich, Rajnish Vasant Nagarkar, Amir Onn, Maya Gottfried, Solomon Stemmer, Maria Rita Migliorino, Francesco Grossi, Paolo Bidoli, Alessandra Bearz, Cesare Gridelli, Carlo Milandri, Marco Platania, Giovanni Luca Ceresoli, Giorgio Cruciani, Francisco Gutierrez Delgado, José Luis Gonzalez Perez, Gabriela Alvarado Luna, Othon Padilla Baca, J.G.J.V. Aerts, J.A. Stigt, A.M.C. Dingemans, G.J.M. Herder, S.J.M. Gans, Jorge Fernando Salas Sánchez, Renzo Luzgardo Alvarez Barreda, Wilbert Rodriguez Pantigoso, Osbert Luis Mejia Palomino, Piotr Jaskiewicz, Andrzej Kazarnowicz, Piotr Serwatowski, Aleksandra Szczesna, Jacek Jassem, Vladimir Lubennikov, Nina Karaseva, Sergey Orlov, Yuri Ragulin, Pilar Garrido, José Luis González Larriba, Carlos Camps, Rosario García Campelo, Pilar Lianes, Manuel Cobo, Enriqueta Felip, Dong-Wan Kim, Sang-We Kim, Joo-Hang Kim, Ji-Youn Han, Young-Chul Kim, Chih-Hsin Yang, Te-Chun Hsia, Yuh-Min Chen, Ying-Huang Tsai, Gee-Chen Chang, Thomas Chang-Yao Tsao, Wu-Chou Su, Ming-Shyan Huang, Ching-Liang Ho, Ruey-Kuen Hsieh, Yuriy Vinnyk, Oleksandr Popovych, Olga Ponomarova, Igor Bondarenko, Iryna Polishchuk, Riyaz Shah, Sanka Mitra, Sanjaykumar Popat, James Spicer, Elizabeth Toy, Toby Talbot, Emma Brown, Sunil Upadhyay, Yvonne Summers, Jayne Gurtler, Luis Meza, John Thropay, Schuler, M, Yang, J, Park, K, Kim, J, Bennouna, J, Chen, Y, Chouaid, C, De Marinis, F, Feng, J, Grossi, F, Kim, D, Liu, X, Lu, S, Strausz, J, Vinnyk, Y, Wiewrodt, R, Zhou, C, Wang, B, Chand, V, Planchard, D, and Bidoli, P
Subjects: 0301 basic medicine, Oncology, Male, Lung Neoplasms, medicine.medical_treatment, Afatinib, Medizin, NSCLC, 0302 clinical medicine, Carcinoma, Non-Small-Cell Lung, Antineoplastic Combined Chemotherapy Protocols, Medicine, heterocyclic compounds, Prospective Studies, skin and connective tissue diseases, Erlotinib Hydrochloride, Hematology, Middle Aged, OPEN-LABEL, Chemotherapy regimen, 030220 oncology & carcinogenesis, SURVIVAL, Disease Progression, Female, Erlotinib, Life Sciences & Biomedicine, CLINICAL-TRIALS, medicine.drug, medicine.medical_specialty, BIBW 2992, Paclitaxel, DISCONTINUATION, ERLOTINIB, Antineoplastic Agents, Disease-Free Survival, GEFITINIB, 03 medical and health sciences, Gefitinib, Internal medicine, TYROSINE KINASE INHIBITORS, Humans, Progression-free survival, Oncology & Carcinogenesis, Lung cancer, neoplasms, Protein Kinase Inhibitors, Chemotherapy, Science & Technology, business.industry, EGFR MUTATIONS, Squamous cell, medicine.disease, respiratory tract diseases, 030104 developmental biology, LUX-Lung 5 Investigators, Quinazolines, Receptor, Epidermal Growth Factor, business, 1112 Oncology And Carcinogenesis, ACQUIRED-RESISTANCE
Abstract: Background: Afatinib has demonstrated clinical benefit in patients with non-small-cell lung cancer progressing after treatment with erlotinib/gefitinib. This phase III trial prospectively assessed whether continued irreversible ErbB-family blockade with afatinib plus paclitaxel has superior outcomes versus switching to chemotherapy alone in patients acquiring resistance to erlotinib/gefitinib and afatinib monotherapy. Patients and methods: Patients with relapsed/refractory disease following ≥ 1 line of chemotherapy, and whose tumors had progressed following initial disease control (≥ 12 weeks) with erlotinib/gefitinib and thereafter afatinib (50 mg/day), were randomized 2:1 to receive afatinib plus paclitaxel (40 mg/day; 80 mg/m2/week) or investigator's choice of single-agent chemotherapy. The primary end point was progression-free survival (PFS). Other end points included objective response rate (ORR), overall survival (OS), safety and patient-reported outcomes. Results: Two hundred and two patients with progressive disease following clinical benefit from afatinib were randomized to afatinib plus paclitaxel (n ≥ 134) or single-agent chemotherapy (n ≥ 68). PFS (median 5.6 versus 2.8 months, hazard ratio 0.60, P ≥ 0.003) and ORR (32.1% versus 13.2%, P ≥ 0.005) significantly improved with afatinib plus paclitaxel. There was no difference in OS. Global health status/quality of life was maintained with afatinib plus paclitaxel over the entire treatment period. The median treatment duration was 133 and 51 days with afatinib plus paclitaxel and single-agent chemotherapy, respectively; 48.5% of patients receiving afatinib plus paclitaxel and 30.0% of patients receiving single-agent chemotherapy experienced drug-related grade 3/4 adverse events. Treatment-related adverse events were consistent with those previously reported with each agent. Conclusion: Afatinib plus paclitaxel improved PFS and ORR compared with single-agent chemotherapy in patients who acquired resistance to erlotinib/gefitinib and progressed on afatinib after initial benefit. LUX-Lung 5 is the first prospective trial to demonstrate the benefit of continued ErbB targeting post-progression, versus switching to single-agent chemotherapy. Trial registration number: NCT01085136 (clinicaltrials.gov).
Published: 2016

27. 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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28. 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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29. 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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30. 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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31. Nodular regenerative hyperplasia: a deleterious consequence of chemotherapy for colorectal liver metastases?

Author: Christine Sempoux, Yves Horsmans, Jacques Rahier, Jean-Pascal Machiels, Antonino Ceratti, Catherine Hubert, Jean-François Gigot, Jean-Luc Canon, and Yves Humblet
Subjects: Male, medicine.medical_specialty, Time Factors, Organoplatinum Compounds, medicine.medical_treatment, Liver Function Tests, Antineoplastic Combined Chemotherapy Protocols, Ascites, medicine, Hepatectomy, Humans, Contraindication, Aged, Hyperplasia, Hepatology, medicine.diagnostic_test, business.industry, Contraindications, Liver Diseases, Liver Neoplasms, Middle Aged, medicine.disease, Liver Regeneration, Surgery, Oxaliplatin, Treatment Outcome, Liver, Chemotherapy, Adjuvant, Liver biopsy, Disease Progression, Portal hypertension, Female, Fluorouracil, Chemical and Drug Induced Liver Injury, medicine.symptom, Colorectal Neoplasms, business, Liver function tests, Varices, Nodular regenerative hyperplasia
Abstract: AIMS: This report describes three patients suffering from nodular regenerative hyperplasia (NRH). METHODS: These patients have received six, 16 and 20 cycles of neoadjuvant 5-fluorouracil and oxaliplatin-based chemotherapy before planned extended hepatectomy. Two patients underwent uneventful portal vein embolization to hypertrophy the future remnant liver. RESULTS: At the end of chemotherapy, liver function tests deteriorated and portal hypertension appeared in two patients, including ascites, splenomegaly and oesophageal varices. Liver biopsy was performed through a percutaneous (two patients) or a transjugular approach (one patient) and allowed the diagnosis of NRH, which was considered to be a contraindication for major liver resection in all three patients, associated with extrahepatic disease progression in one patient. All patients died from neoplastic disease progression despite further chemotherapy at 6, 17 and 31 months following the diagnosis of NRH. One patient developed liver failure and ascites at the time of death. CONCLUSIONS: Physicians should be aware of the potential occurrence and therapeutic impact of NRH in patients suffering from CRLM and treated by neoadjuvant 5FU-oxaliplatin-based chemotherapy before major liver surgery.
Published: 2007
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32. 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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33. Ossification of a rectal tumor: an uncommon finding

Author: Stanislas, Smajda, Etienne, Danse, Maud, Mertens de Wilmars, Yves, Humblet, Alex, Kartheuser, and Anne, Jouret-Mourin
Subjects: Adult, Radiography, Rectal Neoplasms, Ossification, Heterotopic, Humans, Female, Adenocarcinoma
Abstract: The authors report the case of a 29-year-old woman with partially calcified stage cT4N2M0 mucoid adenocarcinoma of the mid-rectum. Concomitant neoadjuvant chemoradiotherapy was administered. Preoperative CT scan and MRI demonstrated stable disease with a marked increase of its mineralized component. Histology confirmed a mucoid adenocarcinoma with ossified matrix. Osteocytes were identified in the tumor. TNM (5th edition) staging was ypT3N2M1. This case illustrates heterotopic ossification of a rectal tumor, a fairly uncommon finding. The mechanism of heterotopic bone formation within gastrointestinal adenocarcinoma has not been fully elucidated. The impact of this particular feature on patient outcome is unknown.
Published: 2015

34. Aflibercept Plus FOLFIRI vs. Placebo Plus FOLFIRI in Second-Line Metastatic Colorectal Cancer: a Post Hoc Analysis of Survival from the Phase III VELOUR Study Subsequent to Exclusion of Patients who had Recurrence During or Within 6 Months of Completing Adjuvant Oxaliplatin-Based Therapy

Author: Hans-Joachim Schmoll, Emmanuelle Dochy, Cristina Grávalos, Joseph McKendrick, David Cunningham, Paul Ruff, Guy van Hazel, Michael L. Andria, Eric Van Cutsem, Radek Lakomý, Raghu L. Vishwanath, Solenn Le-Guennec, Dirk Arnold, Edith P. Mitchell, Teresa Macarulla, Florence Joulain, Vladimir Moiseyenko, Jana Prausová, H. Kröning, Paulo M. Hoff, Josep Tabernero, Yves Humblet, and Albert J. ten Tije
Subjects: 0301 basic medicine, Oncology, Adult, Male, Cancer Research, medicine.medical_specialty, Bevacizumab, Organoplatinum Compounds, Recombinant Fusion Proteins, Population, Leucovorin, 03 medical and health sciences, 0302 clinical medicine, Double-Blind Method, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, Adjuvant therapy, Medicine, Humans, Pharmacology (medical), education, Aflibercept, Aged, Aged, 80 and over, education.field_of_study, business.industry, Hazard ratio, Middle Aged, Survival Analysis, Surgery, Irinotecan, Oxaliplatin, Regimen, 030104 developmental biology, Receptors, Vascular Endothelial Growth Factor, Treatment Outcome, 030220 oncology & carcinogenesis, FOLFIRI, Camptothecin, Female, Fluorouracil, Neoplasm Recurrence, Local, business, Colorectal Neoplasms, medicine.drug
Abstract: The aim of this post hoc analysis of the VELOUR study (ClinicalTrials.gov NCT00561470) was to investigate the treatment effect of adding aflibercept to second-line infusional 5-fluorouracil (5-FU), leucovorin and irinotecan (FOLFIRI) in patients with metastatic colorectal cancer (mCRC) who had failed any prior oxaliplatin-containing regimen. Adjuvant rapid relapsers (ARR), who were enrolled directly following relapse during or within 6 months of completion of oxaliplatin-containing adjuvant chemotherapy (N = 124, including 17 patients who also received bevacizumab as part of their adjuvant therapy), were excluded from the original VELOUR intention-to-treat (ITT) population (N = 1226). After exclusion of the ARR, overall survival (OS) in the ITT minus ARR (ITT-ARR) population (N = 1102) was longer in the aflibercept plus FOLFIRI arm than in the placebo plus FOLFIRI arm [hazard ratio (HR) 0.78, 95 % confidence interval (CI) 0.68–0.90; median survival difference 1.87 months]. In the subgroup of patients assigned to the prior bevacizumab stratum at randomization, OS was numerically longer in the aflibercept plus FOLFIRI arm than in the placebo plus FOLFIRI arm (HR 0.81; 95 % CI 0.63–1.04; median survival difference 2.14 months). Comparison of the post hoc analysis results with the primary analysis from VELOUR suggests that the inclusion of the directly enrolled ARR may have understated the aflibercept treatment benefit for both bevacizumab-pretreated and bevacizumab-naive patients in the strictly second-line setting although no definitive conclusion may be inferred. The benefit associated with the addition of aflibercept to second-line FOLFIRI in patients with mCRC was observed whatever the timing of first-line disease progression. There were no unexpected safety concerns.
Published: 2015

35. Subgruppenanalyse von Patienten mit metasiertem kolorektalen Karzinom (mKRK), die unter Regorafenib (REG) in der CORRECT-Studie ein progressionsfreies Überleben von mehr als 4 Monaten hatten

Author: A. Grothey, L. Mineur, M. Karthaus, Antoine Adenis, Lei Xu, Andrea Wagner, Richard M. Goldberg, Takayuki Yoshino, A. Falcone, Alberto Sobrero, C. Barone, O. Bouche, S. Siena, J. Tabernero, Yves Humblet, M. Ychou, H. J. Lenz, and E. Van Cutsem
Subjects: Gastroenterology
Published: 2015
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36. 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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37. 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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38. Neoadjuvant chemotherapy followed by surgery and adjuvant chemotherapy in patients with primarily unresectable, advanced-stage ovarian cancer

Author: Véronique D'Hondt, Jacques Donnez, Filomena Mazzeo, Joseph Kerger, Martine Berlière, Jean-Paul Squifflet, Lionel Duck, Yves Humblet, and Jean-Pascal Machiels
Subjects: Adult, medicine.medical_specialty, medicine.medical_treatment, Optimal Debulking, Ovary, Disease-Free Survival, Carboplatin, law.invention, Randomized controlled trial, law, Antineoplastic Combined Chemotherapy Protocols, Carcinoma, Humans, Medicine, Aged, Neoplasm Staging, Aged, 80 and over, Ovarian Neoplasms, Chemotherapy, business.industry, Obstetrics and Gynecology, Induction chemotherapy, Middle Aged, medicine.disease, Debulking, Neoadjuvant Therapy, Surgery, medicine.anatomical_structure, Oncology, Chemotherapy, Adjuvant, Female, Cisplatin, business, Ovarian cancer
Abstract: OBJECTIVE: The aim of this review is to report our experience and the feasibility of neoadjuvant chemotherapy in patients with advanced-stage ovarian cancer. METHODS: Forty-five patients with primarily unresectable advanced-stage epithelial ovarian cancer were treated in our center between 1995 and 2002 by platinum-based neoadjuvant chemotherapy followed by surgery and adjuvant chemotherapy. Their files were reviewed retrospectively. RESULTS: At the end of neoadjuvant chemotherapy, according to RECIST criteria, 1 patient (2.2%) had achieved a clinical complete response (CR), 33 (73.4%) a partial response (PR), and 8 (17.8%) had stable disease (SD). Only 3 (6.6%) patients showed disease progression (PD). Surgery was performed in patients with objective response or SD after a median number of 4 courses (range: 2-6) of induction chemotherapy. A complete macroscopic debulking was achieved in 24 (53.3%) out of 39 patients in whom cytoreductive surgery was performed. For the entire group, median overall survival was 29 months. Survival was significantly improved in patients with optimal debulking compared to patients with persistent tumor after surgery: 41 months versus 23 months (P = 0.0062). Median survival for patients responding to neoadjuvant chemotherapy (CR and PR) was 44 months compared to 27 months for patients with SD or PD after initial chemotherapy (P = 0.01). Neither treatment-related deaths nor significant toxicities were observed. CONCLUSION: Neoadjuvant chemotherapy followed by optimal debulking may be a safe and valuable treatment alternative in patients with primarily unresectable advanced-stage bulky ovarian cancer. Patients with an objective response to chemotherapy or absence of macroscopic residual tumor after surgery have a better outcome. This approach is currently being tested in large, prospective randomized clinical trials.
Published: 2003
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39. Association of T-cell infiltration assessed in pretherapeutic biopsies (PTB) of patients with locally advanced rectal adenocarcinoma (LARC) with tumor response and relapse after chemoradiotherapy (CRT) and rectal surgery

Author: Nacilla Haicheur, Christophe Remue, Alex Kartheuser, Carine El Sissy, Jérôme Galon, Cristina Dragean, Etienne Danse, Daniel Léonard, Anne Jouret-Mourin, Radu Bachman, Pamela Baldin, Franck Pagès, Marc Van den Eynde, Amos Kirilovsky, Marie-Armelle Denis, Pierre Scalliet, Florence Marliot, Astrid Decuyper, and Yves Humblet
Subjects: 0301 basic medicine, Cancer Research, medicine.medical_specialty, business.industry, T cell infiltration, Locally advanced, Tumor response, Total mesorectal excision, 03 medical and health sciences, 030104 developmental biology, Oncology, Rectal Adenocarcinoma, Medicine, Rectal surgery, Radiology, business, Chemoradiotherapy, Complete response
Abstract: 3599 Background: Pre-operative CRT followed by total mesorectal excision (TME) is nowadays the standard of care for patient with LARC (cT3-T4N0 or cTxN+). Currently, pathologic complete response occurs in +/- 15% after CRT. Colorectal cancer T-cell infiltration is a strong prognostic factor for survival after primary tumor resection. Our aim was to determine whether T-cell infiltration in PTB could be predictive of tumor response and relapse after CRT + TME. Methods: Between 1999 and 2012, patients with LARC who underwent CRT + TME and with available clinical follow-up and PTB (with sufficient tumor cells density) were identified at the Cliniques universitaires St-Luc. The density of CD3 (T cells) and CD8 (cytotoxic) was quantified on immunostained PTB slides and analyzed with a dedicated image analysis software on whole-slide imaging. Comparisons were made using the Wilcoxon-Mann-Whitney test. Cumulative disease-free survival (DFS) was performed using the Kaplan-Meier estimator and compared by log-rank tests. Cox regression we used for uni- and multi-variate analysis. P value of less than 0.05 was considered statistically significant. Results: 154 patients (sex ratio M/F 1.8; mean age 65 years-old; upper (20%), mid (29%) and low rectum (51%), synchronous metastases (11%)) were analyzed. High CD3 and CD8 PTB densities were significantly associated with a higher pathological response (Dworak 3-4) and lower ypTNM stage after CRT +TME (p < 0,05). Higher CD3 and CD8 PTB densities were associated with higher patient DFS (CD3: HR = 2,30 (CI95%:1,15-4,59) p = 0,02; CD8: HR = 1,95 (CI95%: 1,01-3,75) p = 0,04). These results were confirmed in uni and multivariate analysis. CD3 and CD8 PTB densities added to pathological response (ypTNM/Dworak) but also clinical response (ycTNM) after CRT + TME increases significantly the accuracy prediction of tumor relapse. Conclusions: Pretherapeutic T-cell infiltration of LARC is predictive of tumor response and relapse after CRT +TME. This biomarker could be helpful for patient treatment decision. It must be validated in larger patient cohorts.
Published: 2017
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40. Radical resection of noncolorectal liver metastases: is cure possible?

Author: Kaoutar, Ghammad, David, Heuker, Laurent, Stainier, Catherine, Hubert, Yves, Humblet, Jean-François, Baurain, Lannoy, and Jean- François, Gigot
Subjects: Adult, Male, Time Factors, Liver Neoplasms, Metastasectomy, Reproducibility of Results, Kaplan-Meier Estimate, Middle Aged, Risk Assessment, Disease-Free Survival, Decision Support Techniques, Treatment Outcome, Predictive Value of Tests, Risk Factors, Hepatectomy, Humans, Female, Aged, Proportional Hazards Models, Retrospective Studies
Published: 2014

41. Phase II study of vinorelbine in patients with androgen-independent prostate cancer

Author: A. Caty, A. Monnier, X. Sun, F. Rolland, Yves Humblet, Roland Bugat, Martine Piccart, J. Breza, P. Houyau, Stéphane Oudard, T. Gil, J. Novak, D. Chopin, Marc Beauduin, E. Suc, P. Montcuquet, and Pierre Fumoleau
Subjects: Male, medicine.medical_specialty, Neutropenia, medicine.medical_treatment, Population, Phases of clinical research, Adenocarcinoma, Vinblastine, Vinorelbine, Gastroenterology, Disease-Free Survival, Drug Administration Schedule, Prostate cancer, Internal medicine, medicine, Humans, Neoplasm Metastasis, Bone pain, education, Aged, Pain Measurement, Aged, 80 and over, Chemotherapy, education.field_of_study, business.industry, Prostatic Neoplasms, Leukopenia, Hematology, Middle Aged, Prostate-Specific Antigen, medicine.disease, Antineoplastic Agents, Phytogenic, Surgery, Prostate-specific antigen, Oncology, Androgens, Quality of Life, Hormonal therapy, medicine.symptom, business, medicine.drug
Abstract: Summary Purpose To evaluate the efficacy and toxicity of vinorelbine in a phase ll study in patients with progressive metastatic andro-gen-independent prostate cancer. Patients and methods Forty-seven men with progressive metastatic prostate cancer refractory to first-line or second-line hormonal therapy were treated with vinorelbine, a semi-synthetic vinca-alkaloid. Vinorelbine was given, on an outpatient schedule, at 25 mg/m2 weekly for at least eight weeks or until progression or excessive toxicity. Results Forty-seven patients were included in the study, 33 being evaluable for tumour response, 36 for response to PSA, 21 for clinical benefit and 45 for toxicity. Median actual weekly dose was 19 mg/m2 (range 12.0–26.2 mg/m2). Six of thirty-six patients (17%) demonstrated a biologic response with a 50% or more decline in serum PSA on two consecutive measurements taken at least two weeks apart. The median duration of biologic response was 2.7 months. Two of three patients with measurable disease obtained an objective response but remained unconfirmed. No change disease was reported in 23 patients (49%). On entry into the study, 30 patients had symptomatic bone pain and required narcotic or non-narcotic analgesics. Clinical benefit from vinorelbine was achieved in 15 patients out of 21 (32% of the intent to treat analysis population and 71% of the assessable patients). Due to the low number of questionnaires (QLQ-C30) filled in, it was insufficient to allow any statistical analysis. The median survival was 10.2 months. Toxicity was mainly haematologic with 51% of patients experiencing grade 3 or 4 granulocytopenia. Three patients developed deep vein thrombosis. Non-haematologic toxicity, mainly nausea and neurotoxicity, was mild. Conclusions The administration of weekly vinorelbine appears to be a safe treatment for those patients with androgen-independent prostate cancer and poor prognosis features who require chemotherapy. These results provide data for future investigation of vinorelbine in combination regimens.
Published: 2001
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42. Meropenem versus ceftazidime as empirical monotherapy for febrile neutropenic cancer patients

Author: J Gerain, Bernard Vandercam, Michel Symann, Nicole Straetmans, Augustin Ferrant, Michel Moreau, Georges Wauters, Jacques Longueville, and Yves Humblet
Subjects: Adult, Male, medicine.medical_specialty, Neutropenia, Adolescent, Fever, Nausea, Ceftazidime, Meropenem, Gastroenterology, Neoplasms, Internal medicine, medicine, Humans, Aged, Antibacterial agent, Aged, 80 and over, business.industry, Drug Tolerance, Hematology, General Medicine, Middle Aged, medicine.disease, Anti-Bacterial Agents, Cephalosporins, Surgery, Tolerability, Vomiting, Female, Thienamycins, medicine.symptom, business, Febrile neutropenia, medicine.drug
Abstract: A total of 101 cancer patients with 121 febrile neutropenia episodes were randomised to receive empirical treatment with i.v. meropenem (1g/8 h) or ceftazidime (2 g/8 h). After 3 days, 89% of patients were on unmodified therapy in the meropenem group, compared with 83% in the ceftazidime group. Of the evaluable episodes (n = 106), the success rate with unmodified empirical therapy until the end of the treatment course was slightly higher with meropenem than with ceftazidime (48% vs 38%, P=0.39). Furthermore, initial success with further infections was observed in 22% of episodes treated with meropenem and in 13% of episodes treated with ceftazidime. Glycopeptides were used as first modification in 28% and 39% of meropenem and ceftazidime recipients, respectively. Both treatments were well tolerated and there were no reports of drug-related nausea/vomiting or seizures. No significant differences in response rate or in tolerability were observed when analysing only the first febrile episodes. In conclusion, meropenem seems to be as efficacious and well tolerated as ceftazidime and may be associated with a lesser requirement for the addition of glycopeptides.
Published: 2000
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43. Tumor regressions observed in patients with metastatic melanoma treated with an antigenic peptide encoded by geneMAGE-3 and presented by HLA-A1

Author: J. P. De Greve, Francis Brasseur, Pierre Coulie, N van Baren, M H Tessier, Brigitte Dreno, P. Weynants, A Bourlond, Danielle Lienard, Elke Jäger, Joseph Kerger, E Rankin, P. van der Bruggen, Vincent Brichard, Vincenzo Russo, Marie Marchand, Giuseppe Masucci, Marc Beauduin, Romain Vanwijck, Yves Humblet, Giorgio Parmiani, Thierry Boon, Flavio Arienti, J Atzpodien, and Pierre-Yves Dietrich
Subjects: Oncology, Cancer Research, medicine.medical_specialty, business.industry, medicine.medical_treatment, Melanoma, Antigen presentation, Immunotherapy, T lymphocyte, Active immunization, medicine.disease, Cytolysis, CTL, Internal medicine, Toxicity, Immunology, medicine, business
Abstract: Thirty-nine tumor-bearing patients with metastatic melanoma were treated with 3 subcutaneous injections of the MAGE-3.A1 peptide at monthly intervals. No significant toxicity was observed. Of the 25 patients who received the complete treatment, 7 displayed significant tumor regressions. All but one of these regressions involved cutaneous metastases. Three regressions were complete and 2 of these led to a disease-free state, which persisted for more than 2 years after the beginning of treatment. No evidence for a cytolytic T lymphocyte (CTL) response was found in the blood of the 4 patients who were analyzed, including 2 who displayed complete tumor regression. Our results suggest that injection of the MAGE-3.A1 peptide induced tumor regression in a significant number of the patients, even though no massive CTL response was produced.
Published: 1999
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44. 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

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

Author: Alfredo Falcone, Takayuki Yoshino, O. Bouche, Michael Jeffers, D. Laurent, J. Tabernero, Alexander Stein, Alberto Sobrero, Antoine Adenis, Yves Humblet, Andrea Wagner, Laurent Mineur, A. Grothey, H. J. Lenz, E. Van Cutsem, C. Barone, M. Ychou, Salvatore Siena, and Richard M. Goldberg
Subjects: Mutational analysis, medicine.medical_specialty, History, Family medicine, Gastroenterology, medicine, University hospital
Abstract: 1Bayer HealthCare Pharmaceuticals, Montville, NJ, USA; 2University Hospital Gasthuisberg/Leuven, Leuven, Belgium; 3San Martino Hospital, Genoa, Italy; 4Ospedale Niguarda Ca’ Granda, Milan, Italy; 5University Hospital, Pisa, Italy; 6CRLC Val d’Aurelle, Montpellier, France; 7St-Luc University Hospital, Brussels, Belgium; 8Robert Debre University Hospital, Reims, France; 9Institut Sainte-Catherine, Avignon, France; 10Catholic University of Sacred Heart, Rome, Italy; 11Centre Oscar Lambret, Lille, France; 12Vall d’Hebron University Hospital, Universitat Autonoma de Barcelona, Barcelona, Spain; 13National Cancer Center Hospital East, Kashiwa, Japan; 14University of Southern California/Norris Comprehensive Cancer Center, Keck School of Medicine, Los Angeles, CA, USA; 15Ohio State University School of Medicine, James Cancer Hospital and Solove Research Institute, Columbus, OH, USA; 16Mayo Clinic, Rochester, MN, USA; 17Bayer Pharma AG, Berlin, Germany
Published: 2013
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46. Time course of regorafenib-associated adverse events in the phase III CORRECT study

Author: Antoine Adenis, J. Tabernero, Salvatore Siena, A. Grothey, Andrea Wagner, Alberto Sobrero, Laurent Mineur, C. Barone, M. Ychou, E. Van Cutsem, D. Laurent, Frank Cihon, Yves Humblet, H. J. Lenz, Richard M. Goldberg, Takayuki Yoshino, O. Bouche, Alfredo Falcone, and C Denzlinger
Subjects: Oncology, medicine.medical_specialty, chemistry.chemical_compound, chemistry, business.industry, Internal medicine, Regorafenib, Time course, Gastroenterology, medicine, Phase (waves), business, Adverse effect
Published: 2013
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47. Randomised, placebo-controlled, double-blind, parallel-group phase III study evaluating aflibercept in patients receiving first-line treatment with gemcitabine for metastatic pancreatic cancer

Author: Philippe Rougier, Robert Manges, Armando Santoro, Hanno Riess, Sylvie Assadourian, Yves Humblet, Laurence Hatteville, Philip A. Philip, Petr Karasek, and Carlo Barone
Subjects: Adult, Male, Cancer Research, medicine.medical_specialty, Neutropenia, Recombinant Fusion Proteins, Urology, Placebo, Deoxycytidine, Disease-Free Survival, Drug Administration Schedule, Double-Blind Method, Pancreatic cancer, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, Neoplasm Metastasis, Adverse effect, Aflibercept, Aged, Aged, 80 and over, Settore MED/06 - ONCOLOGIA MEDICA, business.industry, Hazard ratio, Nausea, Middle Aged, medicine.disease, Interim analysis, Gemcitabine, Surgery, Pancreatic Neoplasms, Proteinuria, Receptors, Vascular Endothelial Growth Factor, Treatment Outcome, Oncology, Female, Angiogenesis, business, Progressive disease, medicine.drug
Abstract: Background This phase III study investigated the addition of aflibercept to gemcitabine, in patients with advanced pancreatic cancer. Patients and methods Patients with metastatic pancreatic cancer were randomly assigned to receive either intravenous (i.v.) aflibercept, 4 mg/kg every 2 weeks, or matching placebo combined with gemcitabine, 1000 mg/m2 i.v. weekly for 7 weeks out of 8, then weekly for 3 weeks out of 4 until progressive disease, unacceptable toxicity or withdrawal of consent. The primary objective was to demonstrate an improvement in overall survival (OS) between the treatment arms. Results The study was stopped for futility following a planned interim analysis of OS in 427 randomised patients. With a median follow-up of 7.9 months, based on the 546 patients at study termination, median OS was 7.8 months in the gemcitabine plus placebo arm (n = 275) versus 6.5 months in the gemcitabine plus aflibercept arm (n = 271), which was not significant (hazard ratio 1.165, 95% confidence interval (CI) 0.921-1.473, p = 0.2034). Median progression-free survival was 3.7 months in both arms. Treatment discontinuations due to adverse events were more frequent in the aflibercept than in the placebo-containing arm (23% versus 12%). Conclusion Adding aflibercept to gemcitabine did not improve OS in patients with metastatic pancreatic cancer.
Published: 2013

48. 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

49. 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

50. 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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