M Del Rio1, C Mollevi1, F Bibeau1, N Vie1, J Selves2, J-F Emile3, P Roger4, C Gongora1, J Robert5, N Tubiana-Mathieu6, M Ychou1, P Martineau7. 1. IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, F-34298, France; INSERM, U1194, Montpellier, F-34298, France; Université de Montpellier, Montpellier, F-34090, France; Institut régional du Cancer de Montpellier, Montpellier, F-34298, France. 2. Centre Hospitalier Universitaire de Toulouse, F-31300, France; Centre de Recherche en Cancérologie de Toulouse, Unité Mixte de Recherche 1037 INSERM - Université Toulouse III, France. 3. Université de Versailles, Boulogne, France; Hôpital Ambroise Paré, Boulogne, France. 4. Université de Montpellier, Montpellier, F-34090, France; Service d'Anatomie et Cytologie Pathologiques, CHU Nîmes, Place du Professeur Debré, 30029, Nîmes, France. 5. INSERM U916, Institut Bergonié, Université de Bordeaux, France. 6. Service d'oncologie médicale, CHU Dupuytren, avenue Luther-King, 87000, Limoges, France. 7. IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, F-34298, France; INSERM, U1194, Montpellier, F-34298, France; Université de Montpellier, Montpellier, F-34090, France; Institut régional du Cancer de Montpellier, Montpellier, F-34298, France. Electronic address: pierre.martineau@inserm.fr.
Abstract
BACKGROUND: Currently, metastatic colorectal cancer is treated as a homogeneous disease and only RAS mutational status has been approved as a negative predictive factor in patients treated with cetuximab. The aim of this study was to evaluate if recently identified molecular subtypes of colon cancer are associated with response of metastatic patients to first-line therapy. PATIENTS AND METHODS: We collected and analysed 143 samples of human colorectal tumours with complete clinical annotations, including the response to treatment. Gene expression profiling was used to classify patients in three to six classes using four different molecular classifications. Correlations between molecular subtypes, response to treatment, progression-free and overall survival were analysed. RESULTS: We first demonstrated that the four previously described molecular classifications of colorectal cancer defined in non-metastatic patients also correctly classify stage IV patients. One of the classifications is strongly associated with response to FOLFIRI (P=0.003), but not to FOLFOX (P=0.911) and FOLFIRI + Bevacizumab (P=0.190). In particular, we identify a molecular subtype representing 28% of the patients that shows an exceptionally high response rate to FOLFIRI (87.5%). These patients have a two-fold longer overall survival (40.1 months) when treated with FOLFIRI, as first-line regimen, instead of FOLFOX (18.6 months). CONCLUSIONS: Our results demonstrate the interest of molecular classifications to develop tailored therapies for patients with metastatic colorectal cancer and a strong impact of the first-line regimen on the overall survival of some patients. This however remains to be confirmed in a large prospective clinical trial.
BACKGROUND: Currently, metastatic colorectal cancer is treated as a homogeneous disease and only RAS mutational status has been approved as a negative predictive factor in patients treated with cetuximab. The aim of this study was to evaluate if recently identified molecular subtypes of colon cancer are associated with response of metastatic patients to first-line therapy. PATIENTS AND METHODS: We collected and analysed 143 samples of humancolorectal tumours with complete clinical annotations, including the response to treatment. Gene expression profiling was used to classify patients in three to six classes using four different molecular classifications. Correlations between molecular subtypes, response to treatment, progression-free and overall survival were analysed. RESULTS: We first demonstrated that the four previously described molecular classifications of colorectal cancer defined in non-metastatic patients also correctly classify stage IV patients. One of the classifications is strongly associated with response to FOLFIRI (P=0.003), but not to FOLFOX (P=0.911) and FOLFIRI + Bevacizumab (P=0.190). In particular, we identify a molecular subtype representing 28% of the patients that shows an exceptionally high response rate to FOLFIRI (87.5%). These patients have a two-fold longer overall survival (40.1 months) when treated with FOLFIRI, as first-line regimen, instead of FOLFOX (18.6 months). CONCLUSIONS: Our results demonstrate the interest of molecular classifications to develop tailored therapies for patients with metastatic colorectal cancer and a strong impact of the first-line regimen on the overall survival of some patients. This however remains to be confirmed in a large prospective clinical trial.
Authors: Janneke F Linnekamp; Sander R van Hooff; Pramudita R Prasetyanti; Raju Kandimalla; Joyce Y Buikhuisen; Evelyn Fessler; Prashanthi Ramesh; Kelly A S T Lee; Grehor G W Bochove; Johan H de Jong; Kate Cameron; Ronald van Leersum; Hans M Rodermond; Marek Franitza; Peter Nürnberg; Laura R Mangiapane; Xin Wang; Hans Clevers; Louis Vermeulen; Giorgio Stassi; Jan Paul Medema Journal: Cell Death Differ Date: 2018-01-05 Impact factor: 15.828
Authors: S Cherradi; A Ayrolles-Torro; N Vezzo-Vié; N Gueguinou; V Denis; E Combes; F Boissière; M Busson; L Canterel-Thouennon; C Mollevi; M Pugnière; F Bibeau; M Ychou; P Martineau; C Gongora; M Del Rio Journal: J Exp Clin Cancer Res Date: 2017-06-28