Molecular subtypes of metastatic colorectal cancer are associated with patient response to irinotecan-based therapies |
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| Affiliation: | 1. IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, F-34298, France;2. INSERM, U1194, Montpellier, F-34298, France;3. Université de Montpellier, Montpellier, F-34090, France;4. Institut régional du Cancer de Montpellier, Montpellier, F-34298, France;5. Centre Hospitalier Universitaire de Toulouse, F-31300, France;6. Centre de Recherche en Cancérologie de Toulouse, Unité Mixte de Recherche 1037 INSERM – Université Toulouse III, France;7. Université de Versailles, Boulogne, France;8. Hôpital Ambroise Paré, Boulogne, France;9. Service d''Anatomie et Cytologie Pathologiques, CHU Nîmes, Place du Professeur Debré, 30029, Nîmes, France;10. INSERM U916, Institut Bergonié, Université de Bordeaux, France;11. Service d''oncologie médicale, CHU Dupuytren, avenue Luther-King, 87000, Limoges, France;1. Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, MA, USA;2. Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA, USA;3. Department of Medicine, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA, USA;4. Harvard Medical School, 25 Shattuck Street, Boston, MA, USA;5. Howard Hughes Medical Institute, 4000 Jones Bridge Road, Chevy Chase, MD, USA;1. Digestive Oncology Unit, University Hospital Gasthuisberg, Leuven, Belgium;2. Institute of Pathology, University of Lausanne, Lausanne, Switzerland;3. Department of Hepatogastroenterology, Cliniques universitaires St-Luc, Université Catholique de Louvain, Belgium;4. Swiss Group for Clinical Cancer Research SAKK, Coordinating Center, Bern, Switzerland;5. Bioinformatics Core Facility, SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland;6. Division of Anatomic Pathology, Department of Surgical and Diagnostic Sciences (DISC), University of Genova, Italy;7. Digestive Tumors Unit, Geneva University Hospital, Geneva, Switzerland;8. Ludwig Center for Cancer Research, University of Lausanne, Epalinges, Switzerland;9. Translational Bioinformatics and Statistics, Swiss Cancer Center Lausanne, Department of Oncology, University of Lausanne, Lausanne, Switzerland;1. Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, 03755, Hanover, NH, US;2. Department of Obstetrics & Gynecology, NYC Health + Hospitals/Coney Island, 11235, Brooklyn, NY, US;3. Department of Medicine, Baylor College of Medicine, 77030, Houston, TX, US;4. The Institute for Clinical and Translational Research, Baylor College of Medicine, 77030, Houston, TX, US;1. State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute of Life Sciences (NAILS), School of Life Sciences, Nanjing University, 163 Xianlin Avenue, Nanjing, Jiangsu 210046, China;2. The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University and Clinical Cancer Institute of Nanjing University, 321 Zhongshan Road, Nanjing, Jiangsu 210008, China;3. Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China |
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| Abstract: | BackgroundCurrently, 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 methodsWe 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.ResultsWe 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).ConclusionsOur 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. |
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| Keywords: | Colorectal neoplasms FOLFIRI protocol Folfox protocol Cetuximab Bevacizumab Gene expression profiling |
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