Julien Taieb1, Karine Le Malicot1, Qian Shi1, Frédérique Penault-Llorca1, Olivier Bouché1, Josep Tabernero1, Enrico Mini1, Richard M Goldberg1, Gunnar Folprecht1, Jean Luc Van Laethem1, Daniel J Sargent1, Steven R Alberts1, Jean Francois Emile1, Pierre Laurent Puig1, Frank A Sinicrope1. 1. Affiliations of authors: Department of Gastroenterology and GI Oncology, Université Paris Descartes, Hopital Européen Georges Pompidou, Paris, France (JTai); Fédération Francophone de Cancérologie Digestive (FFCD), Dijon, France (KLM); Alliance Statistics and Data Center, Mayo Clinic, Rochester, MN (QS, DJS); Department of Pathology, Centre Jean Perrin, EA ERTICa, Université d'Auvergne, Clermont-Ferrand, France (FPL); Centre Hospitalier Universitaire Robert Debré, Reims, France (OB); Medical Oncology Department, Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Barcelona, Spain (JTab); Spanish Gastrointestinal Tumors TTD Group, Universitat Autònoma de Barcelona, Barcelona, Spain (JTab); Section of Clinical Pharmacology and Oncology, Department of Health Sciences, University of Florence, Florence, Italy (EM); Division of Medical Oncology, Ohio State University Comprehensive Cancer Center, Columbus, OH (RMG); First Medical Department, University Hospital Carl Gustav Carus, Dresden, Germany (GF); Department of Gastroenterology, Hôpital Universitaire Erasme, Brussels, Belgium (JLVL); Department of Oncology, Mayo Clinic and Mayo Cancer Center, Rochester, MN (SRA, FAS); Pathology Department, Ambroise Paré Hospital, Boulogne, France (JFE); Université Paris Descartes, Sorbonne Paris Cité, France (PLP); Assistance Publique Hôpitaux de Paris, Department of Biology, Hôpital Européen Georges Pompidou, Paris, France (PLP); INSERM UMR-S1147, Paris, France (PLP).
Abstract
Background: The prognostic value of BRAF and KRAS mutations within microsatellite-unstable (MSI) and microsatellite-stable (MSS) subgroups of resected colon carcinoma patients remains controversial. We examined this question in prospectively collected biospecimens from stage III colon cancer with separate analysis of MSI and MSS tumors from patients receiving adjuvant FOLFOX +/- cetuximab in two adjuvant therapy trials. Methods: Three groups were defined: BRAF Mutant, KRAS Mutant, and double wild-type. The analytic strategy involved estimation of study-specific effects, assessment of homogeneity of results, and then analysis of pooled data as no differences in patient outcome were found between treatment arms in both trials. Associations of mutations with patient outcome were analyzed, and multivariable models were adjusted for treatment and relevant factors. Results:Four thousand four hundred eleven tumors were evaluable for BRAF and KRAS mutations and mismatch repair status; 3934 were MSS and 477 were MSI. In MSS patients, all BRAF V600E mutations (hazard ratio [HR] = 1.54, 95% confidence interval [CI] = 1.23 to 1.92, P < .001), KRAS codon 12 alterations, and p.G13D mutations (HR = 1.60, 95% CI = 1.40 to 1.83, P < .001) were associated with shorter time to recurrence (TTR) and shorter survival after relapse (SAR; HR = 3.02 , 95% CI = 2.32 to 3.93, P < .001, and HR = 1.20, 95% CI = 1.01 to 1.44, P = .04, respectively). Overall survival (OS) in MSS patients was poorer for BRAF-mutant patients (HR = 2.01, 95% CI = 1.56 to 2.57, P < .001) and KRAS-mutant patients (HR = 1.62, 95% CI = 1.38 to 1.91, P < .001) vs wild-type. No prognostic role of KRAS or BRAF mutations was seen in MSI patients. Furthermore, no interaction was found between treatment arm (with or without cetuximab) and KRAS and BRAF mutations for TTR or OS in MSS patients. Conclusions: In a pooled analysis of resected stage III colon cancer patients receiving adjuvant FOLFOX, BRAF or KRAS mutations are independently associated with shorter TTR, SAR, and OS in patients with MSS, but not MSI, tumors. Future clinical trials in the adjuvant setting should consider these mutations as important stratification factors.
RCT Entities:
Background: The prognostic value of BRAF and KRAS mutations within microsatellite-unstable (MSI) and microsatellite-stable (MSS) subgroups of resected colon carcinomapatients remains controversial. We examined this question in prospectively collected biospecimens from stage III colon cancer with separate analysis of MSI and MSS tumors from patients receiving adjuvant FOLFOX +/- cetuximab in two adjuvant therapy trials. Methods: Three groups were defined: BRAF Mutant, KRAS Mutant, and double wild-type. The analytic strategy involved estimation of study-specific effects, assessment of homogeneity of results, and then analysis of pooled data as no differences in patient outcome were found between treatment arms in both trials. Associations of mutations with patient outcome were analyzed, and multivariable models were adjusted for treatment and relevant factors. Results: Four thousand four hundred eleven tumors were evaluable for BRAF and KRAS mutations and mismatch repair status; 3934 were MSS and 477 were MSI. In MSSpatients, all BRAFV600E mutations (hazard ratio [HR] = 1.54, 95% confidence interval [CI] = 1.23 to 1.92, P < .001), KRAS codon 12 alterations, and p.G13D mutations (HR = 1.60, 95% CI = 1.40 to 1.83, P < .001) were associated with shorter time to recurrence (TTR) and shorter survival after relapse (SAR; HR = 3.02 , 95% CI = 2.32 to 3.93, P < .001, and HR = 1.20, 95% CI = 1.01 to 1.44, P = .04, respectively). Overall survival (OS) in MSSpatients was poorer for BRAF-mutant patients (HR = 2.01, 95% CI = 1.56 to 2.57, P < .001) and KRAS-mutant patients (HR = 1.62, 95% CI = 1.38 to 1.91, P < .001) vs wild-type. No prognostic role of KRAS or BRAF mutations was seen in MSI patients. Furthermore, no interaction was found between treatment arm (with or without cetuximab) and KRAS and BRAF mutations for TTR or OS in MSSpatients. Conclusions: In a pooled analysis of resected stage III colon cancerpatients receiving adjuvant FOLFOX, BRAF or KRAS mutations are independently associated with shorter TTR, SAR, and OS in patients with MSS, but not MSI, tumors. Future clinical trials in the adjuvant setting should consider these mutations as important stratification factors.
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