O-009 - Prognostic value of BRAFV600E and KRAS exon 2 mutations in microsatellite stable stage III colon cancers from patients treated with FOLFOX + /- cetu...

Date 04 July 2015
Event WorldGI 2015
Session Oral and LBA abstracts
Topics Anti-Cancer Agents & Biologic Therapy
Colon Cancer
Pathology/Molecular Biology
Translational Research
Presenter Julien Taieb
Citation Annals of Oncology (2015) 26 (suppl_4): 108-116. 10.1093/annonc/mdv235
Authors J. Taieb1, J. Tabernero2, R.M. Goldberg3, G. Folprecht4, K. Le Malicot5, F. Penault-Llorca6, O. Bouche7, Q. Shi8, S. Thibodeau8, E. Mini9, Z. Zaanan8, J.L. Van Laethem10, D. Sargent11, S. Alberts8, P. Laurent Puig12, F. Sinicrope11
  • 1Hôpital Européen Georges Pompidou, Paris/FR
  • 2Vall d'Hebron Institute of Oncology, Barcelona/ES
  • 3Columbus/US
  • 4University Hospital Carl Gustav Carus, Dresden/DE
  • 5Fédération Francophone de la Cancérologie Digestive, Dijon/FR
  • 6Centre Jean Perrin, Clermont-Ferrand/FR
  • 7Centre Hospitalier Universitaire Robert Debré, Reims/FR
  • 8Hôpital Europeen Georges Pompidou, Paris/FR
  • 9University of Florence, Florence/IT
  • 10Erasme University Hospital - ULB Brussels, Brussels/BE
  • 11Rochester/US
  • 12Institut National de la Santé et de la Recherche Médicale UMR-S775, Paris/FR

Abstract

Introduction

The prognostic value of BRAF and KRAS mutations in resected CC pts remains controversial due to published studies that include stage II & III, MSI and MSS, colon and rectal tumors and variable treatment regimens. We examined this question in prospectively collected biospecimens from MSS stage III CC pts receiving adjuvant FOLFOX +/- cetuximab.

Methods

Tumors were analyzed for BRAF V600E and KRAS exon 2 mutations; only MSS tumors were included. Three groups were defined: BRAF Mutant, KRAS Mutant and double wild-type (WT). The analytic strategy estimated study- and arm-specific prognostic effects to assess homogeneity of results, and then analysis of pooled data. Associations of mutations with time- to-recurrence (TTR), survival after relapse (SAR) and overall survival (OS) were analysed using a stratified Cox proportional hazards model. Multivariate models were adjusted for treatment and covariates (age, sex, tumor grade, T/N stage, tumor location, ECOG PS).

Results

Of the 5577 pts enrolled, 3934 tumors were MSS and evaluable for BRAF and KRAS; 279 pts were BRAF Mutant, 1450 KRAS Mutant, and 2205 WT. Both mutations were linked to shorter TTR and OS vs WT, and results were confirmed in multivariate analyses (table). Median SAR was 2.57, 2.09 and 1.0 year in WT, KRAS Mutant (HR: 1.20–95%CI: 1.01–1.44, p< 0.0001) and BRAF mutant (HR: 3.01–95%CI: 2.32–3.93, p < 0.0001), respectively. No interaction was found between treatment (with or without cetuximab) and KRAS/BRAF mutations for TTR (p = 0.38) or OS (p = 0.16).

Conclusion

In a large pooled analysis of pts with resected stage III MSS colon cancers receiving adjuvant FOLFOX, BRAFV600E or KRAS exon 2 mutations, including codons 12 or 13, are independent predictors of significantly shorter TTR, SAR and OS. Future clinical trials in the adjuvant setting should consider these mutations as important stratification factors.

Table: O-009