O-021 - Analysis of DNA mismatch repair and clinical outcome in stage III colon cancers from patients treated with adjuvant FOLFOX +/- cetuximab in the PETA...

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 F. Sinicrope
Citation Annals of Oncology (2015) 26 (suppl_4): 108-116. 10.1093/annonc/mdv235
Authors F. Sinicrope1, J. Tabernero2, J. Taieb3, R.M. Goldberg1, A. Zaanan1, G. Folprecht4, K. Le Malicot5, Q. Shi1, E. Mini1, J.L. Van Laethem6, D. Sargent1, S. Alberts7, P. Laurent Puig8, T. Smyrk1, C. Julie7, A. Zawadi9
  • 1Rochester/US
  • 2Vall d'Hebron Institute of Oncology, Barcelona/ES
  • 3Hôpital Européen Georges Pompidou, Paris/FR
  • 4University Hospital Carl Gustav Carus, Dresden/DE
  • 5Fédération Francophone de la Cancérologie Digestive, Dijon/FR
  • 6Erasme University Hospital - ULB Brussels, Brussels/BE
  • 7Hôpital Ambroise Paré, Boulogne-Billancourt/FR
  • 8Institut National de la Santé et de la Recherche Médicale UMR-S775, Paris/FR
  • 9Centre Hospitalier Départemental Les Oudairies, La Roche-sur-Yon/FR

Abstract

Introduction

The prognostic impact of deficient (d) DNA mismatch repair (MMR), including sporadic and familial types, in stage III colon cancer patients (pts) receiving standard adjuvant FOLFOX therapy remains unknown. We examined the association of MMR status with clinical outcome in two phase III clinical trials of adjuvant FOLFOX +/- cetuximab.

Methods

Prospectively collected tumors from both studies were separately analyzed for MMR protein (MLH1, MSH2, MSH6) expression and mutations in BRAF (V600E). Loss of any MMR protein indicated dMMR. Methylation of the MLH1 gene promoter was studied in tumors with loss of MLH1 and wild-type (WT) BRAF. Associations of MMR status with time-to-recurrence (TTR), disease-free survival (DFS) and overall survival (OS) were analyzed 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, BRAF/KRAS).

Results

The frequency of dMMR in the overall cohort was 10.7% (499/ 4674). 3-year (yr) DFS for dMMR vs proficient (p) MMR pts was 75% vs 74% (HR = 0.87; 95% CI, 0.71-1.07; adjusted p = .196). Among pts with complete biomarker data (N = 4339), there were 405 dMMR tumors of which 265 (65.4%) were categorized as sporadic (BRAF mutation or WT with MLH1 methylation) and 140 (34.6%) as familial (BRAF WT and unmethylated MLH1 or loss of MSH2 or MSH6). DFS rates of pts with sporadic and familial dMMR tumors were similar (HR, 1.15; 95% CI, 0.73-1.81; adjusted p = .54). Pts with dMMR tumors had similar DFS rates, as did pts with pMMR tumors without BRAF or KRAS mutations (Table). Consistent results were found for biomarkers and TTR and OS.

Conclusion

In this large cohort of stage III colon cancer pts enrolled in two adjuvant trials testing FOLFOX +/- cetuximab, MMR status was not prognostic. Similar outcomes were found for sporadic and familial dMMR cases, and when each of these dMMR subtypes was compared to pMMR tumors WT for both BRAF and KRAS genes.

Table: O-021