Prognostic value of KRAS mutations in stage III colon cancer: post-hoc analysis of the PETACC8 phase III trial dataset
A partir de données portant sur 1 657 patients atteints d'un cancer du côlon de stade III et inclus dans l'essai de phase III PETACC8 d'un traitement adjuvant (FOLFOX +/- cetuximab), cette étude évalue l'association entre la présence de mutations dans l'exon 2 du gène KRAS et la durée de la période sans récidive
Background : The prognostic value of KRAS mutations in colon adenocarcinoma is controversial. We examined this question as an ancillary study of the PETACC8 phase III trial.
Patients and methods : We analyzed the pronostic impact of KRAS exon 2 mutations in Stage III colon cancer patients (n=1657) receiving adjuvant FOLFOX +/- cetuximab therapy included in the PETACC8 trial. Patients with BRAF mutated cancers were excluded and, as no difference was found for TTR and DFS between treatment arms, both were pooled for analysis. Associations with time to recurrence (TTR) and disease-free survival (DFS) were analysed using a Cox proportional hazards model.
Results : KRAS mutations were found in 638/1657 tumors and linked to shorter TTR (p<0.001). However, when specific mutations were compared to wild type, codon 12 mutations (HR: 1.67; 95% confidence interval [CI] [1.35-2.04]; p<0.001) but not codon 13 (HR: 1.23; 95% confidence interval [CI] [0.85-1.79]; p=0.26) were significantly associated with shorter TTR, independently of other covariates. The interaction test showed that, regarding tumor location (distal vs. proximal), KRAS genotype impacts differently on recurrence (p= 0.02) and DFS (p=0.042). Subgroup analysis showed that KRAS only impacted TTR and DFS in distal tumors (n=1043; 692 wild type; 351 mutated), with an increased risk of relapse (HR: 1.96; 95% confidence interval [CI] [1.51-2.56]; p<0.0001) for KRAS codon 12 mutations and a borderline significance for codon 13 mutations (HR: 1.59; 95% confidence interval [CI] [1.00-2.56]; p=0.051).
Conclusion : KRAS exon 2 mutations are independent predictors of shorter TTR in patients with resected stage III distal colon cancers receiving adjuvant therapy. Future clinical trials in the adjuvant setting should consider both the tumor location and KRAS mutations as important stratification factors.
Clinical trial number : This is an ancillary study of the PETACC8 trial: EUDRACT 2005-003463-23
Annals of Oncology , résumé, 2014