Prognostic impact of deficient DNA mismatch repair in patients with stage III colon cancer from a randomized trial of FOLFOX-based adjuvant chemotherapy

Abstract

Purpose: The association of deficient DNA mismatch repair (dMMR) with prognosis in patients with colon cancer treated with adjuvant fluorouracil, leucovorin, and oxaliplatin (FOLFOX) chemotherapy remains unknown.

Patients and methods: Resected, stage III colon carcinomas from patients (N = 2,686) randomly assigned to FOLFOX ± cetuximab (North Central Cancer Treatment Group N0147 trial) were analyzed for mismatch repair (MMR) protein expression and mutations in BRAF(V600E) (exon 15) and KRAS (codons 12 and 13). Association of biomarkers with disease-free survival (DFS) was determined using Cox models. A validation cohort (Cancer and Leukemia Group B 88903 trial) was used.

Results: dMMR was detected in 314 (12%) of 2,580 tumors, of which 49.3% and 10.6% had BRAF(V600E) or KRAS mutations, respectively. MMR status was not prognostic overall (adjusted hazard ratio [HR], 0.82; 95% CI, 0.64 to 1.07; P = .14), yet significant interactions were found between MMR and primary tumor site (P(interaction) = .009) and lymph node category (N1 v N2; P(interaction) = .014). Favorable DFS was observed for dMMR versus proficient MMR proximal tumors (HR, 0.71; 95% CI, 0.53 to 0.94; P = .018) but not dMMR distal tumors (HR, 1.71; 95% CI, 0.99 to 2.95; P = .056), adjusting for mutations and covariates. Any survival benefit of dMMR was lost in N2 tumors. Mutations in BRAF(V600E) (HR, 1.37; 95% CI, 1.08 to 1.70; P = .009) or KRAS (HR, 1.44; 95% CI, 1.21 to 1.70; P < .001) were independently associated with worse DFS. The observed MMR by tumor site interaction was validated in an independent cohort of stage III colon cancers (P(interaction) = .037).

Conclusion: The prognostic impact of MMR depended on tumor site, and this interaction was validated in an independent cohort. Among dMMR cancers, proximal tumors had favorable outcome, whereas distal or N2 tumors had poor outcome. BRAF or KRAS mutations were independently associated with adverse outcome.

Conflict of interest statement

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Figures

Fig 1.

Association of (A) DNA mismatch repair (MMR) status, mutations in (B) BRAFV600E or (C) KRAS, and (D) primary tumor site with disease-free survival in stage III colon carcinomas. Cox models are adjusted for MMR, KRAS, BRAFV600E, T stage, histologic grade, lymph node category, age, sex, treatment, and tumor site. dMMR, deficient DNA mismatch repair; HR, hazard ratio; M, multivariate; mut, mutant; pMMR, proficient DNA mismatch repair; U, univariate; wt, wild type.

Fig 2.

Impact of mismatch repair (MMR) status on disease-free survival by primary tumor site. Tumor site was categorized as (A) proximal versus (B) distal (see Patients and Methods). Cox models are adjusted for T stage, histologic grade, nodal category, age, sex, treatment, tumor site, and mutation status of KRAS and BRAFV600E. dMMR, deficient DNA mismatch repair; HR, hazard ratio; M, multivariate; pMMR, proficient DNA mismatch repair; U, univariate.

Fig 3.

Analysis of the prognostic impact of lymph node category by mismatch repair (MMR) status on disease-free survival. Lymph node category includes N1 (one to three metastatic nodes) or N2 (≥ four metastatic nodes). MMR status is defined as (A) proficient MMR (pMMR) or (B) deficient MMR (dMMR). Cox models are adjusted for T stage, histologic grade, age, sex, treatment, tumor site, and mutational status of KRAS and BRAFV600E. HR, hazard ratio; M, multivariate; U, univariate.

Fig 4.

Impact of (A and B) BRAFV600E or (C and D) KRAS mutations on disease-free survival according to DNA mismatch repair (MMR) status. MMR status is defined as (A and C) proficient MMR (pMMR) or (B and D) deficient MMR (dMMR; see Patients and Methods). Cox models are adjusted for KRAS, BRAFV600E, T stage, histologic grade, nodal category, age, sex, treatment, and tumor site. HR, hazard ratio; M, multivariate; mut, mutant; U, univariate; wt, wild type.

Fig A1.

Association of BRAFV600E or KRAS mutation status as a combined variable with disease-free survival in stage III colon carcinomas. Cox models are adjusted for T stage, histologic grade, nodal category, age, sex, treatment, tumor site, and mismatch repair status. HR, hazard ratio; M, multivariate; mut, mutant; U, univariate; wt, wild type.