In an analysis reported in the Journal of Clinical Oncology, Frank A. Sinicrope, MD, of the Mayo Clinic and North Central Cancer Treatment Group (NCCTG), and colleagues investigated the association of deficient DNA mismatch repair with prognosis in patients with stage III colon cancer treated with adjuvant FOLFOX (fluorouracil [5-FU], leucovorin, and oxaliplatin) chemotherapy.¹ They found that patients with proximal mismatch repair–deficient tumors had favorable outcome, whereas those with distal or N2 mismatch repair–deficient tumors had poor outcome.

Study Details

The study population consisted of  resected, stage III colon carcinomas from 2,686 patients randomly assigned to FOLFOX alone or combined with the anti-EGFR antibody with or without cetuximab (Erbitux) in the North Central Cancer Treatment Group (NCCTG) N0147 trial. Prospectively collected tumors were analyzed for DNA mismatch repair protein expression and mutations in BRAF V600E (exon 15) and KRAS (codons 12 and 13), and the association of biomarkers with disease-free survival was determined. In this trial, the addition of cetuximab to FOLFOX failed to improve disease-free survival overall or in patients with wild-type KRAS tumors.

In the full study cohort, deficient DNA mismatch repair was detected in 314 (12%) of 2,580 tumors, and mutations in BRAF V600E and KRAS were detected in 14% and 28% of tumors, respectively. The study required centralized KRAS analysis, and after study initiation, the trial was amended to restrict the population to those patients with wild-type KRAS tumors. BRAF V600E and KRAS mutations were found to be mutually exclusive.

The number of cancers located in the proximal or distal colon was equal in the study population. Patients with proximal vs distal tumors were significantly more likely to be older (median age, 61 vs 56 years, P < .001), female (50% vs 45%, P = .02), and to have tumors with high-grade histology (33% vs 18%, P < .001) and higher T stage (T1 or 2 in 12% vs 18%, T3 in 75% vs 72%, and T4 in 13% vs 10%, P < .001 for trend). Proximal vs distal cancers were significantly more likely to exhibit deficient DNA mismatch repair deficiency (21% vs 3%, P < .001) and to have somatic mutations in BRAF V600E (23% vs 4%, P <  .001) or KRAS (33% vs 23%, P < .001).

Mismatch Repair and Key Mutations

Deficient DNA mismatch repair (vs proficient mismatch repair) was significantly associated with older age (median, 62 vs 58 years, P < .001), female sex (59% vs 46%, P < .001), proximal site (88% vs 45%, P < .001), high-grade histology (53% vs 22%, P < .001), and higher T stage (P = .008 for trend). The proportion of patients with N2 vs N1 nodal classification did not differ (40% vs 42%).

As with deficient mismatch repair, mutated BRAF V600E was significantly associated with older age, female sex, proximal site, high-grade histology, and higher T stage. In contrast to mismatch repair deficiency, BRAF V600E mutations were significantly more common in N2 vs N1 tumors. KRAS mutations were significantly associated with proximal site, low-grade histology, and N1 stage.

Mismatch Repair and Tumor Site

Of the tumors with deficient mismatch repair in the NCCTG trial population, 49.3% and 10.6% had BRAF V600E and KRAS mutations, respectively. Deficient vs proficient mismatch repair status was not prognostic overall for disease-free survival (hazard ratio [HR] = 0.82; 95% confidence interval [CI] = 0.64–1.07, P = .14) after adjustment for clinical variables, BRAF V600E, and KRAS status. However, significant interactions were found between mismatch repair status and primary tumor site (P = .009 for interaction) and lymph node category (N1 vs N2, P = .014 for interaction) for disease-free survival.

Importantly, disease-free survival was significantly increased among mismatch repair–deficient proximal tumors (adjusted HR = 0.71; 95% CI =0.53–0.94, P = .018) but not mismatch repair–deficient distal tumors (adjusted HR = 1.71; 95% CI = 0.99–2.95, P = .056). Disease-free survival was significantly worse for mismatch repair–deficient tumors with N2 vs N1 status (adjusted HR = 3.49, P < .001); a similar but weaker association was observed among mismatch repair–proficient tumors (adjusted HR = 2.05, P < .001).

Validation in an Independent Study Cohort

An independent cohort of 1,264 patients with stage III colon cancer randomly assigned to receive 5-FU/leucovorin or 5-FU/leucovorin plus irinotecan in the phase III Cancer and Leukemia Group B 89803 adjuvant trial was used for validation. No differences in survival were observed between the treatment groups in this trial. A significant interaction between mismatch repair status and tumor site for disease-free survival (P = .037 for interaction) was also observed in the validation cohort after adjustment for clinical factors, but not BRAF V600E or KRAS status given that mutation data were available in only 64% of patients in the validation cohort.

Among patients in the validation cohort with proximal cancers, deficient mismatch repair was significantly associated with improved disease-free survival (HR = 0.59; 95% CI = 0.41–0.86, P = .0039) after adjusting for N category, T stage, histologic grade, age, sex, and study arm. Among distal cancers, disease-free survival did not differ significantly by mismatch repair status (adjusted HR = 1.58; 95% CI = 0.72–3.46, P = .2817), although only 14 of 378 patients had distal mismatch repair–deficient tumors. The significant interaction between mismatch repair and nodal status observed in the NCCTG cohort was not confirmed in the validation cohort (adjusted P = .7010).

BRAF V600E and KRAS Status

In the NCCTG cohort, mutations in BRAF V600E (HR = 1.37; 95% CI = 1.08–1.70, P = .009) or mutations in  KRAS (HR = 1.44; 95% CI = 1.21–1.70, P < .001) were independently associated with significantly worse disease-free survival. Disease-free survival among patients with mismatch repair–deficient tumors did not differ significantly according to mutant vs wild-type BRAF V600E (adjusted HR = 1.58; P = .12) or mutant vs wild-type KRAS. Among the larger number of patients with mismatch repair–proficient tumors, mutated BRAF V600E was associated with significantly worse disease-free survival (adjusted HR = 1.32, P = .044), as was mutated KRAS (adjusted HR = 1.45, P < .001). However, neither the mismatch repair by BRAF V600E status (adjusted P = .93) nor the mismatch repair by KRAS status (adjusted P =  .38) interaction tests were statistically significant.

The investigators concluded:

[T]he prognostic impact of [deficient DNA mismatch repair] on [disease-free survival] was dependent on the primary tumor site in patients with stage III colon cancer, and this finding was validated in an independent cohort. Poor prognostic subgroups were observed within [mismatch repair–deficient] cancers that included distal site and N2 disease, which may have contributed to the nonsignificant overall impact of [deficient DNA mismatch repair] on [disease-free survival]. Mutations in BRAF V600E or KRAS were each independently associated with reduced [disease-free survival] and may therefore provide clinically useful prognostic information in FOLFOX-treated patients. ■

Disclosure: The study was supported by National Cancer Institute and National Institutes of Health grants, with support for correlative studies also provided by Bristol-Myers Squibb, ImClone Systems, Sanofi-Aventis, and Pfizer. For full disclosures of the study authors, visit jco.ascopubs.org.

Reference

1. Sinicrope FA, Mahoney MR, Smyrk TC, et al: Prognostic impact of deficient DNA mismatch repair in patients with stage III colon cancer from a randomized trial of FOLFOX-based adjuvant chemotherapy. J Clin Oncol 31:3664-3672, 2013.