Deficient DNA Mismatch Repair Associated With Favorable Prognosis in Proximal Tumors in Stage III Colon Cancer Patients Receiving Adjuvant FOLFOX
In an analysis reported in 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. They found that patients with proximal DNA mismatch repair–deficient tumors had favorable outcome, whereas those with distal or N2 DNA mismatch repair–deficient tumors had poor outcome.
Study Details
In the study, resected, stage III colon carcinomas from 2,686 patients randomly assigned to FOLFOX/cetuximab (Erbitux) in the NCCTG N0147 trial were analyzed for DNA mismatch repair protein expression and mutations in BRAF V600E(exon 15) and KRAS (codons 12 and 13), and association of biomarkers with disease-free survival was determined. In the NCCTG N0147 trial, the addition of cetuximab to FOLFOX failed to improve disease-free survival overall or in patients with wild-type KRAS tumors. 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 88903 adjuvant trial was used for validation. No differences in survival were observed between the treatment groups in this trial.
Interaction of DNA Mismatch Repair and Tumor Site
In the NCCTG N0147 population, deficient DNA mismatch repair was detected in 314 (12%) of 2,580 tumors; of these, 49.3% and 10.6% had BRAF V600Eor KRAS mutations, respectively. Deficient vs proficient DNA mismatch repair status was not prognostic overall for disease-free survival (hazard ratio [HR] = 0.82, P = .14) after adjustment for clinical variables, BRAF V600E, and KRAS status.
However, significant interactions were found between DNA mismatch repair status and primary tumor site (P = .009 for interaction) and lymph node category (N1 vsN2, P = .014 for interaction). Disease-free survival was significantly increased for DNA mismatch repair–deficient proximal tumors (adjusted HR = 0.71, P = .018) but not DNA mismatch repair– deficient distal tumors (adjusted HR = 1.71, P = .056). Disease-free survival was significantly worse for DNA mismatch repair–deficient tumors with N2 vs N1 status (adjusted HR = 3.49, P < .001); a similar but weaker association was observed among DNA mismatch repair–proficient tumors (adjusted HR = 2.05, P < .001).
Significant Interaction in Validation Cohort
A significant interaction between DNA 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; no adjustment for BRAF V600Eor KRAS status was made because mutation data were available in only 64% of patients in the validation cohort. Among patients in the validation cohort with proximal cancers, deficient DNA mismatch repair was significantly associated with improved disease-free survival (HR = 0.59, 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 DNA mismatch repair status (adjusted HR = 1.58, P = .2817), although only 14 of 378 patients had distal DNA mismatch repair–deficient tumors. The significant interaction between DNA mismatch repair and nodal status observed in the NCCTG cohort was not confirmed in the validation cohort (adjusted P = .7010).
Effect of BRAF V600E and KRAS Status
In the NCCTG cohort, disease-free survival among patients with DNA mismatch repair–deficient tumors did not differ significantly according to mutant vs wild-type BRAF (adjusted HR = 1.58, P = .12) or mutant vs wild-type KRAS. Among patients with DNA 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 DNA mismatch repair by BRAF V600E status (adjusted P = .93) nor the DNA mismatch repair by KRAS status (adjusted P = .38) interaction tests were statistically significant. Mutations in BRAF V600E (HR = 1.37, P = .009) and mutations in KRAS (HR = 1.44, P < .001) were independently associated with worse disease-free survival.
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 [DNA 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 V600Eor KRAS were each independently associated with reduced [disease-free survival] and may therefore provide clinically useful prognostic information in FOLFOX-treated patients.”
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.
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