Association of DNA Mismatch Repair and Mutations in BRAF and KRAS With Survival After Recurrence in Stage III Colon CancersA Secondary Analysis of 2 Randomized Clinical Trials

Frank A. Sinicrope, MD^1,2; Qian Shi, PhD³; Carmen J. Allegra, MD⁴; et alThomas C. Smyrk, MD⁵; Stephen N. Thibodeau, PhD⁵; Richard M. Goldberg, MD⁶; Jeffrey P. Meyers, MS³; Kay L. Pogue-Geile, PhD⁷; Greg Yothers, PhD⁸; Daniel J. Sargent, PhD³; Steven R. Alberts, MD²

Author Affiliations Article Information

JAMA Oncol. Published online December 22, 2016. doi:10.1001/jamaoncol.2016.5469

Key Points

Question What is the association of DNA mismatch repair and mutation in the B-Raf proto-oncogene (c.1799T>A [V600E] [BRAF^V600E]) or the KRAS proto-oncogene (KRAS) with survival after recurrence in patients with stage III colon carcinoma treated in 2 trials of folinic acid (leucovorin calcium), fluorouracil, and oxaliplatin (FOLFOX)–based adjuvant chemotherapy?

Findings In a secondary analysis of 2 randomized clinical trials that include 1395 patients with cancer recurrence, tumors with deficient vs proficient mismatch repair had a 30% reduction in mortality. Mutations in BRAF^V600E, but not KRAS, were associated with shorter survival after recurrence in the overall cohort.

Meaning DNA mismatch repair and BRAF mutations can provide prognostic information in patients with tumor recurrence.

Abstract

Importance The association of biomarkers with patient survival after recurrence (SAR) of cancer is poorly understood but may guide management and treatment.

Objective To determine the association of DNA mismatch repair (MMR) status and somatic mutation in the B-Raf proto-oncogene (c.1799T>A [V600E]; BRAF^V600E) or exon 2 of the KRAS proto-oncogene (KRAS) in the primary tumor with SAR in patients with stage III colon carcinomas treated with adjuvant chemotherapy.

Design, Setting, and Participants Patients with resected stage III colon cancers were randomized to adjuvant FOLFOX (folinic acid [leucovorin calcium], fluorouracil, and oxaliplatin) chemotherapy with or without cetuximab (North Central Cancer Treatment Group N0147 trial) or adjuvant FOLFOX chemotherapy with or without bevacizumab (National Surgical Adjuvant Breast and Bowel Project C-08 trial). Associations of biomarkers with SAR were analyzed using Cox proportional hazards models adjusted for clinicopathologic features and time to recurrence (data collected February 10, 2004, to August 7, 2015).

Main Outcomes and Measures The primary study outcome was survival after recurrence of cancer. A secondary outcome measure was the effect of the site of the primary tumor on the association of biomarkers with SAR.

Results Among 871 patients with cancer recurrence in the N0147 trial (472 men [54.2%] and 399 women [45.8%]; mean [SD] age, 57.8 [11.2] years) and 524 in the C-08 trial (269 men [51.3%] and 255 women [48.7%]; mean [SD] age, 57.0 [11.7] years), multivariable analysis revealed that patients whose tumors had deficient vs proficient MMR had significantly better SAR (adjusted hazard ratio [AHR], 0.70; 95% CI, 0.52-0.96; P = .03). Patients whose tumors harbored mutant BRAF^V600E (AHR, 2.45; 95% CI, 1.85-3.25; P < .001) or mutant KRAS (AHR, 1.21; 95% CI, 1.00-1.47; P = .052) had worse SAR compared with those whose tumors had wild-type copies of both genes, although only results for BRAF^V600E achieved statistical significance. Significant interactions were found for MMR (P = .03) and KRAS (P = .02) by primary tumor site for SAR. Improved SAR was observed for patients with deficient MMR tumors of the proximal vs distal colon (AHR, 0.57; 95% CI, 0.40-0.83; P = .003), and worse SAR was observed for tumors of the distal colon with mutant KRAS in codon 12 (AHR, 1.76; 95% CI, 1.30-2.38; P < .001) and codon 13 (AHR, 1.76; 95% CI, 1.08-2.86; P = .02).

Conclusions and Relevance In patients with recurrence of stage III colon cancer, deficient MMR was significantly associated with better SAR, and this benefit was limited to primary tumors of the proximal colon. Mutations in BRAF^V600E were significantly associated with worse SAR, and worse SAR for BRAF^V600E or KRASmutant tumors was more strongly associated with distal cancers. These biomarkers have implications for patient management at recurrence.

Trial Registration clinicaltrials.gov Identifiers: NCT00079274 and NCT00096278