Association of DNA Mismatch Repair and Mutations in <i>BRAF</i> and <i>KRAS</i> With Survival After Recurrence in Stage III Colon Cancers
Authors: Frank A. Sinicrope, Qian Shi, Carmen J. Allegra, Thomas C. Smyrk, Stephen N. Thibodeau, Richard M. Goldberg, Jeffrey P. Meyers, Kay L. Pogue-Geile, Greg Yothers, Daniel J. Sargent, Steven R. Alberts
Journal: JAMA Oncology (2016)

<h3>Importance</h3> The association of biomarkers with patient survival after recurrence (SAR) of cancer is poorly understood but may guide management and treatment. <h3>Objective</h3> To determine the association of DNA mismatch repair (MMR) status and somatic mutation in the B-Raf proto-oncogene (c.1799T&gt;A [V600E];<i>BRAF</i><sup>V600E</sup>) or exon 2 of the KRAS proto-oncogene (<i>KRAS</i>) in the primary tumor with SAR in patients with stage III colon carcinomas treated with adjuvant chemotherapy. <h3>Design, Setting, and Participants</h3> 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). <h3>Main Outcomes and Measures</h3> 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. <h3>Results</h3> 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;<i>P</i> = .03). Patients whose tumors harbored mutant<i>BRAF</i><sup>V600E</sup>(AHR, 2.45; 95% CI, 1.85-3.25;<i>P</i> &lt; .001) or mutant<i>KRAS</i>(AHR, 1.21; 95% CI, 1.00-1.47;<i>P</i> = .052) had worse SAR compared with those whose tumors had wild-type copies of both genes, although only results for<i>BRAF</i><sup>V600E</sup>achieved statistical significance. Significant interactions were found for MMR (<i>P</i> = .03) and<i>KRAS</i>(<i>P</i> = .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;<i>P</i> = .003), and worse SAR was observed for tumors of the distal colon with mutant<i>KRAS</i>in codon 12 (AHR, 1.76; 95% CI, 1.30-2.38;<i>P</i> &lt; .001) and codon 13 (AHR, 1.76; 95% CI, 1.08-2.86;<i>P</i> = .02). <h3>Conclusions and Relevance</h3> 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<i>BRAF</i><sup>V600E</sup>were significantly associated with worse SAR, and worse SAR for<i>BRAF</i><sup>V600E</sup>or<i>KRAS</i>mutant tumors was more strongly associated with distal cancers. These biomarkers have implications for patient management at recurrence. <h3>Trial Registration</h3> clinicaltrials.gov Identifiers:NCT00079274andNCT00096278