Researchers found an association with MSI phenotype and female sex, high grade, and proximal tumors. BRAF mutation was associated with higher grade, N and T stage, female sex, proximal tumors, and vascular invasion or lymphatic infiltration (VELI). Conversely, KRAS mutations were associated with proximal tumors and VELI. 

Further, BRAF V600E mutations were more common in participants with MSI tumors (32.3% vs 6.4% in MSS; P < .001), whereas KRAS mutations were more common in participants with MSS tumors (34.9% vs 17% in MSI; P < .001).


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Overall, the investigators found that KRAS mutation was significantly associated with a shorter overall survival (HR, 1.56; 95% CI, 1.12 – 2.15; P = .008) and shorter disease-free survival (HR, 1.55; 95% CI, 1.23 – 1.95; P < .001) after multivariate analysis. This association was not found with BRAF V600E.

In participants with MSS tumors, those with the KRAS mutation had significantly shorter overall survival (HR, 1.74, 95% CI, 1.21 – 2.41; P = .002) and disease-free survival (HR, 1.64; 95% CI, 1.29 – 2.08; P < .001) after multivariate analysis. Likewise, multivariate analysis revealed an association with a shorter overall survival (HR, 1.84; 95% CI, 1.01 – 3.36; P = .046) and disease-free survival (HR, 1.74; 95% CI, 1.14 – 2.69; P = .01) in participants with MSS and BRAF V600E mutations.  

Interestingly, an association was reported for MSI tumors with BRAF V600F mutations and a longer disease-free survival (HR, 0.23; 95% CI, 0.06 – 0.92; P = .04) but not overall survival (HR, 0.19; 95% CI, 0.03 – 1.24; P = .08) after multivariate analysis. No association was found between MSI and KRAS mutations for overall survival (HR, 0.90; 95% CI, 0.23 – 3.45; P = .88) and disease-free survival (HR, 0.94; 95% CI, 0.32 – 2.74; P = .91).1

“At the end we here have clearly identified that determination of MSI status, BRAF and KRAS mutations in non metastatic colon cancer are important prognostic factors that may be determined to allow adequate stratification of the patients in future clinical trials in the adjuvant setting,” Dr Taieb wrote Cancer Therapy Advisor.

In an editorial, Sabine Tejpar, MD, PhD, of the Molecular Digestive Oncology Unit in Leuven, Belgium, noted that this study highlightss the previously reported “significant interaction of BRAF and KRAS mutations and MSI status.”

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However, Dr Tejpar pointed out several issues with the study, including low power for reliably detecting effects in the BRAF and MSI tumors. Further, due to wide confidence intervals, the author suggested that it was difficult to draw conclusions from these data about prognostic effects for KRAS-mutated MSI tumors.

The editorial supported Dr Taieb and colleagues in stating that the MSI, BRAF, and KRAS status should be considered in patient stratification.2

References

  1. Taieb J, Zaanan A, Le Malicot K, et al. Prognostic effect of BRAF and KRAS mutations in patients with stage III colon cancer treated with leucovorin, fluorouracil, and oxaliplatin with or without cetuximab: a post hoc analysis of the PETACC-8 Trial [published online ahead of print January 14, 2016]. JAMA Oncol. doi: 10.1001/jamaoncol.2015.5225.
  2. Klingbiel D, Tejpar S. Microsatellite instability and BRAF and KRAS mutations in stage III colon cancer: requirements for accurate prognosis assessment [published online ahead of print January 14, 2016]. JAMA Oncol. doi: 10.1001/jamaoncol.2015.5226.