Evaluation of BRAF mutation as a powerful prognostic factor in advanced and recurrent colorectal cancer.

Abstract

413 Background: Alterations in the RAS/RAF/ERK signaling pathways frequently occur in colorectal cancer (CRC). KRAS mutations preclude responsiveness to EGFR-targeted therapies for CRC patients. However, prognostic significance of KRAS mutation is still controversial. The aim of this study is to investigate clinicopathological features of KRAS mutation in codon 12 and 13 as well as of BRAF mutation, and to validate prognostic impact of KRAS/BRAF mutation in advanced and recurrent CRC. Methods: The population consisted of 230 unselected patients who had undergone first-line chemotherapy for advanced and recurrent CRC between November 2002 and June 2010. Cycleave PCR was performed to detect a point mutation at codon 12, 13 or 61 in KRAS, and the V600E mutation in BRAF. Prognostic factors associated with survival were identified using univariate and multivariate logistic and/or Cox proportional hazards analyses. Results: KRAS mutations were present in 34.8% (n= 80) of patients, including 23.5% (n = 54) in codon 12, 11.3% (n = 26) in codon 13, and 0% in codon 61. 6.5% (n = 15) of patients had BRAF mutation. None of the CRC patients carried both KRAS and BRAF mutations. The primary tumor lesions were located on the right side of the colon in 60% of the BRAF mutant patients (p=0.0371). Furthermore, BRAF mutant was significantly associated with the pathological subtypes of poorly differentiated adenocarcinoma/mucinous carcinoma (p<0.0001) and peritoneal metastasis (p=0.0059). The median overall survival for BRAF mutant and KRAS 13 mutant patients was 11.0 and 27.7 months, respectively, which was significantly worse than that for KRAS wild-type (wt)/BRAF wt (40.6 months) (BRAF; HR=3.89, 95% CI 1.83-8.24, p<0.001, KRAS13; HR=2.03, 95% CI 1.10-3.74, p=0.024). After adjustment for significant features by multivariate Cox regression analysis, BRAF mutation was associated with poor overall survival (HR, 3.70, 95% CI, 1.48-9.28; p=0.005), together with performance status 2. Conclusions: This retrospective analysis shows that clinicopathological features of CRC patients with BRAF mutations seem to be distinct from those with wild type BRAF. BRAF mutation is one of the most powerful prognostic factors in advanced and recurrent CRC. No significant financial relationships to disclose.