Abstract 4510: BRAF V600E mutation status and survival after colorectal cancer diagnosis according to patient and tumor characteristics

Abstract

Abstract BACKGROUND. BRAF mutations in colorectal cancer (CRC) are disproportionately observed in tumors that exhibit microsatellite instability (MSI), and are also associated with other tumor and patient characteristics that may be associated with CRC survival. The association between BRAF mutation status and CRC survival, however, remains unclear. OBJECTIVE. We evaluated the association between the BRAF V600E mutation, which accounts for 90% of BRAF mutations in colorectal tumors, and mortality in CRC patients. METHODS. Men and women diagnosed with incident invasive CRC between 1997-2007 in western Washington State were identified using the Surveillance, Epidemiology, and End Results cancer registry. Formalin-fixed paraffin-embedded tumor tissue specimens were collected for BRAF mutation and MSI assays. A total of 1,826 cases were tested for BRAF mutations using 2 assays specific to the V600E mutation; MSI status was determined based on instability at 10 microsatellite repeats and/or staining for 4 DNA mismatch repair proteins. Follow-up for mortality was completed through linkage to the National Death Index. We used Cox proportional hazards regression to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association between BRAF mutation status and both cause-specific and all-cause mortality after CRC diagnosis. Stratified analyses were conducted by MSI status (MSS, MSI-high), tumor site (proximal, distal, rectal), sex, and age at diagnosis (<50, Δ50). RESULTS. BRAF V600E mutations were detected in 13% of cases (N=231). Cases with BRAF-mutated CRC were more likely to have MSI-high disease (54% vs. 10%, respectively), to have a proximal tumor site (79% vs. 35%), to be female (72% vs. 52%), and to be aged β50 years at diagnosis (88% vs. 72%). Overall, BRAF mutation status was not associated with mortality after adjusting for age and stage at diagnosis, sex, and tumor site (HR = 1.11, 95% CI: 0.76-1.61 and HR = 1.11, 95% CI: 0.85-1.43 for cause-specific and all-cause mortality, respectively). Results were similar by tumor site and by sex. However, the BRAF mutation was associated with higher cause-specific mortality in CRC cases diagnosed at ages <50 (HR=3.10, 95% CI: 1.43-6.71) and in cases with MSS CRC (HR=1.62, 95% CI: 1.04-2.53); similar associations were not observed in cases diagnosed at ages β50 (HR=1.15, 95% CI: 0.75-1.76) or with MSI-high disease (HR=0.88, 95% CI: 0.35-2.18). Comparable patterns of association were observed for all-cause mortality, although there was no significant interaction by age or MSI. DISCUSSION. Our results are consistent with prior reports that the BRAF V600E mutation in CRC is associated with a distinct phenotype. Overall, this distinct phenotype does not translate to differences in survival; however, among CRC cases diagnosed at an early age and among those with MSS CRC, presence of a BRAF V600E mutation is associated with poorer survival. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4510. doi:1538-7445.AM2012-4510