Abstract
BackgroundActivating KRAS and BRAF mutations predict unresponsiveness to EGFR-targeting therapies in colorectal cancer (CRC), but their prognostic value needs further validation. In this study, we investigated the impact of KRAS codons 12 and 13, and BRAF mutations on survival from CRC, overall and stratified by sex, in a large prospective cohort study.MethodsKRAS codons 12 and 13, and BRAF mutations were analysed by pyrosequencing of tumours from 525 and 524 incident CRC cases in The Malmö Diet and Cancer Study. Associations with cancer-specific survival (CSS) were explored by Cox proportional hazards regression, unadjusted and adjusted for age, TNM stage, differentiation grade, vascular invasion and microsatellite instability (MSI) status.ResultsKRAS and BRAF mutations were mutually exclusive. KRAS mutations were found in 191/ 525 (36.4%) cases, 82.2% of these mutations were in codon 12, 17.3% were in codon 13, and 0.5% cases had mutations in both codons. BRAF mutations were found in 78/524 (14.9%) cases. Overall, mutation in KRAS codon 13, but not codon 12, was associated with a significantly reduced CSS in unadjusted, but not in adjusted analysis, and BRAF mutation did not significantly affect survival. However, in microsatellite stable (MSS), but not in MSI tumours, an adverse prognostic impact of BRAF mutation was observed in unadjusted, but not in adjusted analysis. While KRAS mutation status was not significantly associated with sex, BRAF mutations were more common in women. BRAF mutation was not prognostic in women; but in men, BRAF mutation was associated with a significantly reduced CSS in overall adjusted analysis (HR = 3.50; 95% CI = 1.41–8.70), but not in unadjusted analysis. In men with MSS tumours, BRAF mutation was an independent factor of poor prognosis (HR = 4.91; 95% CI = 1.99–12.12). KRAS codon 13 mutation was associated with a significantly reduced CSS in women, but not in men in unadjusted, but not in adjusted analysis.ConclusionsResults from this cohort study demonstrate sex-related differences in the prognostic value of BRAF mutations in colorectal cancer, being particularly evident in men. These findings are novel and merit further validation.
Highlights
Activating KRAS and BRAF mutations predict unresponsiveness to epidermal growth factor receptor (EGFR)-targeting therapies in colorectal cancer (CRC), but their prognostic value needs further validation
Prognostic value of BRAF mutation according to microsatellite instability (MSI) status As BRAF mutation has been previously reported to be associated with a poor survival in cases with microsatellite stable (MSS) tumours [8,15,30,31], we examined whether the prognostic value of BRAF mutation differs by MSI status, overall and stratified for sex
BRAF mutation was an independent factor of poor prognosis in MSS tumours
Summary
Activating KRAS and BRAF mutations predict unresponsiveness to EGFR-targeting therapies in colorectal cancer (CRC), but their prognostic value needs further validation. It is becoming increasingly clear that CRC is a highly heterogeneous disease with different genetic and molecular characteristics affecting intrinsic tumour aggressiveness, response to systemic treatment, and, clinical outcome. While KRAS mutation has proven to be predictive of the resistance to epidermal growth factor receptor (EGFR)-inhibiting therapies [3,4], the prognostic value of KRAS mutation in CRC remains unclear. While most studies did not consider specific mutations, accumulating evidence indicates that specific codon 12 and 13 mutations have a stronger impact on the functionality of the KRAS protein, and, its impact on clinical outcome in CRC patients [5,12,13]
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