The impact of BRAF mutation on survival of patients with metastatic colorectal cancer depending on the type of surgical and systemic treatment

Abstract

Introduction . Metastatic colorectal cancer (mCRC) remains a leading cause of cancer-related mortality worldwide. BRAF mutations (predominantly V600E) occur in 5–10% of mCRC cases and are associated with an aggressive disease phenotype, poor response to conventional chemotherapy, and dismal prognosis. In the Russian population, the frequency of BRAF mutations is approximately 5.17 %. The assessment of the impact of mutational status, particularly BRAF, on outcomes of different treatment strategies is of high clinical relevance. Objective . To evaluate median overall survival (OS) in mCRC patients according to RAS and BRAFmutational status, and to analyze the efficacy of surgical interventions and systemic therapy options within these molecular subgroups. Materials and methods . A retrospective analysis of 342 mCRC patients treated at Yaroslavl Regional Clinical Oncology Hospital was performed. Molecular profiles included: wild-type RAS/BRAF (n=149), RAS mutations (n=173), and BRAF mutations (n=20). Treatment groups were defined as follows: I – symptomatic therapy (28.9%, n=99); II – primary tumor resection (44.7%, n=153); III – palliative surgery (15.8%, n=54); IV – combined resection of primary tumor and liver metastases (10.6%, n=36). Third-line regimens included FOLFOX + targeted agent (TA), FOLFIRI + TA, regorafenib, and other schedules. Results . Median OS was 29 months for wild-type, 26 months for RAS-mutant (p=0.28252), and 12 months for BRAF-mutant patients (p<0.001). By treatment modality, median OS was: group I – 16 months (95% CI 10.2–21.8), group II – 33 months (95% CI 26.8–37.2), group III – 30 months (95% CI 18.1–41.9), group IV – 31.5 months (95% CI 17.9–40.1) (p=0.00002). Surgical resection of the primary tumor significantly improved OS, whereas additional metastasectomy did not confer a statistically significant survival benefit (p=0.55254). Among third-line options, FOLFOX + TA achieved the longest median OS of 42 months (95% CI 28.5–55.5), significantly outperforming regorafenib (31 months; p=0.012). Conclusions . BRAF V600E mutation is an independent predictor of extremely poor prognosis in mCRC, with a median OS of only 12 months. Surgical removal of the primary tumor markedly improves survival across all molecular subgroups. In the third-line setting, re-induction with FOLFOX plus a targeted agent appears to be the optimal strategy for patients harboring RAS or BRAF mutations.