Challenges in patient selection for surgical options in V600E BRAF–mutated metastatic colorectal cancer.

280 Background: V600E BRAF mutated metastatic colorectal cancer (mCRC), which represents almost 10% of mCRC, is associated with a decreased disease-free interval and increased risk of recurrence compared to other mCRC molecular subtypes; however, data show wide outcome heterogeneity within this subgroup. Surgery is known to be associated with improved outcomes in patients with mCRC, particularly in those with liver-only disease. While many patients with V600E BRAF have very aggressive disease and never have the chance to undergo surgery, it is not clear how to navigate the clinical heterogeneity and choose patients that might benefit the most from loco-regional treatment. Methods: We retrospectively evaluated V600E BRAF mutated mCRC patients from two independent high-volume institutions (MDACC and IOV IRCCS) who underwent metastectomy from Oct 2009 to Oct 2023. Patients with MSI-H disease and those who had R2 surgery were excluded. Clinicopathological features, such as sex, age, histology, radicality and site of surgery, were collected from institutional datasets. Relapse free survival (RFS) was defined as the time from surgery to first relapse or progression. Overall survival (OS) was defined as the time from surgery to the date of death or last follow up. Survival was estimated with the Kaplan Meier method, and the Cox proportional Hazard model was adopted for survival comparison. Results: We collected data from 71 V600E BRAF mutated mCRC patients (N=37 MDACC, N=34 IOV IRCCS); 49% were female, 61% had right-sided primary tumor and 62% had synchronous metastatic disease. Median age at metastatic disease diagnosis was 62 years old (IQR: 61-28). For 52% of patients, surgery was performed on liver-only disease; 35% involved the peritoneum. There were no emergency interventions. Median RFS was 7.9 months (95% CI: 5.4 – 10.5) and median OS was 39 months (95% CI: 28.8 – 51.7). No clinicopathological features, including sex, sidedness, histology, differentiation, presentation (synchronous, oligometastatic), or site of intervention, were associated with RFS. However, radicality (R1) was associated with worse RFS (HR=3.5 [95% CI: 1.8 – 6.5], p=0.0003) and OS (HR=2.7 [95%CI: 1.3 – 5.6], p=0.0122). Conclusions: In this retrospective evaluation of patients with V600E BRAF mutated mCRC who underwent metastectomy, only surgical radicality, observed in the post-operative setting, was associated with recurrence and survival outcomes. Therefore, while surgery should be evaluated whenever radical resection is feasible, the identification of patients with V600E BRAF mutated mCRC who might benefit the most from metastasectomy during pre-operative prognosis evaluation remains challenging.