What is left in pMMR/MSS BRAF V600E metastatic colorectal cancer (mCRC)? Prognostic role of tumor sidedness and molecular co-mutations.

Abstract

e15608 Background: BRAF V600E-mutated pMMR/MSS mCRC has poor prognosis. However, real-world outcomes are heterogeneous and have recently improved with the introduction of front-line BRAF inhibitor-based combinations. We investigated the prognostic role of clinical and molecular features in this subset of mCRC, focusing on tumor sidedness and recurrent co-mutations. Methods: This retrospective single-center study included consecutive patients (pts) with pMMR/MSS BRAF V600E mCRC treated between September 2010 and September 2025 at the Veneto Institute of Oncology-IRCCS. Overall survival (OS) was estimated using Kaplan-Meier method and compared by log-rank test. Cox proportional hazards models were used for uni- and multivariable analyses. Next-generation sequencing data were available in a molecularly profiled subcohort. Results: Among 200 pts, 83 (42%) had left-sided primary tumor. Median age was 64 years (IQR 53 - 71) and ECOG PS was 0 in 51% of pts. Primary tumor was resected in 77% and disease presentation was synchronous in 74% of pts. Liver metastases (mts) were present in 64% of pts. Left-sided tumors occurred at a younger age than right-sided (median 58 vs 68 years; p = 0.001) and more frequently presented as early-onset disease (≤50 years: 33% vs 14%; p = 0.001). After median follow-up of 84.7 months (mo), median OS (mOS) in the cohort was 18.6 mo. Right-sided tumors showed significantly longer OS compared with left-sided tumors (22.6 vs 14.8 mo; p = 0.019). Multivariable analysis identified left-sided tumor (HR 1.54, 95% CI 1.12–2.08; p = 0.007), synchronous disease (HR 1.47, 95% CI 1.01–2.12; p = 0.042), unresected primary tumor (HR 1.49, 95% CI 1.03–2.17; p = 0.036), and ECOG performance status ≥1 (HR 1.37, 95% CI 1.01–1.85; p = 0.044) as independent factors associated with worse OS. Liver mts and early-onset disease had no prognostic role in univariable analyses and were not included in multivariable model. Among 80 molecularly profiled pts, BRAF V600E was confirmed in 100% of pts (n = 80). Frequent co-mutations included TP53 (76%), APC (36%), and SMAD4 (20%), RNF43 (17%), PIK3CA (15%), PTEN (15%), IRS2 amplification (11%) and MYC amplification (11%). PIK3CA and SMAD4 mutations were enriched in left-sided tumors (26% vs 7%, p = 0.014; 35% vs 11%, p = 0.008). No significant gene enrichment was observed in early vs average onset tumors. PIK3CA mutations were associated with worse OS compared with wild-type tumors (19.0 vs 27.2 mo; HR 2.32, 95% CI 1.22–4.04; p = 0.010). No significant prognostic impact was observed for APC, TP53, SMAD4, RNF43, PTEN, MYC and IRS2 too. Conclusions: Tumor sidedness is an independent prognostic factor in pMMR/MSS BRAF-mutant mCRC, with worse outcomes observed in left-sided tumors. PIK3CA co-mutations are enriched in left-sided disease and may contribute to unfavorable prognosis, suggesting their potential role in future stratification strategies.