Role of sidedness in pMMR/MSS BRAF mutated metastatic colorectal cancer: descriptive and prognostic analyses from a large real-world clinical cohort

BRAF V600E mutation (BRAFmut) is a known negative prognostic factor, especially in pMMR/MSS mCRC. However, its impact on outcome is heterogeneous. A pooled analysis showed no advantage from the triplet over the doublet in left sided primary mCRC subgroup, regardless MSI status. To our knowledge, no data on early onset (<50 years, y) exist. The aim of our study was to evaluate tumor sidedness and age of onset impact in pts with BRAFmut pMMR/MSS mCRC. Methods This retrospective monocentric study included pts with pMMR/MSS BRAF mut mCRC treated at our Institution from September 2010 to June 2025. Outcome in terms of overall survival (OS) was evaluated. Results 199 pts were included. Primary tumor side was left in 82 pts (41%), of whom 24 (12%) had a rectal location. Median age was 64 years (range 53-7153-71) on the whole population, with a significant difference in left (median 58, range 46-6846-68) vs right sided primary ((median 66, 58-7358-73, p<0.001) sided primary tumor. Early onset diagnosis was observed in 42 (21%) of the pts had an early onset diagnosis, with higher incidence among left vs right primary sided location tumors (32% vs 14% in right location, p=0.0002). Totally, 115 (58%) pts were male, with no significant difference (p=0.1) in left vs right sided primary. 111 pts (55%) received a BRAF inhibitor (BRAFi) treatment in first (25, 22.5%), second (65, 58.6%) or third line and beyond (21, 10.6%). At a median follow up of 81.3 months (mo) (95% CI 60 – NR) in the overall population), median OS (mOS) in the overall population was 18.5 mo (95% CI 15.7 – 21.4). mOS was significantly longer in right vs left sided group: 19.8 (95% CI 16.3 – 23.1) vs 15.3 mo (95% CI 11.8 - 19), respectively (log-rank p=0.017). When considering those with late (>50 y) vs early onset (≤ 50 y) mOS was 18.7 (95% CI 15.7 – 21.3) vs 15.4 mo (95% CI 11.5 – 24.1), respectively (log-rank p =0.12). Unexpectedly, the impact of Unexpectedly, age of onset had a opposite impact in left vs right sided primary age of onset was the opposite in left vs right sided primary:: mOS in left sided early vs late onset was 15.9 vs 11.8 mo, right sided early vs late onset 24.1 vs 20.5 mo. Survival, difference between the worst survival subgroup (left/early onset, mOS 11.8 mo) and the best survival subgroup (right/early onset, 24.1 mo) was clinically and statistically high significant (log rank p=0.0068). When limiting analysis toAnalyzing pts treated with BRAFi (any line), median follow up was 39.1 mo (95% CI 24.4 - NR) and a similar survival OS differences wereas observed in the twoamong subgroups (mOS left sided early vs late onset 7 vs 10.6 mo, right sided early vs late onset 14.5 vs 10.6 mo7.0 vs 14.5 in left/early onset vs right/early onset), despite not reaching statistical significance due to the small sample size (p=0.17). In univariable analysis, left sided tumors have an increased higher risk of death compared to right sided (HR 1.45, p=0.0178). Significance was not confirmed for age of onset. Multivariable analysis confirmed left sided tumor as an independent negative prognostic factor, while ECOG PS 0 and resection of the primary tumor showed a positive prognostic impact.