Early-onset <i>BRAF</i> -mutant metastatic colorectal cancer: A distinct clinical and molecular signature.

Abstract

e15533 Background: BRAF V600E–mutant metastatic colorectal cancer (mCRC) is associated with poor prognosis and marked biological heterogeneity. Age at disease onset has emerged as a clinically relevant factor in colorectal cancer, but its influence on the biology of BRAF-mutant mCRC remains unclear. We examined whether early-onset (EO) and average-onset (AO) BRAF-mutant mCRC are biologically and clinically distinct subtypes. Methods: In a cohort of 1,209 metastatic colorectal cancer patients profiled by comprehensive next-generation sequencing and microsatellite stable (MSS), 234 BRAF V600E–mutant cases were identified. Patients were classified as early-onset (EO, ≤50 years; n = 73) or average-onset (AO, &gt; 50 years; n = 161). Clinical characteristics, primary tumor location, first-line treatment, tumor mutational burden (TMB), co-mutation profiles, and overall survival (OS) were compared. Results: EO and AO patients had similar sex distribution and performance status. Primary tumor location differed significantly: EO tumors were more frequently left-sided and rectal (left-sided 77.5%, rectal 57.1%), whereas AO tumors were predominantly right-sided (51.0%, p = 0.00017). EO patients more often received intensive first-line therapy (FOLFOXIRI ± anti-VEGF: 47.9% vs 29.2%, p = 0.0087), but despite more intensive upfront treatment, they experienced significantly shorter OS (median 18.5 vs 26.1 months; log-rank p = 0.048). Molecular profiling revealed marked differences. EO tumors had significantly lower TMB (median 6.2 mut/Mb, IQR 4.0–8.9) compared with AO tumors (median 9.8 mut/Mb, IQR 6.1–14.7; p &lt; 0.001) and fewer hypermutated cases. EO tumors were enriched for oncogenic alterations, including TP53 (82%), PIK3CA (48%), FBXW7 (26%) and PTEN (21%), consistent with a MAPK/PI3K-driven, genomically stable phenotype. In contrast, AO tumors showed higher frequencies of RNF43 (31%), APC (58%) and ARID1A (34%), consistent with a serrated, hypermutated molecular phenotype. Conclusions: Age at onset divides BRAF-mutant mCRC into two biologically and clinically distinct diseases. EO-BRAF tumours exhibit an oncogenic-driven, low-TMB profile associated with poorer survival despite more intensive chemotherapy, whereas AO-BRAF tumours show a serrated, hypermutated phenotype with longer survival. These findings emphasise intrinsic biological heterogeneity within BRAF-mutant mCRC and support age-informed molecular stratification in future clinical trials.