BRAF Mutation Drives Early Multifocal Intrahepatic Recurrence after Curative Resection of Liver-Limited Colorectal Metastases.

Abstract

BRAF mutations occur in only 2% to 5% of patients undergoing hepatectomy for colorectal liver metastases (CRLM), and their mutation-specific recurrence patterns-especially in comparison with KRAS -remain poorly defined. An international, multi-institutional database was queried for adults who underwent curative-intent resection of liver-limited CRLM between 2000 and 2023 (N = 1,729). Multivariable Cox proportional hazards and logistic regression models assessed the association between KRAS / BRAF status and (1) first-site recurrence (intrahepatic vs extrahepatic) and (2) timing of recurrence (early less than 12 months vs late 12 months or more). KRAS and BRAF mutations were present in 287 (16.7%) and 43 (2.5%) patients, respectively. Relapse was intrahepatic in 537 (31.1%) patients, extrahepatic in 288 (16.7%), and absent in 904 (52.3%). BRAF mutation was independently associated with both intrahepatic (hazard ratio [HR] 3.47, 95% CI 1.61 to 7.51, p = 0.001) and extrahepatic recurrence (HR 3.63, 95% CI 1.12 to 11.79, p = 0.032), whereas KRAS mutation was associated only with extrahepatic relapse (HR 3.07, 95% CI 1.64 to 5.75; p = 0.001). Both BRAF (odds ratio 3.69, 1.20 to 11.33; p = 0.023) and KRAS (odds ratio 2.50, 95% CI 1.41 to 4.43; p = 0.003) mutations were linked to early recurrence, with the highest risk observed for BRAF (p < 0.001 vs KRAS ). In early intrahepatic relapse, BRAF -mutant tumors recurred with a greater number of lesions (β = 3.12; p = 0.012) but similar lesion size compared with other genotypes. Overall survival after intrahepatic relapse was worse in the presence of any driver mutation (p = 0.018), whereas survival after extrahepatic relapse was unaffected by genotype  (p = 0.470). BRAF mutation-unlike KRAS -emerged as a powerful, independent marker of early, multifocal intrahepatic recurrence and inferior post-hepatectomy survival in CRLM. These findings support intensified liver-focused surveillance and early combination adjuvant therapy for patients with BRAF -mutant disease.