Background: BRAF mutations occur in only 2–5% of patients undergoing hepatectomy for colorectal liver metastases(CRLM), and their mutation-specific recurrence patterns—especially in comparison with KRAS—remain poorly defined. Study Design: 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 <12 months vs late ≥12 months). Results: KRAS and BRAF mutations were present in 287(16.7%) and 43(2.5%) patients, respectively. Relapse was intrahepatic in 537 patients(31.1%), 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 1.61–7.51; p=0.001) and extrahepatic recurrence(HR:3.63, 1.12–11.79; p=0.032), whereas KRAS mutation was associated only with extrahepatic relapse(HR:3.07, 1.64–5.75; p=0.001). Both BRAF(odds ratio OR:3.69, 1.20–11.33; p=0.023) and KRAS(OR:2.50, 1.41 – 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 poorer in the presence of any driver mutation(p=0.018), whereas survival after extrahepatic relapse was unaffected by genotype(p=0.470). Conclusions: BRAF mutation—unlike KRAS—emerges 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.
Akabane et al. (Wed,) studied this question.