Primary Tumor Biology, Recurrence and Survival After Colorectal Liver Metastasis Resection: The BIO-CRLM Study

OBJECTIVE: To evaluate whether integrated primary tumor biology, combining primary tumor location and RAS/BRAF status, defines recurrence phenotypes and survival trajectories after liver resection for colorectal liver metastases (CRLM). SUMMARY BACKGROUND DATA: Selection for resection remains largely morphology-based, although tumor biology strongly influences post-hepatectomy outcomes. Primary tumor site and RAS/BRAF status are individually prognostic, but whether their integration identifies distinct post-resection trajectories is unclear. METHODS: An international multicenter cohort of patients undergoing liver resection for CRLM between 2017 and 2023 was analyzed. Integrated biology was defined a priori as left-sided-wild-type, right-sided-wild-type, rectal-wild-type, left-sided-RAS-mutant, right-sided-RAS-mutant, rectal RAS-mutant, and BRAF-mutant disease. Primary outcomes were recurrence-free survival (RFS) and overall survival (OS). Secondary outcomes included early recurrence, disseminated first recurrence, and first recurrence phenotype. RESULTS: Among 3162 patients from 44 centers, 2415 (76.4%) developed recurrence and 1342 (42.4%) died. Integrated biology was independently associated with both RFS and OS (global P<0.001 for both). Compared with left-WT tumors, the highest mortality risks were observed in BRAF-mutant disease [hazard ratio (HR): 2.68, 95% CI: 2.02-3.57, P<0.001] and right-RAS-mutant disease (HR: 2.32, 95% CI: 1.94-2.79, P<0.001). Integrated biology was also associated with early recurrence, disseminated first recurrence, and first recurrence phenotype. Rectal-RAS-mutant tumors had the strongest association with lung-only recurrence [relative risk ratio (RRR): 3.38, 95% CI: 2.22-5.13, P<0.001] and disseminated recurrence (RRR: 2.57, 95% CI: 1.86-3.55, P<0.001) relative to liver-only recurrence. CONCLUSIONS: Integrated primary tumor biology identifies clinically distinct post-hepatectomy disease trajectories after CRLM resection. Combining primary tumor site with RAS/BRAF status may support preoperative counseling, surveillance planning, and trial stratification.