Evaluation of the role of the molecular pattern on early recurrence after surgery for colorectal liver metastases

Background: The prognostic and predictive role of molecular tumor profiles in colorectal liver metastases remains controversial, with limited evidence regarding their impact on early recurrence and surgical futility. This prospective multicenter study aimed to evaluate the association between specific molecular alterations (KRAS, NRAS, BRAF, and MSI status), recurrence patterns, and biological futility after curative-intent liver resection. Methods: A total of 337 patients undergoing curative-intent surgery for colorectal liver metastases were prospectively analyzed across multiple HPB centers. Clinicopathologic, morphologic (Tumor Burden Score), and molecular data were collected. Early recurrence was defined as recurrence within 6 months after surgery, and futility was defined as early recurrence not amenable to salvage treatment. Univariate and multivariate analyses were performed to identify independent predictors. Results: Early recurrence occurred in 35.5% of patients, with a futility rate of 26.8%. In the overall cohort, KRAS mutation showed no direct correlation with early recurrence, although the G12A codon mutation emerged as an independent predictor of early recurrence and peritoneal relapse. In patients with synchronous disease and high tumor burden score, mutant KRAS was identified as the only independent predictor of futility (p<0.05). MSI demonstrated a protective effect against hepatic recurrence (p=0.008), whereas mKRAS and mNRAS were inversely associated with liver-only recurrence. Conversely, KRAS (especially G13D, G12A, G12D, and G12V subtypes) was significantly associated with extra-hepatic recurrence, particularly pulmonary, peritoneal, and lymph node relapse. Conclusions: The molecular profile of colorectal liver metastases strongly influences recurrence timing and metastatic patterns. KRAS mutations, especially in patients with synchronous high-TBS disease, predict early recurrence and biological futility, questioning the curative potential of surgery in this subgroup. Kras, Nras, and MSI mutations show a strong association with extrahepatic spread of the disease. Integrating molecular biology and morphologic assessment (TBS) enhances patient stratification, helping to distinguish systemic from truly liver-limited disease and to refine surgical and oncologic strategies. Long-term survival data, ctDNA-based monitoring, and histologic-molecular correlation will be crucial to validate these findings and guide personalized management of colorectal liver metastases.