Genomic Predictors of Recurrence Patterns After Complete Resection of Colorectal Liver Metastases and Adjuvant Hepatic Artery Infusion Chemotherapy

Abstract

Background: Despite curative hepatectomy, most colorectal liver metastasis (CRLM) patients relapse locally within 2 years. Genomic predictors for hepatic recurrence are poorly understood. This study was designed to identify genomic signatures for recurrence in resected CRLM patients treated with adjuvant hepatic artery infusion (HAI) and/or systemic (SYS) chemotherapy. Methods: Patients undergoing curative hepatectomy and adjuvant HAI+SYS or SYS between January 2000 and October 2017 with next-generation sequencing data were catalogued. Gene and signaling-level alterations were checked for association with time to any (AR), liver (LR), and extrahepatic recurrence (ER) by using Kaplan-Meier analysis. Results: Of 172 receiving HAI+SYS, 100 patients recurred, with 69 LR and 83 ER. Five- and ten-year LR-free rates were 57% (95% confidence interval [CI] 48–65%) and 51% (95% CI 41–60%), respectively. Five- and 10-year ER-free, rates were 51% (95% CI 43–58%) and 45% (95% CI 36–54%), respectively. More ER was observed with tumors harboring altered KRAS (38% [95% CI 25–50%] vs. 63% [95% CI 53–71%], p-adj = 0.003) and RAS/RAF (36% [95% CI 25–48%] vs. 66% [95% CI 56–74%], p-adj < 0.001) than wild-type. Co-altered RAS/RAF-TP53 was associated with worse AR (26% [95% CI 14–40%] vs. 48% [95% CI 39–57%], p-unadj < 0.001), ER (30% [95% CI 17–45%] vs. 62% [95% CI 53–70%], p-unadj < 0.001), and LR rate (40% [95% CI 24–57%] vs. 70% [95% CI 60–77%], p-unadj = 0.002). On multivariable analysis, controlling for clinical risk score, ablation, margin status, and primary T-stage, co-altered RAS/RAF-TP53 was associated with increased risk for AR (HR = 2.14, 95% CI 1.38–3.31, p-unadj < 0.001), LR (HR = 1.79, 95% CI 1.06–3.02, p-unadj = 0.029), and ER (HR = 2.81, 95% CI 1.78–4.44, p-unadj < 0.001). Conclusions: Altered KRAS, RAS/RAF, and RAS/RAF-TP53 associated with earlier local and distant recurrence in resected CRLM patients receiving adjuvant HAI+SYS. Co-altered RAS/RAF-TP53 was a novel predictor of LR warranting investigation of whether genomic cooperativity is associated with this relapsing phenotype. Systemic therapies tailored to high-risk tumor biology are needed to reduce distant relapse after hepatectomy.