Worse Survival in Co-Altered RAS-TP53 Patients With Resected Colorectal Liver Metastases.

Background: Next-generation sequencing provides valuable information about mutations within colorectal liver metastases (CRLMs) that impact survival. Existing data focus on prognostic implications of single gene mutations. This study assessed the impact of co-alterations on KRAS/NRAS and TP53 after CRLM resection.

Methods: A retrospective analysis was performed for patients with CRLM who underwent surgical management and had next-generation sequencing (NGS) performed to assess associations with clinical outcomes. Groups were stratified by the presence or absence of RAS-TP53 co-alterations (RTC).

Results: The study cohort consisted of 155 patients with NGS data, with 42 patients (27%) harboring RTC. The baseline characteristics were similar between the groups. The RTC patients had more right-side primary tumors (45% vs. 26%; P = 0.028), presented more frequently with synchronous CRLM (91% vs. 72%; P = 0.017), and were more often deemed initially unresectable (26% vs. 12%; P = 0.038). Medical and surgical management were comparable between the groups, with the majority of the patients receiving systemic therapy (97% overall) and undergoing wedge partial hepatectomies (59% overall). The RTC patients had worse recurrence-free and overall survival, and experienced extrahepatic recurrences sooner (median, 9 vs 14 months; P = 0.014). In the multivariate analyses, RTC (hazard ratio [HR, 2.076; 95% confidence interval [CI], 1.054-4.088; P = 0.035) and post-recurrence locoregional treatments (HR, 0.446; 95% CI 0.222-0.896; P = 0.023) were independently associated with survival.

Conclusions: The RTC patients presented more often with synchronous CRLM, and RTC also was associated with worse oncologic outcomes, suggestive of more aggressive tumor biology. Integration of genome-sequencing data beyond single gene mutations may provide important prognostic information for patients with CRLM to guide management decisions.