RAS Mutation Predicts Positive Resection Margins and Narrower Resection Margins in Patients Undergoing Resection of Colorectal Liver Metastases

Kristoffer Watten Brudvik, Yoshihiro Mise, Michael Hsiang Chung, Yun Shin Chun, Scott E. Kopetz, Guillaume Passot, Claudius Conrad, Dipen M. Maru, Thomas A. Aloia, Jean-Nicolas Vauthey

In patients undergoing resection of colorectal liver metastases (CLM), resection margin status is a significant predictor of survival, particularly in patients with suboptimal response to preoperative therapy. RAS mutations have been linked to more invasive and migratory tumor biology and poor response to modern chemotherapy. The aim of this study was to evaluate the relationship between RAS mutation and resection margin status in patients undergoing resection of CLM. Patients who underwent curative resection of CLM from 2005 to 2013 with known RAS mutation status were identified from a prospectively maintained database. A positive margin was defined as tumor cells <1 mm from the parenchymal transection line. The study included 633 patients, of whom 229 (36.2 %) had mutant RAS. The positive margin rate was 11.4 % (26/229) for mutant RAS and 5.4 % (22/404) for wild-type RAS (p = 0.007). In multivariate analysis, the only factors associated with a positive margin were RAS mutation (hazard ratio [HR] 2.439; p = 0.005) and carcinoembryonic antigen level 4.5 ng/mL or greater (HR 2.060; p = 0.026). Among patients presenting with liver-first recurrence during follow-up, those with mutant RAS had narrower margins at initial CLM resection (median 4 mm vs. 7 mm; p = 0.031). A positive margin (HR 3.360; p < 0.001) and RAS mutation (HR 1.629; p = 0.044) were independently associated with worse overall survival. RAS mutations are associated with positive margins in patients undergoing resection of CLM. Tumors with RAS mutation should prompt careful efforts to achieve negative resection margins.