Mutation Status of <i>RAS, TP53</i>, and <i>SMAD4</i> is Superior to Mutation Status of <i>RAS</i> Alone for Predicting Prognosis after Resection of Colorectal Liver Metastases.

Abstract

Somatic gene mutations have been increasingly recognized to impact prognosis following resection of colorectal liver metastases (CLM). We aimed to determine the impact of combinations of somatic mutations on survival in patients undergoing CLM resection. We identified patients who underwent initial CLM resection during 2007-2017 and had genetic sequencing data available. Risk factors for overall survival (OS) and recurrence-free survival (RFS) were determined using Cox proportional hazards models. Of 1460 patients who underwent CLM resection during the study period, 507 met the inclusion criteria. Multigene testing revealed mutation rates greater than 10% for <i>TP53</i> (mutated in 70.8% of patients), <i>APC</i> (53.5%), <i>RAS</i> (50.7%), <i>PIK3CA</i> (15.8%), and <i>SMAD4</i> (11.0%). <i>BRAF</i> was mutated in 2.0% of patients. <i>BRAF, RAS, TP53</i>, and <i>SMAD4</i> mutations were significantly associated with OS, and <i>RAS, TP53</i>, and <i>SMAD4</i> mutations were significantly associated with RFS. Coexisting mutations in <i>RAS, TP53</i>, and <i>SMAD4</i> were associated with significantly worse OS and RFS than coexisting mutations in any 2 of these genes and mutations in 1 or none of these genes. Coexisting mutations in 2 genes conferred significantly worse OS and RFS than single mutation or no mutations. OS and RFS did not differ significantly between patients with <i>RAS</i> mutation and wild-type <i>TP53</i> and <i>SMAD4</i> and patients with wild-type <i>RAS</i> (<i>P</i> = 0.858 and 0.729, respectively). <i>RAS</i> mutation status alone is not sufficient for precisely predicting prognosis after CLM resection.