Clinical Features and Outcomes of Patients with Colorectal Cancers Harboring NRAS Mutations

Abstract

<b>Purpose:</b><i>NRAS</i> mutations are now routinely included in RAS testing prior to EGFR inhibitor therapy for metastatic colorectal cancer (mCRC). The clinical implications of <i>NRAS</i> mutation beyond lack of response to anti-EGFR therapy, however, are not known. We undertook this study to determine the clinical features and treatment outcomes of patients with <i>NRAS</i>-mutant mCRC.<b>Experimental Design:</b> We reviewed clinical characteristics, concurrent mutations, and outcomes for all mCRC cases with <i>NRAS</i> mutations undergoing standard genotyping at our institution from 2008 to 2015. Comparison groups consisted of <i>RAS</i> wild-type and <i>KRAS</i>-mutant mCRC consecutive cases genotyped from 2008 to 2012.<b>Results:</b> Three percent (87/2764) of mCRC patients had <i>NRAS</i>-mutant tumors (45% exon 2 and 55% exon 3), including three cases with concurrent <i>NRAS</i> and <i>KRAS</i> mutations. Left-sided primary site and African American self-reported race were associated with <i>NRAS</i> mutation (<i>P</i> < 0.01). Resection rate at 12 months was lower for <i>NRAS</i>-mutant mCRC than for <i>RAS</i> wild-type or <i>KRAS</i>-mutant mCRC. Median survival from time of first known metastasis was 33 months for <i>NRAS</i>-mutant, 47 months for <i>KRAS</i>-mutant, and 78 months for <i>RAS</i> wild-type cases (<i>P</i> < 0.001). Multivariate analysis assigned an HR for overall survival of 2.0 for <i>NRAS</i> mutation and 1.5 for <i>KRAS</i> mutation (<i>P</i> < 0.01).<b>Conclusions:</b><i>NRAS</i> defines a molecular subset with distinct clinical characteristics from <i>KRAS</i>-mutant and wild-type mCRC. <i>NRAS</i> mutations are enriched in left-sided primary tumors and among African Americans. Mutations in <i>NRAS</i> are associated with poor survival and worse outcomes than either <i>KRAS</i>-mutant or wild-type mCRC. <i>Clin Cancer Res; 23(16); 4753-60. ©2017 AACR</i>.