Clinical features and outcomes of patients with colorectal cancers harboring NRAS mutations

Purpose:  NRAS mutations are now routinely included in RAS testing prior to EGFR (epidermal growth factor receptor) inhibitor therapy for metastatic colorectal cancer (mCRC).  The clinical implications of NRAS 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 NRAS mutant mCRC.<br />Experimental Design: We reviewed clinical characteristics, concurrent mutations, and outcomes for all mCRC cases with NRAS mutations undergoing standard genotyping at our institution from 2008-2015.  Comparison groups consisted of RAS wild-type and KRAS mutant mCRC consecutive cases genotyped from 2008-2012.<br />Results: Three percent (87/2764) of mCRC patients had NRAS mutant tumors (45% exon 2, 55% exon 3), including three cases with concurrent NRAS and KRAS mutations.  Left-sided primary site and African-American self-reported race were associated with NRAS mutation (p<0.01).  Resection rate at 12 months was lower for NRAS mutant mCRC than for RAS wild-type or KRAS mutant mCRC.  Median survival from time of first known metastasis was 33 months for NRAS mutant, 47 months for KRAS mutant, and 78 months for RAS wild-type cases (p<0.001).  Multivariate analysis assigned a hazard ratio for overall survival of 2.0 for NRAS mutation and 1.5 for KRAS mutation (p<0.01).<br />Conclusions: NRAS defines a molecular subset with distinct clinical characteristics from KRAS mutant and wild-type mCRC. NRAS mutations are enriched in left-sided primary tumors and among African Americans.  Mutations in NRAS are associated with poor survival and worse outcomes than either KRAS mutant or wild-type mCRC.

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