Atypical <i>RAS</i> Mutations in Metastatic Colorectal Cancer.

Abstract

To describe the clinical and molecular features of metastatic colorectal cancers (mCRCs) bearing uncommon atypical <i>RAS</i> (At-<i>RAS</i>) mutations at codons other than 12, 13, 59, 61, 117, and 146. By exploiting five next-generation sequencing sources (Italian collaboration, Memorial Sloan Kettering Cancer Center, Samsung Medical Center, the Biomarker Research for Anti-EGFR Monoclonal Antibodies by Comprehensive Cancer Genomics (BREAC) study, and the Foundation Medicine database), we retrieved 175 At-<i>RAS</i> mutated cases. Molecular data were obtained from 163 samples from Memorial Sloan Kettering Cancer Center and the Foundation Medicine database. Clinical data were available for 27 At-<i>RAS</i>-positive and 467 negative cases from the Italian collaboration, Memorial Sloan Kettering Cancer Center, Samsung Medical Center, and the BREAC study. At-<i>RAS</i> mutations were identified in 163 (0.9%) of 18,270 mCRCs. Among 133 with evaluable microsatellite instability status, 11 (8%) were microsatellite instability high. POLE exonuclease domain mutations had higher frequency (7%) than expected and were found only in microsatellite-stable tumors with high tumor mutational burden (TMB). Overall, 17% (28 of 163) of At-<i>RAS</i> cases had TMB greater than 20 mutations/Mb. Co-occurring typical <i>RAS</i>/BRAF V600E mutations and <i>NF1</i> mutations, presumed to cause RAS activation, were found in 30% and 12% of samples, respectively (up to 43% and 50%, respectively, in TMB-high samples). Patients with <i>RAS/BRAF</i> wild-type mCRC achieved a median overall survival (OS) of 42.1 months, whereas those harboring isolated At-<i>RAS</i>, typical <i>RAS</i>, or BRAF V600E mutations showed a median OS of 32.3, 30.0, and 17.9 months, respectively (<i>P</i> < .001). No significant OS difference (<i>P</i> = .240) was found between patients with At-<i>RAS</i> versus typical <i>RAS</i>-mutated mCRC. Only one of six patients evaluable for primary resistance to anti-epidermal growth factor receptors achieved tumor response. At-<i>RAS</i> mutations may be a marker for RAS pathway activation and can be associated with high co-occurrence of POLE exonuclease domain mutations.