Biomaterial Database

Atypical RAS Mutations in Metastatic Colorectal Cancer. 2019

Filippo Pietrantonio, and Rona Yaeger, and Alexa B Schrock, and Giovanni Randon, and Sandra Romero-Cordoba, and Daniele Rossini, and Giovanni Fucà, and Jeffrey S Ross, and Daisuke Kotani, and Russell Madison, and Seung Tae Kim, and Lisa Salvatore, and Alessandra Raimondi, and Filippo Pagani, and Beatrice Borelli, and Federica Perrone, and Maria Di Bartolomeo, and Vincent A Miller, and Siraj M Ali, and Jeeyun Lee, and Takayuki Yoshino, and Filippo de Braud, and Alfredo Falcone, and Jaclyn F Hechtman, and Chiara Cremolini

Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

OBJECTIVE To describe the clinical and molecular features of metastatic colorectal cancers (mCRCs) bearing uncommon atypical RAS (At-RAS) mutations at codons other than 12, 13, 59, 61, 117, and 146. METHODS 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-RAS 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-RAS-positive and 467 negative cases from the Italian collaboration, Memorial Sloan Kettering Cancer Center, Samsung Medical Center, and the BREAC study. RESULTS At-RAS 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-RAS cases had TMB greater than 20 mutations/Mb. Co-occurring typical RAS/BRAF V600E mutations and NF1 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 RAS/BRAF wild-type mCRC achieved a median overall survival (OS) of 42.1 months, whereas those harboring isolated At-RAS, typical RAS, or BRAF V600E mutations showed a median OS of 32.3, 30.0, and 17.9 months, respectively (P < .001). No significant OS difference (P = .240) was found between patients with At-RAS versus typical RAS-mutated mCRC. Only one of six patients evaluable for primary resistance to anti-epidermal growth factor receptors achieved tumor response. CONCLUSIONS At-RAS mutations may be a marker for RAS pathway activation and can be associated with high co-occurrence of POLE exonuclease domain mutations.