TY - JOUR
T1 - Atypical RAS mutations in metastatic colorectal cancer
AU - Pietrantonio, Filippo
AU - Yaeger, Rona
AU - Schrock, Alexa B.
AU - Randon, Giovanni
AU - Romero-Cordoba, Sandra
AU - Rossini, Daniele
AU - Fucà, Giovanni
AU - Ross, Jeffrey S.
AU - Kotani, Daisuke
AU - Madison, Russell
AU - Kim, Seung Tae
AU - Salvatore, Lisa
AU - Raimondi, Alessandra
AU - Pagani, Filippo
AU - Borelli, Beatrice
AU - Perrone, Federica
AU - Di Bartolomeo, Maria
AU - Miller, Vincent A.
AU - Ali, Siraj M.
AU - Lee, Jeeyun
AU - Yoshino, Takayuki
AU - De Braud, Filippo
AU - Falcone, Alfredo
AU - Hechtman, Jaclyn F.
AU - Cremolini, Chiara
N1 - Publisher Copyright:
© 2019 by American Society of Clinical Oncology.
PY - 2019
Y1 - 2019
N2 - PURPOSE 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. MATERIALS AND 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. CONCLUSION At-RAS mutations may be a marker for RAS pathway activation and can be associated with high cooccurrence of POLE exonuclease domain mutations.
AB - PURPOSE 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. MATERIALS AND 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. CONCLUSION At-RAS mutations may be a marker for RAS pathway activation and can be associated with high cooccurrence of POLE exonuclease domain mutations.
UR - https://www.scopus.com/pages/publications/85086258615
U2 - 10.1200/PO.19.00136
DO - 10.1200/PO.19.00136
M3 - Article
AN - SCOPUS:85086258615
SN - 2473-4284
VL - 3
SP - 1
EP - 11
JO - JCO Precision Oncology
JF - JCO Precision Oncology
ER -
