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Oncotarget. 2017 Feb 2. doi: 10.18632/oncotarget.15030. [Epub ahead of print]

Molecular profiling of metastatic colorectal tumors using next-generation sequencing: A single-institution experience.

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  • 1Department of Medical Oncology, City of Hope National Medical Center, Duarte, CA, USA.

Abstract

BACKGROUND:

Recent molecular characterization of colorectal tumors has identified several molecular alterations of interest that are considered targetable in metastatic colorectal cancer (mCRC).

METHODS:

We conducted a single-institution, retrospective study based on comprehensive genomic profiling of tumors from 138 patients with mCRC using next-generation sequencing (NGS) via FoundationOne.

RESULTS:

Overall, RAS mutations were present in 51.4% and RAF mutations were seen in 7.2% of mCRC patients. We found a novel KRASR68S1 mutation associated with an aggressive phenotype. RAS amplifications (1.4% KRAS and 0.7% NRAS), MET amplifications (2.2%), BRAFL597Ralterations (0.7%), ARAFS214F alterations (0.7%), and concurrent RAS+RAF (1.4%), BRAF+RAF1 (0.7%), and rare PTEN-PIK3CA-AKT pathway mutations were identified and predominantly associated with poor prognosis. ERBB2 (HER2) amplified tumors were identified in 5.1% and all arose from the rectosigmoid colon. Three cases (2.2%) were associated with a hypermutated profile that was corroborated with findings of high tumor mutational burden (TMB): 2 cases with MSI-H and 1 case with a POLE mutation.

CONCLUSIONS:

Comprehensive genomic profiling can uncover alterations beyond the well-characterized RAS/RAF mutations associated with anti-EGFR resistance. ERBB2 amplified tumors commonly originate from the rectosigmoid colon, are predominantly RAS/BRAF wild-type, and may predict benefit to HER2-directed therapy. Hypermutant tumors or tumors with high TMB correlate with MSI-H status or POLE mutations and may predict a benefit from anti-PD-1 therapy.

KEYWORDS:

FoundationOne; comprehensive genomic profiling; metastatic colorectal cancer; next-generation sequencing; retrospective

PMID:
28178681
DOI:
10.18632/oncotarget.15030
[PubMed - as supplied by publisher]
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