Molecular profiling of metastatic colorectal tumors using next-generation sequencing: a single-institution experience.
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.
Department of Medical Oncology, City of Hope National Medical Center, Duarte, CA, USA.
Jun
J
Gong
Department of Medical Oncology, City of Hope National Medical Center, Duarte, CA, USA.
May
M
Cho
Department of Medical Oncology, City of Hope National Medical Center, Duarte, CA, USA.
Marvin
M
Sy
Department of Medical Oncology, City of Hope National Medical Center, Duarte, CA, USA.
Ravi
R
Salgia
Department of Medical Oncology, City of Hope National Medical Center, Duarte, CA, USA.
Marwan
M
Fakih
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology*; D005260:Female; D005784:Gene Amplification; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D011518:Proto-Oncogene Proteins / Q000235:genetics; D012189:Retrospective Studies
D014408:Biomarkers, Tumor; D011518:Proto-Oncogene Proteins
FoundationOne; comprehensive genomic profiling; metastatic colorectal cancer; next-generation sequencing; retrospective