Identification of Actionable Fusions as an Anti-EGFR Resistance Mechanism Using a Circulating Tumor DNA Assay
Rich, Thereasa A.
Raymond, Victoria M.
Pereira, Allan Andresson Lima
Loree, Jonathan M.
Bauer, Todd M.
Chae, Young Kwang
Nezami, Mohammad Amin
Wainberg, Zev A.
AffiliationUniv Arizona, Ctr Canc
MetadataShow full item record
PublisherAMER SOC CLINICAL ONCOLOGY
CitationClifton, K., Rich, T. A., Parseghian, C., Raymond, V. M., Dasari, A., Pereira, A. A. L., ... & Sherrill, G. (2019). Identification of actionable fusions as an anti-EGFR resistance mechanism using a circulating tumor DNA assay. JCO Precision Oncology, 3, 1-15.
JournalJCO PRECISION ONCOLOGY
Rights© 2019 by American Society of Clinical Oncology. Licensed under the Creative Commons Attribution 4.0 License.
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AbstractPURPOSE: Gene fusions are established oncogenic drivers and emerging therapeutic targets in advanced colorectal cancer. This study aimed to detail the frequencies and clinicopathological features of gene fusions in colorectal cancer using a circulating tumor DNA assay. METHODS: Circulating tumor DNA samples in patients with advanced colorectal cancer were analyzed at 4,581 unique time points using a validated plasma-based multigene assay that includes assessment of fusions in FGFR2, FGFR3, RET, ALK, NTRK1, and ROS1. Associations between fusions and clinicopathological features were measured using Fisher's exact test. Relative frequencies of genomic alterations were compared between fusion-present and fusion-absent cases using an unpaired t test. RESULTS: Forty-four unique fusions were identified in 40 (1.1%) of the 3,808 patients with circulating tumor DNA detected: RET(n = 6; 36% of all fusions detected), FGFR3 (n = 2; 27%), ALK(n = 10, 23%), NTRK1 (n = 3; 7%), ROS1 (n = 2; 5%), and FGFR2 (n = 1; 2%). Relative to nonfusion variants detected, fusions were more likely to be subclonal (odds ratio, 8.2; 95% CI, 2.94 to 23.00; P < .001). Mutations associated with a previously reported anti-epidermal growth factor receptor (anti-EGFR) therapy resistance signature (subclonal RAS and EGFR mutations) were found with fusions in FGFR3 (10 of 12 patients), RET(nine of 16 patients), and ALK(seven of 10 patients). For the 27 patients with available clinical histories, 21 (78%) had EGFR monoclonal antibody treatment before fusion detection. CONCLUSION: Diverse and potentially actionable fusions can be detected using a circulating tumor DNA assay in patients with advanced colorectal cancer. Distribution of coexisting subclonal mutations in EGFR, KRAS, and NRAS in a subset of the patients with fusion-present colorectal cancer suggests that these fusions may arise as a novel mechanism of resistance to anti-EGFR therapies in patients with metastatic colorectal cancer.
NoteOpen access article
VersionFinal published version
SponsorsNational Cancer Institute T32 Grant [CA009666]; National Cancer Institute K12 Grant [CA088084]
Except where otherwise noted, this item's license is described as © 2019 by American Society of Clinical Oncology. Licensed under the Creative Commons Attribution 4.0 License.