Identification of Actionable Fusions as an Anti-EGFR Resistance Mechanism Using a Circulating Tumor DNA Assay
Katherine Clifton1, Thereasa A Rich2, Christine Parseghian1
1The University of Texas MD Anderson Cancer Center, Houston, TX.
JCO Precision Oncology
|October 5, 2020
Summary
Gene fusions were detected in 1.1% of advanced colorectal cancer patients using circulating tumor DNA. These fusions, particularly RET, FGFR3, and ALK, may indicate resistance to anti-EGFR therapies.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Gene fusions are recognized as key drivers of oncogenesis and are emerging as therapeutic targets in advanced colorectal cancer.
- Understanding the prevalence and characteristics of these fusions is crucial for developing targeted treatment strategies.
Purpose of the Study:
- To determine the frequencies and clinicopathological features of gene fusions in advanced colorectal cancer.
- To investigate the potential role of gene fusions as a mechanism of resistance to anti-EGFR therapies.
Main Methods:
- Analysis of circulating tumor DNA (ctDNA) from patients with advanced colorectal cancer using a plasma-based multigene assay.
- Assessment for fusions in key genes including FGFR2, FGFR3, RET, ALK, NTRK1, and ROS1.
- Statistical analysis to compare frequencies and correlate fusions with clinicopathological features and genomic alterations.
Main Results:
- Forty-four unique gene fusions were identified in 1.1% of 3,808 patients with detectable ctDNA.
- RET, FGFR3, and ALK fusions were the most prevalent.
- Fusions were significantly more likely to be subclonal compared to non-fusion variants.
- Subclonal mutations associated with anti-EGFR therapy resistance were frequently observed in patients with fusions.
Conclusions:
- Circulating tumor DNA assays can effectively detect diverse and potentially actionable gene fusions in advanced colorectal cancer.
- The co-occurrence of gene fusions and resistance mutations suggests a novel mechanism of resistance to anti-EGFR therapies in metastatic colorectal cancer.
- These findings highlight the importance of comprehensive genomic profiling for guiding treatment decisions.
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