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Circulating Tumor DNA Identifies Diverse Landscape of Acquired Resistance to Anti-Epidermal Growth Factor Receptor
James T Topham1, Chris J O'Callaghan2, Harriet Feilotter2
1BC Cancer, University of British Columbia, Vancouver, BC, Canada.
Purpose:
Anti-epidermal growth factor receptor (EGFR) antibodies are effective treatments for metastatic colorectal cancer. Improved understanding of acquired resistance mechanisms may facilitate circulating tumor DNA (ctDNA) monitoring, anti-EGFR rechallenge, and combinatorial strategies to delay resistance.
Methods:
Patients with treatment-refractory metastatic colorectal cancer (n = 169) enrolled on the CO.26 trial had pre-anti-EGFR tissue whole-exome sequencing (WES) compared with baseline and week 8 ctDNA assessments with the GuardantOMNI assay. Acquired alterations were compared between patients with prior anti-EGFR therapy (n = 66) and those without. Anti-EGFR therapy occurred a median of 111 days before ctDNA assessment.
Results:
ctDNA identified 12 genes with increased mutation frequency after anti-EGFR therapy, including EGFR (P = .0007), KRAS (P = .0017), LRP1B (P = .0046), ZNF217 (P = .0086), MAP2K1 (P = .018), PIK3CG (P = .018), BRAF (P = .048), and NRAS (P = .048). Acquired mutations appeared as multiple concurrent subclonal alterations, with most showing decay over time. Significant increases in copy-gain frequency were noted in 29 genes after anti-EGFR exposure, with notable alterations including EGFR (P < .0001), SMO (P < .0001), BRAF (P < .0001), MET (P = .0002), FLT3 (P = .0002), NOTCH4 (P = .0006), ERBB2 (P = .004), and FGFR1 (P = .006). Copy gains appeared stable without decay 8 weeks later. There were 13 gene fusions noted among 11 patients, all but one of which was associated with prior anti-EGFR therapy. Polyclonal resistance was common with acquisition of ≥ 10 resistance related alterations noted in 21% of patients with previous anti-EGFR therapy compared with 5% in those without (P = .010). Although tumor mutation burden (TMB) did not differ pretreatment (P = .63), anti-EGFR exposure increased TMB (P = .028), whereas lack of anti-EGFR exposure resulted in declining TMB (P = .014).
Conclusion:
Paired tissue and ctDNA sequencing identified multiple novel mutations, copy gains, and fusions associated with anti-EGFR therapy that frequently co-occur as subclonal alterations in the same patient.
Insights
Circulating tumor DNA (ctDNA) analysis revealed novel resistance mechanisms to anti-epidermal growth factor receptor (EGFR) antibodies in metastatic colorectal cancer. These findings aid in monitoring treatment resistance and developing new therapeutic strategies.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Anti-epidermal growth factor receptor (EGFR) antibodies are crucial for treating metastatic colorectal cancer (mCRC).
- Understanding acquired resistance mechanisms is vital for optimizing anti-EGFR therapy and patient outcomes.
- Circulating tumor DNA (ctDNA) offers a non-invasive method for monitoring cancer evolution.
Purpose of the Study:
- To identify novel genetic alterations and mechanisms of acquired resistance to anti-EGFR therapy in mCRC using ctDNA.
- To compare acquired alterations in patients with and without prior anti-EGFR therapy.
- To explore the role of ctDNA in monitoring treatment resistance and informing future therapeutic strategies.
Main Methods:
- Whole-exome sequencing (WES) of pre-anti-EGFR tumor tissue from 169 mCRC patients.
- Baseline and week 8 ctDNA assessments using the GuardantOMNI assay.
- Comparison of acquired alterations between patients with prior anti-EGFR therapy (n=66) and those without.
Main Results:
- ctDNA identified increased mutation frequencies in genes including EGFR, KRAS, BRAF, and NRAS post-anti-EGFR therapy.
- Significant increases in copy-gain frequencies were observed in genes such as EGFR, BRAF, MET, and ERBB2.
- Polyclonal resistance, characterized by multiple concurrent subclonal alterations, was common, particularly after anti-EGFR exposure.
Conclusions:
- Paired tissue and ctDNA sequencing revealed novel mutations, copy gains, and fusions associated with anti-EGFR therapy.
- These resistance alterations frequently co-occur as subclonal events within the same patient.
- Findings support the utility of ctDNA for monitoring resistance and developing combinatorial strategies to overcome treatment failure.
