Acquired EGFR Inhibitor Resistance Alterations Identified in ctDNA Analysis in Patients With Refractory Metastatic Colorectal Cancer

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In a study reported in the Journal of Clinical Oncology by Topham et al, circulating tumor DNA (ctDNA) analysis indicated significantly increased frequencies of multiple potential EGFR inhibitor resistance alterations among patients with refractory metastatic colorectal cancer with vs without prior exposure to anti-EGFR therapy.

The study population consisted of 169 patients in a phase II trial (CO.26) assessing the addition of durvalumab/tremelimumab to best supportive care. Among these patients, 66 had received prior anti-EGFR antibody therapy. Tissue whole-exome sequencing performed prior to the study and before anti-EGFR therapy in those who received it was compared with baseline and week 8 ctDNA evaluations during the study. Identified alterations were compared between patients with vs without prior exposure to anti-EGFR therapy. Anti-EGFR therapy occurred a median of 111 days before ctDNA assessment. 

Key Findings

Compared with patients who had no prior anti-EGFR therapy, those with prior treatment had an increased frequency of mutations in 12 genes, 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). Mutations were present as multiple concurrent subclonal alterations, with most showing decay between baseline and week 8 ctDNA analyses.  

Significant increases in copy gain frequency were observed for 29 genes among patients with vs without prior anti-EGFR treatment, including alterations in 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 did not appear to decay over 8 weeks.

A total of 13 gene fusions, including FGFR3 and RET fusions, were found in 11 patients, of whom 10 had received prior anti-EGFR treatment.

Polyclonal resistance was more common in patients with vs without prior anti-EGFR treatment, with ≥ 10 acquired resistance-related alterations found in 21% vs 5% of patients (P = .010).

No difference in tumor mutational burden was found in tissue samples from patients who did not receive anti-EGFR therapy vs those who subsequently received therapy (P = .63). ctDNA analysis showed a significant increase in tumor mutational burden in those who received anti-EGFR therapy (P = .028) and a significant decrease in those who did not (P = .014).

The investigators concluded, “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.”

Jonathan M. Loree, MD, MS, of BC Cancer, University of British Columbia, Vancouver, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by philanthropic donations received through the BC Cancer Foundation and funding from the Terry Fox Research Institute. For full disclosures of the study authors, visit

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