Study Sheds Light on Acquired Treatment Resistance in Colorectal Cancer

By sequencing circulating tumor DNA (ctDNA) from patients with metastatic colorectal cancer (CRC) before and after treatment with anti-epidermal growth factor receptor (EGFR) antibodies, a team led by scientists from the University of British Columbia has identified mutation patterns associated with acquired treatment resistance. The findings, reported this week in the Journal of Clinical Oncology, may help in the discovery of vulnerabilities in CRC tumors that emerge during therapy. In the study, 169 patients with treatment-refractory metastatic CRC underwent pre-anti-EGFR tissue whole-genome sequencing, followed by ctDNA assessments using Guardant Health's GuardantOMNI assay eight weeks after the start of treatment. Acquired genetic alterations were then compared between patients with prior anti-EGFR therapy and those without. The investigators find that anti-EGFR therapy is associated with multiple polyclonal mutations affecting a spectrum of genes and encompassed single-nucleotide variant/indel, copy amplification, and gene fusion events. Anti-EGFR exposure was also found to increase tumor mutation burden, although it was not associated with a change in sensitivity to downstream immunotherapy. The work reveals "a diverse landscape of acquired resistance mechanisms occurring in patients, typically with polyclonal nature that decays over time, indicating potential for serial ctDNA analysis to guide therapeutic rechallenge in patients," the authors write. The mechanisms identified in the study will facilitate improved tracking of and potential combinatorial strategies to delay or overcome resistance, the researchers add.