Higher frequency of subclonal anti-EGFR resistance mutations in post-treatment samples from patients with colorectal cancer liver metastases following anti-EGFR-based conversion chemotherapy

Abstract

Background/aims Initially unresectable colorectal liver metastases may become resectable after chemotherapy. The acquisition of somatic mutations has been demonstrated to indicate evolving tumor subclones resistant to therapy and hinder R0 resection. However, the added value of mutational profiling in a real-world setting remains to be elucidated. The objective of the present study was to identify recurrent molecular profiles in colorectal cancer liver metastases that had been pre-treated with anti-EGFR monoclonal antibodies plus chemotherapy. Methods A retrospective, single-centre analysis of colorectal cancer liver metastases samples from 30 patients (9 pre-therapy/21 post-therapy) who received chemotherapy and anti-EGFR agents between January 2008 and February 2014 was conducted. Targeted next-generation resequencing (NGS) was performed. Subsequently, the results were compared to publicly available genomic datasets of primary colorectal cancer and colorectal cancer liver metastasis. Results 145 mutations were identified (mean, 5.2 ± 1.3 mutations per sample; range 0–28, median 2, IQR 3.75). Neither mutation count nor RAS status did correlate with the achievement of resectability. NGS confirmed prior identified KRAS mutations in 4/29 patients (14.8%) and revealed further somatic RAS alterations in 5 cases. In addition to the classical colorectal cancer driver mutations, tumors exhibited recurrent mutations in genes implicated in anti-EGFR resistance such as HNF1A (34.4%, 10/29), FGFR2 (31%, 9/29), VHL (27.5%, 8/29) and PDGFR (27.5%, 8/29), ERBB2 (24.1%, 7/29), ABL1 (24.1%, 7/29), SMO (24.1%, 7/29), GNA11 (20.6%, 6/29), RET (20.6%, 6/29), STK11 (20.6%, 6/29), HRAS (20.6%, 6/29) and NRAS (17.2%, 5/29). Conclusion In the current study, we describe a higher frequency of potential anti-EGFR treatment resistance mutations in patients who respond well to the combination of chemotherapy and anti-EGFR monoclonal antibody treatment. Nevertheless, subclonal mutations associated with resistance to anti-EGFR therapy did not affect the secondary resectability of colorectal liver metastases.