Pathological complete response to immune checkpoint inhibitor in patients with colorectal cancer liver metastases harboring exonuclease domain mutation.

Patients with polymerase epsilon () exonuclease domain mutation (EDM) exhibits distinct clinical characteristics and extremely high tumor mutation burden (TMB). There is a paucity of data on the therapeutic efficacy of immune checkpoint inhibitors (ICIs) for the treatment of colorectal cancer liver metastases (CRLM) patients with EDM. Clinical characteristics, radiological and pathological response, as well as oncological outcomes of four CRLM patients harboring EDM and treated by ICI plus chemotherapy were retrospectively collected and analyzed. TMB and genomic mutation profiling were also assessed in resected CRLM patients harboring different molecular characteristics. The four CRLM patients received toripalimab or sintilimab plus chemotherapy (FOLFOX or FOLFIRI or XELOX) with or without bevacizumab after EDM were detected. All four patients achieved a radiological partial response. Staged or simultaneous complete surgical resection of the primary tumor and liver metastases was conducted. Pathological complete response was achieved in all four patients. After a median follow-up of 14 (range 9-20) months, all four patients maintained non-evidence of disease status until the last follow-up. EDM patients showed a larger set of mutational genes compared with non- EDM patients. TMB of patients harboring EDM was significantly higher than those with microsatellite instability-high (median, 313.92 vs 42.24 mutations/Mb, p<0.05), non-EDM (313.92 vs 4.80, p<0.001), and MSS subtypes (313.92 vs 4.80, p<0.001). Despite being a rare phenotype, CRLM patients with EDM exhibit ultra-high TMB and, more importantly, significant clinical response to ICI-based combination therapy. Therefore, the complete sequencing of exonuclease domains is recommended in CRLM patients clinically.