RT Journal Article SR Electronic T1 Pathological complete response to immune checkpoint inhibitor in patients with colorectal cancer liver metastases harboring POLE exonuclease domain mutation JF Journal for ImmunoTherapy of Cancer JO J Immunother Cancer FD BMJ Publishing Group Ltd SP e004487 DO 10.1136/jitc-2022-004487 VO 10 IS 7 A1 Lei Wen A1 Zhigang Chen A1 Xiaomeng Ji A1 William Pat Fong A1 Qiong Shao A1 Chao Ren A1 Yanyu Cai A1 Binkui Li A1 Yunfei Yuan A1 Deshen Wang A1 Yuhong Li YR 2022 UL http://jitc.bmj.com/content/10/7/e004487.abstract AB Patients with polymerase epsilon (POLE) 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 POLE EDM. Clinical characteristics, radiological and pathological response, as well as oncological outcomes of four CRLM patients harboring POLE 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 POLE 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. POLE EDM patients showed a larger set of mutational genes compared with non-POLE EDM patients. TMB of patients harboring POLE EDM was significantly higher than those with microsatellite instability-high (median, 313.92 vs 42.24 mutations/Mb, p<0.05), POLE 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 POLE EDM exhibit ultra-high TMB and, more importantly, significant clinical response to ICI-based combination therapy. Therefore, the complete sequencing of POLE exonuclease domains is recommended in CRLM patients clinically.The dataset used during the study are available from the corresponding author on a reasonable request.