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

Abstract

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.

Keywords: Biomarkers, Tumor; Gastrointestinal Neoplasms; Immunotherapy.

Figure 1

Treatment timeline, radiological and pathological response to second-line sintilimab plus FOLFIRI in a 71-year-old man with stage IVa/cT4aN1M1a, right-sided CRLM harboring POLE EDM (case 2). Radiographic imaging shows resectable multiple metastases (A) in different liver segments originating from the ascending colon (B) at initial diagnoses. The patient received first-line chemotherapy (FOLFOX), which progressed shortly. (C, D) Then he received second-line ICI plus chemotherapy (sintilimab +FOLFIRI) and a notable tumor regression could be seen both in liver metastases (E) and primary tumor (F). simultaneous colectomy and liver metastasectomy were then conducted (G). primary tumor at initial diagnosis was observed using colonoscopy (H) and resection specimens of obvious shrunken colon cancer (I) after ICI plus chemotherapy treatment. H&E staining shows primary tumor at initial diagnosis (J) and pathological complete regression of liver metastases (K) after ICI plus chemotherapy. fibrosis and an infiltration with viable density of many lymphocytes (K, arrowheads) could be seen. IHC showing more CD3 and CD8 tumor-infiltrating lymphocytes (TILs) using a serial section following treatment (N, O) tumor tissue compared with pretreatment (I, M). The comparisons were statistically significant (p<0.01). IHC, immnuohistochemistry; CRLM, colorectal cancer liver metastases; ICI, immune checkpoint inhibitor; pCR, pathological complete response; PD, progressive disease; PR, partial response.

Figure 2

Dynamic changes in serum CEA and circulating NPY/SEPT9/WIF1 DNA methylation of 4 CRLM patients. Bev, bevacizumab; CEA, carcinoembryonic antigen; chemo, chemotherapy; CRLM, colorectal cancer liver metastases; ICI, immune checkpoint inhibitor; meth-cfDNA, circulating cell-free DNA methylation; pCR, pathological complete response.

Figure 3

Molecular classification scheme, tumor mutation burden, and altered genes in different molecular subtypes in 296 CRLM patients by next-generation sequencing. (A) Classification scheme for molecular subtypes: POLE-EDM, MSI-H, POLE non-EDM, and MSS. (B) Tumor mutation burden in four molecular subtypes in 296 CRLM patients. (C) Heatmap for altered genes in four molecular subtypes. CNV, copy number variation; CRLM, colorectal cancer liver metastases; DDR, DNA damage repair; EDM, exonuclease domain mutation; MSI-H, microsatellite instability-high; MSS, microsatellite stable; SNV, single-nucleotide variant.