Ultra-Hypermutation Driven by POLE Mutation in Metastatic Colorectal Cancer: A Case for Immunotherapy Without dMMR

Abstract Colorectal cancer (CRC) is among the leading causes of cancer-related mortality globally. Metastatic colorectal cancer (mCRC) with ultra-hypermutation is uncommon and its underlying pathogenesis remains incompletely characterized. Additionally, the response to immunotherapy in ultra-hypermutated mCRC is not well defined. Here we report a unique case of a 33-year-old Chinese woman with right-sided colon adenocarcinoma harboring somatic mutations in the POLE (p.A465V), MSH6 (p.G237*), and MSH2 (p.T934M) genes. Despite the presence of MSH6 and MSH2 mutations, immunohistochemistry (IHC) did not show mismatch repair deficiency (dMMR). Genomic analysis revealed high microsatellite instability (MSI-H) and an markedly elevated tumor mutational burden (TMB) of 275.25 Mut/Mb. The patient was initially treated with a combination of nivolumab, capecitabine, and oxaliplatin. Following a favorable response observed through CT and MRI scans after the first treatment cycle, the patient has commenced a second cycle of therapy. To our knowledge, this is the first reported case of ultra-hypermutated mCRC with rare mutations in POLE (p.A465V), MSH6 (p.G237*), and MSH2 (p.T934M) without dMMR, evaluating the efficacy of immune checkpoint inhibitors in this setting.