S3991 When Stable Isn’t Silent: A Case of Microsatellite-Stable Colorectal Cancer With Rare POLE P286R Mutation That Responded Excellently to Pembrolizumab Monotherapy

Introduction: Colorectal cancer (CRC) is the third most diagnosed cancer and third leading cause of cancer-related death in the U.S. Molecular biomarkers now guide metastatic CRC (mCRC) treatment, with NCCN recommending testing for KRAS/NRAS/BRAF, HER2, and MSI/MMR status. Around 3% of MSS CRCs carry POLE/POLD1 mutations, causing hypermutation and high TMB. Pathogenic POLE mutations like P286R may respond to immunotherapy due to neoantigen-driven checkpoint upregulation. Case Description/Methods: A 52-year-old man with uncontrolled diabetes and tobacco use presented with abdominal pain and was found to have a large right colonic mass causing obstruction. He underwent urgent hemicolectomy, which revealed a 9.8 cm, moderately differentiated adenocarcinoma invading the terminal ileum with negative lymph nodes and margins. Initially staged as non-metastatic MSS disease, he later developed peritoneal metastases. He began FOLFOX chemotherapy but genomic testing revealed an ultramutated tumor with TMB of 193 mut/Mb and a pathogenic POLE P286R mutation. Therapy was switched to pembrolizumab, resulting in immediate symptom relief and radiologic improvement, highlighting the impact of immunotherapy in MSS tumors with POLE mutations. Discussion: This case describes a rare instance of MSS metastatic colorectal cancer with a POLE P286R mutation and ultra-high tumor mutational burden (193 mutations/Mb). Molecular profiling guided a shift in management from FOLFOX to immunotherapy, highlighting its critical value when standard treatment fails.