Response to PD-1 Blockade in Microsatellite Stable Metastatic Colorectal Cancer Harboring a POLE Mutation
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Recent clinical evidence has demonstrated that microsatellite instability (MSI) or defective mismatch repair (MMR) and high tumor mutational load can predict response to the programmed cell death 1 (PD-1) receptor inhibitor pembrolizumab in metastatic colorectal cancer (mCRC). Mutations in polymerase ε (POLE), a DNA polymerase involved in DNA replication and repair, contribute to an ultramutated but microsatellite stable (MSS) phenotype in colorectal tumors that is uniquely distinct from MSI tumors. This report presents the first case in the literature describing a clinical response to pembrolizumab in an 81-year-old man with treatment-refractory mCRC characterized by an MSS phenotype and POLE mutation identified on genomic profiling by next-generation sequencing. On tumor immunostaining, a large amount of CD8-positive tumor infiltrating lymphocytes (TILs) were present, with >90% of these expressing PD-1. More than 99% of PD-L1 expression was identified on nontumor cells in the tumor microenvironment that were close to the PD-1–positive CD8 TILs. mCRC tumors harboring POLE mutations represent a hypermutated phenotype that may predict response to anti–PD-1 therapy.
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mCRC that originates via Pol epsilon mutations displays relatively higher tumor mutational burden, and these patients show increased response to ICB therapy.
“mCRC that originates via Pol epsilon mutations displays relatively higher TMB, and these patients show increased response to ICB therapy [146].”
From Recent Advances in Therapeutic Strategies to Improve Colorectal Cancer Treatment (2024) · cites this paper as [146]
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- Authors
- Gong, J., Wang, C., Lee, P. P., Chu, P., & Fakih, M.
- Affiliations
- Beckman Research Institute (US)
- City Of Hope National Medical Center (US)
- Corresponding author
- Fakih, Marwan
- Venue
- Journal of the National Comprehensive Cancer Network
- Publisher
- Harborside Press, LLC
- Published
- 2017-02
- Volume
- 15
- Issue
- 2
- Pages
- 142-147
- ISSN
- 1540-1405 (ISSN-L)
- 1540-1413
- OpenAlex
- W2593200928
- Cited by
- 207
- References
- 15
- Citations by year
- 2026: 3 · 2025: 9 · 2024: 17 · 2023: 17 · 2022: 32 · 2021: 43 · 2020: 26 · 2019: 31 · 2018: 26 · 2017: 3
- FWCI
- 10.37
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of the National Comprehensive Cancer Network (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Keywords
- metastatic colorectal cancer, POLE mutation, pembrolizumab, anti-PD-1 therapy, anti-PD-1 therapy response, tumor mutational burden, PD-L1 expression, treatment-refractory cancer, predictive biomarkers
- MeSH terms
- Poly-ADP-Ribose Binding Proteins, Adenocarcinoma, Aged, 80 and over, Antineoplastic Agents, Antineoplastic Combined Chemotherapy Protocols, Biopsy, Carcinoembryonic Antigen, Colonoscopy, DNA Mutational Analysis, DNA Polymerase II, Humans, Male, Mutation, Neoplasm Recurrence, Local, Tomography, X-Ray Computed, Colorectal Neoplasms, Lymphocytes, Tumor-Infiltrating, Proto-Oncogene Proteins p21(ras), CD8-Positive T-Lymphocytes, Microsatellite Repeats, Drug Resistance, Neoplasm, Gene Expression Profiling, High-Throughput Nucleotide Sequencing, Tumor Microenvironment, B7-H1 Antigen, Programmed Cell Death 1 Receptor, Antibodies, Monoclonal, Humanized
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