Response to PD-1 Blockade in Microsatellite Stable Metastatic Colorectal Cancer Harboring a POLE Mutation

• Published in: Journal of the National Comprehensive Cancer Network Vol. 15; no. 2; p. 142
• Main Authors: Gong, Jun, Wang, Chongkai, Lee, Peter P, Chu, Peiguo, Fakih, Marwan
• Format: Journal Article
• Language: English
• Published: United States 01.02.2017
• Subjects: Adenocarcinoma - drug therapy; Adenocarcinoma - genetics; Adenocarcinoma - pathology; Aged, 80 and over; Antibodies, Monoclonal, Humanized - administration & dosage; Antibodies, Monoclonal, Humanized - therapeutic use; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - therapeutic use; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; B7-H1 Antigen - metabolism; Biopsy; Carcinoembryonic Antigen - analysis; CD8-Positive T-Lymphocytes - metabolism; Colonoscopy; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Colorectal Neoplasms - pathology; DNA Mutational Analysis; DNA Polymerase II - genetics; Drug Resistance, Neoplasm; Gene Expression Profiling - methods; High-Throughput Nucleotide Sequencing; Humans; Lymphocytes, Tumor-Infiltrating - metabolism; Male; Microsatellite Repeats - genetics; Mutation; Neoplasm Recurrence, Local; Poly-ADP-Ribose Binding Proteins; Programmed Cell Death 1 Receptor - antagonists & inhibitors; Programmed Cell Death 1 Receptor - metabolism; Proto-Oncogene Proteins p21(ras) - genetics; Tomography, X-Ray Computed; Tumor Microenvironment
• ISSN: 1540-1413
• DOI: 10.6004/jnccn.2017.0016

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 ( ), 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 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 mutations represent a hypermutated phenotype that may predict response to anti-PD-1 therapy.