Response to PD-1 blockade in microsatellite stable metastatic colorectal cancer harboring a POLE mutation

J Gong, C Wang, PP Lee, P Chu, M Fakih - Journal of the National …, 2017 - jnccn.org
J Gong, C Wang, PP Lee, P Chu, M Fakih
Journal of the National Comprehensive Cancer Network, 2017jnccn.org
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 …
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.
Colorectal cancer (CRC) represents the third-leading cause of cancer death in both men and women in the United States, with an estimated 49,190 deaths in 2016. 1 The treatment landscape for metastatic CRC (mCRC) is becoming more molecularly driven. The addition of epidermal growth factor receptor (EGFR)–targeting agents to conventional cytotoxic therapy based on RAS and BRAF mutation status in mCRC serves as a recent example of selecting optimal therapy according to patient genomic profiles and molecular phenotypes. 2 This report presents a case in which the programmed cell death 1 (PD-1) receptor inhibitor pembrolizumab was offered based on comprehensive genomic profiling, which identified a polymerase ε (POLE) mutation associated with an ultramutated tumor in a patient with KRAS-mutated, microsatellite stable (MSS) metastatic colon adenocarcinoma.
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