Microsatellite Instability as a Biomarker for PD-1 Blockade
By J. Dudley, Ming-Tseh Lin, D. Le, J. Eshleman. Clinical Cancer Research, 2016
789 citations recorded by the source corpus.
Initial results by Le and colleagues, which were published in the June 25, 2015 issue of the New England Journal of Medicine, report significant responses of cancers with microsatellite instability (MSI) to anti–PD-1 inhibitors in patients who failed conventional therapy. This finding fits into a broader body of research associating somatic hypermutation and neoepitope formation with response to immunotherapy, with the added benefit of relying on a simple, widely used diagnostic test. This review surveys the pathogenesis and prognostic value of MSI, diagnostic guidelines for detecting it, and the frequency of MSI across tumors, with the goal of providing a reference for its use as a biomarker for PD-1 blockade. MSI usually arises from either germline mutations in components of the mismatch repair (MMR) machinery (MSH2, MSH6, MLH1, PMS2) in patients with Lynch syndrome or somatic hypermethylation of the MLH1 promoter. The result is a cancer with a 10- to 100-fold increase in mutations, associated in the colon with poor differentiation, an intense lymphocytic infiltrate, and a superior prognosis. Diagnostic approaches have evolved since the early 1990s, from relying exclusively on clinical criteria to incorporating pathologic features, PCR-based MSI testing, and immunohistochemistry for loss of MMR component expression. Tumor types can be grouped into categories based on the frequency of MSI, from colorectal (20%) and endometrial (22%–33%) to cervical (8%) and esophageal (7%) to skin and breast cancers (0%–2%). If initial results are validated, MSI testing could have an expanded role as a tool in the armamentarium of precision medicine. Clin Cancer Res; 22(4); 813–20. ©2016 AACR.
Subfields: Cancer Research, Oncology, Pathology and Forensic Medicine
View Paper: https://www.semanticscholar.org/paper/8eff88e272aedf9f425c9ac00d9647e30bb9f814
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Citations in the corpus
- GEPIA2: an enhanced web server for large-scale expression profiling and interactive analysis (2019, background): “For instance, MSI and MSS colorectal cancers respond differently to chemotherapy and immunotherapy (12).”
- The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of squamous cell carcinoma of the head and neck (HNSCC) (2019, background): “While pembrolizumab received FDA approval in 2017 for the treatment of adult and pediatric patients with unresectable or metastatic solid tumors that have been identified as being microsatellite instability-high (MSIH) [70], the frequency of MSI-H HNSCC tumors is relatively low, at about 1–3% [71, 7”
- Landscape of Microsatellite Instability Across 39 Cancer Types (2017, positive): “Identification ofMSI in novel tumor types may lead to an expanded role for immunotherapy and a broader scope of clinicalMSI testing.(82) In addition,MSI is known to be prognostic within colorectal cancer,(83) which may apply in other cancer types as well.”
- Triple-Negative Breast Cancer: A Brief Review About Epidemiology, Risk Factors, Signaling Pathways, Treatment and Role of Artificial Intelligence (2022, background): “Pembrolizumab was approved in 2017 as an anti-PD-1 antibody (Dudley et al., 2016).”
- Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair-Deficient Cancer: Results From the Phase II KEYNOTE-158 Study. (2020, background): “It has been hypothesized that, when these are presented by the major histocompatibility complex, the tumor appears foreign to the patient’s immune system.(5,12) This immunogenic phenotype dictated by the tumor’s genotype renders these tumors susceptible to a potent reactivation of an antitumor respo”