Is There a Role for Programmed Death Ligand-1 Testing and Immunotherapy in Colorectal Cancer With Microsatellite
Esmeralda Celia Marginean1, Barbara Melosky1
1From the Department of Pathology, University of Ottawa, Ottawa, Ontario, Canada (Dr Marginean); the Gastrointestinal Pathology Section, The Ottawa Hospital, Ottawa (Dr Marginean); the Department of Medical Oncology, University of British Columbia, Vancouver, Canada (Dr Melosky); and the Department of Oncology, British Columbia Cancer Agency, Vancouver (Dr Melosky).
Context:
- The world of oncology has changed dramatically in the past few years with the introduction of checkpoint inhibitors and immunotherapy. The promising findings of a small, phase 2 clinical trial that led to the US Food and Drug Administration breakthrough designation and approval of the anti-programmed death receptor-1 (PD-1) drug pembrolizumab (Keytruda, Merck, Kenilworth, New Jersey) to treat metastatic/refractory microsatellite instability-high colorectal cancer (CRC) has significantly boosted interest in immunomodulatory therapies in microsatellite instability-high CRC.
Objectives:
- To review the immune response to cancer and the role of immune checkpoints, focusing on the technical and interpretation challenges of PD-1/programmed death ligand-1 (PD-L1) testing by pathologists and the clinical implications of the test and the therapeutic potential of treating CRC with checkpoint inhibitors.
Data Sources:
- A PubMed review was performed of articles pertaining to CRC, microsatellite instability and mismatch repair systems, molecular classification, immune response, PD-1/PD-L1, and immunotherapy.
Conclusions:
- Exciting success with anti-PD-1/PD-L1 and anticytotoxic T-lymphocyte-associated protein 4 (CTLA4) checkpoint inhibitors has already been reported in melanoma and in lung and renal carcinomas. Recently, microsatellite instability-high CRCs, expressing PD-L1 by immunohistochemistry, regardless of the level of that PD-L1 expression, appeared to respond to checkpoint blockades with anti-PD-1 or anti-PD-L1 agents, whereas microsatellite-stable tumors were much less responsive. With microsatellite instability routinely tested by most centers, studies that include larger cohorts are required to study the predictive role of PD-1/PD-L1 expression in microsatellite instability-high CRC, to assess which immunohistochemistry antibodies to use, to refine the scoring criteria, and to critically analyze the interpretation pitfalls.
Insights
Immunotherapy with checkpoint inhibitors shows promise for microsatellite instability-high colorectal cancer (CRC). PD-1/PD-L1 testing is crucial for predicting response to these treatments in CRC patients.
Area of Science:
- Oncology
- Immunology
- Gastroenterology
Background:
- The advent of immunotherapy, including checkpoint inhibitors, has revolutionized cancer treatment.
- Pembrolizumab (Keytruda) has shown efficacy in metastatic/refractory microsatellite instability-high colorectal cancer (CRC), increasing interest in immunomodulatory therapies for this subtype.
- Understanding the immune response in CRC is critical for developing effective treatments.
Purpose of the Study:
- To review the immune response to cancer and the role of immune checkpoints in CRC.
- To examine the technical and interpretation challenges of PD-1/programmed death ligand-1 (PD-L1) testing in CRC.
- To discuss the clinical implications and therapeutic potential of checkpoint inhibitors for CRC.
Main Methods:
- A comprehensive PubMed literature review was conducted.
- Searched terms included colorectal cancer, microsatellite instability, mismatch repair systems, molecular classification, immune response, PD-1/PD-L1, and immunotherapy.
- Analysis focused on studies relevant to immunotherapy in CRC.
Main Results:
- Checkpoint inhibitors (anti-PD-1/PD-L1, anti-CTLA4) have demonstrated success in various cancers like melanoma and lung carcinoma.
- Microsatellite instability-high CRCs expressing PD-L1 responded well to PD-1/PD-L1 blockade, irrespective of PD-L1 expression level.
- Microsatellite-stable tumors showed significantly less responsiveness to these immunotherapies.
Conclusions:
- Further research with larger cohorts is needed to validate the predictive role of PD-1/PD-L1 expression in microsatellite instability-high CRC.
- Standardization of immunohistochemistry antibodies and scoring criteria for PD-1/PD-L1 testing is essential.
- Critical analysis of interpretation pitfalls in PD-1/PD-L1 testing is required for optimal clinical application.
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