optimizing Biomarker Confirmation in Metastatic Colorectal Cancer: A deep dive into MSI-High/dMMR Testing
The landscape of metastatic colorectal cancer (mCRC) treatment is rapidly evolving,with immunotherapy demonstrating meaningful efficacy in patients harboring microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) tumors. Accurate and reliable biomarker confirmation is paramount for identifying those most likely to benefit from these therapies. this article provides a comprehensive overview of the challenges and best practices surrounding MSI-H/dMMR testing in mCRC, drawing from recent clinical trial data - specifically, insights gleaned from the CheckMate 8HW trial – and current clinical perspectives as of November 9, 2025. The focus is on maximizing sensitivity while acknowledging the practical limitations faced in routine clinical settings.
Understanding MSI-H/dMMR and its Clinical significance
Microsatellites are repetitive DNA sequences found throughout the genome. A functional mismatch repair (MMR) system ensures the fidelity of DNA replication, correcting errors that occur during this process. When the MMR system is deficient (dMMR), errors accumulate, leading to MSI-H. This genomic instability creates neoantigens, making the tumor more recognizable to the immune system and, consequently, more susceptible to immunotherapy.
Recent data from the National Cancer Institute indicates that approximately 5-10% of mCRC patients harbor MSI-H/dMMR tumors. These patients experience substantially improved outcomes with immune checkpoint inhibitors like pembrolizumab and nivolumab, as demonstrated in trials like KEYNOTE-177. Identifying these patients accurately is therefore crucial for personalized treatment strategies.
However, the path to accurate identification isn’t always straightforward.
The CheckMate 8HW Trial and Centralized Confirmation
The CheckMate 8HW trial, investigating nivolumab plus ipilimumab versus chemotherapy in previously treated mCRC, highlighted the importance of rigorous biomarker assessment. The trial protocol stipulated central confirmation of MSI-H/dMMR status, utilizing either immunohistochemistry (IHC) to assess MMR protein expression or polymerase chain reaction (PCR) to directly detect microsatellite instability.
Specifically, the trial defined a positive result as confirmation from one central test - either IHC or PCR. This approach was designed to maximize sensitivity, recognizing that neither test is perfect on its own. IHC assesses the presence or absence of MMR proteins (MLH1, MSH2, MSH6, PMS2), while PCR directly measures the length of microsatellite sequences. Discrepancies can occur due to factors like tumor heterogeneity, sampling errors, and technical variations between laboratories.
The CheckMate 8HW trial employed central confirmation of MSI-H/dMMR status using either IHC or PCR methodologies to maximize sensitivity in identifying patients likely to respond to immunotherapy.
Balancing Sensitivity and Feasibility in Clinical Practice
While the dual-testing approach employed in CheckMate 8HW offers optimal sensitivity, its implementation in routine clinical practice can be challenging.As noted by Ghanem and Pérez-Wert, access to both IHC and PCR testing isn’t universally available. Furthermore, the turnaround time and cost associated with performing both tests can be prohibitive.
So, what are the practical alternatives?
* Prioritize PCR: When resources are limited, PCR-based MSI testing is generally preferred due to its higher analytical sensitivity and specificity.
* Local Laboratory Validation: Ensure that the laboratory performing the testing has undergone rigorous validation and participates in external quality assurance programs. The College of American Pathologists (CAP) offers accreditation programs for molecular pathology laboratories.
* Reflex Testing: Implement a reflex testing strategy. Begin with IHC. If the results are ambiguous or discordant, proceed with PCR confirmation.
* Liquid Biopsy: Emerging technologies like liquid biopsy (ctDNA analysis) offer a non-invasive choice for MSI-H
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