MMR/MSI Testing Strategies and Managing Discordance in Colorectal Cancer

This segment focuses on best practices for MMR and MSI testing in CRC, emphasizing that biomarker assessment is a critical and “never-miss” step prior to treatment decision-making. Dr Parikh opens by describing institutional reflex testing workflows, in which all newly diagnosed colorectal carcinomas, regardless of stage, automatically undergo immunohistochemistry (IHC) for loss of MMR proteins, rather than universal PCR-based MSI testing.

The panel discusses real-world challenges despite reflex protocols, noting that testing can still be missed and requires active clinician vigilance. Several faculty highlight the unease that arises when pathology reports lack MMR results, reinforcing the importance of confirming biomarker status before initiating systemic therapy. The discussion then turns to discordance between testing modalities, which, although uncommon, carries significant clinical implications if MSI-H/dMMR disease is overlooked.

Panelists describe scenarios in which IHC suggests MMR deficiency but clinical behavior raises concern for a false-positive result, prompting confirmatory testing with MSI PCR or next-generation sequencing (NGS). Importantly, the group emphasizes that Lynch syndrome status alone does not guarantee that a given tumor will be dMMR, underscoring the need for tumor-specific testing rather than assumptions based on germline genetics.

Institutional approaches vary but increasingly include comprehensive baseline profiling with tissue-based NGS and liquid biopsy, particularly in metastatic disease. Liquid biopsy is valued for its rapid turnaround and complementary assessment of circulating disease, whereas tissue NGS provides deeper characterization. Tumor mutational burden is discussed as an informal cross-check in rare cases of discordance.

The panel concludes by reinforcing that dual-modality testing (MMR IHC plus molecular confirmation) helps mitigate false results, particularly for challenging proteins such as PMS2 and MSH6. Universal, early, and confirmatory testing is framed as essential to ensuring optimal outcomes for patients with CRC.