A recent study published in JCO Precision Oncology by Caris Life Sciences demonstrates the critical role of next-generation sequencing (NGS) in assessing microsatellite instability (MSI) and mismatch repair deficiency (dMMR) in solid tumors. The study, involving over 190,000 patients, reveals high concordance between NGS-based MSI (NGS-MSI) and immunohistochemistry-based MMR (IHC-MMR) measurements, suggesting NGS as a reliable alternative to IHC.
NGS as a Robust Alternative to IHC-MMR
The research compared NGS-MSI and IHC-MMR results across a wide range of cancer types. The findings indicated only a 0.31% discordance between the two methods, with no significant difference in overall survival observed in discordant tumors. This suggests that NGS can effectively identify dMMR-driven tumors, which are often responsive to immune checkpoint inhibitors (ICIs).
Advantages of NGS Beyond MMR Assessment
According to David Spetzler, MS, PhD, MBA, President of Caris, NGS can detect dMMR cases that IHC might miss, while IHC can identify some cases that NGS may not. However, the study emphasizes that NGS provides valuable information on other actionable biomarkers, making it a comprehensive tool for determining a patient’s eligibility for ICIs and other targeted therapies.
Clinical Implications and Personalized Therapy
The study also assessed molecular characteristics, immunological landscape, and clinical outcomes. As expected, dMMR/MSI-H tumors showed better overall and post-immunotherapy survival compared to MMR-proficient/MSI-Stable tumors. NGS data revealed that high tumor mutational burden (TMB), another biomarker for immunotherapy response, was more prevalent in dMMR/MSI-H tumors, further supporting their eligibility for ICI therapy.
Caris Life Sciences' MI Cancer Seek
Caris Life Sciences recently received FDA approval for MI Cancer Seek as a companion diagnostic (CDx) to identify cancer patients who may benefit from targeted therapies. MI Cancer Seek utilizes NGS-based whole exome sequencing (WES) and whole transcriptome sequencing (WTS) for molecular profiling of solid tumors, including MSI status assessment. This assay includes pan-cancer and tumor-specific indications for FDA-approved therapies like pembrolizumab in MSI-H solid tumors and pembrolizumab plus lenvatinib in ‘not MSI-H’ endometrial carcinomas.
Expert Commentary
George W. Sledge, Jr., MD, EVP and Chief Medical Officer of Caris, stated that accurate MMR assessment is critical for ensuring patients receive the most appropriate treatment. He added that Caris has demonstrated that NGS is not only a robust alternative to IHC-MMR but also offers additional advantages, such as the ability to identify other biomarkers critical for guiding therapy selection.
