Dr Bou Farhat on a Retrospective Study of NGS vs IHC Sensitivity for dMMR CRC and Endometrial Cancer

EP: 1.Complementary NGS Improves dMMR Detection With IHC in CRC and Endometrial Cancer

EP: 2.Discordant dMMR/IHC Status Correlates With Improved Treatment Outcomes in CRC and Endometrial Cancer

EP: 3.Dr Nassar on MMR Determination by IHC and NGS in CRC and Endometrial Cancer

EP: 4.Bou Farhat and Nassar on the Use of NGS Mutation Signature vs IHC for Identifying dMMR Tumors

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EP: 5.Dr Bou Farhat on a Retrospective Study of NGS vs IHC Sensitivity for dMMR CRC and Endometrial Cancer

Elias Bou Farhat, MD, postdoctoral research fellow, Department of Medicine, Brigham and Women’s Hospital, discusses the methodology and significance of an investigation of the sensitivity of next-generation sequencing (NGS) vs standard immunohistochemistry (IHC) alone in the assessment of mismatch repair deficiency (dMMR) for patients with colorectal cancer (CRC) or endometrial cancer.

The retrospective study primarily included patients with advanced CRC or endometrial cancer diagnosed by Brigham and Women's Hospital pathologists, Bou Farhat begins. These patients had undergone IHC and Oncopanel/Profile NGS analysis at Dana-Farber Cancer Institute using the same tumor sample, he details. A subset of these patients who received at least one dose of checkpoint inhibitor therapy was monitored for survival outcomes. IHC staining was performed for 4 genes: MLH1, MSH2, PMS2, and MSH6, with results categorized as either intact or absent. An absence was noted if 1 of these proteins did not stain positively, Bou Farhat adds.

NGS defined a MRR signature as the presence of more than 1 single nucleotide insertion or deletion in a homopolymer region or 2 or more mononucleotide repeats, Bou Farhat states. Sometimes, IHC results can be subclonal, with some cells staining and others not, potentially leading to misdiagnosis, Bou Farhat notes.

The study found that NGS identified an additional 1.0% of patients with CRC and 5.9% of patients with endometrial cancer as dMMR that had been deemed intact by IHC. Patients with dMMR tumors who were missed by IHC but detected by NGS-based mutation signature (NGS/IHC discordant) experienced similar clinical outcomes with immunotherapy as those identified as dMMR by both IHC and NGS mutation signature (NGS/IHC concordant) in both cancer types. Moreover, patients with discordant results had improved outcomes compared with those with concordant MMR-proficient (pMMR) results. Patients with CRC or endometrial cancer who had discordant results and were treated with checkpoint inhibitors achieved prolonged overall survival vs checkpoint inhibitor–naive patients who received other systemic therapies.

The analysis concluded that MMR signature by NGS is somewhat more sensitive than IHC analysis in identifying dMMR tumors, Bou Farhat reports. If applied nationwide, more patients with CRC and endometrial cancer could be identified and benefit from immunotherapy, he says. These findings suggest revisiting MMR diagnostic guidelines and emphasizing the benefits of NGS MMR analysis to identify patients who are missed by IHC, Bou Farhat emphasizes. Such patients would then become candidates for immunotherapy, who otherwise might not receive it, he concludes.