Elias Bou Farhat, MD,  discusses an investigation of NGS sensitivity vs standard IHC alone in the assessment of dMMR colorectal cancer or endometrial cancer.

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.

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In today’s episode, we had the pleasure of speaking with Amin Nassar, MD, and Elias Bou Farhat, MD, regarding their evaluation of the feasibility and accuracy of using next-generation sequencing (NGS) mutation signature for assessing and identifying mismatch repair–deficient (dMMR) tumors compared with standard MMR immunohistochemistry (IHC) testing. Dr Nassar is a hematology/oncology fellow at Yale University in New Haven, Connecticut. Dr Bou Farhat is a postdoctoral research fellow in the Department of Medicine at Brigham and Women’s Hospital in Boston, Massachusetts.

The retrospective study found that an additional 6.9% of patients with dMMR colorectal or endometrial cancer that were missed by IHC but detected by NGS-based mutation signature (NGS/IHC discordant) experienced comparable clinical outcomes to those of patients identified as dMMR by both IHC and mutation signature (NGS/IHC concordant) across tumor types. Moreover, improvements in overall survival (OS) and time to treatment failure were observed in the discordant group vs those with concordant MMR-proficient (pMMR) tumors. The median OS was also prolonged in patients with discordant CRC or endometrial tumors who received immune checkpoint inhibitors vs those who were not previously exposed to checkpoint inhibitors and received other systemic therapies.

Ultimately, investigators concluded that tumor-only NGS demonstrated high sensitivity for detecting MMR signature analysis in patients with CRC or endometrial cancer and could be employed as a complementary test alongside IHC to improve the identification of patients who may benefit from immunotherapy.

In our exclusive interview, Drs Nassar and Bou Farhat explained how tumor-only NGS could address the limitations of IHC testing for MMR mutation signatures across several tumor types, discussed primary findings and concordance rates from the study, and proposed revisiting guideline recommendation on diagnostic testing to reduce the impact of misdiagnosis of MMR status on treatment outcomes.

That’s all we have for today! Thank you for listening to this episode of 

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Drs Nassar and Bou Farhat explain how tumor-only NGS could address the limitations of IHC testing for MMR mutation signatures across several tumor types. 

Elias Bou Farhat, MD

Articles

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

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