Dr Nassar on MMR Determination by IHC and NGS in CRC and Endometrial Cancer

Amin Nassar, MD, clinical fellow, hematology/oncology, Yale University, Yale School of Medicine, discusses the investigation of next-generation sequencing (NGS) alongside standard immunohistochemistry (IHC) to detect mismatch repair (MMR) deficiency (dMMR) in patients with colorectal cancer (CRC) or endometrial cancer.

The rationale behind evaluating the concordance between determining MMR status by IHC and NGS stemmed from the need to enhance the detection of dMMR in patients with CRC and endometrial cancer. Although standard IHC is currently the preferred dMMR detection method due to its accessibility and prompt turnaround time, its reliance on antigen-antibody binding may overlook cases where a mutation in the epitope preserves antigen expression but disrupts functionality, leading to misclassification of tumors as MMR proficient, Nassar begins. Recognizing that some patients with dMMR disease might be missed by IHC, the aim of the investigation was to quantify this patient subset and determine whether dMMR status could be identified using NGS, potentially identifying additional patients who might benefit from immunotherapy despite being overlooked by IHC, he reports.

Compared with IHC, which solely focuses on the antigen-antibody binding site, NGS offers a broader detection approach by genotyping multiple regions in the genome, he expands. Investigators hypothesized that NGS would offer greater sensitivity and accuracy compared with IHC, although this assertion lacked empirical evidence, Nassar explains. Despite ongoing discussions among various organizations, the absence of data demonstrating the efficacy of NGS in identifying patients who could benefit from immunotherapy has hindered its incorporation into clinical guidelines, he elucidates.

A prior study highlighted the consequences of misdiagnosis in MMR status and microsatellite instability with immune checkpoint inhibitors, Nassar continues, adding that although immune checkpoint inhibition is highly effective in dMMR patients, a subset of patients with dMMR disease does not derive benefit from this treatment approach. Investigation revealed that many of these patients were misdiagnosed as dMMR, raising concerns about potential false positives with IHC, he notes. Hence, exploring NGS as a method to minimize false positives and false negatives becomes crucial for improving patient outcomes and optimizing immunotherapy efficacy, Nassar concludes.