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Elias Bou Farhat, MD

Job Title

Post-doctoral Research Fellow

Academic Rank

Fellow or Postdoc




Elias Bou Farhat, Elio Adib, Melissa Daou, Abdul Rafeh Naqash, Alexander Gusev, Ursula Matulonis, Kimmie Ng, Lynette M. Sholl, Amin H. Nassar, David J. Kwiatkowski

Principal Investigator

David J. Kwiatkowski



Benchmarking Mismatch Repair Testing for Patients with Cancer Receiving Immunotherapy

Scientific Abstract

Mismatch repair deficiency (MMR-D) is an FDA-approved indication for immune checkpoint inhibitor (ICI) treatment. MMR-D can be identified through immunohistochemistry (IHC) for the MMR proteins or genetic microsatellite instability (MSI) assessment. We examined the possibility that NGS analysis for MSI using the BWH/DFCI Oncopanel assay would be more sensitive and accurate than IHC. 1768 colorectal cancer (CRC) and endometrial carcinoma (EC) patients who had both NGS MSI (NGSd = deficient or NGSp = proficient) and MMR IHC (IHC- = absent or IHC+ = intact) assays performed were assessed. Discordant NGSd/IHC+ results were identified in 1% of CRC and 5% of EC cases that were IHC+. Importantly, patients with discordant NGSd/IHC+ and concordant NGSd/IHC- results, showed a similar overall survival and time to treatment failure with ICI treatment which contrasted with results for patients with concordant NGSp/IHC+ results (p = 0.0021 and p < 0.001 respectively). Patients with EC or CRC and discordant NGSd/IHC+ results had better survival when treated with ICI-based regimens, compared to those who received non-ICI treatments. We conclude that genetic MSI analysis is superior to IHC analysis for MMR-D detection, and ICI treatment of patients with NGSd/IHC+ leads to an improved clinical outcome.

Lay Abstract

Mismatch repair deficiency (MMR-D) is a genetic condition that is common in cancer. There are two methods to determine MMR-D, one based on tumor staining, the other based on DNA sequencing. Patients with MMR-D typically respond well to treatment with immune drugs. In this study, using a large BWH/DFCI population (1768 patients with colorectal cancer or endometrial cancer) that had both tests done, we found that in about 2% of cases, the two tests did not give the same results. The DNA sequencing test was positive while the staining test was negative. Furthermore, this set of patients with only a positive DNA sequencing result showed a markedly better response to immune therapy than to other treatments. This suggests that DNA sequencing analysis is superior to staining for detection of MMR-D. If this were applied across the USA, this would result in identification of thousands of cancer patients who would benefit from immune therapy.

Clinical Implications

NGS analysis outperforms IHC for MSI detection in cancer specimens, identifying thousands more MMR-D CRC and EC patients across the USA. Our findings suggest reevaluating MMR diagnostic guidelines emphasizing the benefit of NGS MSI analysis.