96P - Analysis of concordance between microsatellite instability by next generation sequencing (NGS-MSI) and mismatch repair deficiency by immunohistochemistry (IHC-MMR) in endometrial cancer (EC) patients

Background

Determination of MMR functioning in EC is recommended by international guidelines. Its deficiency leads to MSI with intermediate prognosis. Available data have shown a reasonable concordance between IHC-MMR and NGS-MSI. We aim at evaluating the sensitivity and specificity of NGS-MSI obtained from a comprehensive cancer genome profiling (CGP) assay compared with the gold standard IHC-MMR.

Methods

Selected EC patients were profiled using TruSight Oncology500 High Throughput solution. MSI status was determined by 130 noncoding homopolymer regions and at least 40 sites were assessed to provide a score (threshold MSI high>20). IHC-MMR evaluation was collected from standard pathology report.

Results

From March 2022 to May 2023, 404 EC were enrolled. NGS-MSI evaluation was available for 354 (87%; see table). Cohort characteristics are reported in the table. Sensitivity and specificity of NGS-MSI testing compared to IHC-MMR were 99% (n=223/224) and 52% (n= 68/130) respectively, with a concordance rate of 82% (Cohen Kappa = 0.58; p < .0001). The positive predictive value of NGS-MSI was 78% (n=223/285), while the negative predictive value was 99% (n= 68/69). Among the 62 misclassified cases, 19 were MSH6 + MSH2 deficient, 42 MLH1 + PMS2 deficient and 1 was deficient for PMS2, MLH1 and MSH6. 38 MLH1 + PMS2 deficient patients were addressed to MLH1 promoter methylation analysis: results are available for 15 cases (11 hypermethylated, 2 partially hypermethylated). All 19 MSH6 + MSH2 deficient were addressed to genetic counselling: results are available only for 3 patient (1 displaying a MSH2 pathogenic variant). Table: 96P

Conclusions

A moderate concordance between IHC-MMR and NGS-MSI was reported in our study. However, given the approval of immunotherapy in several settings it is important to further characterize the misclassified cases.

Editorial acknowledgement

Clinical trial identification

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

C. Nero: Non-Financial Interests, Personal, Other: Illumina. D. Lorusso: Financial Interests, Personal, Invited Speaker: Clovis, GSK, MSD, AZ, PharmaMar.G. Scambia: Financial Interests, Personal, Invited Speaker: MSD, Clovis, Tesaro, J&J. All other authors have declared no conflicts of interest.