Cost-effectiveness of a two-protein panel PMS2/MSH6 for detecting mismatch repair deficiency in endometrial cancer: A single institution study.

Abstract

e17613 Background: Several societies have advocated for universal Lynch syndrome screening in endometrial cancer (EC). Mismatch repair proteins (MMR) are examined using immunohistochemistry (IHC) including MLH1, PMS2, MSH2, MSH6 with reflex MLH1 methylation testing in cases with loss of MLH1/PMS2. Typically, these genes form a heterodimer complex; if MLH1 is absent, then PMS2 is absent and if MSH2 is absent, MSH6 is absent. However, PMS2 and MSH6 can be absent independent of their co-proteins. Therefore, by detecting the presence or absence of PMS2 and MSH6 one can in theory detect all cases of mismatch repair deficiency (MMRd), both as an independent loss and co-protein loss. With the expansion of additional molecular biomarkers in EC, there is a need to address cost-effectiveness of screening tools, while maintaining accuracy with the diagnosis. Methods: We conducted a retrospective chart review of all patients with newly diagnosed EC from 2014-2020 at a single institution. All tumors underwent MMR screening by IHC for MLH1, PMS2, MSH2, MSH6 with reflex MLH1 hypermethylation. At our institution, the cost of 1 immunostain was $130.00, 2 immunostains $235.00, 4 immunostains $445.00. The cost of MLH1 hypermethylation testing was $175.00. Results: We identified 1702 cases of newly diagnosed endometrial cancer who underwent surgical excision and MMR IHC staining. Of these cases, 408 (24.0%) were MMRd and 1,294 (76%) were MMRp. In the MMRd population for MLH1/PMS2: 311 (76.2%) had MLH1 promoter hypermethylation, 14 (3.4%) MLH1-/PMS2-/MLH1 non-methylated, 8 (2.0%) MLH1-/PMS2-/no methylation testing performed, 14 (3.4%) MLH1+/PMS2-, 1 (0.2%) MLH1-/PMS2+/MLH1 non-methylated. For MSH2/MSH6: 24 (5.9%) MSH2-/MSH6-, 31 (7.6%) MSH2+/MSH6-, 0 (0%) MSH2-/MSH6+. There were 3 (0.7%) MLH1-/PMS2-/MSH6-/MLH1 promoter hypermethylation, and 2 (0.5%) MLH1-/PMS2-/MSH6-/MLH1 non-methylated. The sensitivity of the two-protein testing strategy of PMS2 and MSH6 alone was 99.8%. The total cost of IHC for 1702 cases using 4 immunostains ($445.00) was $757,390.00. The additional cost of reflex methylation testing ($175.00 each) performed on 339 tumors was $59,325.00. Thus, the total cost for a complete MMR evaluation was $816,715.00 for the cohort. Performing a two-protein PMS2/MSH6 test ($235.00) with reflex MLH1 methylation testing when cases had loss of PMS2 alone ($175.00) would cost $461,570.00 for this cohort. This would result in a cost savings of $355,145.00. Conclusions: A two-protein MMR IHC screen for Lynch syndrome and biomarker assessment is highly sensitive. With expanding use of IHC testing in the management of EC, strategies to reduce health care and resource utilization will be critical.