MLH1 Methylation Testing as an Integral Component of Universal Endometrial Cancer Screening—A Critical Appraisal

SIMPLE SUMMARY: Often in endometrial cancer (EC), the mismatch repair (MMR) system, which helps fix DNA mistakes, goes haywire because of MLH1 promoter hypermethylation (MLH1-PHM). We set out to find out how many ECs have MLH1-PHM, understand the impact of reflex MLH1-PHM testing and evaluate the associated costs within the publicly funded Canadian healthcare system. We looked at 2504 EC samples and found that in 534 of them (21.4%), the MMR system was deficient due to dual MLH1/PMS2-deficiency. Out of the 418 cases with available data, 404 (96.7%) had MLH1-PHM, while only 14 (3.3%) didn’t. Reflex MLH1-PHM tests cost CAD 231.90 per case, amounting to CAD 123,834.60 for 534 cases, with 30 tests needed per additional candidate for MLH1 germline analysis (CAD 6,957.00 per candidate). This raises a provocative question: can we assume that the majority of the MLH1-deficient ECs are due to PHM and forgo further testing in healthcare systems with finite resources? ABSTRACT: MLH1/PMS2 loss due to MLH1 promoter hypermethylation (MLH1-PHM) is the most common cause of mismatch repair (MMR) deficiency in endometrial cancer (EC). This study aimed to determine the proportion of MLH1-deficient EC with PHM, assess the impact of the reflex MLH1-PHM testing strategy, and evaluate the associated costs within the publicly funded Canadian healthcare system. In a cohort of 2504 EC samples, 534 (21.4%) exhibited dual MLH1/PMS2 loss, prompting MLH1-PHM testing. Among 418 cases with available testing results, 404 (96.7%) were MLH1-hypermethylated, while 14 (3.3%) were non-methylated. The incidence of MLH1 non-methylated cases in our cohort was 14/2504 (0.56%) of all ECs, underscoring the prevalence of hypermethylation-driven MLH1/PMS2 loss in ECs universally screened for MMR deficiency. Reflex MLH1-PHM testing incurs substantial costs and resource utilization. Assay cost is CAD 231.90 per case, amounting to CAD 123,834.60 for 534 cases, with 30 tests needed per additional candidate for MLH1 germline analysis (CAD 6957.00 per candidate). This raises a provocative question: can we assume that the majority of the MLH1-deficient ECs are due to PHM and forgo further testing in healthcare systems with finite resources? It is imperative to assess resource utilization efficiency and explore optimized approaches that encompass clinical correlation, family history and judicious utilization of methylation testing to ensure it is provided only to those who stand to benefit from it.