| Summary: | MLH1/PMS2 loss due to <i>MLH1</i> promoter hypermethylation (<i>MLH1</i>-PHM) is the most common cause of mismatch repair (MMR) deficiency in endometrial cancer (EC). This study aimed to determine the proportion of <i>MLH1</i>-deficient EC with PHM, assess the impact of the reflex <i>MLH1</i>-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 <i>MLH1</i>-PHM testing. Among 418 cases with available testing results, 404 (96.7%) were <i>MLH1</i>-hypermethylated, while 14 (3.3%) were non-methylated. The incidence of <i>MLH1</i> 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 <i>MLH1</i>-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 <i>MLH1</i> 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.
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