Genomic and DNA methylomic factors associated with the efficacy of oral medroxyprogesterone acetate on endometrial neoplastic disease

Objective

There is growing demand for fertility-sparing treatments in women with endometrial neoplastic disease who wish to conceive. Although progestins, such as medroxyprogesterone acetate (MPA), have conventionally been used for this purpose, their efficacy remains inconsistent, even when patients are selected based on clinicopathological criteria, including eligible histology or the absence of myometrial invasion or extra-uterine disease. There is thus an urgent need to identify potential biomarkers to stratify patients for improved MPA efficacy. In this study, we sought to identify candidate biomarkers associated with an efficacious response to MPA among women with endometrial disease.

Methods

We retrospectively conducted exome sequencing, DNA methylation microarray analysis, and hormone receptor immunohistochemistry on the samples from 62 patients with atypical endometrial hyperplasia and endometrial carcinoma, all of whom had received oral MPA treatment.

Results

We identified that molecular subtype, tumor mutation burden, maximal allele frequency, and DNA methylomic subtype were associated with MPA efficacy, as measured by patient response, disease recurrence, and progression-free survival. In multivariate analysis, we found independent associations of maximal allele frequency with responders (those with complete or partial remission), and of the copy-number-high subtype with shorter progression-free survival. Using region-set analyses, we also revealed that DNA methylation status of progesterone receptor-binding sites is a significant factor for distinguishing DNA methylomic subtypes for which MPA would be effective or ineffective.

Conclusions

These findings not only provide a foundation for identifying effective biomarkers for MPA efficacy, but also reveal deeper insights into the mechanism of action of progestins.