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Hormonal therapy could be applied in tumors across the four molecular subgroups of endometrial cancer, benefiting patients in terms of reduced toxicity and more convenience compared with use of chemotherapy or immunotherapy.

Hormonal therapy can be considered the first available targeted treatment option for endometrial cancer and can be effective in early-stage disease as well as advanced-stage disease. The application of chemotherapy has increased during the past few decades, while the use of hormonal therapy has decreased. However, recent studies emphasize that the efficacy of hormonal therapy is higher in selected subgroups of patients with hormone receptor–positive tumors.

In a recent "Comments and Controversies" article in the , Johanna M.A. Pijnenborg, MD, PhD, of Radboud University Medical Center Nijmegen in the Netherlands, and colleagues reviewed the current status of the use of hormonal therapy in endometrial cancer in the era of molecular classification.

The authors were not available for comment, and the answers here are from the text of the report.

What does this article add to the literature?

Despite the lack of rigorous studies in the past, a number of good-quality and promising studies on the use of hormonal therapy in endometrial cancer have recently been conducted or are ongoing. We strongly believe that the position of hormonal drugs for preselected groups of patients with endometrial cancer should be redefined in the context of the molecular classification.

What is the advantage of combining hormonal therapy with targeted therapies?

Hormonal therapy has been investigated in combination with other targeted therapies. This can be an attractive option, as combined therapy can interfere with tumor development and progression through multiple mechanisms. For example, the combination of hormonal drugs with mammalian target of rapamycin (mTOR) inhibitors has been tested extensively.

Although combined progestins with the mTOR inhibitor temsirolimus resulted in excessive thrombotic complications, thus hampering any clinical use, the was tested in 38 patients and showed a response rate of 32%. Everolimus/letrozole can therefore be an alternative to progestin therapy in advanced and recurrent endometrial cancer.

Advances in our knowledge of the molecular mechanisms underlying tumor growth and the interplay between hormone with other intracellular signaling pathways have also increased the interest in the combination of hormonal therapy with other targeted treatments including AKT inhibitors, PI3K pathway inhibitors, and CDK inhibitors.

What are the best available predictive biomarkers?

Immunohistochemical expression of estrogen receptor (ER) and progesterone receptor (PR) in tumor tissue are the most commonly used predictive biomarkers for efficacy of hormonal therapy. Mechanistically, progestin therapy inhibits estrogen-driven tumor growth by binding to progesterone receptor. The resultant progestin-PR complex moves intracellularly, where it serves as a strong inhibitor of estrogenic actions. Thus, the mechanistic rationale for using ER and PR as predictive biomarkers is quite strong.

What are the challenges that hamper routine use of predictive biomarkers in clinical practice?

First, the currently used cutoff values for ER/PR positivity by immunohistochemistry are adopted from breast cancer, and have not been validated for endometrial cancer. Awaiting prospective validation, the currently used cutoff for hormone receptor positivity might need to be adjusted.

Second, during endometrial cancer progression and recurrence, PR expression is frequently lost, which may result in reduced sensitivity to progestins, underlining the relevance of recent (pretreatment) biopsy when hormonal therapy is considered in recurrent endometrial cancer.

Finally, tumor heterogeneity is a common challenge in targeting cancer treatment. Determination of the percentage of ER/PR positivity within the tumor biopsy might be a first step toward understanding whether the tumor is heterogeneous for ER/PR expression. Yet, as sampling errors are inherent to patients with multiple tumor localizations, this will remain difficult to tackle. The recent innovations of using an might help to determine the ER positivity in relation to all tumor localization (ratio fluoroestradiol F18-positron emission tomography–PET/PET scan).

So far, PR tracers are not yet available in the clinic, but might be even more important in the future of hormonal therapy.

How can molecular subgroups be integrated with predictive biomarkers?

Now that the development and validation of the molecular classification in endometrial cancer is completed, it is ready for integration with existing predictive biomarkers. The has been investigated in recent studies within The Cancer Genome Atlas groups, and remains clinically relevant. The prognostic value of ER expression appears most relevant in the "no specific molecular profile" (NSMP) group. However, ER-/PR-positive tumors are seen throughout all four molecular subgroups.

Molecular biomarkers such as polymerase epsilon (POLE), microsatellite instability (MSI), and p53 could also have predictive value in relation to hormonal therapy.

Finally, to define the position of hormonal therapy in endometrial cancer, we also need to better understand the biology of hormone signaling and identify biomarkers that better predict response. To this end, proper selection of patients by using recent pretreatment biopsies assessing ER/PR immunohistochemistry with validated cutoff values and ER/PR pathway activity tests are necessary. In this context, it is encouraging that novel powerful mRNA-based tools measuring the activation of the downstream hormone signaling cascade have been developed and show promising prediction of hormone responsiveness in breast cancer.

What's the main take-home message for practicing oncologists?

Hormonal drugs represent valuable therapeutic agents in the treatment of endometrial cancer, both in the early stage and as palliative treatment.

Application of hormonal therapy in patients with endometrial cancer should be based on ER/PR expression. Preliminary data support the integration of hormone signaling biomarkers that better reflect hormone signaling activation to facilitate clinical use of hormonal therapy. Results from active trials are awaited to better understand how and to whom hormonal drugs should be indicated.

Finally, yet importantly, hormonal therapy is cost-effective and can be administered orally, allowing application in regions with impaired accessibility to specialized infrastructures and low resources.

Read the "Comments and Controversies" article here and expert commentary about it here.