# Endocrine Therapy for Endometrial Carcinoma: Current Evidence, Resistance Mechanisms, and Biomarker-Driven Patient Selection

## TL;DR

This paper reviews how endocrine therapy for endometrial cancer is evolving, combining it with new drugs to improve effectiveness and personalize treatment.

## Contribution

The paper highlights novel combination therapies and biomarker-driven approaches to enhance endocrine therapy efficacy in endometrial cancer.

## Key findings

- Combining endocrine therapy with CDK4/6 and mTOR inhibitors improves outcomes in specific molecular subgroups.
- Patients with TP53 wild-type and CTNNB1 mutations respond exceptionally well to these combinations.
- Next-generation SERDs and predictive biomarkers are promising for personalized endocrine therapy.

## Abstract

Endometrial cancer is the most common gynecological cancer in developed countries, with a rising global incidence. Traditionally, endocrine therapy served as a low-toxicity alternative to chemotherapy, although its efficacy as monotherapy was often limited. Recently, however, promising results have been reported for combinations involving endocrine therapies and molecularly targeted agents. Additionally, advances in molecular classification suggest the existence of specific patient populations highly responsive to endocrine therapies. This review synthesizes current evidence regarding endocrine monotherapy and combination regimens, exploring resistance mechanisms and optimal patient selection. By evaluating ongoing clinical trials and future prospects, this review serves as an important educational resource for clinicians seeking to understand endocrine therapy-based treatment strategies, including emerging combination approaches, within the evolving landscape of endometrial cancer treatment.

The treatment landscape for endometrial carcinoma (EC) is undergoing a paradigm shift from traditional histopathological dualism to precision medicine grounded in the Cancer Genome Atlas (TCGA) molecular classification. The “No Specific Molecular Profile” (NSMP) subgroup, the largest molecular cohort, has emerged as a particularly promising target for endocrine-based strategies. While endocrine therapy (ET) has been a mainstay for over 60 years due to its favorable safety profile, its efficacy as monotherapy remains modest. This review provides a comprehensive overview of current endocrine strategies, including traditional agents like progestins and aromatase inhibitors, and focuses on novel combination therapies designed to overcome resistance. Recent clinical trials have demonstrated that integrating molecularly targeted agents, such as CDK4/6 and mTOR inhibitors, significantly improves clinical outcomes. Specifically, patients with TP53 wild-type status and CTNNB1 mutations exhibit exceptional responses to these combinations. Furthermore, we discuss the potential of next-generation selective estrogen receptor degraders (SERDs) and the importance of refining patient selection through robust predictive biomarkers. Driven by molecular insights, endocrine therapy is transitioning from a secondary palliative option into a definitive cornerstone of precision oncology, offering a personalized and effective treatment for patients with advanced or recurrent endometrial carcinoma.