# The Influence of Molecular Factors on the Effectiveness of New Therapies in Endometrial Cancer—Latest Evidence and Clinical Trials

## TL;DR

This paper reviews how molecular traits in endometrial cancer tumors affect new therapies, aiming to improve personalized treatment and patient outcomes.

## Contribution

The paper provides updated evidence on molecular factors influencing therapy effectiveness and outlines a path toward personalized treatment strategies.

## Key findings

- Molecular subtypes like POLE-ultramutated and MSI-hypermutated respond well to immunotherapy.
- Targeted therapies such as PI3K/AKT/mTOR inhibitors and hormone treatments are effective in specific molecular subtypes.
- Combining molecular profiles with clinical staging enables personalized treatment approaches.

## Abstract

Endometrial cancer, a common type affecting the womb lining, is on the rise due to factors like aging populations and obesity, making it urgent to improve treatment success. This review examines how specific molecular and genetic traits in tumors influence the effectiveness of emerging therapies, such as immune-boosting drugs, targeted treatments, and hormone options, with the goal of enabling more personalized care for patients. By highlighting these connections, the findings could guide scientists and doctors toward better-tailored strategies, potentially enhancing survival rates and inspiring new studies on innovative biomarkers and combined approaches to tackle this disease more effectively.

Endometrial cancer (EC) is the most common gynecological cancer in developed countries, with approximately 417,000 new cases reported worldwide in 2020. Its incidence has been rising for the past 30 years, primarily due to population aging, obesity, and type 2 diabetes; obesity accounts for almost half of cases due to excessive estrogen production. The classic division into types I and II was replaced in 2013 by the molecular TCGA classification, which distinguishes four subtypes: POLE-ultramutated (best prognosis), MSI-hypermutated, copy-number low, and copy-number high (worst prognosis). This classification (refined in ProMisE and TransPORTEC) enables precise treatment: immunotherapy (pembrolizumab, dostarlimab) works excellently in dMMR/MSI-H tumors, PI3K/AKT/mTOR inhibitors and trastuzumab deruxtecan in selected molecular subtypes, and hormone therapy in ER-positive tumors. ctDNA monitoring supports therapeutic decisions. Integrating the molecular profile with FIGO allows for truly personalized treatment, although MMRp/MSS tumors remain a challenge. The future lies in multi-omics, new biomarkers, and combination therapies.