Biomarker-driven therapy in endometrial cancer

Area of Science:

• Gynecologic Oncology
• Molecular Pathology
• Translational Cancer Research

Background:

• Endometrial cancer exhibits significant molecular heterogeneity.
• The Cancer Genome Atlas (TCGA) has classified four validated molecular subtypes: dMMR/MSI-H, CNH/p53abn, CNL/NSMP, and POLEmut.
• These subtypes have distinct prognostic implications and treatment responses.

Purpose of the Study:

• To review current and emerging treatments for endometrial cancer based on molecular subtype.
• To highlight the prognostic and therapeutic significance of molecular subtyping in guiding patient management and clinical trial design.

Main Methods:

• Review of recent clinical trial data and regulatory approvals for endometrial cancer treatments.
• Analysis of therapeutic strategies tailored to specific molecular subtypes, including immunotherapy, targeted agents, and hormonal therapy.
• Discussion of ongoing research and treatment de-escalation strategies.

Main Results:

• Pembrolizumab and dostarlimab (anti-PD-1 antibodies) are approved for advanced/recurrent dMMR/MSI-H endometrial cancer.
• Pembrolizumab/lenvatinib combination is approved for mismatch repair proficient/microsatellite stable endometrial cancer (including p53abn/CNH and NSMP/CNL subtypes).
• Trastuzumab is indicated for HER2-positive serous endometrial cancer (primarily p53abn/CNH). Selinexor shows potential in p53-wildtype cases, and novel combinations are under investigation.

Conclusions:

• Molecular subtyping is crucial for personalized endometrial cancer treatment.
• Targeted therapies and immunotherapies are increasingly integrated into treatment algorithms based on subtype.
• Further research is needed to optimize treatment de-escalation and novel combination strategies for all subtypes.