Title : Precision oncology in gynecologic cancers: Molecular taxonomy, biomarker-guided therapeutics, and the challenge of therapeutic resistance

Background: The clinical management of gynecologic malignancies—endometrial (EC), ovarian (OC), and cervical (CC) carcinomas—has been historically guided by histomorphology and staging. This paradigm fails to capture profound molecular heterogeneity, resulting in suboptimal outcomes including both over-treatment and under-treatment of patients. Precision oncology, through molecular taxonomy and biomarker-guided therapy, aims to address this critical gap.

Objective: This review synthesizes the current landscape of precision oncology in gynecologic cancers by analyzing established molecular classifications, the evidence for biomarker-guided therapies, mechanisms of therapeutic resistance, and emerging diagnostic and trial paradigms.

Methods: We conducted a comprehensive analysis of the peer-reviewed literature and key clinical trial data, with particular emphasis on molecular reclassification systems including The Cancer Genome Atlas (TCGA) for endometrial and ovarian carcinomas, and the subsequent clinical translation of targeted therapeutic agents.

Results: Molecular reclassification has successfully identified prognostically and therapeutically relevant subtypes across gynecologic malignancies. This has enabled remarkable clinical translation of several targeted approaches: (1) PARP inhibitors (olaparib, niraparib) for homologous recombination deficient (HRD) ovarian cancer, demonstrating significant progression-free survival benefits; (2) Immune checkpoint inhibitors (pembrolizumab, dostarlimab) for mismatch repair deficient/microsatellite instability-high (dMMR/MSI-H) endometrial and cervical cancers, yielding durable responses in previously refractory populations; and (3) Antibody-drug conjugates (ADCs) including mirvetuximab soravtansine targeting folate receptor-alpha in ovarian cancer and tisotumab vedotin in cervical cancer, offering new options for heavily pretreated patients. However, acquired resistance to these therapies driven by tumor evolution, genomic heterogeneity, and adaptive signaling pathways remains a pivotal barrier to long-term disease control.

Conclusions: The convergence of deep molecular phenotyping with rationally designed targeted therapy represents a cornerstone of modern gynecologic oncology care. Future directions require overcoming therapeutic resistance through: (a) novel diagnostic platforms including liquid biopsy for continuous molecular monitoring; (b) next-generation therapeutics targeting emerging resistance mechanisms; and (c) innovative adaptive clinical trial designs. Equitable access to molecular testing and targeted agents is imperative to prevent widening health disparities. The field is rapidly evolving toward a model of dynamic, molecularly informed adaptive therapy to improve outcomes for patients with gynecologic cancers.

Shanza Waseem is a Pakistani PhD student in the Department of Gynecology and Obstetrics at West China Second University Hospital, Sichuan University, Chengdu, China. She is affiliated with the Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), Tianfu Jincheng Laboratory, and the Laboratory of Stem Cell & Embryo Development at West China Second Hospital. Her doctoral research, supervised by Dr. Xue Xiao, focuses on precision oncology in gynecologic cancers, with emphasis on molecular mechanisms of therapeutic resistance and biomarker discovery in ovarian and endometrial carcinomas. She is co-author of a review on precision oncology in gynecologic cancers currently under review in Frontiers in Oncology. (ORCID: 0000-0002-8834-6510)