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HER2 in gynecological malignancies: Bridging the gap between standardized pathological assessment and precision
Gian Franco Zannoni1, Angela Santoro1, Giuseppe Angelico2
1Pathology Unit, Department of Woman and Child's Health and Public Health Sciences, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome 00168, Italy; Pathology Institute, Catholic University of Sacred Heart, Rome 00168, Italy.
Abstract:
HER2 is a transmembrane tyrosine kinase receptor involved in cell proliferation, survival, and differentiation. While its role in breast and gastric cancers is well established, increasing attention is being paid to HER2 expression in gynecologic malignancies. In endometrial cancer, HER2 overexpression is most commonly associated with serous endometrial carcinoma (SEC), where it occurs in approximately 30 % of cases and correlates with poor prognosis, platinum resistance, and TP53 mutations. HER2-low expression, defined by IHC scores of 1 + or 2 + without gene amplification, has also emerged as a potential therapeutic target. Trastuzumab-based therapy has shown survival benefit in HER2-positive SEC, leading to its inclusion in current treatment guidelines. In ovarian cancer, HER2 amplification is most frequent in mucinous subtypes but also appears in clear cell and endometrioid carcinomas. The prognostic value remains debated, though recent trials of antibody-drug conjugates (e.g., T-DXd) show promise. In cervical cancer, HER2 is more commonly expressed in adenocarcinomas, particularly gastric-type variants, with gene amplification linked to adverse features. HER2 positivity is rare in vulvar and vaginal cancers but is notably present in extramammary Paget disease. Accurate HER2 testing relies on IHC with ISH confirmation and may be complemented by NGS or PCR in select cases. Diagnostic challenges include variable scoring systems, intratumoral heterogeneity, and HER2-low classification. Standardization of testing criteria and further clinical validation of HER2-targeted strategies across gynecologic tumors are essential to guide personalized therapy and improve outcomes.
Insights
HER2 receptor is a target in gynecologic cancers like endometrial and ovarian. HER2-targeted therapies show promise, but standardized testing is crucial for personalized treatment and improved patient outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Gynecologic Oncology
Background:
- HER2 (Human Epidermal growth factor Receptor 2) is a tyrosine kinase receptor crucial for cell growth.
- Its role in breast and gastric cancers is established, with growing interest in gynecologic malignancies.
- HER2 overexpression and amplification are implicated in various gynecologic cancers, affecting prognosis and treatment response.
Purpose of the Study:
- To review the role of HER2 expression and amplification in gynecologic cancers.
- To discuss the clinical significance and therapeutic implications of HER2 targeting.
- To highlight diagnostic challenges and the need for standardized testing.
Main Methods:
- Literature review of studies on HER2 in endometrial, ovarian, cervical, vulvar, and vaginal cancers.
- Analysis of diagnostic methods including immunohistochemistry (IHC), in situ hybridization (ISH), and next-generation sequencing (NGS).
- Evaluation of therapeutic strategies targeting HER2, including trastuzumab and antibody-drug conjugates.
Main Results:
- HER2 overexpression is common in serous endometrial carcinoma (SEC), associated with poor prognosis and resistance.
- HER2 amplification occurs in ovarian cancers, particularly mucinous subtypes, with emerging data on antibody-drug conjugates.
- HER2 expression in cervical cancer is linked to adenocarcinomas and adverse features; its role in vulvar/vaginal cancers is less common but notable in Paget disease.
- Diagnostic challenges include heterogeneity and evolving HER2-low definitions.
Conclusions:
- HER2 is a significant biomarker and therapeutic target across various gynecologic cancers.
- Trastuzumab-based therapies and novel antibody-drug conjugates demonstrate efficacy in HER2-positive cases.
- Standardization of HER2 testing and further clinical validation are essential for optimizing personalized treatment strategies.
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