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Review
. 2025 Apr:195:152-164.
doi: 10.1016/j.ygyno.2025.03.011. Epub 2025 Mar 20.

Diagnostic and therapeutic advances for HER2-expressing or amplified gynecologic cancers

Elizabeth K Lee  1 , David L Kolin  2 , Ursula A Matulonis  3 , Britt K Erickson  4
Affiliations
Review

Diagnostic and therapeutic advances for HER2-expressing or amplified gynecologic cancers

Elizabeth K Lee et al. Gynecol Oncol. 2025 Apr.

Abstract

HER2-targeting therapies are well-described in breast, gastric, and lung cancers, however accumulating data supports a role for HER2-targeted therapies in gynecologic cancers. Despite varied methodologies for HER2 testing, evidence supports that a substantial proportion of endometrial, ovarian, cervical, and vulvar cancers overexpress HER2. This underscores the rationale for HER2-targeted therapies in these malignancies, including the use of HER2-directed tyrosine kinase inhibitors, antibody-drug conjugates, and immune-stimulating antibody conjugates. Understanding mechanisms of resistance to HER2-targeted therapies will inform possible combinatorial strategies.

Keywords: Antibody drug conjugate; Biomarker testing; Her2; Therapeutic antibody; Tyrosine kinase inhibitor.

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Conflict of interest statement

Declaration of competing interest EKL: Grant from NCI Ovarian Cancer SPORE; travel support from GOG/NRG; participation in advisory board for Aadi Bioscience. DLK: Stock options in Abbott Laboratories, Alcon Inc., Becton Dickinson, Novartis, Pfizer, UnitedHealth Group. UAM: Honoraria from Med Learning Group; participation in advisory boards for Symphogen, Alkermes, Tango Therapeutics, ProfoundBio, Eisai, Eli Lilly, Novartis, Curelab, Immunogen, Allarity, Nextcure, Ovarian Cancer Research Alliance, Rivkin Foundation, Pfizer. BKE: R50 grants from NCI and GOG Foundation scholar award; consulting for Gilead; honoraria from Kaplan, Curio Science, participation in advisory boards for AstraZeneca, Merck, GSK.

Figures

Fig. 1.
Fig. 1.
Circumferential vs basolateral HER2 staining. Both circumferential and basolateral expression of HER2 immunohistochemistry can be seen in gynecologic malignancies. (A) Hematoxylin and eosin photomicrograph of uterine serous carcinoma (400×) with (B) strong circumferential HER2 staining (400×). (C) Hematoxylin and eosin photomicrograph of muciznous ovarian carcinoma (400×) with (D) strong basolateral HER2 staining (400×). Figure courtesy of D. Kolin.
Fig. 2.
Fig. 2.
Mechanisms of resistance to HER2-directed therapies. Resistance to HER2-directed therapies include 1) modification or truncation of the HER2 ECD, such as that seen with p95 HER2 isoforms and splice variants, leading to loss of epitopes required for HER2-directed Ab and ADC binding, and concurrently 2) generate HER2 isoforms capable of forming covalently-bound, constitutively active homodimers; 3) mutations within pro-survival downstream signaling pathways, such as the PI3K/AKT and MAPK pathways; 4) recycling of endosomes containing HER2 and/or HER2-bound Abs and ADCs; and 5) efflux of cytotoxic ADC payloads via multidrug efflux pumps. Ab = antibody; ADC = antibody drug conjugate; ECD = extracellular domain.
See this image and copyright information in PMC

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