J Transl Med. 2026 Jul 3. doi: 10.1186/s12967-026-08546-8. Online ahead of print.
ABSTRACT
BACKGROUND: Gynecologic cancers remain a substantial clinical challenge, particularly in advanced stages, where treatment options are often associated with limited efficacy and poor prognosis. Given the emerging success of HER2-targeted antibody-drug conjugates (ADCs) across solid tumors, accurate evaluation of HER2 status is essential. This study investigated intratumoral HER2 heterogeneity in gynecologic cancers to refine detection accuracy and improve patient stratification for targeted therapy.
METHODS: A retrospective cohort of 416 patients with gynecologic malignancies was analyzed using immunohistochemistry (IHC) testing on separate dual formalin-fixed paraffin-embedded (FFPE) tumor blocks. HER2 expression was scored according to ASCO/CAP gastric criteria, and heterogeneity was defined as discordant IHC scores across blocks. Statistical analyses were performed using McNemar’s test, and clinical predictors of discordance were identified through multivariate logistic regression.
RESULTS: Across all tumors, HER2 IHC scores were distributed as 0 (49.5%), 1+ (33.9%), 2+ (15.6%), and 3+ (1.0%). HER2 overexpression was most frequent in uterine serous carcinoma, uterine endometrioid carcinoma, and ovarian clear cell carcinoma in our cohort. Intratumoral discordance was observed in 20.7% of cases, with the highest rates in uterine (23.9%, 21/88), ovarian (21.4%, 39/182), and cervical (18.2%, 26/143) tumors. Dual-block assessment revealed that most discrepancies resulted from incremental shifts in HER2 expression, primarily from 0 to 1 + or 1 + to 2+. This approach reclassified 13.5% of tumors originally reported as HER2-0 to HER2 expression.
CONCLUSION: Intratumoral HER2 heterogeneity is common in gynecologic cancers and frequently results in underestimation of HER2 expression when single-block assessment is used. Dual-block evaluation improves detection sensitivity and may refine patient selection for HER2-targeted antibody-drug conjugates.
PMID:42399958 | DOI:10.1186/s12967-026-08546-8
