Evaluating HER2 Scoring Criteria in Endometrial Carcinoma: Gynecologic Versus Gastric Guidelines for Trastuzumab and Trastuzumab-Deruxtecan Selection

Background/Objectives: HER2 overexpression and/or amplification defines a molecularly distinct subset of endometrial carcinomas (ECs) that may benefit from HER2-targeted therapies. However, HER2 testing algorithms remain non-standardized and vary across institutions. This study is a large single-institution audit of EC HER2 testing practices, using both gynecologic (ISGyP) and gastric cancer-specific scoring algorithms at a major academic center with a reference gynecologic oncology service and biomarker laboratory. Methods: HER2 immunohistochemistry (IHC) and whole-slide fluorescence in situ hybridization (FISH) were interpreted by subspecialty breast and gynecologic pathologists, with HER2 IHC performed on 494 tumor samples (2021–2025) and reflex FISH for equivocal cases. Results: Using ISGyP criteria, 15.0% (74/494) of tumors were HER2 IHC 3+, 44.5% (220/494) equivocal (2+), and 40.5% (200/494) were negative (0/1+). Among equivocal cases, 28.2% (58/205) demonstrated ERBB2 amplification, yielding an overall HER2-positive rate of 27.5% (132/480). Re-assessment with gastric scoring criteria demonstrated variability in HER2 classification, with high concordance in cytology specimens (100%) and resections (90.8%; K = 0.842, p < 0.001) but substantially lower concordance in biopsies (60.6%; K = 0.401, p < 0.001), mainly due to reclassification of equivocal cases. Notably, 47.9% (n = 34) of ISGyP-equivocal biopsy specimens were reclassified as HER2 IHC 3+ using gastric biopsy criteria, potentially expanding eligibility for T-DXd therapy. Conclusions: These findings highlight the evolving nature of HER2 testing in EC and demonstrate the significant impact of scoring methodology on HER2 interpretation. Our results support the development of EC-specific HER2 testing guidelines and a dual-reporting approach incorporating both ISGyP and gastric scoring criteria, with selective confirmatory FISH testing, to optimize patient selection for HER2-targeted therapies.