Clinicopathological characterization and prognostic significance of HER2-low expression in endometrial cancer: a ProMisE molecular classification-based analysis

Abstract

Antibody–drug conjugates have renewed interest in tumors with low-level HER2 expression. However, the clinicopathological distribution and prognostic significance of HER2-low status in endometrial cancer, particularly across ProMisE molecular subtypes, remain uncertain. This single-center retrospective cohort study included 385 patients with primary endometrial cancer treated surgically. HER2 and ProMisE analyses were performed exclusively on formalin-fixed, paraffin-embedded hysterectomy-derived tumor tissue. For the primary analysis, HER2 status was classified using breast cancer ASCO/CAP criteria as HER2-zero, HER2-low (IHC 1 + or IHC 2+/ISH-non-amplified), or HER2-positive. Clinicopathological associations and overall and progression-free survival were evaluated using multivariable Cox regression. All tumors were additionally rescored using gastric cancer criteria. HER2-zero, HER2-low, and HER2-positive tumors accounted for 47.8% (184/385), 46.0% (177/385), and 6.2% (24/385), respectively. HER2-low expression occurred across all four ProMisE subtypes, whereas HER2-positive tumors were concentrated in the p53-abnormal subtype. HER2-low tumors showed intermediate frequencies of high-risk histology, substantial lymphovascular space invasion, advanced-stage disease, and lymph node metastasis. After multivariable adjustment, HER2-low status remained associated with poorer overall survival (adjusted hazard ratio, 1.67; 95% CI, 1.03–2.70; P = 0.037) and progression-free survival (adjusted hazard ratio, 1.58; 95% CI, 1.02–2.45; P = 0.041) compared with HER2-zero status. Within the p53-abnormal subtype, the association between HER2-low status and progression-free survival persisted after adjustment for serous histology (adjusted hazard ratio, 2.14; 95% CI, 1.03–4.45; P = 0.042). Gastric-based rescoring increased the HER2-positive proportion to 9.9% and changed the three-category classification of 10.4% of tumors. HER2-low expression was common and associated with adverse clinicopathological features and survival outcomes. These findings require external validation and do not establish HER2-low status as a predictive biomarker for HER2-directed therapy.