Endometrial cancer (EC) is the most common gynecologic malignancy in women with an estimated 67,880 new cases to be diagnosed and over 13,250 deaths in 2024 [1]. It is one of the rare malignancies that is increasing in incidence and mortality [2]. EC is most frequently diagnosed in women between the ages of 55 and 64 and differences in incidence and prognosis exist across races and ethnicities [1,2]. When corrected for hysterectomy prevalence, Black women have a 15 % to 20 % higher incidence rate compared to White women, are more likely to be diagnosed at advanced stages, and have twice the mortality of white women [3,4].

In the last ten to fifteen years, a better understanding of the molecular underpinnings of EC has emerged. The Cancer Genome Atlas (TCGA) characterized 373 ECs and revealed four distinct subclasses: POLE ultramutated, microsatellite instability hypermutated, copy-number low and copy-number high [5]. Prognosis differed significantly among the subclasses with POLE tumors having the best prognosis and copy-number high having the worst prognosis. Specific gene alterations were associated with specific subclasses including near universal p53 mutations and frequent ERBB2 amplification in the copy-number high group. While the majority of the copy-number high tumors were serous histology, there were other histologic types in this group suggesting that molecular subclassing may more accurately predict prognosis than histology and could therefore influence treatment choices.

In an attempt to simplify EC molecular classification and expand its use, the Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) was developed [6]. This classification combined immunohistochemistry (IHC) for p53 and mismatch repair proteins with POLE sequencing. Based on the stepwise PROMISE algorithm, tumors are classified as POLE mutated, mismatch repair deficient (dMMR), p53 abnormal or non-specific molecular profile (NSMP). As with the TCGA subclasses, each subtype has distinct clinical behavior and response to treatment [[7], [8], [9]].

HER2 (also known as ERBB2) is a tyrosine kinase receptor closely related to the epidermal growth factor receptor (EGFR) and amplification with resulting overexpression results in cellular transformation [10]. HER2 amplification has been successfully targeted in breast cancer, transforming the prognosis and treatment of HER2+ breast cancer. A new class of targeted oncologic therapy, antibody drug conjugates (ADC), capitalize on tumor-specific expression of specific cancer associated proteins and targets potent chemotherapy to those tumor cells. HER2 expression has been targeted with ADCs in several cancer types including breast and gynecologic malignancies. Due to the development and activation of HER2 ADC trials, our institution began assessing HER2 expression in all newly diagnosed EC. This study aimed to determine the proportion of endometrial cancers that are HER2 expressing by IHC across histologic and molecular subtypes.