HER2-positive endometrial cancer subtype carries poor prognosis

Endometrial cancer (EC) is a hormone-dependent, most frequent malignancy of the female genital tract, yet no molecular subtype classification based receptor status (estrogen receptor [ER], progesterone receptor [PR], human epidermal growth factor receptor 2 [HER2]) has been established so far. Assuming that molecular subtypes might differ fundamentally in EC, we analyzed expression levels of ER, PR, and HER2 with immunohistochemistry and aimed to determine clinical significance of four molecular subtypes: ER+/PR+/HER2+; ER+/PR+/HER2-, ER-/PR-/HER2+, and ER-/PR-/HER2-. The study included 400 formalin-fixed paraffin-embedded primary tumor EC samples which covered all stages of endometrial carcinoma, from IA to IVB. ER-/PR-/HER2+ subtype correlated with the poorest outcome, ER+/PR+/HER2- subtype was associated with the most favorable prognosis (p = 0.002). Molecular subtype division remained an independent prognostic factor in multivariate analysis, accompanying parameters such as diabetes, hypertension, stage, myometrial infiltration, and metastases, all of which yielded hazard ratios between 1.39 and 2.23. ER+/PR+/HER2+ and ER+/PR+/HER2- subtypes had low average TP53 and TOP2A expression levels when compared with ER-/PR-/HER2+ and ER-/PR-/HER2- (both p < 0.00001). Molecular subtypes in EC do show diversity in terms of prognosis, clinicopathological, and molecular characteristics. ER-/PR-/HER2+ subtype exhibit is exceptionally aggressive tumor characteristics. Subtype differentiation might aid prediction of treatment response in EC.