HER2 expression in a molecularly defined cohort of endometrial cancer patients: The SPECTRUM study

HER2 antibody-drug conjugates like Trastuzumab deruxtecan (TDxd) have shown efficacy in HER2-low cancers, however the prevalence and clinical impact of HER2-low in endometrial cancer (EC) remains unclear. This study investigates HER2 expression in EC, focusing on HER2-low frequency, its distribution across histologic and molecular subtypes, intratumoral heterogeneity, and prognostic significance.

This retrospective analysis included EC patients categorized histologically and molecularly, using ASCO/CAP HER2 scoring guidelines for endometrial, gastric, and breast cancers. The main aim was to determine HER2-low frequency by molecular subtype, with secondary goals of assessing HER2 heterogeneity, changes between primary and recurrent tumors, guidelines concordance and the impact of HER2 status on recurrence-free (RFS) and overall survival (OS).

193 EC patients were included, 111 low grade endometrioid EC and 82 high grade EC with various histotypes. Based on endometrial criteria, 69.9 % were HER2-negative, 25.8 % HER2-low, and 4.3 % HER2-positive, with HER2-low being most common in POLEmut (66.7 %) and p53abn (45.1 %) subtypes. Low heterogeneity in HER2 expression was observed between different tumors areas and between primary tumors and their recurrences. The endometrial and gastric criteria had high concordance (88.7 %), with endometrial guidelines detecting more HER2-low cases. Neither HER2-low nor HER2-positivity versus HER2-negativity had an impact on RFS or OS, with the stage at diagnosis being the only factor associated with survival, while age was associated only with OS.

This study highlights the distribution of HER2-low across EC molecular subtypes, with endometrial criteria proving more sensitive for identifying HER2-low cases, though HER2 status had no prognostic value in this cohort.