Introduction HER2-targeted therapy improves outcomes of HER2-positive endometrial cancer (EC). A novel class of HER2-directed antibody drug conjugate (ADC) that has demonstrated significant benefit in HER2-Low breast carcinoma, is being evaluated in clinical trials for other solid tumors, including uterine carcinoma with varying levels of HER2 expression. ADC efficacy in HER2-Low cancers may be partially attributed to bystander effect in tumors with heterogenous HER2 expression. We characterize the spectrum of HER2 expression in EC cases tested in a large tertiary care centre.

Methods An audit of HER2 testing in EC was conducted, utilizing ISGyP criteria for immunohistochemistry (IHC) scoring. Akin to the DESTINY clinical trials, HER2-P (positive) was defined as IHC score 3+ or FISH-amplified; HER2-L (low) defined as IHC2+ (not-amplified) or IHC1+ and HER2-N (negative) defined as IHC score 0.

Results There were 95 primary, 4 local recurrences and 10 metastatic EC HER2 tests, with 33 (30%) HER2-N, 46 (42%) HER2-L and 30 (28%) HER2-P. 60 were serous carcinoma, 29 high-grade EC, 9 carcinosarcomas, 8 Endometrioid and 3 others. Among 79 p53 abnormal cases, 22 (28%), 34 (43%), 23 (29%) were HER2-N, HER2-L and HER2-P, respectively. Table 1 summarizes p53, MMR and ER status by IHC and presence of pathogenic POLE mutations. None of the POLE-mutated or MMR-deficient molecular subgroup cases were HER2-P.

Conclusion/Implications The majority of ECs tested by IHC/FISH demonstrated some level of HER2 expression, with 42% meeting the criteria for HER2-L designation, potentially doubling the patients that may be considered for novel ADC therapies compared to the legacy HER2 targeted therapies.