HER2 expression in a molecularly characterized cohort of patients with endometrial cancer (EC): SPECTRUM study.

5610 Background: Human epidermal growth factor receptor 2 (HER2)-low is a new category defined by HER2 1+ or 2+ by immunohistochemistry (IHC) and lack of HER2 amplification by in situ hybridization (ISH). Trastuzumab deruxtecan demonstrated antitumor activity in HER2-expressing gynecologic tumors. Little is known about HER2-low frequency in EC subtypes, the heterogeneity of the expression, the best scoring criteria or the prognostic value. Methods: This is a single center, retrospective study including patients diagnosed with EC amenable to curative treatment from 2003 to 2019. Two tissue cores of each sample were selected for the creation of 5 tissue microarrays (TMA). Molecular subrogated (MS) classification (WHO 5ed) was performed: polymerase epsilonmutated (POLEmut), mismatch repair deficient (dMMR), TP53 abnormal (p53abn) or non-specific molecular profile (NSMP). HER2 was assessed by IHC (4B5) and ISH on TMAs. HER2 scoring was done according to ASCO/CAP guidelines for breast and the proposed endometrial criteria. HER2 heterogeneity was defined as a difference in HER2 IHC ≥2+ or discrepancy in HER2 ISH between cores. Primary objective was to describe the frequency of HER2-low in MS. Secondary objectives included to assess heterogeneity, concordance between breast and endometrial criteria and the impact of HER2-low on recurrence-free (RFS) and overall survival (OS). Results: 193 patients were analyzed. Median age was 66.4 years (31-90). According to FIGO 2009 classification, stage I, II and III-IV corresponded to 71.5%, 14% and 14.5% of patients. Most cases (57.5%) were low-grade endometrioid followed by 14% serous, 11.9% high-grade endometrioid, 5.2% clear cell, 2.6% carcinosarcoma and 8.7% other histology. Regarding MS, 3.1% were POLEmut, 25.4% dMMR, 28% p53abn, 40.9% NSMP and 2.6% unclassifiable. Considering the entire cohort, 69.9% were HER2-negative (0+), 25.8% HER2-low and 4.3% HER2-positive (3+ or ISH+). The frequency of HER2-low was highest for POLEmut (66.7%) followed by p53abn (42.6%) (Table). Low heterogeneity in HER2 expression was demonstrated, with an agreement between cores in 84.5% of cases. Breast and endometrial criteria showed concordance in 85.5% of patients, with a kappa of 0,624 (p<0,05). HER2-low nor HER2-positive versus HER2-negative had an impact on RFS or OS. Conclusions: This is the first study showing the spectrum of HER2 expression in a MS cohort of EC. HER2-low is more frequent in POLEmut and p53abn subtypes. HER2-low had no prognostic significance. [Table: see text]