HER2 low hormone positive breast cancer: Unveiling the driver.

e12561 Background: A new HER2 targeting drug, Trastuzumab deruxtecan, has shown effectiveness among a subgroup of breast cancer (BC) patients previously reported as HER2 negative, challenging the established classification. HER2 low (IHC 1+ or IHC +2/ISH negative) require further study to understand their clinicopathological features and prognosis to determine whether they are indeed distinctly different from the HER2 negative subgroup. Methods: This retrospective study of 1029 early BC patients diagnosed between 2014 and 2022 in Alexandria university hospitals. Tumors originally reported as HER2 negative were reclassified into HER2 0 and HER2 low and stratified based on hormone receptor (HR) status. Clinical and pathological features were compared. Disease free survival (DFS), overall survival (OS) and time to recurrence (TTR) were calculated. Results: Out of the 1029 patients, 779 (75.7%) were reported as HER2 negative, after reviewing their files, 441 (56%) of them were found to be IHC 0, and 338 (43%) were HER2 low. 192 (18.7%) HER2 positive patients and 58 (5.6%) patients with undetermined HER2 status were excluded. HER2-low tumors were found to be positively associated with HR positive status compared to HER2-0 (302 89.3% vs. 368 83.4%; P=0.019). The rate of HER2-low significantly increased as the level of ER expression increased, from 37 of 190 (19.5%) ER-negative to 40 of 143 (28%) ER-low, 94 of 264(35.6%) ER-moderate and 167 of 432(38.7%) ER strong, p=<0.001. ER2-low were more likely to be ductal carcinoma (88.1% vs. 80.4%; p=0.004), and to have Ki67 level <20 (55% vs. 33%; p=0.008). When stratified according to HR status, ductal histology was still significantly higher in the HER2 low HR positive subgroup compared to the HER2-0 HR positive (87.6% vs. 80.3%; p=0.011). No significant difference between HER2-0 and HER2-low regarding age at presentation, menopausal status, tumor size, lymph node status, lymphovascular invasion, high grade, multifocality or extensive intraductal component. Median follow-up duration was 55 months, no significant differences between HER2-0 and HER2 low groups regarding relapse rate (22.6% vs. 21.6%), 5-year DFS (76.4% vs. 78%) or 5-year OS (81.7% vs. 87.4%), however TTR was significantly longer in the HER2 low HR positive group compared to the HER2-0 HR positive group (41.6 months vs. 31.3 months; p= 0.031). Conclusions: A positive correlation was observed between HER2 low and estrogen receptor positivity, as well as its level of expression. No significant differences were found between HER2 low and HER2-0 to support classifying HER2 low as a distinct group.