163P Characterization of HER2-low breast cancer in young women with germline BRCA1/2 pathogenetic variants: Results of a large international retrospective cohort study

Breast cancer (BC) in women aged≤40 years carrying germline pathogenetic variants (PVs) in BRCA1/2 genes is infrequent but often associated to aggressive features. HER2-low-expressing BC has recently emerged as a novel therapeutic target but has not been characterized in this rare patient subset. Women aged≤40 years with newly diagnosed early-stage HER2-negative BC (HER2-0 and HER2-low) and germline BRCA1/2 PVs from 78 health care centers worldwide were retrospectively included. Chi-square test and Student's t-test were used to describe variable distribution between HER2-0 and HER2-low. Associations with HER2-low status were assessed with logistic regression. Kaplan-Meier method and Cox regression analysis were used to assess disease-free survival (DFS) and overall survival (OS). Statistical significance was considered for p≤0.05. Of 3,547 included patients, 32.3% had HER2-low BC, representing 46.3% of hormone receptor-positive (HR+) and 21.3% of triple-negative (TN) tumors. HER2-low vs. HER2-0 BC were more often of grade 1/2 (p<0.001), HR+ (p<0.001), and node-positive (p=0.003). BRCA2 PVs were more associated to HER2-low than BRCA1 (p<0.001). HER2-low vs. 0 showed better DFS (hazard ratio HR: 0.86, 95% confidence interval CI: 0.76–0.97) in the overall population and more favorable DFS (HR: 0.78, 95%CI: 0.64-0.95) and OS (HR: 0.65, 95%CI: 0.46–0.93) in the TN subgroup. Luminal A-like tumors in HER2-low (p=0.014), and TN and Luminal A-like in HER2-0 (p=0.019) showed the worst DFS. In young HER2-negative BC patients with germline BRCA1/2 PVs, HER2-low disease was less frequent than expected, more frequently linked to BRCA2 PVs and associated with luminal-like disease. HER2-low status was associated to modestly improved prognosis. Nevertheless, women with Luminal A-like tumors had worse prognosis regardless of HER2 status, highlighting the need for a better understanding of the biology underlying this tumor subgroup in young patients with germline BRCA1/2 PVs.