HER2-low-positive features a distinct subtype in estrogen receptor-positive breast cancer associated with endocrine therapy resistance

Background: HER2-low-positive breast cancers are reported to have distinct clinical and molecular features from HER2-zero tumors in ER-positive breast cancer. However, the association between HER2-status with response to endocrine therapy is largely unknown. Methods: In this study, we conducted a retrospective analysis to compare the response of ER-positive breast cancer to neoadjuvant endocrine therapy (NET), neoadjuvant chemotherapy (NCT) and survival according to HER2-status. Results: Pathological complete response (pCR) in primary tumor (ypT0/isNx) is significantly lower in HER2-low-positive breast cancer than in HER2-zero tumors for NET cohort (18 out of 233 [7.7%] vs 9 out of 45 [20%]) but not for NCT cohort (28 out of 204 [13.3%] vs 5 out of 36 [13.9%]). HER2-zero tumors consistently show higher ypT0/isNx pCR ratio than HER2-low-positive breast cancer in all endocrine therapy duration groups including 3-10months, 11-20months and 21-30months groups. Multi-variable logistic regression analyses showed that HER2-low-positive expression is a risk factor for poor response to NET. In patients receiving NET, HER2-low-positve breast tumors has better disease-free survival compared with HER2-zero while no significance difference was detected with overall survival. Conclusions: Our results demonstrated that HER2-low-positive breast tumors was a distinct subtype in ER-positive breast cancers and was associated with endocrine therapy resistance.