Clinicopathological characteristics and response to neoadjuvant chemotherapy in HER2-low hormone receptor-positive breast cancer: a retrospective cohort study.

BACKGROUND: HER2-low breast cancer constitutes a substantial proportion of hormone receptor-positive (HR+) cases, yet its biological behavior and responsiveness to neoadjuvant chemotherapy (NACT) remain incompletely characterized. This study aimed to compare clinicopathological features and pathological complete response (pCR) rates between HER2-low and HER2-zero expression in HR+ breast cancer patients receiving NACT. MATERIALS AND METHODS: This retrospective cohort study included 178 HR+/HER2-negative breast cancer patients who received NACT followed by surgery at Yichang Central People's Hospital between January 2020 and December 2024. Patients were categorized into HER2-low (immunohistochemistry [IHC] 1+ or 2+/in situ hybridization [ISH]-, n=102) and HER2-zero (IHC 0, n=76) groups. Clinicopathological characteristics, pCR rates, residual cancer burden (RCB), Ki-67 changes, and treatment responses were compared. The primary outcome was total pathological complete response (tpCR, ypT0/is ypN0). Multivariable logistic regression and subgroup analyses were performed. RESULTS: The HER2-low group exhibited significantly higher proportions of Ki-67 index ≥20% (57.8% vs. 38.2%, P = 0.01) and grade III histology (45.1% vs. 28.9%, P = 0.03) compared to the HER2-zero group. The tpCR rate was significantly lower in the HER2-low group than in the HER2-zero group (11.8% vs. 25.0%, P = 0.02). Multivariable analysis identified HER2-low status as an independent negative predictor of tpCR (odds ratio [OR]=0.40, 95% confidence interval [CI]: 0.18-0.89, P = 0.02). The HER2-low group showed significantly smaller median Ki-67 reduction (-14.5% vs. -23.8%, P = 0.02). Subgroup analyses revealed that the negative impact of HER2-low status on pCR was more pronounced in patients with Ki-67 ≥20% (interaction P = 0.03) and grade III disease (interaction P = 0.04). CONCLUSIONS: In this retrospective cohort of HR+ breast cancer patients, HER2-low expression was associated with more aggressive clinicopathological features and a significantly lower pCR rate compared to HER2-zero expression. After multivariable adjustment, HER2-low status remained significantly associated with reduced pCR odds (OR = 0.40, 95% CI: 0.18-0.89). These findings suggest that HER2-low may represent a clinically relevant subgroup within HR+ breast cancer, but the observational design precludes causal interpretation, and these hypothesis-generating results require validation in prospective, adequately powered studies before any clinical treatment recommendations can be made.