# Role of HER2 in Response to Neoadjuvant Endocrine Therapy in Luminal Breast Cancer

## TL;DR

Low HER2 expression in luminal breast cancer does not affect response to neoadjuvant endocrine therapy, but lower Ki67 levels after treatment are linked to better outcomes.

## Contribution

This study is the first to show that HER2-low status does not influence neoadjuvant endocrine therapy response in luminal breast cancer.

## Key findings

- Low HER2 expression does not significantly impact neoadjuvant endocrine therapy response in luminal tumors.
- Ki67 levels after short-term neoadjuvant endocrine therapy correlate with longer progression-free survival.
- Estrogen receptor levels, histological subtype, and grade influence neoadjuvant endocrine therapy response.

## Abstract

Interest in the new HER2-low subtype of breast cancer is increasing. Currently, this subtype is classified and treated the same as HER2-negative tumors. This study aimed to determine whether response to neoadjuvant endocrine therapy (NET) is affected by low levels of HER2 expression in luminal tumors. Our findings suggest that low HER2 expression does not significantly impact the response to neoadjuvant endocrine therapy (NET) in luminal tumors compared to HER2-zero cases. Additionally, it does not affect other clinical or histopathological features. Rather, NET response may be influenced by factors such as estrogen receptor (ER) levels, histological subtype and grade, and early Ki67 changes. A decrease in Ki67 after short-term NET may be associated with longer progression-free survival (PFS).

Purpose: Recently, authors have shown increasing interest in the emerging HER2-low subtype in breast cancer. These tumors are currently classified and treated as HER2-negative tumors. Neoadjuvant endocrine therapy (NET) has been used to achieve tumor downstaging and assess treatment response in postmenopausal women with low-grade luminal HER2-negative tumors. This study aimed to determine whether the response to NET was affected by low levels of HER2 expression in luminal tumors. Methods: The study was a single-centered retrospective investigation. Data were gathered from the medical records of patients from 2017 to 2023. All patients had luminal HER2-negative tumors and were treated with NET and subsequent surgery. Results: In total, 175 tumors were analyzed; 24.0% of the tumors were HER2-zero, 48.0% were HER2-low 1+, and 28.0% were HER2-low 2+. No significant differences were found when assessing NET response between the three groups, nor when evaluating tumor features. Response to NET was influenced by estrogen receptor levels, histological subtype and histological grade at diagnosis, Ki67 levels at interim biopsy, and NET duration. No differences were found for progression-free survival (PFS) or overall survival (OS) between HER2 groups. The group with Ki67 ≤ 10% at interim biopsy had longer PFS than the Ki67 > 10% group (p < 0.05). No differences for OS were found between these groups. Conclusions: Response to NET was not influenced by low levels of HER2 expression in luminal tumors when compared to HER2-zero tumors. PFS was longer for patients who had lower Ki67 levels at interim biopsy after NET.