# Early Predictive Markers and Histopathological Response to Neoadjuvant Endocrine Therapy in Postmenopausal Patients with HR+/HER2− Early Breast Cancer

## TL;DR

This study shows that early changes in Ki-67 and PgR levels can predict how well postmenopausal breast cancer patients respond to hormone therapy before surgery.

## Contribution

The study identifies early biomarker changes as predictive markers for response to neoadjuvant endocrine therapy in HR+/HER2− breast cancer.

## Key findings

- NET significantly reduced tumor size and histological aggressiveness in postmenopausal patients.
- Early declines in Ki-67 and PgR were associated with favorable biological response to therapy.
- HER2 status conversion occurred in 6.4% of patients during treatment.

## Abstract

Neoadjuvant endocrine therapy (NET) is a treatment option for postmenopausal patients with hormone receptor-positive (HR+)/HER2-negative early breast cancer, aimed at shrinking tumors before surgery. In this prospective study, we evaluated the effectiveness of NET with letrozole and explored early changes in tumor biology, including the proliferation marker Ki-67 and progesterone receptor (PgR) expression. We found that NET significantly reduced tumor size and histological aggressiveness. Early declines in Ki-67 and PgR were associated with favorable biological response and could help predict which patients benefit most from this therapy. Our findings support the use of dynamic biomarker monitoring to personalize treatment and improve outcomes in HR+/HER2− breast cancer.

Purpose: Neoadjuvant endocrine therapy (NET) represents a valuable treatment option for hormone receptor-positive (HR+)/HER2-negative breast cancer, particularly in postmenopausal women. This study aimed to evaluate the clinical and histopathological efficacy of NET and to explore early and late changes in Ki-67 and progesterone receptor (PgR) expression as indicators of endocrine response. Methods: A prospective cohort of 127 postmenopausal patients with stage cT1–4N0–3M0 HR+/HER2− breast cancer was enrolled between 2019 and 2021. Patients received NET (mostly letrozole) for a mean of 7.7 months. In 80 cases, a second core biopsy was performed after four weeks. Tumor size, histological grade, and biomarkers (Ki-67, PgR) were assessed pre- and post-treatment. Results: NET led to a significant reduction in tumor size, with median shrinkage of 47.0% (from 32.0 mm to 17.0 mm, p < 0.0001). Breast-conserving surgery (BCS) was performed in 52.2% of patients and lymph node negativity (pN0) was observed in 50.4%. Median Ki-67 decreased from 20.0% at baseline to 5.0% after four weeks (p < 0.0001) and remained low in surgical specimens (median 5.0%, p < 0.0001). In 33.3% of patients, Ki-67 dropped below 2.7%, and 67.0% showed a concordant decrease in both Ki-67 and PgR. PgR expression declined significantly during treatment (p < 0.0001). HER2 status conversion was noted in 6.4% of patients during treatment. Pathological complete response (pCR) occurred in 3.5%, while minimal or moderate residual disease (RCB I–II) was identified in 71.3% of cases. Conclusions: NET effectively reduced tumor burden and histological aggressiveness, enabling higher rates of BCS. Early reduction in Ki-67 and PgR may serve as surrogate markers of endocrine responsiveness, supporting their use for treatment stratification and monitoring during NET in HR+/HER2− breast cancer.