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

<b>Purpose</b>: 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 <i>Ki-67</i> and progesterone receptor (PgR) expression as indicators of endocrine response. <b>Methods</b>: 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 (<i>Ki-67</i>, PgR) were assessed pre- and post-treatment. <b>Results</b>: NET led to a significant reduction in tumor size, with median shrinkage of 47.0% (from 32.0 mm to 17.0 mm, <i>p</i> < 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 (<i>p</i> < 0.0001) and remained low in surgical specimens (median 5.0%, <i>p</i> < 0.0001). In 33.3% of patients, <i>Ki-67</i> dropped below 2.7%, and 67.0% showed a concordant decrease in both <i>Ki-67</i> and PgR. PgR expression declined significantly during treatment (<i>p</i> < 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. <b>Conclusions</b>: NET effectively reduced tumor burden and histological aggressiveness, enabling higher rates of BCS. Early reduction in <i>Ki-67</i> 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.