Aromatase inhibitors: cellular and molecular effects

Area of Science:

• Oncology
• Pharmacology

Background:

• Postmenopausal breast cancer treatment often involves endocrine therapies.
• Aromatase inhibitors (AIs) are widely used, but their neoadjuvant effects on tumor biology require further elucidation.

Purpose of the Study:

• To investigate the cellular and molecular changes in estrogen receptor (ER)-rich breast cancers following neoadjuvant treatment with aromatase inhibitors (anastrozole, exemestane, letrozole).
• To compare these changes with those induced by tamoxifen and to analyze early molecular responses.

Main Methods:

• Analysis of tumor biopsies from postmenopausal breast cancer patients undergoing neoadjuvant therapy with anastrozole, exemestane, or letrozole.
• Assessment of pathological responses, histological grading, and expression of proliferation marker Ki67 and progesterone receptor (PgR).
• RNA analysis of sequential biopsies to study gene expression patterns.

Main Results:

• Aromatase inhibitors induced pathological responses in the majority of ER-rich tumors, characterized by reduced cellularity and increased fibrosis.
• Significant decrease in Ki67 expression (82% of tumors) and changes in PgR expression (reduction) were observed, differing from tamoxifen effects.
• Early decreases in Ki67 were noted within 14 days of letrozole treatment, preceding clinical response.

Conclusions:

• Neoadjuvant aromatase inhibitors induce rapid and significant molecular and cellular changes in ER-rich breast cancers.
• Distinct molecular profiles emerge, potentially allowing for the identification of patient subgroups with varying sensitivity to AIs.
• Early molecular changes, while not predicting clinical response, offer insights into treatment dynamics and resistance mechanisms.