# Predicting Endocrine Therapy Response In Male Breast Tumors

> **NIH NIH R37** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2024 · $604,746

## Abstract

PROJECT SUMMARY/ABSTRACT
Male breast cancer is critically understudied due to both the rarity of the disease and the exclusion of men
from breast cancer trials leading to a significant knowledge gap about how male breast tumors respond to
therapy. The efficacy of existing endocrine therapies in men with ER+/HER2- breast cancer have never
been compared prospectively, and this is the goal of the ongoing ETHAN trial. In this trial, 60 patients are
randomized to 3 endocrine regimens for a 3-week window phase, followed by biopsy, then a 4-month
neoadjuvant phase +/- the CDK4/6 inhibitor abemaciclib, followed by surgical resection. The trial is well
powered to compare differences in response rates, measured in the window phase by a 50% reduction in
Ki-67, and in the neoadjuvant phase by residual cancer burden index. This design creates an
unprecedented opportunity for translational studies using samples from pre and post treatment timepoints
annotated with clinically relevant response endpoints. The goal of this proposal is to leverage patient
samples from the ETHAN trial to understand and predict how male breast tumors respond to therapy. We
hypothesize that multigene response signatures will predict response to ET in men with ER+ breast
tumors. To test this hypothesis, in Aim1 we will determine endocrine therapy response signatures using
whole transcriptome sequencing of pre and post treatment specimens. We will determine how each drug
treatment results in changes in gene expression and compare these to female predictors and response
signatures. We will perform stratified analysis of responders and non-responders to discover biomarkers
which will be validated using large cohorts of patients with ER+/HER2- breast cancer treated with
endocrine therapy. In Aim2, we will utilize our single cell processing pipeline which we used to show
distinct responses in malignant cell subpopulations within female ER+/HER2- breast tumors, to dissect
heterogeneity in endocrine therapy response within male breast tumors. This analysis will define features
of low abundance cell populations that may be driving the resistance phenotype. Finally, in Aim3, we will
address a critical lack of experimental models of male breast cancer by using our organoid infrastructure
to generate male patient derived organoids. We will use organoids to test estrogen receptor gene
regulatory function and assess the preclinical efficacy of targeted therapeutic strategies. Cumulatively,
these studies will address a significant knowledge gap of why therapies are effective or i neffective in men
with breast cancer. These findings will generate predictors of response, identify pathways driving
resistance, and generate and utilize experimental models to uncover the intrinsic biology of male breast
tumors. If successful, these insights will lead to more precise treatment regimens and improve outcomes
for men with breast cancer.

## Key facts

- **NIH application ID:** 10940688
- **Project number:** 1R37CA292075-01
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Jose P. Leone
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $604,746
- **Award type:** 1
- **Project period:** 2024-07-01 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10940688

## Citation

> US National Institutes of Health, RePORTER application 10940688, Predicting Endocrine Therapy Response In Male Breast Tumors (1R37CA292075-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10940688. Licensed CC0.

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