# Defining mechanisms of resistance to hormonal therapy in breast cancer

> **NIH NIH R01** · SLOAN-KETTERING INST CAN RESEARCH · 2021 · $410,835

## Abstract

ABSTRACT
Hormonal therapy remains a mainstay of systemic treatment for the 70% of breast cancers that express the
estrogen receptor (ER), but responses vary and intrinsic and acquired resistance are major clinical challenges.
Recently, ligand-binding domain mutations in the estrogen receptor (ER) gene (ESR1) were found to occur and
to mediate hormonal therapy resistance in approximately 35% of ER-positive (ER+) breast cancer patients. In
the remaining two-thirds of cases, the molecular basis of hormonal therapy resistance is largely unknown. In
preliminary data, based on targeted sequencing of 1756 breast cancer patients with recurrent or metastatic
disease, we identified enrichment for alterations in diverse effectors of MAP kinase signaling (ERBB2 mutation,
EGFR amplification, NF1 mutation, and others) in ESR1-wildtype breast cancers collected after disease
progression on anti-estrogen therapy. This proposal is based on the hypothesis that recent advances in
sequencing methodology and analysis of cell-free DNA (cfDNA) can prospectively identify molecular alterations
that confer resistance to hormonal therapy in patients with breast cancer and that co-targeting such alterations
alongside ER could prevent or delay the emergence of drug-resistant clones. Three specific aims are
proposed. In Aim 1, paired tumor samples and cfDNA collected from breast cancer patients before and during
treatment and at the time of disease progression on hormonal therapy will be used to define the landscape and
timing of molecular changes that arise under the selective pressure of therapy. Our preliminary data indicate
that ERBB2 mutation is a mechanism of both intrinsic and acquired resistance to hormonal therapy. We have
also found that the HER kinase inhibitor neratinib can induce profound therapeutic responses that are limited
by the induction of ER activity and consequent emergence of drug resistance. Thus, in Aim 2, we will use
paired pretreatment and disease-progression tumor biopsies, cfDNA collected at regular intervals during
treatment with neratinib alone or with the ER degrader fulvestrant, and engineered isogenic models and
patient-derived xenografts to identify and validate mechanisms of resistance to these therapeutic agents.
Finally, our genomic analysis identified RAS/ERK pathway alterations in ~10% of tumors collected following
disease progression on hormonal therapy. In Aim 3, we will explore the functional significance of this finding
and seek to develop therapeutic strategies for overcoming hormonal therapy resistance in this molecularly
defined population. The long-term objective of this project is to develop therapeutic strategies for ER+ breast
cancer guided by real-time, non-invasive molecular monitoring of tumor evolution. The work proposed will also
generate valuable preclinical models of HER2-mutant and NF1-mutant ER+ breast cancer that can be used in
future studies to assess promising novel therapeutic approaches for these molecularly defi...

## Key facts

- **NIH application ID:** 10054178
- **Project number:** 5R01CA234361-03
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** Sarat Chandarlapaty
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $410,835
- **Award type:** 5
- **Project period:** 2018-12-05 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10054178

## Citation

> US National Institutes of Health, RePORTER application 10054178, Defining mechanisms of resistance to hormonal therapy in breast cancer (5R01CA234361-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10054178. Licensed CC0.

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