# Novel estrogen receptor mutations as a biomarker dictating therapy response in advanced endocrine-resistant estrogen receptor-positive breast cancer

> **NIH NIH R03** · JOHNS HOPKINS UNIVERSITY · 2024 · $163,750

## Abstract

PROJECT SUMMARY
While there have been tremendous advances in the treatment of estrogen receptor-positive (ER+) breast
cancer, late-stage ER+ metastatic breast cancer (MBC) has very poor prognosis. The chief reason for this is
tumor endocrine resistance, wherein tumors do not respond to ER-targeting therapies. Endocrine resistance is
the major reason for breast cancer mortality, and a primary challenge in the treatment of ER+ MBC. The most
well known mechanism of endocrine resistance is hotspot activating mutations in ER that lead to ligand
independence. These hotspot mutations are effectively inhibited by the newest class of endocrine therapy,
novel oral selective ER degraders (SERDs), and serve as a biomarker for SERD responsive tumors.
We found a novel non-hotspot ER variant of unknown significance, and double hotspot mutations (in cis, on the
same ER molecule) from clinical whole-exome sequencing of tumors with acquired resistance to ER inhibition.
These single and double mutations are frequent, with the latter present in ~5% of resistant tumors. Without
preclinical characterization, these variants represent an unknown entity in terms of biology and therapy
response. In pilot studies, we found they confer strong resistance to select ER and CDK4/6-targeting therapies,
and that structure modeling suggests they are predicted to alter ER binding to its ligand, inhibitors, and/or
transcriptional co-factors. Robust preclinical studies in well-established models of breast cancer are required
before these findings can be translated to the clinic.
In this application, we propose comprehensive preclinical characterization of these prevalent novel ER variants
through two specific aims: 1) assess oncogenic potential and downstream signaling by novel ER variants,
specifically to determine how they dysregulate downstream ER transactivation, through transcriptomic,
epigenomic, and proteomic profiling, reporter assays, and structure modeling, and 2) profile their response to
targeted therapies in cell line, patient-derived organoid, and animal xenograft models. At the end of the grant
term, we expect to a) validate novel ER variants as potential biomarkers that may predict resistance to ER and
CDK4/6 inhibitors, particularly the novel SERDs, b) identify the structural basis by which these novel variants,
and particularly, double hotspot mutations dysregulate ER, and c) identify potential targetable nodes for tumors
that acquire these novel ER mutations. Our results would help design clinical trials to overcome resistance,
and that may avoid unnecessary additional burden of toxicity in heavily pre-treated patients. Developing
biomarkers that predict response to oral SERDs will also enable the stratification of patients whose tumors
express these novel ER variants onto alternate therapeutic regimens without delay (precision medicine). These
studies have strong potential to reduce the mortality associated with breast cancer, and are thus, well-aligned
with the m...

## Key facts

- **NIH application ID:** 10954053
- **Project number:** 1R03CA293120-01
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Utthara Nayar
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $163,750
- **Award type:** 1
- **Project period:** 2024-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10954053

## Citation

> US National Institutes of Health, RePORTER application 10954053, Novel estrogen receptor mutations as a biomarker dictating therapy response in advanced endocrine-resistant estrogen receptor-positive breast cancer (1R03CA293120-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10954053. Licensed CC0.

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