ctDNA and tumor-based biomarkers of giredestrant response in acelERA breast cancer
Endocrine therapy (ET) resistance in estrogen receptor positive (ER+) advanced breast cancer is often linked to ESR1 mutations, yet responses to oral selective ER degraders vary within mutant subgroups. Through a biomarker analysis of acelERA Breast Cancer (NCT04576455), we show that tumor ER transcriptional activity as well as circulating tumor DNA (ctDNA) genomics and dynamics effectively stratify response to ET, including giredestrant. We find that following first-line therapy, the ctDNA genomic landscape is diverse and influenced by CDK4/6 inhibitor exposure. Despite this complexity, ER activity in ESR1-mutant tumors remains comparable to early breast cancer but is reduced in most non-mutant cases. This maintained ER activity is associated with giredestrant benefit. Furthermore, early ctDNA clearance identifies responding patients, and the combination of low ER activity and high ctDNA burden predicts rapid clinical progression. These findings provide a framework for personalizing future breast cancer therapies by integrating liquid biopsies with tissue-based signatures.
Authors
- Lincoln W. Pasquina (ORCID: https://orcid.org/0009-0009-5461-9777)
- Xiaopeng Sun (ORCID: https://orcid.org/0009-0009-5219-8964)
- Alejandro Chibly (ORCID: https://orcid.org/0000-0001-7747-4990)
- Stephanie Hilz (ORCID: https://orcid.org/0000-0002-6995-6719)
- Tharu M. Fernando (ORCID: https://orcid.org/0000-0001-9672-6428)
- Heather M. Moore (ORCID: https://orcid.org/0000-0002-7098-3888)
- Ann Collier (ORCID: https://orcid.org/0000-0003-3410-3238)
- Miguel Martín
- Chunzhe Duan
- Aditya Bardia
- Joohyuk Sohn
- Elgene Lim
- Pablo Diego Pérez-Moreno
- Mariana Chavez-MacGregor
Institutions
- The University of Texas MD Anderson Cancer Center (US)
- Garvan Institute of Medical Research (AU)
- University of California, Los Angeles (US)
- Yonsei University (KR)
- Hospital General Universitario Gregorio Marañón (ES)
- UNSW Sydney (AU)
- Gene Therapy Laboratory (FR)
- Roche (China) (CN)
- St Vincent's Clinic (AU)
- Centro de Investigación Biomédica en Red de Cáncer (ES)
- GEICAM – Spanish Breast Cancer Group (ES)
- Foundation Medicine (United States)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-03-12
- DOI
- https://doi.org/10.1038/s41467-026-70335-0
- Primary Topic
- Estrogen and related hormone effects
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Bristol-Myers Squibb
- Eli Lilly and Company
- Pfizer
- AstraZeneca
- Sanofi
- Gilead Sciences
- American Society of Clinical Oncology
- F. Hoffmann-La Roche
- Les Laboratories Pierre Fabre
- Hope Foundation
- Puma Biotechnology
- Seagen
- University of New South Wales
- Daiichi-Sankyo
- Genentech
- Foundation Medicine
- Daiichi Sankyo Europe