Year: 2026
Type: article
Abstract: 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.
Source: Nature Communications
Institutions: Genentech, Roche (China), The University of Texas MD Anderson Cancer Center, University of California, Los Angeles, Hospital General Universitario Gregorio Marañón, Centro de Investigación Biomédica en Red de Cáncer, GEICAM – Spanish Breast Cancer Group, Garvan Institute of Medical Research, UNSW Sydney, Yonsei University, Yonsei University Health System
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $6,990
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
OpenAlex ID: W7135019125