Beyond ESR1 : Multi-pathway genomic drivers of endocrine resistance in HR⁺/HER2⁻ breast cancer.
Year: 2026
Type: conference-abstract
Abstract: 1071 Background: Endocrine resistance in HR⁺/HER2⁻ breast cancer is often associated with acquisition of ESR1 point mutations, but many patients at progression remain ESR1 wild type. Identifying ESR1 -independent, multi-pathway acquired resistance mechanisms is critical for guiding subsequent therapy. Methods: We analyzed 1,429 HR⁺/HER2⁻ breast cancer samples (468 tissue, 1,171 cfDNA), including 210 paired cases, from patients with metastatic breast cancer undergoing molecular testing for treatment guidance or disease monitoring. Next-generation sequencing performed at Datar Cancer Genetics assessed SNVs, CNAs, and gene fusions. Alterations implicated in endocrine resistance were analysed for incidence, specimen type, and co-alteration patterns. Results: ESR1 -wild-type tumors frequently harbored clinically relevant endocrine resistance mechanisms, most commonly involving the PI3K/AKT, FGFR, ERBB2, MAPK , and cell-cycle pathways. At least one resistance-associated alteration was identified in 40.4% (473/1172) of evaluable ESR1 -wild-type cases, while 14.8% (173/1172) harbored alterations across multiple resistance pathways, highlighting substantial ESR1 -independent resistance biology. Among ESR1 -driven mechanisms, ESR1 SNVs were detected slightly more frequently in cfDNA than tissue (13.7% vs 12.8%), despite inclusion of cfDNA samples obtained during clinical surveillance, supporting the sensitivity of liquid biopsy for detecting emergent resistance. ESR1 fusions represented a distinct, non-overlapping resistance mechanism, identified in 7.4% (28/379) of tissue samples, most commonly ESR1–CCDC170 (71%) and ESR1–AKAP12 (14%); 21 fusion-positive cases lacked ESR1 SNVs, underscoring the need for fusion assessment to fully capture ESR1 -driven resistance. Dynamic pathway activation was further supported by acquired PI3K pathway mutations, detected in cfDNA in 3.3% (4/122) of cases initially PIK3CA -wild-type in paired tissue samples. Conclusions: Endocrine resistance in HR⁺/HER2⁻ breast cancer is mediated by multiple actionable genomic pathways beyond ESR1 , including PI3K/AKT, FGFR, ERBB2, MAPK , and cell-cycle alterations. These findings expand opportunities to personalize therapy and guide clinical trial selection by targeting non- ESR1 resistance mechanisms. Incidence of endocrine resistance-associated genomic alterations beyond ESR1 point mutations in tissue and liquid biopsy for HR⁺/HER2⁻ breast cancer. Endocrine Resistance Biomarker ESR1 -Mutant Cases (%) ESR1 Wild-Type Cases (%) ESR1 fusions 11.1 6.7 FGFR1 alterations 13.2 7.0 CCND1 amplification 15.2 7.0 FGFR2/3 alterations 3.7 2.0 HER2 -mutant, non-amplified 2.5 2.6 PIK3CA mutation 43.7 25.1 PTEN mutation 2.0 1.6 AKT1 mutation 5.6 3.6 MAPK Pathway( RAS/RAF/MEK ) 4.6 4.0
Source: Journal of Clinical Oncology
Authors: Humaid Obaid Al-Shamsi, Massimo Cristofanilli, Muzammil Shaikh, Ashok K. Vaid, Sewanti Atul Limaye, Amish Vora, Niyati Krunal Shah, Darshana Suresh Patil, Rajan Datar, Navin Srivastava, Vineet Datta, Kinner Shah, Ashok Sebastian Komaranchath, Dorthe Schaffrin-Nabe, Tim Crook, Shiroma De Silva-Minor
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W7162530607
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