Purpose: We aimed to characterize the genomic landscape of hormone receptor-positive (HR+)/HER2-negative breast cancer in patients with hormone therapy-resistant and -sensitive phenotypes.
Methods: HR+/HER2-negative patients who were disease-free for ≥2 years were considered hormone therapy-sensitive (n = 19), while those who experienced disease progression within 2 years were considered hormone therapy-resistant (n = 48). Whole-exome sequencing (WES) was performed on paired (treatment-naïve and relapse-site) tumor and germline-derived DNA from resistant patients (n = 19), and targeted next-generation sequencing (NGS) was performed on plasma-derived circulating tumor DNA (ctDNA) from resistant (n = 35) and sensitive (n = 19) patients.
Results: In 19 resistant patients, the mutation burden was higher in relapse-site compared with treatment-naïve samples (median 0.883 vs 0.655 mutations/mb, p = 0.03), there were 64 driver mutations (median treatment-naïve versus relapse-site; 2/sample vs. 3/relapse), of which 21 mutations in 8 genes in 15 (78.9%) patients were classified as actionable, and branching evolutionary trajectories were seen in 18 (94.7%) patients, with the presence of PIK3CA and/or TP53 mutations in stem clones of 13 (68.4%) patients. ctDNA analysis in 35 resistant patients identified 27 actionable hotspot mutations, such as PIK3CA H1047X, AKT1 p.E17K, CDH1 p.R63X, CDKN2A p.X50*, ERBB2 p.D769Y, and ESR1 p.E380Q, in 25 (71.4%) patients. Among 19 patients with hormone therapy-sensitive disease who were in remission at the time of sample collection, ctDNA analysis showed driver mutations in 10 (52.6%) patients, of whom 2 patients subsequently experienced relapse and died.
Conclusion: Hormone therapy-resistant HR+/HER2-negative breast cancers are polyclonal, acquire actionable alterations at relapse, and moderate-depth ctDNA successfully identifies many clonal mutations, suggesting a role for liquid biopsy monitoring in these patients.
Keywords: Actionable mutations; Breast cancer; Circulating tumor DNA; Hormone therapy resistance; Liquid biopsy.
© 2025. The Author(s).