Comprehensive Liquid Biopsy Testing in Metastatic Hormone Receptor-Positive HER2-Negative Breast Cancer Patients: First Results from Routine Clinical Practice.

Liquid biopsy (LBx) is a minimally invasive diagnostic approach that allows molecular profiling of circulating tumor DNA. In hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer, early detection of actionable mutations is critical for guiding therapy. ESR1 mutations mediate resistance to aromatase inhibitors and predict response to (oral) selective estrogen receptor degraders. Despite its clinical relevance, data on the real-world application of LBx remain limited. We retrospectively analyzed 162 patients with HR-positive, HER2-negative metastatic breast cancer who underwent LBx testing in routine clinical care. Hybrid capture-based next-generation sequencing with high read depth (∼5,000-7,000×) was used to assess mutation profiles across a multigene panel, rather than single-gene assays such as ddPCR. Particular focus was placed on the detection of ESR1 mutations and their therapeutic implications. Of 162 patients, ESR1 mutations were detected in n = 46 (28.4%). Among these, 20 (43.5%) patients received elacestrant based on the molecular findings. LBx was feasible, rapidly implemented (∼8.7 days), and repeatable in routine practice. Detection of ESR1 mutations directly influenced treatment decisions, enabling the timely initiation of targeted endocrine therapy. Other recurrent mutations included PIK3CA, PTEN, and AKT, with potential therapeutic relevance. These real-world data support the clinical utility of LBx guidance in the metastatic setting. It is a rapid, minimally invasive, and informative diagnostic method for identifying resistance mutations such as ESR1 and guiding endocrine therapy decisions, including the use of elacestrant. LBx should be integrated as early as possible in the treatment algorithm and not reserved for late treatment stages when therapeutic options are limited. Repeating LBx at the time of progression of disease should be discussed depending on possible therapeutic implications.