Accurate risk stratification at the initiation of systemic therapy remains a major challenge in patients with HR+/HER2− advanced breast cancer (ABC). Improved identification of patients with an unfavorable disease course is essential to guide treatment decisions in early lines. The primary aim of this thesis was to enhance the clinical characterization of HR+/HER2− ABC by evaluating whether plasma-derived genomic profiling and quantitative circulating tumor DNA (ctDNA) metrics improve prognostic assessment beyond conventional clinicopathologic parameters. In addition, potential biological differences between HER2-low and HER2-0 tumors were explored. To address the need for reliable liquid biopsy-based testing and extend the clinical applicability of ctDNA-based analyses, a nation-wide initiative was implemented to evaluate plasma-based ESR1 mutation testing in patients with HR+/HER2− ABC, assessing its feasibility for identifying candidates for elacestrant while providing insight into molecular heterogeneity in a real-world setting. Using a tumor-agnostic sequencing approach, the ctDNA-derived genomic landscapes were characterized, and quantitative tumor-derived metrics were assessed. The genomic profiles in the early treatment lines were consistent with known features of HR+/HER2− disease, including recurrent alterations in PIK3CA, TP53, and ESR1. ESR1 mutations were more frequent in later treatment lines, reflecting therapy-driven clonal selection. Integration of mutation-based and genome-wide ctDNA metrics improved detection sensitivity and enabled a more comprehensive assessment of tumor burden. Most ctDNA-derived measures were associated with clinical outcomes, and their integration with established baseline clinical variables improved prognostic stratification compared with conventional factors alone. Exploratory ctDNA analyses revealed largely similar genomic profiles between HER2-low and HER2-0 tumors. Plasma-based ESR1 testing proved to be feasible in a more advanced and heterogeneous clinical setting, underscoring its relevance for treatment-guided decision-making. In summary, ctDNA-based profiling represents a practical and minimally invasive tool for personalized management of HR+/HER2− ABC, enabling improved risk stratification and supporting clinically driven molecular testing to inform treatment selection.
Circulating Tumor DNA in Metastatic Hormone Receptor-Positive Breast Cancer Patients With Focus on HER2 Biology
Dobrić, N. (Autor/-in). 2026
Studienabschlussarbeit: Dissertation