Real-World Implementation of Molecular Testing and Biomarker-Guided Therapies in HR+/HER2− Metastatic Breast Cancer

Background/Objectives: The introduction of biomarker-guided therapies, including PI3K, AKT and PARP inhibitors as well as Selective Estrogen Receptor Degraders (SERDs), has expanded treatment options and delayed the need for chemotherapy in hormone receptor positive (HR+)/human epidermal growth factor receptor 2 negative (HER2-) metastatic breast cancer (mBC). Nevertheless, evidence regarding their implementation in routine clinical practice remains limited. This study evaluated the real-world use of molecular testing and biomarker-guided therapies in patients with HR+/HER2− mBC. Methods: Patients with HR+/HER2− mBC treated at the Medical University of Vienna, Austria, between July 2020 (EMA approval of alpelisib, marking the introduction of biomarker-guided therapies in HR+/HER2− mBC) and April 2025 were identified through a retrospective chart review. Patient and disease characteristics, molecular testing patterns, utilization of biomarker-guided therapies, and oncological outcome were assessed. Biomarker-guided therapies included alpelisib and capivasertib for PI3K/AKT pathway alterations, elacestrant for ESR1 mutations, and PARP inhibitors for BRCA1/2 mutations. Descriptive statistics summarized patient characteristics, molecular testing, and biomarker-guided therapies. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan–Meier method, and prognostic factors were evaluated using univariable and multivariable Cox regression analyses. Results: A total of 274 patients with HR+/HER2− mBC were included. 63.5% (174/274) of patients had undergone at least one molecular test. Overall, 59.8% (104/174) of patients harbored at least one actionable molecular alteration. Of these, 54.8% (57/104) received a biomarker-matched therapy. Of the 47 patients who had not received a matched therapy, 25 remained on first-line CDK4/6 inhibitor-based treatment and were therefore not yet candidates for subsequent biomarker-guided therapy. 12.8% (6/47) of patients with a targetable alteration did not receive a biomarker-matched therapy but transitioned to chemotherapy or an ADC. Concurrent actionable alterations were uncommon. Among 12 patients with concurrent PI3K/AKT pathway and ESR1 alterations, four received PI3K/AKT-directed therapy only and three ESR1-directed therapy only. Among four patients with concurrent PI3K/AKT pathway and BRCA1/2 alterations, three received PI3K/AKT-directed therapy only, whereas none received a PARP inhibitor. No patient with concurrent actionable alterations in different pathways received more than one biomarker-matched therapy sequentially. Biomarker-guided therapies achieved median treatment durations ranging from 3.5 to 14.5 months and postponed the need for chemotherapy or antibody-drug conjugates (ADCs) by a median of 9 months. Conclusions: Molecular testing was implemented in a substantial proportion of patients with HR+/HER2− mBC and identified actionable alterations in the majority of tested patients. The use of biomarker-guided therapies delayed treatment escalation to chemotherapy or ADCs.