Molecular Profiling of Endocrine Resistance in HR+/HER2-Metastatic Breast Cancer: Insights from Extracellular Vesicles-Derived DNA and ctDNA in Liquid Biopsies

• Published in: International journal of molecular sciences 2024-12, Vol.25 (23), p.13045
• Main Authors: Martínez-Rodríguez, Ana, Fuentes-Antrás, Jesús, Lorca, Víctor, López de Sá, Alfonso, Pérez-Segura, Pedro, Moreno, Fernando, García-Sáenz, Jose Angel, García-Barberán, Vanesa
• Format: Article
• Language: English
• Subjects: Adjuvants; Adult; Aged; Antineoplastic Agents, Hormonal - pharmacology; Antineoplastic Agents, Hormonal - therapeutic use; Aromatase Inhibitors - pharmacology; Aromatase Inhibitors - therapeutic use; Biomarkers; Biomarkers, Tumor - genetics; Biopsy; Biosynthesis; Breast cancer; Breast Neoplasms - blood; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Cancer; Cancer therapies; Cell death; Circulating Tumor DNA - blood; Circulating Tumor DNA - genetics; Class I Phosphatidylinositol 3-Kinases - genetics; Clinical trials; DNA; Drug Resistance, Neoplasm - genetics; Estrogen Receptor alpha - genetics; Estrogen Receptor alpha - metabolism; Estrogens; Extracellular vesicles; Extracellular Vesicles - genetics; Extracellular Vesicles - metabolism; Female; Fulvestrant; Genetic aspects; Genetic research; Humans; Liquid Biopsy - methods; Metastasis; MicroRNAs; Middle Aged; Mutation; Neoplasm Metastasis; Precision medicine; Prognosis; Receptor, ErbB-2 - genetics; Receptor, ErbB-2 - metabolism; Receptors, Estrogen - genetics; Receptors, Estrogen - metabolism; Receptors, Progesterone - genetics; Receptors, Progesterone - metabolism; Tumors
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms252313045

Standard treatments in hormone receptor-positive (HR+)/HER2-metastatic breast cancer (mBC) typically involve endocrine therapy (ET) combined with CDK4/6 inhibitors, yet resistance to ET remains a persistent challenge in advanced cases. A deeper knowledge of the use of liquid biopsy is crucial for the implementation of precision medicine in mBC with real-time treatment guidance. Our study assesses the prognostic value of and mutations in DNA derived from extracellular vesicles (EV-DNA) in longitudinal plasma from 59 HR+/HER2-mBC patients previously exposed to aromatase inhibitors, with a comparative analysis against circulating tumor DNA (ctDNA). Mutations were evaluated by digital PCR. and mutations were found in 22 and 25% of patients. Baseline mutations in EV-DNA were associated with shorter progression-free survival (PFS) across the cohort, with the Y537S mutation showing a particularly strong impact on the outcome of fulvestrant-treated patients. In contrast, mutations in EV-DNA did not significantly correlate with PFS, whereas in ctDNA, they were linked to poor outcomes. Altogether, this study positions EV-DNA as a valuable biomarker alongside ctDNA, enriching the understanding of different analytes in liquid biopsy and supporting strategies for HR+/HER2-mBC in precision oncology.