Personalized prediction of sequential therapeutic responses in HR+/HER2-low breast cancer using patient-derived organoids.

Abstract

Background: The clinically recommended treatment for hormone receptor-positive/human epidermal growth factor receptor 2-low (HR+/HER2-low) advanced breast cancer involves endocrine therapy (e.g., fulvestrant) followed by antibody-drug conjugates (ADCs) such as trastuzumab deruxtecan (T-DXd; formerly DS-8201) and sacituzumab govitecan (SG). However, the therapeutic outcomes of this sequential regimen remain suboptimal, and direct evidence is lacking as to whether this sequence is optimal. Additionally, the sequence of DS-8201 and SG is also unknown. Patient-derived organoids (PDOs) have emerged as a promising preclinical tool, shown to predict personalized drug responses and correlate well with clinical outcomes. Therefore, using PDOs from HR+/HER2-low breast cancer, this study aims to systematically evaluate the antitumor effects of different administration sequences involving fulvestrant and ADCs (i.e., DS-8201 or SG), as well as DS-8201 and SG and to provide evidence for optimizing treatment sequencing.

Methods: PDOs were established from fresh breast cancer tissues and characterized by immunohistochemistry (IHC), hematoxylin and eosin (H&E) staining, and immunofluorescence (IF) to confirm histopathological and phenotypic features fidelity to original tumors. Organoid viability was assessed using the CellTiter-Glo 3D (CTG-3D) assay, and morphological changes were monitored by bright-field microscopy. After treatment with fulvestrant, DS-8201, or SG alone, IHC and IF were performed to detect key proteins involved in the mechanism of action of SG and DS-8201.

Results: Our results demonstrated that administering DS-8201 or SG followed by fulvestrant yielded superior antitumor effects compared with the reverse sequence (fulvestrant followed by ADCs). Moreover, organoids revealed marked patient heterogeneity in response to the sequential administration of DS-8201 and SG (i.e., DS-8201 then SG vs. SG then DS-8201). Notably, relying solely on expression levels of biomarkers alone was insufficient to accurately predict ADCs sensitivity in organoids that had received prior therapy.

Conclusions: The sequence of DS-8201/SG followed by fulvestrant is a more suitable treatment regimen than the conventional sequence (fulvestrant followed by ADCs) for HR+/HER2-low breast cancer. This study provides important preclinical evidence supporting the optimization of therapy sequences in personalized medicine and advances the application of organoid-based models in oncology research.