Abstract Background: Breast cancer is the leading cause of cancer-related mortality in women worldwide. Chemotherapy resistance remains a critical barrier to durable outcomes, and no robust predictive biomarkers are available for standard regimens. Consequently, many patients are exposed to empirically applied polychemotherapy with suboptimal efficacy and unnecessary toxicity. Recent evidence indicates that the clinical benefit of many combinations reflects independent drug action (IDA),whereby distinct patients benefit from distinct agents rather than from true pharmacologic synergy. This model highlights an opportunity to replace empiric combinations with personalized monotherapies. Methods: We established a functional precision oncology platform using PDOs to evaluate drug responses in breast cancer. Thirty biopsies from 29 patients with invasive carcinomas treated with the AC-T regimen (doxorubicin/cyclophosphamide and paclitaxel) were collected. PDOs were successfully established in 22 cases (76%) and preserved the histopathological and immunohistochemical profiles of parental tumors (ER/PR/HER2, Ki-67). Drug responses were quantified using Growth Rate (GR)metrics and integrated into a Sequential Efficacy of Chemotherapy (SEC) score aligned with clinically relevant free (unbound) plasma concentrations (Cmax, corrected for protein binding). Results: When challenged with the complete AC-T regimen, PDOs revealed that 20% of tumors were resistant and 80% were sensitive. Within the sensitive group, however, only 32% demonstrated evidence of synergistic interaction between doxorubicin and cyclophosphamide, whereas in 68% the effect could be attributed to a single agent, consistent with the Independent Drug Action (IDA) paradigm. Dissection of individual drugs confirmed pronounced heterogeneity:43% of PDOs were resistant to doxorubicin, 25% to 4-hydroxy-cyclophosphamide, and 71% to paclitaxel, with 6% showing cross-resistance to both anthracycline and taxane. Importantly, PDO profiling uncovered alternative vulnerabilities, such as sensitivity to epirubicin in some doxorubicin-resistant cases and to docetaxel in a subset resistant to paclitaxel. These results demonstrate that PDO assays can disentangle the relative contribution of each drug within combination regimens, providing a functional basis to understand clinical benefit as arising from patient-to-patient variability rather than from true pharmacologic synergy. Conclusions: PDO-based assays capture interindividual heterogeneity in drug response and align with the IDA paradigm, explaining why most patients benefit from only a subset of drugs in standard combinations. By prospectively identifying the most effective single agent per patient, PDO-guided therapy could shift breast cancer management from empiric polychemotherapy toward individualized monotherapies. This approach offers the dual advantage of maximizing efficacy and minimizing toxicity, with the potential to fundamentally redefine precision chemotherapy in breast cancer. Citation Format: E. T. Costa, L. D. Simões, D. G. Giannotti, E. X. dos Santos, A. R. A. Canteli, C. H. dos Anjos, J. L. B. Bevilacqua, R. M. Junior, P. C. M. da Silva, P. A. d. Teixeira, L. A. J. Moyses, L. A. Yamashita, C. R. Saccarelli, A. C. S. D. Barros. Patient-derived organoids (PDO) as functional models to capture interindividual heterogeneity in breast cancer chemotherapy response. abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS4-02-05.
Costa et al. (Tue,) studied this question.