Organoid-evaluable clinical biomarkers predict drug responses and guide new breast cancer therapies

Bui, T. B. V.; Wolf, D. M.; Bruck, M. C.; Moore, K.; Lien, J.; Choi, S. D.; Warhadpande, S.; Parizadeh, A.; Dillon, D.; Overmoyer, B.; Lynce, F.; I-SPY 2 Investigators,; Nijman, I. J.; Burgering, B. M.; Harris, I. S.; Esserman, L. J.; Van 't Veer, L. J.; Rosenbluth, J. M.

doi:10.1101/2025.08.24.671810

bioRxiv · 10.1101/2025.08.24.671810

Organoid-evaluable clinical biomarkers predict drug responses and guide new breast cancer therapies

Bui, T. B. V.·Wolf, D. M.·Bruck, M. C.·Moore, K.·Lien, J.·Choi, S. D.·Warhadpande, S.·Parizadeh, A.·Dillon, D.·Overmoyer, B.·Lynce, F.·I-SPY 2 Investigators,·Nijman, I. J.·Burgering, B. M.·Harris, I. S.·Esserman, L. J.·Van 't Veer, L. J.·Rosenbluth, J. M.

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Abstract

Poor therapeutic response in subsets of breast cancer (BC) patients poses an ongoing challenge. Here, we present a biomarker-guided characterization of 44 patient-derived BC organoids, with the aim of modeling resistant disease with greater fidelity and developing an in-vitro system grounded in clinical data for testing alternative treatment strategies. We utilized patient transcriptomic and outcome data from the I-SPY2 clinical trial to develop predictive models of response to a range of therapies, using only organoid-detectable biomarkers as input. A model predicting response to veliparib-platinum chemotherapy (VP) in triple-negative BC (TNBC) was validated in organoids, showing that in vitro drug responses matched predictions from the patient data-derived model. A drug screen in VP-resistant TNBC organoids identified combination treatments that overcame resistance to cisplatin, including pro-apoptotic therapies. This demonstrates that gene expression-based resistance models derived from patient data can be successfully modeled in organoids that can then be used for therapeutic evaluation.

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Bui, T. B. V., Wolf, D. M., Bruck, M. C., Moore, K., Lien, J., Choi, S. D., Warhadpande, S., Parizadeh, A., Dillon, D., Overmoyer, B., Lynce, F., I-SPY 2 Investigators,, Nijman, I. J., Burgering, B. M., Harris, I. S., Esserman, L. J., Van 't Veer, L. J., Rosenbluth, J. M.. 2025-08-28. Organoid-evaluable clinical biomarkers predict drug responses and guide new breast cancer therapies. https://doi.org/10.1101/2025.08.24.671810

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