Researchers at UC San Francisco have developed a new method to predict how different types of breast cancer will respond to treatment, using patient data from the I-SPY2 breast cancer trial and rapid testing on lab-grown mini tumors.
The advance could hasten more personalized treatments for breast cancer, including the triple negative type, which is especially aggressive and hard to treat.
In their study , which appeared Aug. 6 in Cell Reports Medicine, the researchers found that the organoids were able to mimic a tumor's response to treatment.
"The breast tumor organoids modeled how corresponding patient tumors responded to therapies and identified candidate combination therapies for cancers that don't respond to standard treatment," said the study's senior author Jennifer M. Rosenbluth , MD, PhD, a medical oncologist and the Sulochana Pradhan, MD, Endowed Professor in Breast Cancer at UCSF. "These findings support organoid modeling as a bridge between clinical biomarkers and precision treatment strategies in breast cancer."
The researchers created the breast cancer organoids by placing patient-derived tumor cells into a gel designed to support the original tumor's biology. Over several weeks, the cells clustered into tiny spheres that reflected the structure and biology of the original tumor. Each cluster contained up to thousands of cells — too small to see clearly without a microscope — the largest appearing as translucent clusters in the gel.
The researchers then evaluated this biobank of early-stage invasive breast cancer organoids to study mechanisms of therapy resistance. Response predictive subtypes – molecular subtypes developed during the course of the I-SPY2 trial – provided the researchers with a framework of anticipated tumor responses to current therapies, including immunotherapy, PARP-inhibitors, platinum chemotherapy drugs, and dual-HER2 targeted therapies. With access to clinical patient data, they used the response predictive subtypes and the biomarker data of tumors from patients in the I-SPY2 trial to predict treatment responses in organoids.
Since many of the organoids were derived from triple-negative breast cancer tumors, those organoids were chosen to validate a model predicting response to veliparib-platinum chemotherapy (VP). Platinum chemotherapies and combination therapies like VP are often prescribed to patients with triple-negative breast cancer (TNBC) – even though TNBC can be highly treatment resistant.
With the aim of finding alternative treatment strategies to overcome tumors' resistance to platinum chemotherapy, the researchers selected tumor organoid TORG40, with the highest predicted and subsequently validated resistance to VP. The team performed a drug screen of 386 small-molecule inhibitors on this organoid, including ABT-263, a type of drug that helps to eliminate damaged cells. They then compared ABT-263 alone with ABT-263 in combination with the chemotherapy drug cisplatin. This drug combination in the organoid enhanced activity against resistant tumor cells, having a uniquely potent effect on TORG40.
The organoid drug screen also revealed other promising hits, including a class of drugs called HSP90 inhibitors; and the researchers were able to link what they observed in the lab to a subset of I-SPY patients who had responded better to these types of drugs.
"The breast cancer organoids were found to express important cancer biomarkers — many of which can be targeted with drugs," said Tam Binh V. Bui , MD, MSc, the study's first author, who is a PhD candidate at UCSF member of the Rosenbluth Lab and Van 't Veer/I-SPY lab at UCSF. "These organoids allowed us to study the effects of drugs directly in human tissue and prioritize the most promising therapies for this subtype."
The study did not test how organoid-guided treatment decisions would perform over time. And the organoids could not reflect the complexity of a whole organ and could not mimic the environment inside the body, which includes blood vessels, immune cells and other processes that influence the signals that the tumor cells receive.
But the researchers hope that one day physicians may be able to use patient-derived organoids to develop personalized approaches to cancer care.
"By combining computational analyses of large molecular and clinical datasets with organoid model systems, this proof-of-principle study demonstrated the utility of matching I-SPY2 resistance biomarkers and signatures to residual disease tumor organoid cultures," Rosenbluth said. "Our findings highlight the value of a reverse translational approach that integrates patient-level clinical trial data and testing in organoid models to inform drug discovery and future personalized treatment strategies for patients."
About I-SPY Trial Consortium: For more than a decade, the UCSF-led I-SPY trial consortium has worked to accelerate the development of new therapeutics for early-stage, high-risk breast cancer. The current I-SPY 2.2 trial tests multiple cancer therapies simultaneously among different breast cancer subtypes. The trial uses clinical biomarkers of response and resistance – measurable features of the tumor that predict its response to therapy. Using these biomarkers, researchers have been able to take a more personalized approach to therapy to optimize treatment based on individual patient responses.
Additional UCSF Authors: Denise M. Wolf, Michael C. Bruck, Jessica Lien, Sarah D.W. Choi, Shruti Warhadpande, Amirabbas Parizadeh, Lamorna Brown-Swigart, Gillian L. Hirst, Christina Yau, Laura J. Esserman, and Laura J. van 't Veer.
Other Authors: Kaitlin Moore, Deborah Dillon, Beth Overmoyer, Filipa Lynce, Isaac J. Nijman, Boudewijn Burgering, and Isaac S. Harris.
Funding: The DF/HCC Breast SPORE: Specialized Program of Research Excellence (SPORE) (NCI 1P50CA168504); the National Institutes of Health, (under award number R01CA281361), the Susan G. Komen Foundation, and METAvivor (to J.M.R.), and Breast Cancer Foundation (to L.V.V. and J.M.R.). T.B.V.B. was supported by the ROSANNA Fund, Hendrik Muller Fund, Netherland-America Foundation, the Foundation of Renswoude, and the Nijbakker-Morra Foundation.
Disclosures: Laura J. van 't Veer is a part-time employee and stockholder of Agendia. Laura J. Esserman reported that she is an uncompensated board member of the Quantum Leap Healthcare Collaborative, which sponsors the I-SPY trial. No potential conflicts of interest were disclosed by the other authors.
About UCSF Health: UCSF Health is recognized worldwide for its innovative patient care, reflecting the latest medical knowledge, advanced technologies and pioneering research. It includes the flagship UCSF Medical Center, which is a highly-ranked hospital, as well as UCSF Benioff Children's Hospitals, with campuses in San Francisco and Oakland; two community hospitals, UCSF Health Stanyan Hospital and UCSF Health Hyde Hospital; Langley Porter Psychiatric Hospital; UCSF Benioff Children's Physicians; and the UCSF Faculty Practice. These hospitals serve as the academic medical center of the University of California, San Francisco, which is world-renowned for its graduate-level health sciences education and biomedical research. UCSF Health has affiliations with hospitals and health organizations throughout the Bay Area. Visit http://www.ucsfhealth.org/ . Follow UCSF Health on Facebook , Threads
