Modeling Drug Responses and Evolutionary Dynamics Using Patient-Derived Xenografts Reveals Precision Medicine Strategies for Triple-Negative Breast Cancer
The intertumor and intratumor heterogeneity of triple-negative breast cancers, which is reflected in diverse drug responses, interplays with tumor evolution. In this study, we developed a preclinical experimental and analytical framework using patient-derived tumor xenografts (PDTX) from patients with treatment-naïve triple-negative breast cancers to test their predictive value in personalized cancer treatment approaches. Patients and their matched PDTXs exhibited concordant drug responses to neoadjuvant therapy using two trial designs and dosing schedules. This platform enabled analysis of nongenetic mechanisms involved in relapse dynamics. Treatment resulted in permanent phenotypic changes, with functional and therapeutic consequences. High-throughput drug screening methods in ex vivo PDTX cells revealed patient-specific drug response changes dependent on first-line therapy. This was validated in vivo, as exemplified by a change in olaparib sensitivity in tumors previously treated with clinically relevant cycles of standard-of-care chemotherapy. In summary, PDTXs provide a robust tool to test patient drug responses and therapeutic regimens and to model evolutionary trajectories. However, high intermodel variability and permanent nongenomic transcriptional changes constrain their use for personalized cancer therapy. This work highlights important considerations associated with preclinical drug response modeling and potential uses of the platform to identify efficacious and preferential sequential therapeutic regimens. Significance: Patient-derived tumor xenografts from treatment-naïve breast cancer samples can predict patient drug responses and model treatment-induced phenotypic and functional evolution, making them valuable preclinical tools.
Authors
- Oscar M. Rueda (ORCID: https://orcid.org/0000-0003-0008-4884)
- Wendy Greenwood (ORCID: https://orcid.org/0000-0002-2509-8695)
- Daniel Guerrero-Romero
- Dimitra Georgopoulou
- Jean Abraham (ORCID: https://orcid.org/0000-0003-0688-4807)
- Louise Grybowicz
- Abigail Shea (ORCID: https://orcid.org/0000-0001-7029-1745)
- Martin O’Reilly (ORCID: https://orcid.org/0000-0003-1095-0328)
- Jonny Lay
- Sophia Wix (ORCID: https://orcid.org/0000-0002-7467-4185)
- Agnese Giovannetti (ORCID: https://orcid.org/0000-0001-5207-7243)
- Karen McAdam (ORCID: https://orcid.org/0000-0002-5545-2982)
- Elham Esmaeilishirazifard (ORCID: https://orcid.org/0000-0002-8661-8797)
- Helen Bardwell (ORCID: https://orcid.org/0009-0000-7345-575X)
- Raquel Manzano García (ORCID: https://orcid.org/0000-0002-5124-8992)
- Yaniv Lubling (ORCID: https://orcid.org/0000-0003-3461-9621)
- Giulia Lerda (ORCID: https://orcid.org/0009-0003-8851-6932)
- Maurizio Callari (ORCID: https://orcid.org/0000-0001-5239-0918)
- Alistair Martin (ORCID: https://orcid.org/0000-0001-9735-2149)
- A. Nagano (ORCID: https://orcid.org/0000-0002-2354-660X)
- Riccardo Masina (ORCID: https://orcid.org/0000-0002-9236-616X)
- Elena Provenzano (ORCID: https://orcid.org/0000-0003-3345-3965)
- Alejandra Bruna (ORCID: https://orcid.org/0000-0003-1214-9665)
- Steven Kupczak
- Carlos Caldas (ORCID: https://orcid.org/0000-0003-3547-1489)
- Justine Kane (ORCID: https://orcid.org/0009-0005-1523-6504)
- Yi Cheng
- Wei Cope (ORCID: https://orcid.org/0000-0002-5661-3522)
- Lisa Young
Institutions
- Institute of Cancer Research (GB)
- National Institute of Agricultural Botany (GB)
- Queen Mary University of London (GB)
- University of Cambridge (GB)
- Breast Cancer Now (GB)
- Casa Sollievo della Sofferenza (IT)
- Cancer Research UK (GB)
- Cambridge University Hospitals NHS Foundation Trust (GB)
- Cancer Research UK Cambridge Center (GB)
- Fondazione Michelangelo (IT)
- Wellcome/MRC Institute of Metabolic Science (GB)
- MRC Biostatistics Unit (GB)
- Cambridgeshire and Peterborough NHS Foundation Trust (GB)
- Lancashire Care NHS Foundation Trust (GB)
Publication Details
- Journal
- Cancer Research
- Published
- 2024-11-08
- DOI
- https://doi.org/10.1158/0008-5472.can-24-1703
- Citations
- 3
- Primary Topic
- Bioinformatics and Genomic Networks
- Type
- article
- Field-Weighted Citation Impact
- 0.70
Funders
- U.S. Department of State
- AstraZeneca
- Cancer Research UK
- National Institute for Health and Care Research
- US-UK Fulbright Commission
- University of Cambridge
- European Commission
- Cambridge University Hospitals
- National Institutes of Health
- Medical Research Council
- NIHR Cambridge Biomedical Research Centre
- Cancer Research UK Cambridge Institute, University of Cambridge