A phenocopy signature of TP53 loss predicts response to chemotherapy
In preclinical studies, p53 loss of function impacts chemotherapy response, but this has not been consistently validated clinically. We trained a TP53-loss phenocopy gene expression signature from pan-cancer clinical samples in the TCGA. In vitro, the TP53-loss phenocopy signature predicted chemotherapy response across cancer types. In a clinical dataset of 3003 breast cancer samples treated with neoadjuvant chemotherapy, the TP53-loss phenocopy samples were 56% more likely to have a pathologic complete response (pCR), with a significant association between TP53-loss phenocopy and pCR in both ER positive and ER negative tumors. In an independent clinical validation in the I-SPY2 trial (N = 987), we confirmed the association with neoadjuvant chemotherapy pCR and found higher rates of chemoimmunotherapy response in TP53-loss phenocopy tumors compared to non-TP53-loss phenocopy tumors (64% vs. 28%). The TP53-loss phenocopy signature predicts chemotherapy response across cancer types in vitro, and in a proof-of-concept clinical validation is associated with neoadjuvant chemotherapy response across multiple clinical breast cancer cohorts.
Authors
- Tracy J. Berg (ORCID: https://orcid.org/0009-0006-1560-7827)
- Matthew R. Chrostek (ORCID: https://orcid.org/0000-0002-9457-1431)
- Hamza Bakhtiar (ORCID: https://orcid.org/0000-0001-7412-5525)
- Kyle T. Helzer (ORCID: https://orcid.org/0000-0003-3853-5564)
- Martin Sjöström (ORCID: https://orcid.org/0000-0002-2629-9966)
- Kari B. Wisinski (ORCID: https://orcid.org/0000-0003-3535-0652)
- Yue Shi (ORCID: https://orcid.org/0000-0002-2860-2666)
- Marina N. Sharifi (ORCID: https://orcid.org/0000-0003-0128-3033)
- S. Carson Callahan (ORCID: https://orcid.org/0000-0002-0152-2666)
- Grace C. Blitzer (ORCID: https://orcid.org/0000-0003-3178-3004)
- Matthew L. Bootsma (ORCID: https://orcid.org/0000-0003-0879-5066)
- Shuang George Zhao (ORCID: https://orcid.org/0000-0002-9166-6507)
- Ruth O’Regan (ORCID: https://orcid.org/0000-0001-6984-3741)
- Malinda West (ORCID: https://orcid.org/0000-0002-2773-6320)
- V. Carreño (ORCID: https://orcid.org/0009-0009-3297-8541)
- Tianfu Andy Shang
Institutions
- University of Wisconsin–Madison (US)
- University of California, San Francisco (US)
- University of Wisconsin Carbone Cancer Center (US)
- William S. Middleton Memorial Veterans Hospital (US)
- University of Rochester (US)
Publication Details
- Journal
- npj Precision Oncology
- Published
- 2024-10-02
- DOI
- https://doi.org/10.1038/s41698-024-00722-7
- Citations
- 2
- Primary Topic
- Glioma Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 0.88
Funders
- Doris Duke Charitable Foundation
- University of Wisconsin Carbone Cancer Center
- National Institutes of Health
- Division of Graduate Education