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Blood-based gene expression signature associated with metastatic castrate-resistant prostate cancer patient response to abiraterone plus prednisone or enzalutamide

Prostate Cancer and Prostatic Diseases volume 24, pages 448–456 (2021)Cite this article

Subjects

Abstract

Background

Precision medicine approaches for managing patients with metastatic castrate-resistant prostate cancer (mCRPC) are lacking. Non-invasive approaches for molecular monitoring of disease are urgently needed, especially for patients suffering from bone metastases for whom tissue biopsy is challenging. Here we utilized baseline blood samples to identify mCRPC patients most likely to benefit from abiraterone plus prednisone (AAP) or enzalutamide.

Methods

Baseline blood samples were collected for circulating tumor cell (CTC) enumeration and qPCR-based gene expression analysis from 51 men with mCRPC beginning treatment with abiraterone or enzalutamide.

Results

Of 51 patients (median age 68 years [51–82]), 22 received AAP (abiraterone 1000 mg/day plus prednisone 10 mg/day) and 29 received enzalutamide (160 mg/day). The cohort was randomly divided into training (n = 37) and test (n = 14) sets. Baseline clinical variables (Gleason score, PSA, testosterone, and hemoglobin), CTC count, and qPCR-based gene expression data for 141 genes/isoforms in CTC-enriched blood were analyzed with respect to overall survival (OS). Genes with expression most associated with OS included MSLN, ARG2, FGF8, KLK3, ESRP2, NPR3, CCND1, and WNT5A. Using a Cox-elastic net model for our test set, the 8-gene expression signature had a c-index of 0.87 (95% CI [0.80, 0.94]) and was more strongly associated with OS than clinical variables or CTC count alone, or a combination of the three variables. For patients with a low-risk vs. high-risk gene expression signature, median OS was not reached vs. 18 months, respectively (HR 5.32 [1.91–14.80], p = 0.001). For the subset of 41 patients for whom progression-free survival (PFS) data was available, the median PFS for patients with a low-risk vs high-risk gene expression signature was 20 vs. 5 months, respectively (HR 2.95 [1.46–5.98], p = 0.003).

Conclusions

If validated in a larger prospective study, this test may predict patients most likely to benefit from second-generation antiandrogen therapy.

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Fig. 1: Baseline CTCs and clinical characteristics.
Fig. 2: Assessment of clinical outcomes by risk groups.

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Acknowledgements

NBH and MJL contributed equally to this work. NBH, DS, KEW, and ELC conceptualized this study, and MJL, NBH, YC, KCN, BF, JP, DS, THB, KJM, SSY, TAB, SG, SLS, EJM, QL, and ELC acquired, analyzed, and interpreted the data. MJL, YC, THB, and ELC drafted this manuscript, and NBH, KCN, DS, SKP, JOJ, MH, and SSY revised it critically. NBH, DJV, and RA provided care for enrolled patients as well as clinical input on patient characteristics. MJL, NBH, YC, KCN, DS, THB, SSY, and ELC prepared the manuscript for publication and agree to be accountable for the accuracy and integrity of all aspects of this study. The authors thank the Abramson Cancer Center for support from the Cancer Center Support Grant P30CA016520.

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Author notes

  1. These authors contributed equally: Naomi B. Haas, Michael J. LaRiviere

Authors and Affiliations

  1. Division of Hematology/Oncology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA

    Naomi B. Haas, Thomas H. Buckingham, David J. Vaughn, Ravi Amaravadi, Samantha L. Savitch, Krishna J. Majmundar, Taylor A. Black, Stephanie S. Yee & Erica L. Carpenter

  2. Department of Radiation Oncology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA

    Michael J. LaRiviere

  3. Janssen, Pharmaceutical Companies of Johnson and Johnson, Spring House, PA, USA

    Yauheniya Cherkas, Karl Calara-Nielsen, Brad Foulk, Jaymala Patel, Steven Gross & Denis Smirnov

  4. Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA

    Kathryn E. Wellen

  5. Department of Medical Oncology and Therapeutics Research, City of Hope, Duarte, CA, USA

    Miaoling He, Jeremy O. Jones & Sumanta K. Pal

  6. Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA

    Eun Jeong Min & Qi Long

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Correspondence to Erica L. Carpenter.

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Conflict of interest

YC, KCN, SG, BF, JP, and DS are or were employed by Janssen. QL receives research funding from Bayer and Pfizer. ELC, NBH, and JJ receive funding from Janssen. ELC receives research funding from Merck. The authors thank the Abramson Cancer Center for support from the Cancer Center Support Grant P30CA016520.

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Haas, N.B., LaRiviere, M.J., Buckingham, T.H. et al. Blood-based gene expression signature associated with metastatic castrate-resistant prostate cancer patient response to abiraterone plus prednisone or enzalutamide. Prostate Cancer Prostatic Dis 24, 448–456 (2021). https://doi.org/10.1038/s41391-020-00295-z

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