Article | Published:

p53 status in the primary tumor predicts efficacy of subsequent abiraterone and enzalutamide in castration-resistant prostate cancer

Prostate Cancer and Prostatic Diseasesvolume 21pages260268 (2018) | Download Citation

Abstract

Background

We tested whether tissue-based analysis of p53 and PTEN genomic status in primary tumors is predictive for subsequent sensitivity to abiraterone and enzalutamide in castration-resistant prostate cancer (CRPC).

Methods

We performed a retrospective analysis of 309 consecutive patients with CRPC treated with abiraterone or enzalutamide. Of these, 101 men (33%) had available primary tumor tissue for analysis. We screened for deleterious TP53 missense mutations and PTEN deletions using genetically validated immunohistochemical assays for nuclear accumulation of p53 protein and PTEN protein loss, with sequencing confirmation of TP53 mutations in a subset. Overall survival (OS) and progression-free survival (PFS) were compared between patients with and without p53 and/or PTEN alterations.

Results

Forty-eight percent of the evaluable cases had PTEN loss and 27% had p53 nuclear accumulation. OS and PFS did not differ according to PTEN status, but were significantly associated with p53 status. Median OS was 16.7 months (95% CI, 14–21.9 months) and 31.2 months (95% CI, 24.5–43.4) for men with and without p53 nuclear accumulation, respectively (HR 2.32; 95% CI 1.19–4.51; P = 0.0018). Similarly, median PFS was 5.5 months (95% CI, 3.2–9.9 months) and 10.9 months (95% CI, 8–15.2 months) in men with and without p53 nuclear accumulation, respectively (HR 2.14, 95%CI 1.20–3.81; P = 0.0008). In multivariable analyses, p53 status was independently associated with PFS (HR 2.15; 95% CI 1.03–4.49; P = 0.04) and a HR of 2.19 for OS (95% CI 0.89–5.40; P = 0.087).

Conclusions

p53 inactivation in the primary tumor (but not PTEN loss) may be predictive of inferior outcomes to novel hormonal therapies in CRPC.

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Acknowledgments

We are grateful to our patients for their participation in this and other studies and allowing us to be involved in their care.

Author contributions

BLM: Designed the project, performed research, interpreted data, wrote the initial draft, reviewed/approved the final manuscript. LBG: performed research, reviewed/approved the final manuscript. KB: Performed the statistical analysis, reviewed/approved the final manuscript. GR: Provided the reagents, reviewed/approved the final manuscript. ZL: Provided reagents, reviewed/approved the final manuscript. SK: Provided reagents, reviewed/approved the final manuscript. RZ: Provided reagents, reviewed/approved the final manuscript. ESA: Designed the project, interpreted data, reviewed/approved the final manuscript, provided project supervision. TLL: Designed the project, interpreted data, performed research, reviewed/approved the final manuscript, provided project supervision. All authors had access to all of the data and were involved in the writing of the manuscript.

Funding

This work was funded in part by a CDMRP Prostate Cancer Research Program Transformative Impact Award to TLL (W81XWH-12-PCRP-TIA). BLM received funding from the ASCO/Conquer Cancer Foundation (Young Investigator Award).

Statement of relevance

We tested the hypothesis that loss of p53 and/or PTEN in primary tumor specimens is associated with reduced response to subsequent treatment with abiraterone or enzalutamide in patients with CRPC. We find that p53 inactivation, but not PTEN loss, is associated with significantly worse overall and progression-free survival with abiraterone or enzalutamide treatment, suggesting that p53 status is predictive of response to androgen receptor-targeted therapies years later when CRPC develops.

Author information

Author notes

    • Benjamin L. Maughan

    Present address: Department of Oncology, Huntsman Cancer Center, University of Utah, Salt Lake City, UT, USA

  1. Emmanuel S. Antonarakis and Tamara L. Lotan contributed equally to this work.

Affiliations

  1. Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    • Benjamin L. Maughan
    • , Emmanuel S. Antonarakis
    •  & Tamara L. Lotan
  2. Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    • Liana B. Guedes
    •  & Tamara L. Lotan
  3. Huntsman Cancer Center, University of Utah, Salt Lake City, UT, USA

    • Kenneth Boucher
  4. Pathline Emerge Pathology Services, Ramsey, NJ, USA

    • Gaurav Rajoria
    • , Zach Liu
    • , Szczepan Klimek
    •  & Roberto Zoino
  5. Department of Urology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    • Emmanuel S. Antonarakis

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Conflict of interest

ESA is a paid consultant/advisor to Janssen, Astellas, Sanofi, Dendreon, Medivation, and Essa. He has received research funding from Janssen, Jonhson & Johnson, Sanofi, Dendreon, Aragon, Exelixis, Genentech, Novartis, and Tokai. GR, ZL, SK, and RZ are employees of Pathline Emerge Pathology Services. The remaining authors declare that they have no conflict of interest.

Corresponding author

Correspondence to Benjamin L. Maughan.

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DOI

https://doi.org/10.1038/s41391-017-0027-4