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.
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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.
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Maughan, B.L., Guedes, L.B., Boucher, K. et al. p53 status in the primary tumor predicts efficacy of subsequent abiraterone and enzalutamide in castration-resistant prostate cancer. Prostate Cancer Prostatic Dis 21, 260–268 (2018). https://doi.org/10.1038/s41391-017-0027-4
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DOI: https://doi.org/10.1038/s41391-017-0027-4
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