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Cancer Therapy: Clinical

Association of Tissue Abiraterone Levels and SLCO Genotype with Intraprostatic Steroids and Pathologic Response in Men with High-Risk Localized Prostate Cancer

Elahe A Mostaghel, Eunpi Cho, Ailin Zhang, Mohammad Alyamani, Arja Kaipainen, Sean Green, Brett Marck, Nima Sharifi, Jonathan L Wright, Roman Gulati, Lawrence D True, Massimo Loda, Alvin M. Matsumoto, Daniel Tamae, Trevor N Penning, Steven P. Balk, Philip W. Kantoff, Peter S. Nelson, Mary-Ellen Taplin and Bruce Montgomery
Elahe A Mostaghel
Clinical Research, Fred Hutchinson Cancer Research Center
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  • For correspondence: emostagh@fhcrc.org
Eunpi Cho
Oncology, Palo Alto Medical Foundation
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Ailin Zhang
Clinical Research, Fred Hutchinson Cancer Research Center
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Mohammad Alyamani
Cleveland Clinic
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Arja Kaipainen
Clinical Research, Fred Hutchinson Cancer Research Center
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Sean Green
Clinical Research, Fred Hutchinson Cancer Research Center
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Brett Marck
GRECC, V.A. Puget sound
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Nima Sharifi
Cancer Biology, Cleveland Clinic
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Jonathan L Wright
Department of Urology, University of Washington
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Roman Gulati
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center
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Lawrence D True
Department of Pathology, University of Washington
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Massimo Loda
Division of Cancer Studies, King's College London
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Alvin M. Matsumoto
Geriatric Research, Education and Clinical Center, VA Puget Sound Health Care System
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Daniel Tamae
University of Pennsylvania
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Trevor N Penning
Perelman School of Medicine, University of Pennsylvania
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Steven P. Balk
Division of Hematology/Oncology, Department of Medicine, Beth Israel Deaconess Medical Center
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Philip W. Kantoff
Department of Medicine, Memorial Sloan Kettering Cancer Center
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Peter S. Nelson
Division of Clinical Research, Fred Hutchinson Cancer Research Center
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Mary-Ellen Taplin
Oncology, Dana-Farber Cancer Institute
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Bruce Montgomery
Department of Medicine, University of Washington
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DOI: 10.1158/1078-0432.CCR-16-2245
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Abstract

Purpose: Germline variation in solute carrier organic anion (SLCO) genes influences cellular steroid uptake and is associated with prostate cancer (PCa) outcomes. We hypothesized that, due to its steroidal structure, the CYP17A inhibitor abiraterone may undergo SLCO-mediated transport and that SLCO gene variation may influence intracellular abiraterone levels and outcomes.<br /><br />Experimental Design: Steroid and abiraterone levels were measured by mass spectrometry in serum and tissue from 58 men with localized PCa in a clinical trial of LHRH agonist plus abiraterone acetate plus prednisone for 24 weeks prior to prostatectomy. Germline DNA was genotyped for 13 single nucleotide polymorphisms (SNPS) in 6 SLCO genes.<br /><br /> <p>Results:Abiraterone levels spanned a broad range (serum median 28ng/ml, 108nM; tissue median 77ng/ml, 271nM) and were correlated (r=0.355, p=0.001). Levels correlated positivey with steroids upstream of CYP17A (pregnenolone, progesterone), and inversely with steroids downstream of CYP17A (DHEA, AED, testosterone). Serum PSA and tumor volumes were higher in men with undetectable vs detectable tissue abiraterone at prostatectomy (median 0.10 vs 0.03ng/dl, p=0.02; 1.28 vs 0.44cc, p=0.09, respectively).  SNPs in SLCO2B1 associated with significant differences in tissue abiraterone (rs1789693, p=0.0008; rs12422149, p=0.03) and higher rates of minimal residual disease (tumor volume <0.5cc; rs1789693, 67% vs 27%, p=0.009; rs1077858, 46% vs 0%, p=0.03). LNCaP cells expressing SLCO2B1 showed 2-4 fold higher abiraterone levels compared to vector controls (p<0.05).</p> <p>Conclusions: Intraprostatic abiraterone levels and genetic variation in SLCO genes are associated with pathologic responses in high-risk localized PCa. Variation in SLCO genes may serve as predictors of response to abiraterone treatment.

  • Received September 9, 2016.
  • Revision received March 25, 2017.
  • Accepted April 3, 2017.
  • Copyright ©2017, American Association for Cancer Research.
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Published OnlineFirst April 7, 2017
doi: 10.1158/1078-0432.CCR-16-2245

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Association of Tissue Abiraterone Levels and SLCO Genotype with Intraprostatic Steroids and Pathologic Response in Men with High-Risk Localized Prostate Cancer
Elahe A Mostaghel, Eunpi Cho, Ailin Zhang, Mohammad Alyamani, Arja Kaipainen, Sean Green, Brett Marck, Nima Sharifi, Jonathan L Wright, Roman Gulati, Lawrence D True, Massimo Loda, Alvin M. Matsumoto, Daniel Tamae, Trevor N Penning, Steven P. Balk, Philip W. Kantoff, Peter S. Nelson, Mary-Ellen Taplin and Bruce Montgomery
Clin Cancer Res April 7 2017 DOI: 10.1158/1078-0432.CCR-16-2245

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Association of Tissue Abiraterone Levels and SLCO Genotype with Intraprostatic Steroids and Pathologic Response in Men with High-Risk Localized Prostate Cancer
Elahe A Mostaghel, Eunpi Cho, Ailin Zhang, Mohammad Alyamani, Arja Kaipainen, Sean Green, Brett Marck, Nima Sharifi, Jonathan L Wright, Roman Gulati, Lawrence D True, Massimo Loda, Alvin M. Matsumoto, Daniel Tamae, Trevor N Penning, Steven P. Balk, Philip W. Kantoff, Peter S. Nelson, Mary-Ellen Taplin and Bruce Montgomery
Clin Cancer Res April 7 2017 DOI: 10.1158/1078-0432.CCR-16-2245
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Clinical Cancer Research
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