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 T. Marck, Nima Sharifi, Jonathan L. Wright, Roman Gulati, Lawrence D. True, Massimo Loda, Alvin M. Matsumoto, Daniel Tamae, Trevor N. Penning, Steven P. Balk, Phillip W. Kantoff, Peter S. Nelson, Mary Ellen Taplin, R. Bruce Montgomery

Research output: Contribution to journalArticle

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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 outcomes. We hypothesized that, due to its steroidal structure, the CYP17A inhibitor abiraterone may undergo transport by SLCO-encoded transporters and that SLCO gene variation may influence intracellular abiraterone levels and outcomes. Experimental Design: Steroid and abiraterone levels were measured in serum and tissue from 58 men with localized prostate cancer in a clinical trial of LHRH agonist plus abiraterone acetate plus prednisone for 24 weeks prior to prostatectomy. Germline DNA was genotyped for 13 SNPs in six SLCO genes. Results: Abiraterone levels spanned a broad range (serum median 28 ng/mL, 108 nmol/L; tissue median 77 ng/mL, 271 nmol/L) and were correlated (r = 0.355, P = 0.001). Levels correlated positively 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 versus detectable tissue abiraterone at prostatectomy (median 0.10 vs. 0.03 ng/dL, P = 0.02; 1.28 vs. 0.44 cc, 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 < 0.5 cc; rs1789693, 67% vs. 27%, P = 0.009; rs1077858, 46% vs. 0%, P = 0.03). LNCaP cells expressing SLCO2B1 showed two- to fourfold higher abiraterone levels compared with vector controls (P < 0.05). Conclusions: Intraprostatic abiraterone levels and genetic variation in SLCO genes are associated with pathologic responses in high-risk localized prostate cancer. Variation in SLCO genes may serve as predictors of response to abiraterone treatment.

Original languageEnglish (US)
Pages (from-to)4592-4601
Number of pages10
JournalClinical Cancer Research
Volume23
Issue number16
DOIs
StatePublished - Aug 15 2017

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Anions
Prostatic Neoplasms
Steroids
Genotype
Genes
Residual Neoplasm
Prostatectomy
Tumor Burden
Single Nucleotide Polymorphism
Serum
Organic Anion Transporters
abiraterone
Pregnenolone
Dehydroepiandrosterone
Prednisone
Gonadotropin-Releasing Hormone
Progesterone
Testosterone
Research Design
Clinical Trials

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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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. / Mostaghel, Elahe A.; Cho, Eunpi; Zhang, Ailin; Alyamani, Mohammad; Kaipainen, Arja; Green, Sean; Marck, Brett T.; Sharifi, Nima; Wright, Jonathan L.; Gulati, Roman; True, Lawrence D.; Loda, Massimo; Matsumoto, Alvin M.; Tamae, Daniel; Penning, Trevor N.; Balk, Steven P.; Kantoff, Phillip W.; Nelson, Peter S.; Taplin, Mary Ellen; Montgomery, R. Bruce.

In: Clinical Cancer Research, Vol. 23, No. 16, 15.08.2017, p. 4592-4601.

Research output: Contribution to journalArticle

Mostaghel, EA, Cho, E, Zhang, A, Alyamani, M, Kaipainen, A, Green, S, Marck, BT, Sharifi, N, Wright, JL, Gulati, R, True, LD, Loda, M, Matsumoto, AM, Tamae, D, Penning, TN, Balk, SP, Kantoff, PW, Nelson, PS, Taplin, ME & Montgomery, RB 2017, 'Association of tissue abiraterone levels and SLCO genotype with intraprostatic steroids and pathologic response in men with high-risk localized prostate cancer', Clinical Cancer Research, vol. 23, no. 16, pp. 4592-4601. https://doi.org/10.1158/1078-0432.CCR-16-2245
Mostaghel, Elahe A. ; Cho, Eunpi ; Zhang, Ailin ; Alyamani, Mohammad ; Kaipainen, Arja ; Green, Sean ; Marck, Brett T. ; Sharifi, Nima ; Wright, Jonathan L. ; Gulati, Roman ; True, Lawrence D. ; Loda, Massimo ; Matsumoto, Alvin M. ; Tamae, Daniel ; Penning, Trevor N. ; Balk, Steven P. ; Kantoff, Phillip W. ; Nelson, Peter S. ; Taplin, Mary Ellen ; Montgomery, R. Bruce. / Association of tissue abiraterone levels and SLCO genotype with intraprostatic steroids and pathologic response in men with high-risk localized prostate cancer. In: Clinical Cancer Research. 2017 ; Vol. 23, No. 16. pp. 4592-4601.
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title = "Association of tissue abiraterone levels and SLCO genotype with intraprostatic steroids and pathologic response in men with high-risk localized prostate cancer",
abstract = "Purpose: Germline variation in solute carrier organic anion (SLCO) genes influences cellular steroid uptake and is associated with prostate cancer outcomes. We hypothesized that, due to its steroidal structure, the CYP17A inhibitor abiraterone may undergo transport by SLCO-encoded transporters and that SLCO gene variation may influence intracellular abiraterone levels and outcomes. Experimental Design: Steroid and abiraterone levels were measured in serum and tissue from 58 men with localized prostate cancer in a clinical trial of LHRH agonist plus abiraterone acetate plus prednisone for 24 weeks prior to prostatectomy. Germline DNA was genotyped for 13 SNPs in six SLCO genes. Results: Abiraterone levels spanned a broad range (serum median 28 ng/mL, 108 nmol/L; tissue median 77 ng/mL, 271 nmol/L) and were correlated (r = 0.355, P = 0.001). Levels correlated positively 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 versus detectable tissue abiraterone at prostatectomy (median 0.10 vs. 0.03 ng/dL, P = 0.02; 1.28 vs. 0.44 cc, 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 < 0.5 cc; rs1789693, 67{\%} vs. 27{\%}, P = 0.009; rs1077858, 46{\%} vs. 0{\%}, P = 0.03). LNCaP cells expressing SLCO2B1 showed two- to fourfold higher abiraterone levels compared with vector controls (P < 0.05). Conclusions: Intraprostatic abiraterone levels and genetic variation in SLCO genes are associated with pathologic responses in high-risk localized prostate cancer. Variation in SLCO genes may serve as predictors of response to abiraterone treatment.",
author = "Mostaghel, {Elahe A.} and Eunpi Cho and Ailin Zhang and Mohammad Alyamani and Arja Kaipainen and Sean Green and Marck, {Brett T.} and Nima Sharifi and Wright, {Jonathan L.} and Roman Gulati and True, {Lawrence D.} and Massimo Loda and Matsumoto, {Alvin M.} and Daniel Tamae and Penning, {Trevor N.} and Balk, {Steven P.} and Kantoff, {Phillip W.} and Nelson, {Peter S.} and Taplin, {Mary Ellen} and Montgomery, {R. Bruce}",
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T1 - Association of tissue abiraterone levels and SLCO genotype with intraprostatic steroids and pathologic response in men with high-risk localized prostate cancer

AU - Mostaghel, Elahe A.

AU - Cho, Eunpi

AU - Zhang, Ailin

AU - Alyamani, Mohammad

AU - Kaipainen, Arja

AU - Green, Sean

AU - Marck, Brett T.

AU - Sharifi, Nima

AU - Wright, Jonathan L.

AU - Gulati, Roman

AU - True, Lawrence D.

AU - Loda, Massimo

AU - Matsumoto, Alvin M.

AU - Tamae, Daniel

AU - Penning, Trevor N.

AU - Balk, Steven P.

AU - Kantoff, Phillip W.

AU - Nelson, Peter S.

AU - Taplin, Mary Ellen

AU - Montgomery, R. Bruce

PY - 2017/8/15

Y1 - 2017/8/15

N2 - Purpose: Germline variation in solute carrier organic anion (SLCO) genes influences cellular steroid uptake and is associated with prostate cancer outcomes. We hypothesized that, due to its steroidal structure, the CYP17A inhibitor abiraterone may undergo transport by SLCO-encoded transporters and that SLCO gene variation may influence intracellular abiraterone levels and outcomes. Experimental Design: Steroid and abiraterone levels were measured in serum and tissue from 58 men with localized prostate cancer in a clinical trial of LHRH agonist plus abiraterone acetate plus prednisone for 24 weeks prior to prostatectomy. Germline DNA was genotyped for 13 SNPs in six SLCO genes. Results: Abiraterone levels spanned a broad range (serum median 28 ng/mL, 108 nmol/L; tissue median 77 ng/mL, 271 nmol/L) and were correlated (r = 0.355, P = 0.001). Levels correlated positively 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 versus detectable tissue abiraterone at prostatectomy (median 0.10 vs. 0.03 ng/dL, P = 0.02; 1.28 vs. 0.44 cc, 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 < 0.5 cc; rs1789693, 67% vs. 27%, P = 0.009; rs1077858, 46% vs. 0%, P = 0.03). LNCaP cells expressing SLCO2B1 showed two- to fourfold higher abiraterone levels compared with vector controls (P < 0.05). Conclusions: Intraprostatic abiraterone levels and genetic variation in SLCO genes are associated with pathologic responses in high-risk localized prostate cancer. Variation in SLCO genes may serve as predictors of response to abiraterone treatment.

AB - Purpose: Germline variation in solute carrier organic anion (SLCO) genes influences cellular steroid uptake and is associated with prostate cancer outcomes. We hypothesized that, due to its steroidal structure, the CYP17A inhibitor abiraterone may undergo transport by SLCO-encoded transporters and that SLCO gene variation may influence intracellular abiraterone levels and outcomes. Experimental Design: Steroid and abiraterone levels were measured in serum and tissue from 58 men with localized prostate cancer in a clinical trial of LHRH agonist plus abiraterone acetate plus prednisone for 24 weeks prior to prostatectomy. Germline DNA was genotyped for 13 SNPs in six SLCO genes. Results: Abiraterone levels spanned a broad range (serum median 28 ng/mL, 108 nmol/L; tissue median 77 ng/mL, 271 nmol/L) and were correlated (r = 0.355, P = 0.001). Levels correlated positively 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 versus detectable tissue abiraterone at prostatectomy (median 0.10 vs. 0.03 ng/dL, P = 0.02; 1.28 vs. 0.44 cc, 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 < 0.5 cc; rs1789693, 67% vs. 27%, P = 0.009; rs1077858, 46% vs. 0%, P = 0.03). LNCaP cells expressing SLCO2B1 showed two- to fourfold higher abiraterone levels compared with vector controls (P < 0.05). Conclusions: Intraprostatic abiraterone levels and genetic variation in SLCO genes are associated with pathologic responses in high-risk localized prostate cancer. Variation in SLCO genes may serve as predictors of response to abiraterone treatment.

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