title: Association of Tissue Abiraterone Levels andSLCOGenotype 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 bySLCO-encoded transporters and thatSLCOgene 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 sixSLCOgenes.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 inSLCO2B1associated 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 inSLCOgenes are associated with pathologic responses in high-risk localized prostate cancer. Variation inSLCOgenes may serve as predictors of response to abiraterone treatment.Clin Cancer Res; 23(16); 4592-601. ©2017 AACR.
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, Washington. emostagh@fhcrc.org.
authors.forename: Elahe A
authors.initials: EA
authors.lastname: Mostaghel
authors.affiliation: Palo Alto Medical Foundation, Palo Alto, California.
authors.forename: Eunpi
authors.initials: E
authors.lastname: Cho
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Ailin
authors.initials: A
authors.lastname: Zhang
authors.affiliation: Lerner Research Institute, Glickman Urological and Kidney Institute, and Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Alyamani
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Arja
authors.initials: A
authors.lastname: Kaipainen
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Sean
authors.initials: S
authors.lastname: Green
authors.affiliation: Geriatric Research, Education and Clinical Center, VA Puget Sound Health Care System, Seattle, Washington.
authors.forename: Brett T
authors.initials: BT
authors.lastname: Marck
authors.affiliation: Lerner Research Institute, Glickman Urological and Kidney Institute, and Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Nima
authors.initials: N
authors.lastname: Sharifi
authors.affiliation: University of Washington, Seattle, Washington.
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Wright
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Roman
authors.initials: R
authors.lastname: Gulati
authors.affiliation: University of Washington, Seattle, Washington.
authors.forename: Lawrence D
authors.initials: LD
authors.lastname: True
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Massimo
authors.initials: M
authors.lastname: Loda
authors.affiliation: Geriatric Research, Education and Clinical Center, VA Puget Sound Health Care System, Seattle, Washington.
authors.forename: Alvin M
authors.initials: AM
authors.lastname: Matsumoto
authors.affiliation: Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Daniel
authors.initials: D
authors.lastname: Tamae
authors.affiliation: Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Trevor N
authors.initials: TN
authors.lastname: Penning
authors.affiliation: Beth Israel Deaconess Medical Center, Boston, Massachusetts.
authors.forename: Steven P
authors.initials: SP
authors.lastname: Balk
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Phillip W
authors.initials: PW
authors.lastname: Kantoff
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Nelson
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Mary-Ellen
authors.initials: ME
authors.lastname: Taplin
authors.affiliation: University of Washington, Seattle, Washington.
authors.forename: R Bruce
authors.initials: RB
authors.lastname: Montgomery
mesh_terms: D000069501:Abiraterone Acetate / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D005838:Genotype; D018095:Germ-Line Mutation; D007987:Gonadotropin-Releasing Hormone / Q000819:agonists; D006801:Humans; D008297:Male; D027361:Organic Anion Transporters / Q000235:genetics / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D011241:Prednisone / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism*; D011467:Prostate / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D017430:Prostate-Specific Antigen / Q000097:blood; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D013739:Testosterone / Q000097:blood; D016896:Treatment Outcome
chemical_list: D027361:Organic Anion Transporters; D007987:Gonadotropin-Releasing Hormone; D013739:Testosterone; D017430:Prostate-Specific Antigen; D000069501:Abiraterone Acetate; D011241:Prednisone