title: Statin Use at the Time of Initiation of Androgen Deprivation Therapy and Time to Progression in Patients With Hormone-Sensitive Prostate Cancer.
abstract: OBJECTIVE
  Statin use has been associated with improved prostate cancer outcomes. Dehydroepiandrosterone sulfate (DHEAS) is a precursor of testosterone and a substrate for SLCO2B1, an organic anionic transporter. We previously demonstrated that genetic variants of SLCO2B1 correlated with time to progression (TTP) during receipt of androgen deprivation therapy (ADT). Statins also use SLCO2B1 to enter cells, and thus we hypothesized that they may compete with DHEAS uptake by the tumor cells.
  
  
  OBJECTIVE
  To evaluate whether statin use prolongs TTP during ADT for hormone-sensitive prostate cancer.
  
  
  METHODS
  In vitro studies were performed using prostate cancer cell lines at an academic, comprehensive cancer center. Statin use was retrospectively analyzed in 926 patients who had received ADT for biochemical or metastatic recurrence or de novo metastatic prostate cancer between January 1996 and November 2013.
  
  
  METHODS
  To determine whether statins interfere with DHEAS uptake, we performed in vitro studies using prostate cancer cell lines. Next, we queried our institutional clinical database to assess for an association between statin use and TTP during ADT using multivariable Cox regression analysis and adjusted for known prognostic factors.
  
  
  RESULTS
  In vitro, we demonstrated that statins block DHEAS uptake by competitively binding to SLCO2B1. In our ADT cohort of 926 patients, 283 (31%) were taking a statin at ADT initiation. After a median follow-up of 5.8 years, 644 patients (70%) had experienced disease progression while receiving ADT. Median TTP during ADT was 20.3 months (95% CI, 18-24 months). Men taking statins had a longer median TTP during ADT compared with nonusers (27.5 [95% CI, 21.1-37.7] vs 17.4 [95% CI, 14.9-21.1] months; P < .001). The association remained statistically significant after adjusting for predefined prognostic factors (adjusted hazard ratio, 0.83 [95% CI, 0.69-0.99]; P = .04). The positive statin effect was observed for both patients with and without metastases (adjusted hazard ratio, 0.79 [95% CI, 0.58-1.07] for M0 disease and 0.84 [95% CI, 0.67-1.06] for M1 disease; P for interaction = .72).
  
  
  CONCLUSIONS
  Statin use at the time of ADT initiation was associated with a significantly longer TTP during ADT even after adjustment for known prognostic factors. Our in vitro finding that statins competitively reduce DHEAS uptake, thus effectively decreasing the available intratumoral androgen pool, affords a plausible mechanism to support the clinical observation of prolonged TTP in statin users.
authors.affiliation: Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Lauren C
authors.initials: LC
authors.lastname: Harshman
authors.affiliation: Gelb Center for Translational Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Wang
authors.affiliation: Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Mari
authors.initials: M
authors.lastname: Nakabayashi
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Wanling
authors.initials: W
authors.lastname: Xie
authors.affiliation: Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Loana
authors.initials: L
authors.lastname: Valenca
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Lillian
authors.initials: L
authors.lastname: Werner
authors.affiliation: Gelb Center for Translational Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts4Department of Urology, Shanghai Jiao Tong University School of Medicine, Xinhua Hospital, Shanghai, China.
authors.forename: Yongjiang
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Apple Tree Partners, New York, New York.
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Kantoff
authors.affiliation: Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Sweeney
authors.affiliation: Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts.
authors.forename: Lorelei A
authors.initials: LA
authors.lastname: Mucci
authors.affiliation: Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Mark
authors.initials: M
authors.lastname: Pomerantz
authors.affiliation: Gelb Center for Translational Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Gwo-Shu Mary
authors.initials: GS
authors.lastname: Lee
authors.affiliation: Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts2Gelb Center for Translational Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Philip W
authors.initials: PW
authors.lastname: Kantoff
mesh_terms: D000726:Androgen Antagonists / Q000627:therapeutic use*; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D001667:Binding, Competitive; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016009:Chi-Square Distribution; D019314:Dehydroepiandrosterone Sulfate / Q000378:metabolism; D018450:Disease Progression; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000378:metabolism / Q000627:therapeutic use*; D008297:Male; D015999:Multivariate Analysis; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D027361:Organic Anion Transporters / Q000235:genetics / Q000378:metabolism; D016016:Proportional Hazards Models; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D034622:RNA Interference; D012189:Retrospective Studies; D012307:Risk Factors; D013997:Time Factors; D014162:Transfection; D016896:Treatment Outcome
chemical_list: D000726:Androgen Antagonists; D018931:Antineoplastic Agents, Hormonal; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D027361:Organic Anion Transporters; C450859:SLCO2B1 protein, human; D019314:Dehydroepiandrosterone Sulfate