Statin Use at the Time of Initiation of Androgen Deprivation Therapy and Time to Progression in Patients With Hormone-Sensitive Prostate Cancer | Cardiology | JAMA Oncology | JAMA Network
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1.
Pressler  H, Sissung  TM, Venzon  D, Price  DK, Figg  WD.  Expression of OATP family members in hormone-related cancers: potential markers of progression.  PLoS One. 2011;6(5):e20372.PubMedGoogle ScholarCrossref
2.
Wright  JL, Kwon  EM, Ostrander  EA,  et al.  Expression of SLCO transport genes in castration-resistant prostate cancer and impact of genetic variation in SLCO1B3 and SLCO2B1 on prostate cancer outcomes.  Cancer Epidemiol Biomarkers Prev. 2011;20(4):619-627.PubMedGoogle ScholarCrossref
3.
Fujimoto  N, Kubo  T, Inatomi  H,  et al.  Polymorphisms of the androgen transporting gene SLCO2B1 may influence the castration resistance of prostate cancer and the racial differences in response to androgen deprivation.  Prostate Cancer Prostatic Dis. 2013;16(4):336-340.PubMedGoogle ScholarCrossref
4.
Yang  M, Xie  W, Mostaghel  E,  et al.  SLCO2B1 and SLCO1B3 may determine time to progression for patients receiving androgen deprivation therapy for prostate cancer.  J Clin Oncol. 2011;29(18):2565-2573.PubMedGoogle ScholarCrossref
5.
Bansal  D, Undela  K, D’Cruz  S, Schifano  F.  Statin use and risk of prostate cancer: a meta-analysis of observational studies.  PLoS One. 2012;7(10):e46691.PubMedGoogle ScholarCrossref
6.
Park  HS, Schoenfeld  JD, Mailhot  RB,  et al.  Statins and prostate cancer recurrence following radical prostatectomy or radiotherapy: a systematic review and meta-analysis.  Ann Oncol. 2013;24(6):1427-1434.PubMedGoogle ScholarCrossref
7.
Bonovas  S, Filioussi  K, Sitaras  NM.  Statin use and the risk of prostate cancer: a metaanalysis of 6 randomized clinical trials and 13 observational studies.  Int J Cancer. 2008;123(4):899-904.PubMedGoogle ScholarCrossref
8.
Scosyrev  E, Tobis  S, Donsky  H,  et al.  Statin use and the risk of biochemical recurrence of prostate cancer after definitive local therapy: a meta-analysis of eight cohort studies.  BJU Int. 2013;111(3, pt B):E71-E77.PubMedGoogle ScholarCrossref
9.
Huggins  CS, Hodges  C.  Studies in prostatic cancer. II. the effects of castration on advanced cancer of the prostate gland.  Arch Surg. 1941;43:209-223.Google ScholarCrossref
10.
Oh  WK, Hayes  J, Evan  C,  et al.  Development of an integrated prostate cancer research information system.  Clin Genitourin Cancer. 2006;5(1):61-66.PubMedGoogle ScholarCrossref
11.
Ross  RW, Xie  W, Regan  MM,  et al.  Efficacy of androgen deprivation therapy (ADT) in patients with advanced prostate cancer: association between Gleason score, prostate-specific antigen level, and prior ADT exposure with duration of ADT effect.  Cancer. 2008;112(6):1247-1253.PubMedGoogle ScholarCrossref
12.
Peng  X, Li  W, Yuan  L, Mehta  RG, Kopelovich  L, McCormick  DL.  Inhibition of proliferation and induction of autophagy by atorvastatin in PC3 prostate cancer cells correlate with downregulation of Bcl2 and upregulation of miR-182 and p21.  PLoS One. 2013;8(8):e70442.PubMedGoogle ScholarCrossref
13.
Chou  Y-C, Wang  Y-K, Charng  M-J, Ueng  Y-F.  Determination of serum atorvastatin concentrations in lipid-controlling patients with and without myalgia syndrome.  J Food Drug Anal. 2013;21(2):147-153.Google ScholarCrossref
14.
Chang  SL, Harshman  LC, Presti  JC  Jr.  Impact of common medications on serum total prostate-specific antigen levels: analysis of the National Health and Nutrition Examination Survey.  J Clin Oncol. 2010;28(25):3951-3957.PubMedGoogle ScholarCrossref
15.
Hamilton  RJ, Banez  LL, Aronson  WJ,  et al.  Statin medication use and the risk of biochemical recurrence after radical prostatectomy: results from the Shared Equal Access Regional Cancer Hospital (SEARCH) Database.  Cancer. 2010;116(14):3389-3398.PubMedGoogle ScholarCrossref
16.
Platz  EA, Leitzmann  MF, Visvanathan  K,  et al.  Statin drugs and risk of advanced prostate cancer.  J Natl Cancer Inst. 2006;98(24):1819-1825.PubMedGoogle ScholarCrossref
17.
Boudreau  DM, Yu  O, Buist  DS, Miglioretti  DL.  Statin use and prostate cancer risk in a large population-based setting.  Cancer Causes Control. 2008;19(7):767-774.PubMedGoogle ScholarCrossref
18.
Freedland  SJ, Hamilton  RJ, Gerber  L,  et al.  Statin use and risk of prostate cancer and high-grade prostate cancer: results from the REDUCE study.  Prostate Cancer Prostatic Dis. 2013;16(3):254-259.PubMedGoogle ScholarCrossref
19.
Platz  EA, Tangen  CM, Goodman  PJ,  et al.  Statin drug use is not associated with prostate cancer risk in men who are regularly screened.  J Urol. 2014;192(2):379-384.PubMedGoogle ScholarCrossref
20.
Mucci  LA, Stampfer  MJ.  Mounting evidence for prediagnostic use of statins in reducing risk of lethal prostate cancer.  J Clin Oncol. 2014;32(1):1-2.PubMedGoogle ScholarCrossref
21.
Zheng  X, Cui  XX, Gao  Z,  et al.  Atorvastatin and celecoxib in combination inhibits the progression of androgen-dependent LNCaP xenograft prostate tumors to androgen independence.  Cancer Prev Res (Phila). 2010;3(1):114-124.PubMedGoogle ScholarCrossref
22.
Murtola  TJ, Pennanen  P, Syvälä  H, Bläuer  M, Ylikomi  T, Tammela  TL.  Effects of simvastatin, acetylsalicylic acid, and rosiglitazone on proliferation of normal and cancerous prostate epithelial cells at therapeutic concentrations.  Prostate. 2009;69(9):1017-1023.PubMedGoogle ScholarCrossref
23.
Corona  G, Boddi  V, Balercia  G,  et al.  The effect of statin therapy on testosterone levels in subjects consulting for erectile dysfunction.  J Sex Med. 2010;7(4, pt 1):1547-1556.PubMedGoogle ScholarCrossref
24.
Schooling  CM, Au Yeung  SL, Freeman  G, Cowling  BJ.  The effect of statins on testosterone in men and women, a systematic review and meta-analysis of randomized controlled trials.  BMC Med. 2013;11:57.PubMedGoogle ScholarCrossref
25.
Goldstein  JL, Brown  MS.  Regulation of the mevalonate pathway.  Nature. 1990;343(6257):425-430.PubMedGoogle ScholarCrossref
26.
Nielsen  SF, Nordestgaard  BG, Bojesen  SE.  Statin use and reduced cancer-related mortality.  N Engl J Med. 2012;367(19):1792-1802.PubMedGoogle ScholarCrossref
27.
Boudreau  DM, Yu  O, Johnson  J.  Statin use and cancer risk: a comprehensive review.  Expert Opin Drug Saf. 2010;9(4):603-621.PubMedGoogle ScholarCrossref
28.
Park  C, Lee  I, Kang  WK.  Lovastatin-induced E2F-1 modulation and its effect on prostate cancer cell death.  Carcinogenesis. 2001;22(10):1727-1731.PubMedGoogle ScholarCrossref
29.
Weis  M, Heeschen  C, Glassford  AJ, Cooke  JP.  Statins have biphasic effects on angiogenesis.  Circulation. 2002;105(6):739-745.PubMedGoogle ScholarCrossref
30.
Wu  J, Wong  WW, Khosravi  F, Minden  MD, Penn  LZ.  Blocking the Raf/MEK/ERK pathway sensitizes acute myelogenous leukemia cells to lovastatin-induced apoptosis.  Cancer Res. 2004;64(18):6461-6468.PubMedGoogle ScholarCrossref
31.
http://clinicaltrials.gov website. Accessed November 22, 2014.
Original Investigation
July 2015

Statin Use at the Time of Initiation of Androgen Deprivation Therapy and Time to Progression in Patients With Hormone-Sensitive Prostate Cancer

Author Affiliations
  • 1Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
  • 2Gelb Center for Translational Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
  • 3Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts
  • 4Department of Urology, Shanghai Jiao Tong University School of Medicine, Xinhua Hospital, Shanghai, China
  • 5Apple Tree Partners, New York, New York
  • 6Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts
JAMA Oncol. 2015;1(4):495-504. doi:10.1001/jamaoncol.2015.0829
Abstract

Importance  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.

Design, Setting, and Participants  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.

Main Outcomes and Measures  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 and Relevance  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.

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