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.
Written by:
Lauren C. Harshman, MD1; Xiaodong Wang, PhD2; Mari Nakabayashi, MD1; Wanling Xie, MS3; Loana Valenca, MD1; Lillian Werner, MS3; Yongjiang Yu, PhD2, 4; Aaron M. Kantoff, BS5; Christopher J. Sweeney, MBBS1; Lorelei A. Mucci, ScD6; Mark Pomerantz, MD1; Gwo-Shu Mary Lee, PhD2; Philip W. Kantoff, MD1, 2 Are you the author?
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
Reference: JAMA Oncol. Published online May 07, 2015.
doi: 10.1001/jamaoncol.2015.0829