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

• Published in: JAMA oncology Vol. 1; no. 4; p. 495
• Main Authors: Harshman, Lauren C, Wang, Xiaodong, Nakabayashi, Mari, Xie, Wanling, Valenca, Loana, Werner, Lillian, Yu, Yongjiang, Kantoff, Aaron M, Sweeney, Christopher J, Mucci, Lorelei A, Pomerantz, Mark, Lee, Gwo-Shu Mary, Kantoff, Philip W
• Format: Journal Article
• Language: English
• Published: United States 01-07-2015
• Subjects: Androgen Antagonists - therapeutic use; Antineoplastic Agents, Hormonal - therapeutic use; Binding, Competitive; Cell Line, Tumor; Cell Proliferation - drug effects; Chi-Square Distribution; Dehydroepiandrosterone Sulfate - metabolism; Disease Progression; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors - metabolism; Hydroxymethylglutaryl-CoA Reductase Inhibitors - therapeutic use; Male; Multivariate Analysis; Neoplasms, Hormone-Dependent - drug therapy; Neoplasms, Hormone-Dependent - genetics; Neoplasms, Hormone-Dependent - metabolism; Neoplasms, Hormone-Dependent - pathology; Organic Anion Transporters - genetics; Organic Anion Transporters - metabolism; Proportional Hazards Models; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Retrospective Studies; Risk Factors; RNA Interference; Time Factors; Transfection; Treatment Outcome
• ISSN: 2374-2445
• DOI: 10.1001/jamaoncol.2015.0829

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.
To evaluate whether statin use prolongs TTP during ADT for hormone-sensitive prostate cancer.
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.
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.
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).
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.