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

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) on androgen deprivation therapy (ADT). Objective Since statins utilize SLCO2B1 to enter cells, we hypothesized that they may compete with DHEAS uptake and that statin use might prolong TTP while on ADT. Design In vitro studies using prostate cancer cell lines. A retrospective analysis of statin use in 926 patients who had received ADT from January 1996 until November 2013. Setting Academic, comprehensive cancer center. Participants Patients who had received ADT for biochemical or metastatic recurrence or de novo metastatic prostate cancer. Main Outcomes and Measures To determine if 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 on ADT. TTP was estimated using multivariable Cox regression 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 progressed on ADT. Median TTP on ADT was 20.3 months (95% CI: 18,24). Men on statins had a longer median TTP on ADT compared to non-users (27.5 vs. 17.4 months, p=0.0005). The association remained statistically significant after adjusting for pre-defined prognostic factors [adjusted HR=0.83 (p=0.039)]. The positive statin effect was observed for both patients with and without metastases. Conclusions and Relevance Statin use at the time of ADT initiation was associated with a significantly longer TTP on ADT even after adjusting for known prognostic factors. Our in vitro findings that statins competitively reduce DHEAS uptake and thus, effectively decrease the available intratumoral androgen pool, affords a plausible mechanism to support the clinical observation of prolonged TTP in statin users.

Identification of Novel SNPs Associated with Risk and Prognosis in Patients with Castration-Resistant Prostate Cancer

“…Evidence suggests that decreasing serum cholesterol slows prostate tumor development, at least in part, due to reductions in the uptake of androgens and androgen precursors into prostate tumor tissues [31]. The human bile acid pool undergoes enterohepatic recirculation, which occurs multiple times per meal.…”

The current evidence on statin use and prostate cancer prevention: are we there yet?

“…Furthermore, a study comparing pre-operative and postoperative use of statins in 2,137 Korean men who underwent radical prostatectomy between 1998 and 2011 found that postoperative statin use prolonged recurrence-free survival over a median follow-up period of 32 months, especially in patients with high-risk disease (Gleason score ≥7; HR 0.27; 95% CI 0.13–0.59; P = 0.001), but preoperative statin use did not change pathological outcomes 107 . Finally, one study with a median follow-up time of 70 months reported that statin use significantly prolonged time to progression in 926 men receiving androgen deprivation therapy, even after adjusting for known prognostic factors such as biopsy-based Gleason score, type of primary therapy and presence of metastases at initiation of androgen deprivation (HR 0.83; 95% CI 0.69–0.99; P = 0.04) 108 .…”

Sex steroids in the tumor microenvironment and prostate cancer progression

“…These SLCO2B1 variants result in increased DHEA transport into cells. Statins are recognized inhibitors of SLCO2B1 transport and may explain why a longer time to progression for men treated with a statin at the time of ADT initiation was seen in a large cohort of men receiving ADT (Harshman et al 2015). This was seen in men with and without metastases after adjusting for prognostic factors.…”