Data were obtained from a prospectively maintained cohort of men undergoing AS between 1995 and 2016 at our institution. All men satisfied the low-risk criteria: Gleason score <7, <4 positive cores, <50% involvement of any core, and prostate-specific antigen level <10.0 ng/dL. Kaplan–Meier curves and multivariable Cox proportional hazards were used to assess statin exposure at diagnosis and at the time to pathological progression (failing to meet the low-risk criteria at biopsy) and therapeutic progression (first of pathological progression or initiation of definitive therapy). Reclassification at confirmatory biopsy (first post-diagnostic biopsy) and progression beyond confirmatory biopsy were evaluated independently.
Low-risk criteria were met by 797 men. Reclassification at the confirmatory biopsy occurred in 194 (24%) men, 51 (26%) of whom were statin users. Statin use was not associated with reclassification at confirmatory biopsy (odds ratio (OR): 1.24, 95% confidence interval (CI): 0.77–1.99). Among the remaining 603 men (median age: 63 years; follow-up: 60 months; 23% statin users), 149 (24%) had pathologic progression, while 200 (33%) had therapeutic progression. Statin exposure was not associated with pathological (multivariable hazard ratio (HR) 0.79, 95% CI: 0.51–1.23) or therapeutic (multivariable-HR 0.81, 95% CI: 0.55–1.19) progression beyond the confirmatory biopsy. Sensitivity analyses did not alter conclusions.
In our study, statin use at diagnosis was not significantly protective against pathological or therapeutic progression in men undergoing AS for localized, low-risk prostate cancer
Introduction: Due to the long natural history of prostate cancer and the morbidity of active treatment, active surveillance (AS)— closely monitoring men with localized, low-risk prostate cancer and initiating definitive treatment (surgery or radiation) upon pathological progression—is emerging as the treatment of choice for managing low-risk patients 1. Identifying factors that modify the risk of and time to progression in AS holds broad implications for improving the quality of life among men with prostate cancer.
Recent efforts to delay the progression of prostate cancer have focused on using pharmaceutical or chemoprevention agents. 5-α-Reductase inhibitors (5-ARIs) were found to not only reduce prostate cancer incidence but also delay progression on AS 2-4. Statins, which inhibit the rate-limiting step in hepatic cholesterol synthesis (3-hydroxy-3- methylglutaryl coenzyme A), have also shown promise. Statins are a tempting chemopreventative as they have a favorable safety profile and cardioprotective efficacy. Despite considerable interest over the last decade, the state of the evidence for statins in prostate cancer remains inconclusive 5. Statins appear to lower prostate-specific antigen (PSA) 6, 7 and may modestly inversely associate with reduced overall risk of prostate cancer; statins have also been shown to be associated with a 20% reduction in high-grade or advanced prostate cancer risk, and are favorably associated with prostate cancer-specific mortality 8–10. To date, no studies have explored whether statins may have a role in delaying progression on AS.
Methods: Patient selection and data collection: Men who initiated AS for prostate cancer between 1995 and 2016 were identified from a prospectively maintained database at the Princess Margaret Cancer Center. Data collection was completed on 20 July 2016. Only men with low-risk prostate cancer at diagnosis (Gleason score <7, <4 positive cores, <50% involvement of any one core, and PSA <10.0 ng/dL), who had not undergone active treatment, were eligible. Research ethics board approval and patient consent were obtained.
Electronic patient chart reviews provided medication (type, dose, start, stop, and last reported physician-confirmed use for each: statins, non-steroidal anti-inflammatory drugs (NSAIDs), and 5-ARI), demographic (age at diagnosis, ethnicity, family history, body mass index (BMI)), clinical (cancer status, type and date of progression (pathological or therapeutic)), pathological (Gleason score, number of positive cores, percent core involving cancer, transrectal ultrasound (TRUS) volume at diagnosis), and laboratory (serum PSA at diagnosis) information. Patient questionnaires completed at clinic visits supplemented demographic and medication information.
Outcome and exposure assessment: All biopsies at our institution were performed by one of three urologic-radiologists using a standardized approach; all biopsies were read by one of four genitourinary pathologists, maintaining a high level of grading consistency. The patient was followed periodically between five uro-oncologists with digital rectal examination (DRE) and PSA measures every 3 months, or every 6 months in stable patients. All patients had a TRUS-guided confirmatory biopsy within 24 months of diagnosis. Subsequent biopsies were typically performed every 2–3 years, based on clinical concern. Of the 987 men in our AS dataset, 189 patients were excluded as they did not have a confirmatory biopsy within 24 months of diagnosis (n = 188) and were missing clinical data (n = 1); 797 men were included in the final analyses. Patients were censored at either (1) the last known visit to our center for AS follow-up or (2) the earliest confirmed date of pathological or therapeutic progression.
We considered any evidence of medication use (chart review or questionnaire) sufficient to consider an individual a user. A man was considered a statin user if one of the following criteria were fulfilled: (1) statin use was reported on the date of diagnosis; (2) dates for statin use encompassed the date of diagnosis; or (3) statin use was noted within 3 months after prostate cancer diagnosis. Statin-type and dose data were captured wherever available (Supplementary Table 1).
The co-primary analyses evaluated statin users vs. nonusers and time to pathological (Gleason score ≥7, ≥4 positive cores, or >50% core involvement) and therapeutic (first of pathological progression, or initiation of definitive treatment without pathologic indication) progression beyond the confirmatory biopsy. Statin exposure was considered a time-dependent covariate in a secondary analysis.
Statistical analyses: Men who were reclassified at the confirmatory biopsy were evaluated independently using multivariable logistic regressions. Since all men had a confirmatory biopsy, statin use and reclassification at confirmatory biopsy was considered a binary outcome and evaluated using multivariable logistic regression (n = 797). Kaplan–Meier curves evaluated the relationship between statin use at the time of diagnosis and time to pathological and therapeutic progression in men who did not progress at the confirmatory biopsy. Univariate and multivariable Cox proportional hazard regressions examined the co-primary outcomes (n = 603), and reported results as hazard ratios (HRs) with 95% confidence intervals (CIs). The a priori multivariable model included age (years), previous negative biopsies (yes, no), positive findings on DRE (yes, no), log-PSA (ng/mL), logTRUS-measured prostate volume (mL), number of positive cores (1, 2, or 3), log-max percent core involvement (%), and NSAID (yes, no) and 5-ARI (yes, no) use at diagnosis.
We performed three sensitivity analyses on our primary multivariable model: (i) with a family history of prostate cancer (yes, no), BMI (kg/m2 ) and ethnicity (Caucasian, African-American, Asian, or other) as additional covariates where data were available (n = 407); (ii) with year of diagnosis as an additional covariate (n = 603); (iii) with 5- ARI users excluded (n = 574). A subgroup analysis evaluated the influence of statin type (lipophilic vs. hydrophilic) on the primary multivariable model (n = 588).
The impact of duration of statin exposure was examined by treating statin exposure as a time-dependent covariate in our primary model (n = 467). Start of statin exposure was considered the first-mentioned date of post-diagnostic use, or the date of diagnosis for patients with pre-diagnostic exposure. Stop date was considered the date an explicit stop date was reported or the latest reported date of use. Thus, a patient who started a statin after diagnosis would first contribute person-time to the non-user cohort, and then begin contributing person-time to the statin user cohort upon statin initiation.
Statin exposure and biochemical recurrence (PSA ≥0.2 ng/mL after radical prostatectomy, a PSA ≥2 ng/mL above the nadir after radiation therapy, or the initiation of salvage therapy), and survival outcomes in men who received definitive therapy after AS were explored as a post hoc analysis.
Clinical and pathological characteristics were compared between statin use categories using analysis of variance and χ2 tests and reported as medians with interquartile ranges (IQRs). All statistical analyses were performed using SAS v.9.4 (SAS Institute Inc., Cary, NC, USA); statistical significance was considered a two-sided p-value <0.05.
Results: Participant characteristics: Among 797 men with localized low-risk prostate cancer, 188 (24%) were using a statin at diagnosis. Clinical characteristics of the cohort are summarized in Table 1. Our cohort was followed for a median of 41 months (IQR: 15–82). Most men were Caucasian (82%) and had no family history of prostate cancer (75%) or prior biopsies (80%). At diagnosis, median PSA was 4.9 ng/mL (IQR: 3.6–6.4), TRUS-volume was 42 mL (IQR: 32–55), and 21% of men had a positive DRE finding. Pathologically, men most often had one positive core (65%) and a median maximum of 5% (IQR: 2–10) malignant involvement of any core. Compared to statin non-users, statin users were older (62 years vs. 65 years), more often overweight or obese (80% vs. 69%), and more frequently used NSAIDs (8% vs. 48%) and 5-ARIs (3% vs. 11%).
Reclassification at the confirmatory biopsy: Confirmatory biopsies were undertaken at a median of 11 months (IQR: 5–14). Fifty-one statin users (27%) and 143 non-users (23%) were reclassified at the confirmatory biopsy (Table 2). Statin use at the time of diagnosis was not associated with reclassification at the confirmatory biopsy in univariate (OR 1.21, 95% CI: 0.84–1.7) nor multivariable (OR 1.24, 95% CI: 0.77–1.99) models (Table 3).
Progression beyond the confirmatory biopsy: Median follow-up from diagnosis among men who did not reclassify at the confirmatory biopsy was 60 months (IQR: 31–93). Of these 603 men, 137 (23%) used a statin at diagnosis. In total, 149 (25%) progressed pathologically (98 (16%) for grade and 95 (16%) for volume), and 200 (33%) progressed therapeutically (51 (8%) for physician/patient concern). Rates of progression were similar across statin use categories (Table 2). Statin exposure at the time of diagnosis was not significantly associated with pathological (univariate-HR 0.84, 95% CI: 0.56–1.25; multivariable-HR 0.79, 95% CI: 0.51–1.23) nor therapeutic (univariate-HR 0.82, 95% CI: 0.58–1.17; multivariable-HR 0.81, 95% CI: 0.55–1.19) progression beyond the confirmatory biopsy (Fig. 1 and Table 3).
Including family history, BMI, and ethnicity as covariates in the primary model (n = 406) supported a protective trend for both time to pathological (multivariable-HR 0.66, 95% CI: 0.38–1.15) and therapeutic (multivariable-HR 0.73, 95% CI: 0.45–1.18) progression (Table 3). The overall association nor the HRs changed when adjusting for year of diagnosis. While the overall association did not reach resistant disease (n = 1) and metastatic disease (n = 6) and one statin non-user died of metastatic prostate cancer.
Discussion: While statins may modify prostate cancer aggressiveness, its impact in the setting of AS is uncertain. To our knowledge, we are the first to report on statin use in the context of AS. We found no significant association between statin use at diagnosis and the time to pathological or therapeutic progression in a cohort of men undergoing AS for localized, low-risk prostate cancer. These findings remained unchanged in multivariable models and when treating statin exposure as a time-dependent covariate.
Despite consistent mechanistic evidence for statins in promoting prostate cancer cell cycle arrest, apoptosis, and inhibiting proliferation and invasion 5, the clinical correlation remains inconsistent 11. The epidemiological body of evidence is most convincing for a statin benefit in aggressive or advanced disease, wherein statins may prevent high-risk prostate cancers by up to 20% 8. In the most up-to-date meta-analysis of 36 observational studies, Tan et al. 9 found that statins reduce the incidence of advanced or high-grade prostate cancer by 12–17%, without any benefit for a localized or low-grade disease. In another meta-analysis of 34 observational studies, Raval et al. 10 reported 20–24% risk reductions for metastases, biochemical recurrence, and prostate cancer-specific mortality among statin users. In a recent study of approximately 6500 men with prostate cancer, Murtola et al. 12 identified a 20% reduction in the risk of prostate cancer-specific mortality among post-diagnostic statin users, with significant dose-dependent and duration-dependent associations. Interestingly, subgroup analyses found no association among men with low-grade disease (Gleason <7) nor men undergoing expectant management; in fact, the only subcohort of men benefitting from statins were concurrently undergoing androgen deprivation therapy, a finding consistent with recent studies 13, 14. Our results support these recent findings, showing no apparent benefit of statins for men with low-risk disease, adding to our understanding of statins and their potential uses in prostate cancer chemoprevention.
It is unclear why statins may preferentially benefit advanced prostate cancers. One explanation may relate to a selective benefit of statins in more mutationally aberrant tumors. The mutational profile of low-risk prostate tumors (i.e., men eligible for AS) is bland compared to the mutational profile of intermediate or aggressive subtypes 15, 16. Indeed, one study identified a significant decrease in the risk of prostate cancer recurrence among statins users whose tumors expressed either Ki-67 or ERG, compared to non-expressing users 17. Another study showed that statins inhibit PLA2G7, a phospholipase more commonly associated with prostate cancer aggressiveness and invasion than low-risk disease 18. Another explanation may relate to the influence of statins on intraprostatic cholesterol metabolism. While hypercholesterolemia promotes high-risk prostate cancer specifically 19, Schnoeller et al. 20 recently found that hypercholesterolemic men on statins had nearly 3-fold lower rates of high-grade disease compared to hypercholesterolemic men not on statins, suggesting that statins may moderate the negative impact of cholesterol on aggressive prostate cancer development 20. Thus, statins may preferentially influence the biology of only more aggressive or more mutated cancers, explaining in part why we did not appreciate a statin advantage for men on AS.
Other factors may also contribute to why no association was seen. The spectrum of statin type, dose, duration of exposure, and degree of antihypercholesterolemic efficacy captured in our cohort may overshadow statin subtypes that preferentially benefit men with prostate cancer. Lipophilic statins appear to have greater intraprostatic penetration and accumulation compared to hydrophilic statins; whether this leads to a clinically meaningful difference in chemoprotective efficacy remains unclear 5, 11. In our cohort, a subgroup analysis by statin type (lipophilic vs. hydrophilic) suggested a stronger protective trend for lipophilic statins. Statin users in our study were older, more often obese or overweight, and more often NSAID and 5-ARI users. While elevated BMI both negatively impact tumor behavior and progression in AS 21, obesity may also independently negatively interact with statins’ antineoplastic effects 22, 23. Support for obesity as a potential confounder is seen in our study, as adjusting for it (model 2) decreased the risk of progression by a further 12%. NSAIDs and 5-ARIs have both been reported to have protective associations in AS 4, 24–26; however, their interactions with statins remain unclear 27–30. Excluding 5-ARI users in our primary analysis strengthened the protective trend observed. Similarly, it is possible that germline or somatic genetic variants may modify the sensitivity of prostatic tumors to statins 31 by indirectly altering statin metabolism and availability 32, or directly altering statin-mediated antineoplastic effects 33
Our study has several limitations. First, statin users and non-users differed in baseline characteristics—statin users were older, used more medications, and were more often overweight or obese. Although multivariable models accounted for these discrepancies, potential residual confounding from other unmeasured variables and metabolic factors may bias against statin use. Second, the data available in patient health records limited our ability to adequately explore potential subgroup differences by statin type, dose, or duration. Third, our time-dependent analyses were limited by the relatively small sample size. Lastly, our data were underpowered to detect significant differences in outcomes beyond AS; longer follow-ups with larger sample sizes would better define any benefits of statin exposure throughout AS on long-term survival outcomes.
Conclusions: AS is increasing in popularity for the management of men with localized, low-risk prostate cancer. The potential to use a common medication, such as statins, with a low toxicity profile to delay prostate cancer progression is tantalizing. In our study, statin use at diagnosis did not significantly protect against pathological or therapeutic progression in men undergoing AS for localized, low-risk prostate cancer. Patient-specific and tumor-specific factors and statin subtype may modify the susceptibility of prostate cancers to statins, and may in part explain the lack of an observed association. Though we saw trends towards protective associations, our results were sensitive to the method of analysis. There is merit in evaluating this association in other, well-powered, active surveillance cohorts.
Funding: This work was supported by grants from Prostate Cancer Canada (PCC) and the Canadian Cancer Society Research Institute (CCSRI).
Compliance with ethical standards
Conflict of interest: The authors declare that they have no conflict of interest.
Authors: Viranda H. Jayalath1,2, Madhur Nayan1, Antonio Finelli1, Maria Komisarenki1, Narhari Timilshina1, Girish S. Kulkarni1, Neil E. Fleshner1, Bimal Bhindi1,3, Andrew Evans4, Alexandre R. Zlotta5, Robert J. Hamilton1
Author Affiliations:
1. Division of Urology, Department of Surgery, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON, Canada
2. Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
3. Department of Urology, Mayo Clinic, Rochester, Minnesota, United States
4. Department of Pathology, University Health Network, University of Toronto, Toronto, Ontario, Canada
5. Department of Uro-Oncology, Mount Sinai Hospital, Toronto, Ontario, Canada
Jayalath, Viranda H. et al. "Statin Use and Time to Progression in Men on Active Surveillance for Prostate Cancer," Prostate Cancer and Prostatic Diseases, 21, (Jun 2018): 509–515, https://doi.org/10.1038/s41391-018-0053-x
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