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Research Articles

Serum 25-Hydroxyvitamin D Concentrations and Risk of Prostate Cancer: Results from the Prostate Cancer Prevention Trial

Jeannette M. Schenk, Cathee A. Till, Catherine M. Tangen, Phyllis J. Goodman, Xiaoling Song, Kathleen C. Torkko, Alan R. Kristal, Ulrike Peters and Marian L. Neuhouser
DOI: 10.1158/1055-9965.EPI-13-1340 Published August 2014

Abstract

Background: Epidemiologic studies have reported inconsistent associations of vitamin D and prostate cancer risk; however, few have adequately controlled for detection bias related to prostate-specific antigen (PSA) screening, and the results of many studies may be affected by occult prostate cancers among controls.

Methods: Data for this nested case–control analysis (n = 1,695 cases/1,682 controls) are from the Prostate Cancer Prevention Trial. Baseline serum was analyzed for 25-hydroxyvitamin D [25(OH)D]. The presence or absence of cancer was subsequently determined by prostate biopsy. Polytomous logistic regression models were used to estimate associations of 25(OH)D with risk of total, Gleason 2–6, Gleason 7, and Gleason 8–10 prostate cancer. Results are presented for placebo and finasteride arms separately and combined.

Results: There were no associations of serum 25(OH)D with total prostate cancer risk. For Gleason 2–6 cancers, results were inconsistent across treatment arms with a suggestion of increased risk in the placebo arm only; however, there was no dose–response relationship. For Gleason 8–10 prostate cancers, 25(OH)D concentrations were associated with a linear decrease in risk among combined treatment arms [quartile 4 vs. 1: OR, 0.55; 95% confidence interval (CI), 0.32–0.94; Ptrend = 0.04]. These findings were somewhat stronger among men ≥65 versus 55–64 years at baseline (quartile 4 vs. 1: OR, 0.40; 95% CI, 0.18–0.88 vs. OR, 0.73; 95% CI, 0.35–1.52, respectively; Pinteraction = 0.52).

Conclusions: Higher serum 25(OH)D may modestly increase risk of Gleason 2–6 disease and more substantially reduce risk of Gleason 8–10 prostate cancer.

Impact: Vitamin D may have different effects for different stages of prostate cancers. Cancer Epidemiol Biomarkers Prev; 23(8); 1484–93. ©2014 AACR.

See related commentary by Schwartz, p. 1447, and article by Kristal et al., p. 1494

Introduction

Prostate cancer is the most common cancer and the second leading cause of cancer deaths among men in the United States (1, 2). Despite the high prevalence of prostate cancer, there are very few known modifiable risk factors. There is considerable interest in the potential role for vitamin D in prostate cancer etiology. Vitamin D is a pro-hormone primarily recognized for its role in bone health (3); however, other identified functions include roles in cellular proliferation, differentiation, and apoptosis, all of which have relevance to cancer (4).

Many lines of evidence suggest an important role for vitamin D in the pathogenesis or progression of prostate cancer. Prostate cells express vitamin D receptors (VDR) and are able to convert 25-hydroxyvitamin D [25(OH)D], the primary circulating form of vitamin D, to the biologically active form of the vitamin, 1,25(OH)D (5). In experimental studies, 1,25(OH)D inhibits proliferation and induces differentiation, cell-cycle arrest, and apoptosis in prostatic cells, prostate cancer cell lines, and in animal models of prostate cancer (6–9). Two well-established risk factors for prostate cancer, older age and African American race, are associated with a decreased synthesis of vitamin D (10). In addition, ecologic studies indicate that ultraviolet radiation (UVR) exposure, one of the principal determinants of vitamin D status in humans, is inversely associated with prostate cancer risk (11).

Although there is strong biologic support for the association between vitamin D and prostate cancer, epidemiologic studies of the association of vitamin D concentration with risk have been inconsistent. Several observational studies reported an increased risk of prostate cancer among men with low (12, 13) or high (14–17) serum vitamin D concentrations, and one study found that men with the highest as well as lowest serum concentrations of vitamin D were at increased risk of prostate cancer (18). In contrast, many other studies found no association between vitamin D concentration and prostate cancer risk (19–32). Some of the inconsistencies in these studies may be related to small sample sizes or occult prostate cancer cases in the control group, and few studies were able to adequately control for detection bias, which often occurs in populations where screening via prostate-specific antigen (PSA) is common (33).

Here, we examine the association of serum 25(OH)D with prostate cancer risk using a nested case–control study of nearly 1,700 cases and 1,700 controls from the Prostate Cancer Prevention Trial (PCPT). In addition to the large sample size, several unique aspects of the PCPT address the limitations of previous studies: all participants underwent standardized annual prostate screening, the presence or absence of prostate cancer was established by biopsy, and cancer grade was determined by centralized, uniform pathology. Thus, detection bias and misclassification of disease was minimized, and pathologic grading of cases was rigorous.

Materials and Methods

Data for this nested case–control study are from the PCPT, a randomized double-blind, placebo-controlled trial of finasteride for the primary prevention of prostate cancer (34). Briefly, 18,880 men aged 55 years or older with normal digital rectal examination (DRE) results, PSA levels of 3 ng/mL or less, and no history of prostate cancer, severe lower urinary tract symptoms, or clinically significant coexisting conditions were randomized to receive finasteride (5 mg/d) or placebo. During the PCPT, participants underwent DRE and PSA determination annually, and men with an abnormal DRE or a PSA [adjusted for the effect of finasteride (ref. 35)] above 4.0 ng/mL were referred for a prostate biopsy. At the end of 7 years, all men not previously diagnosed with prostate cancer were asked to undergo an end-of-study biopsy per the primary trial protocol to determine the presence or absence of prostate cancer (34). Six core samples were collected under transrectal ultrasonographic guidance, and biopsies were reviewed for adenocarcinoma by both the local study site pathologist and a central pathology laboratory. In the case of discordant results, a referee pathologist reviewed cases until concordance was reached. Clinical stage was assigned locally, and tumors were graded centrally using the Gleason scoring system. All participants signed written informed consent, and the Institutional Review Board of the Fred Hutchinson Cancer Research Center (Seattle, WA), which serves as the statistical center for the PCPT, approved this study.

Case and control selection

Cases (n = 1,695) were all men with biopsy-confirmed prostate cancer, identified either by a “for-cause” (following a PSA > 4 ng/mL or abnormal DRE) biopsy (n = 803) or at the end-of-study biopsy (n = 892), who had baseline blood samples available for analysis. Controls (n = 1,682) were selected from men who had no evidence of prostate cancer on the end-of-study biopsy and had baseline blood samples. Controls were frequency matched to cases on distributions of age, first-degree family history of prostate cancer and PCPT treatment arm, and included all available non-Whites.

Data collection and laboratory methods

Information on age, race/ethnicity, family history of prostate cancer in first-degree relatives, level of physical activity, usual alcohol consumption, and history of smoking and diabetes was collected at baseline using standardized self-administered questionnaires.

Participants' height and weight were measured at the randomization clinic visit, and body mass index (BMI) was calculated as weight (kg)/height (m2). One year after randomization, waist and hip circumferences were measured, and intakes of alcohol, vitamin D, and calcium were assessed using a food frequency questionnaire and a structured dietary supplement-use questionnaire (36, 37). Latitude from the Equator was assigned to each participant based on the study site from which the participant was randomized and using a publicly available database (38).

Nonfasting blood was collected at recruitment (3 months before randomization) into a tube without anticoagulant and kept at room temperature for 30 to 60 minutes before centrifugation. Following centrifugation, serum was extracted and shipped on dry ice overnight to a central repository. Upon receipt, the sample was thawed to remove an aliquot for PSA, total and high-density lipoprotein (HDL) cholesterol analysis, and the remaining serum was frozen in 0.5-mL aliquots. 25(OH)D concentration was measured from using one 0.5-mL serum sample.

Serum 25(OH)D concentration was measured using the LIAISON 25 OH Vitamin D TOTAL Assay (DiaSorin Inc.), following manufacturer's instructions. The lower limit of quantitation (LoQ) of the 25(OH)D assay is 4 ng/mL. No specimens had results below the LoQ. All batches were balanced for number of cases and controls, and laboratory personnel were blinded to case status. Assays were completed by the Fred Hutchinson Cancer Research Center Public Health Sciences Biomarkers Laboratory. The coefficient of variation (CV) for 86 blinded, embedded quality control samples from pooled specimens was 8.31%.

Statistical analysis

The distribution of characteristics for case and control participants was compared using t tests (for continuous variables) and χ2 tests (for categorical variables). The distribution of serum 25(OH)D concentrations was right-skewed; therefore, values were log-transformed. Unadjusted linear regression models were used to determine whether participant characteristics were associated with log-transformed 25(OH)D concentrations.

Serum vitamin D concentrations were standardized for month of blood collection using the residual method (39), in which the residual from a regression model of month (12 categories) and 25(OH)D concentration was added to the population mean 25(OH)D concentration (60.74 nmol/L). The resulting month-standardized 25(OH)D concentrations were then categorized into quartiles based on the distribution among controls. In addition, 25(OH)D was parameterized using clinically relevant cut points (37.5, 50, and 75 nmol/L; ref. 40); however, associations were similar to those using quartiles (data not shown).

Multivariate logistic and polytomous logistic regression models were used to estimate odds ratios and 95% confidence intervals for the associations of 25(OH)D concentration with risks of total, Gleason 2–6, Gleason 7, and Gleason 8–10 disease. Because finasteride reduces prostate cancer risk (34), and both vitamin D and finasteride are involved in androgen metabolism (41), analyses of the association between vitamin D and prostate cancer risk were conducted in the finasteride and placebo arm separately and combined. All models were adjusted for race (White, African American, other race). Analyses in combined PCPT arms were also adjusted for treatment (finasteride, placebo). Further control for matching variables, including age and family history of prostate cancer, as well as other factors believed to potentially confound the association between Vitamin D and prostate cancer risk in this cohort, including serum cholesterol concentration, BMI, physical activity, history of diabetes, latitude of study site, and total calcium intake, did not change the estimated effect by more than 10% and were not included in final models.

Because vitamin D synthesis is lower in older men (42) and obese men have lower concentrations of 25 (OH)D (43), analyses were also stratified by age (<65, ≥65 years) and BMI (<25, 25–29, ≥30 kg/m2). In addition, analyses were stratified by whether the diagnostic biopsy was “for-cause” or not. Tests for linear trend across quartiles were based on an ordinal variable corresponding to rank (lowest to highest quartile). Tests for differences in associations across strata were based on interaction terms between 25(OH)D concentration and categorical indicator variables for treatment (finasteride, placebo), age (<65, ≥65 years), and a nominal variable for BMI (<25, 25–29, ≥30 kg/m2). Sensitivity analyses were also completed removing cases diagnosed within 1 year of baseline. All tests were 2-sided and considered statistically significant at P < 0.05. Statistical analyses were performed using SAS version 9.2 (SAS Institute Inc.).

Results

Table 1 gives distributions of participants' characteristics and geometric mean of 25(OH)D concentrations. Participants were mostly White, overweight, sedentary, or minimally active, nondiabetic, former smokers, had no family history of prostate cancer, and were moderate drinkers (<30 grams of alcohol per day). Compared with controls, men with prostate cancer were more likely to be from a high latitude study site and were less likely to have a history of diabetes. 25(OH)D concentrations were lower among participants who were non-White, overweight or obese, less physically active, diabetic, current smokers, or from a higher latitude study site, and among participants who consumed less alcohol or calcium.

View this table:
Table 1.

Baseline characteristics of PCPT participants

Table 2 gives associations of serum 25(OH)D concentration with total, Gleason 2–6, Gleason 7, and Gleason 8–10 prostate cancer in placebo and finasteride arms separately and combined. In the placebo arm, risk of total, Gleason 2–6, and Gleason 7 cancer tended to be increased for 25(OH)D concentrations ≥ 56.8 nmol/L (quartiles 3 and 4), whereas risk of Gleason 8–10 cancer tended to be decreased for increasing concentrations of 25(OH)D. The linear trend for Gleason 2–6 cancer was borderline significant (Ptrend = 0.05); however, there were no clear monotonic trends in these associations. In the finasteride-only arm, increasing 25(OH)D concentrations were not associated with risk of total, Gleason 2–6, or Gleason 7 prostate cancer; however, there was a suggestive, but not significant, decrease in risk for Gleason 8–10 prostate cancer (Table 2). There were no statistically significant differences between placebo and finasteride arms in associations of 25(OH)D and risk of total, Gleason 2–6, Gleason 7, and Gleason 8–10 prostate cancer (Pinteraction = 0.58, 0.77, 0.84, and 0.50, respectively); thus, results are also presented for treatment arms combined. In combined treatment arms, there was a suggestion of an increase in risk of Gleason 2–6 prostate cancer with increasing 25(OH)D concentrations, although the trend was borderline statistically significant and none of the point estimates for individual quartiles were significant. In addition, increasing 25(OH)D concentrations were associated with a significant linear decrease in risk of Gleason 8–10 prostate cancer (Ptrend = 0.04). Results were similar for sensitivity analyses excluding cases diagnosed within the first year (data not shown).

View this table:
Table 2.

Multivariable-adjusted associations of serum 25(OH)D concentrations and prostate cancer risk in the PCPT, by prostate cancer grade and treatment arm

In combined PCPT treatment arms, associations of 25(OH)D with risk of total, Gleason 2–6, and Gleason 7 prostate cancer were similar across strata defined by age; however, associations with risk of Gleason 8–10 prostate cancer tended to be stronger among older (≥65 years) men, although the difference between younger and older men was not statistically significant (Table 3). There were no statistically significant differences in associations of 25(OH)D with risk of total, Gleason 2–6, Gleason 7, or Gleason 8–10 prostate cancer across strata defined by BMI (Table 3). There was a suggestion that associations of 25(OH)D with Gleason 8–10 prostate cancer were stronger among cancers diagnosed “not-for-cause” [OR (95% CI) of Q4 vs. Q1 for 0.31 (0.10–1.01]; however, the number of Gleason 8–10 cases diagnosed “not-for-cause” is very small (n = 27) and no associations for individual strata reached statistical significance (data not shown).

View this table:
Table 3.

Multivariable-adjusted associations for combined PCPT treatment arms of serum 25(OH)D concentrations and prostate cancer risk in the PCPT by age and BMI

Discussion

In this nested case–control study in the PCPT, there were no associations of serum 25(OH)D and risk of total prostate cancer; however, there were differential associations among some subgroups. There was a suggestion of an increased risk of 25(OH)D concentrations with risk of Gleason 2–6 prostate cancer that was limited to the placebo arm; however, there was no evidence of a dose–response relationship. In addition, increasing 25(OH)D concentrations were associated with a linear decrease in Gleason 8–10 prostate cancer risk. This association was consistent across subgroups defined by PCPT treatment arm (finasteride, placebo) and BMI (<25, 25–29, ≥30 kg/m2) and was slightly stronger among older men (≥65 years).

Investigations of the association of vitamin D and prostate cancer risk are important to inform public health recommendations on vitamin D intake and solar exposure. The Institute of Medicine recently reviewed literature on vitamin D and risk of cancer and reported there was insufficient evidence to draw conclusions about a role for vitamin D in reducing prostate cancer risk (3). Despite the lack of evidence, popularized health reports and consumer literature emphasize the apparent widespread vitamin D insufficiency and deficiency. As a result, annual sales of vitamin D supplements have increased more than 10-fold, from $42 million in 2002 to $605 million in 2011 (44), and the prevalence of supplemental vitamin D use among men aged 60 and older has increased from 23.7% (1988–1994) to 44% (2003–2006; ref. 45). It is important to gain a better understanding of the risks and benefits of high vitamin D status on prostate cancer risk before recommendations can be made with respect to the use of supplemental vitamin D for prostate cancer prevention.

Two prior studies reported inverse associations of serum 25(OH)D and prostate cancer risk. In an update of the Health Professionals Follow-up Study (HPFS; n = 1,260 total cases), men in the highest quartile of 25(OH)D had a 57% lower risk of lethal prostate cancer (Ptrend = 0.002) but no association with overall prostate cancer (Ptrend = 0.45; ref. 13). In the Helsinki Heart Study (n = 149 total cases), men with 25(OH)D concentrations greater than 40 nmol/L had a 41% lower risk of total prostate cancer, and this association was stronger among younger men (<52 years; ref. 12). This study also reported that younger men with 25(OH)D concentrations greater than 40 nmol/L had a lower risk of “non-localized” prostate cancer.

In contrast to HPFS and the Helsinki Heart Study, 5 previous studies have reported inconsistencies in the direction of associations between vitamin D concentration and risk of prostate cancer (14–18). One study of Nordic men (n = 622 cases) reported that risk of total prostate cancer was greatest among men with the lowest (≤19 nmol/L) and highest (≥80 nmol/L) 25(OH)D concentrations (18). Several other studies report positive associations between serum 25(OH)D and prostate cancer risk. In an initial report from the HPFS (n = 684 cases), risk of total and high-grade prostate cancer was 38% and 58% lower, respectively, among men with 25(OH)D concentrations lower than 15 ng/ml (37.44 nmol/L; ref. 17). In the Malmo Diet and Cancer Study, men with serum 25(OH)D between 91 and 106 nmol/L had the highest risk of total prostate cancer (16), and in the Alpha-Tocopherol Beta-Carotene study cohort (n = 1,000 cases), there was a significant dose–response increase in risk of total and aggressive prostate cancer across increasing quintiles of serum vitamin D (14). Also, in the Janus Serum Bank cohort (n = 2,106 cases), 25(OH)D concentrations were associated with a linear increase in risk of total prostate cancer, but only among men with blood collected in summer or autumn (15). In addition, numerous other nested case–control studies have reported no association between serum 25(OH)D concentrations and prostate cancer risk (19–32). Taken together, the totality of the evidence neither support nor refute a protective role for vitamin D in prostate carcinogenesis.

The reasons for the inconsistencies in results across studies are unclear. There are considerable differences in populations across these studies. Several were conducted in Northern European populations (12, 14–16, 18) in which the range of 25(OH)D concentration was smaller and the proportion with deficient 25(OH)D concentrations (<50 nmol/L) was greater; however, there was no consistency in the associations reported by these studies. It is possible that serum 25(OH)D concentrations are a marker of other health-related behaviors. For example, PSA screening is associated with healthy dietary behaviors and use of dietary supplements (46), and men who receive PSA screening are more likely to have prostate cancer detected (47); thus, results from studies that did not adjust for PSA screening may be biased. It is also possible that variations in assay techniques could account for some of the differences in findings across studies.

We hypothesized a priori that the association of 25(OH)D with prostate cancer risk might differ by PCPT treatment arm. In the PCPT, finasteride substantially reduced prostate cancer risk (34); therefore, we examined associations of 25(OH)D and prostate cancer separately by treatment arm. In addition, we investigated a potential interaction between 25(OH)D and finasteride. Finasteride inhibits the conversion of testosterone into dihydrotestosterone, and there is evidence to suggest the vitamin D plays a role in androgen signaling (48). For example, in animal and prostate cancer cell line studies, the effect of vitamin D on growth inhibition is androgen-dependent and is reversed after adding anti-androgens or castration (48). In addition, variants in the VDR and 5α−reductase type II genes combine to increase prostate cancer risk (49). Although there is strong biologic rationale to support these analyses, the associations of serum 25(OH)D and prostate cancer risk in the finasteride arm were only modestly attenuated in the PCPT, and there was no evidence of an interaction between serum 25(OH)D and treatment arm.

When stratified by Gleason score, we found a modest but significant inverse association of serum 25(OH)D concentration and risk of Gleason 8–10 cancer and a suggestive positive association for Gleason 2–6 cancer. Of the 15 nested case–control studies that stratified by stage or grade, 4 have reported inconsistent associations for 25(OH)D and risk of advanced prostate cancer. Ahonen and colleagues (12) reported that younger men (<52 years) with high (>40 nmol/L) 25 (OH)D had a lower risk of “nonlocalized” prostate cancer, and Shui and colleagues (13) found that men in the highest quartile of 25(OH)D concentration had the lowest risk of “lethal” prostate cancer (metastases or prostate cancer–specific death). However, Mikhak and colleagues (17) found that men with sufficient (>37.5nmol/L) 25 (OH)D had an increased risk of high-grade (Gleason ≥7) cancer, and Albanes and colleagues (14) reported that men with the highest concentration of 25(OH)D had a 1.7-fold increased risk of aggressive (Gleason ≥ 8 or stage III or IV) disease. One additional study reported 25(OH)D concentrations greater than the lowest quintile were associated with increased risk of aggressive disease; however, the association was marginally statistically significant (22). No studies reported significant associations of 25(OH)D concentrations with risk of low-grade or nonaggressive prostate cancer. Ten additional nested case–control studies reported no association of 25(OH)D with high-grade or aggressive disease (18–21, 25–27, 30, 32).

Because serum 25(OH)D concentrations decline with age (50) and are lower in overweight and obese individuals due to sequestration of the fat-soluble vitamin in adipose tissue (43), we conducted exploratory analyses to examine whether the associations between 25(OH)D and prostate cancer risk differed by age or BMI. The association of 25(OH)D with risk of Gleason 8–10 cancer was slightly stronger among older than among younger men, although the numbers of cases among older men is small, associations were not linear and the differences between younger and older men were not statistically significant (Pinteraction = 0.52). In the PCPT, obesity was associated with an increased risk of high-grade but decreased risk of low-grade cancer (51). Thus, it is possible that the effect of obesity on the association between 25(OH)D and prostate cancer risk differed for low- and high-grade cancer. The directions of associations of 25(OH)D with Gleason 2–6 and Gleason 7 differed slightly; however, these differences were not statistically significant (Pinteractions = 0.41 and 0.28, respectively). There were no significant differences in associations of 25(OH)D with total or Gleason 8–10 cancer risk between normal weight, overweight, and obese men in this study.

There are several elements of the PCPT that serve to minimize bias in this study. First, all men in the PCPT had annual PSA and DRE tests, which substantially minimizes the potential for screening-related detection bias. Second, the absence or presence of prostate cancer was confirmed by biopsy in all men either during (cases only) or at the end of the trial; thus reducing the possibility that undetected cancers could affect study results. In addition, cancer grade was available for the majority of cases and was determined by centralized, uniform pathology. Finally, the PCPT recruited participants from more than 200 clinical sites, and thus represents a diverse U.S. geography.

Several limitations should also be noted. The use of a single measurement of vitamin D concentration may not be representative of an individual's long-term vitamin D status; although, measurements of serum 25(OH)D collected over 5 years have been shown to be reasonably stable in healthy individuals over 5 years (52). The standardized screening protocol in the PCPT minimized the potential for detection bias, but it is possible that vitamin D status differed among men who were more likely to comply with a biopsy recommendation or elect to undergo the end of study biopsy. This, in part, may explain the slight positive association of 25(OH)D with risk of Gleason 2–6 prostate cancer. Although the end of study biopsy allowed confirmation of the absence of prostate cancer among controls, the majority of cancers detected were low-grade (77%), and the clinical significance of these cancers is unclear. Also, there were very few high-grade cancers diagnosed during the trial (n = 127); therefore, these results are based on a relatively small sample size. In addition, there were few African Americans in the PCPT, which is particularly relevant because African Americans have the highest risk of prostate cancer (1) and tend to have lower serum 25(OH)D concentrations (53). Even though we oversampled non-White controls, power was limited to detect differential associations among African Americans. Finally, few deaths from prostate cancer occurred in the PCPT, thus we were unable to examine mortality as an endpoint.

In conclusion, the findings from this large nested case–control study of vitamin D status and prostate cancer risk suggest a potential protective association between serum 25(OH)D concentration and risk of high-grade prostate cancer; however, these findings also suggest that serum 25(OH)D concentrations may be associated with an increased risk of low-grade prostate cancers. These differential associations require further study in sufficiently powered studies. While further research needs to be conducted to determine the most appropriate approaches for optimizing vitamin D status, particularly among older men who have decreased endogenous synthesis, these results suggest that the associations of vitamin D and prostate cancer risk may differ for low- and high-grade cancers.

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Authors' Contributions

Conception and design: J.M. Schenk, C.M. Tangen, K.C. Torkko, A.R. Kristal, U. Peters, M.L. Neuhouser

Development of methodology: J.M. Schenk, C.M. Tangen, K.C. Torkko, A.R. Kristal, U. Peters

Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): C.M. Tangen, X. Song, K.C. Torkko, A.R. Kristal, U. Peters, M.L. Neuhouser

Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): J.M. Schenk, C.A. Till, C.M. Tangen, P.J. Goodman, K.C. Torkko, A.R. Kristal, U. Peters, M.L. Neuhouser

Writing, review, and or revision of the manuscript: J.M. Schenk, C.A. Till, C.M. Tangen, P.J. Goodman, X. Song, K.C. Torkko, A.R. Kristal, U. Peters, M.L. Neuhouser

Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): C.M. Tangen, P.J. Goodman, X. Song, A.R. Kristal

Study supervision: C.M. Tangen, A.R. Kristal, M.L. Neuhouser

Grant Support

The study was supported by R01 CA138639 (C.A. Till, C.M. Tangen, P.J. Goodman, X. Song, K.C. Torkko, A.R. Kristal, U. Peters, M.L. Neuhouser), P01 CA108964 (C.M. Tangen, P.J. Goodman, A.R. Kristal, M.L. Neuhouser), and U01 CA37429 (C.M. Tangen, P.J. Goodman).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Acknowledgments

The authors thank SWOG and the SWOG PCPT Biorepository at the University of Colorado, Denver, CO.

  • Received December 18, 2013.
  • Revision received May 12, 2014.
  • Accepted May 23, 2014.

References

  1. 1.↵
    1. Merrill RM,
    2. Brawley OW
    . Prostate cancer incidence and mortality rates among white and black men. Epidemiology 1997;8:126–39.
    OpenUrlPubMed
  2. 2.↵
    1. Siegel R,
    2. Naishadham D,
    3. Jemal A
    . Cancer statistics, 2013. CA Cancer J Clin 2013;63:11–30.
    OpenUrlCrossRefPubMed
  3. 3.↵
    1. Ross AC,
    2. Taylor CL,
    3. Yaktine AL,
    4. Del Valle HB
    Institute of Medicine (US) Committee to Review Dietary Reference Intakes for Vitamin D and Calcium; Ross AC, Taylor CL, Yaktine AL, Del Valle HB , editors. Dietary reference intakes for calcium and vitamin D. Washington, DC: The National Academies Collection: Reports funded by NIH; 2011.
  4. 4.↵
    1. Deeb KK,
    2. Trump DL,
    3. Johnson CS
    . Vitamin D signalling pathways in cancer: potential for anticancer therapeutics. Nature 2007;7:684–700.
    OpenUrl
  5. 5.↵
    1. Miller GJ,
    2. Stapleton GE,
    3. Ferrara JA,
    4. Lucia MS,
    5. Pfister S,
    6. Hedlund TE,
    7. et al.
    The human prostatic carcinoma cell line LNCaP expresses biologically active, specific receptors for 1α, 25-dihydroxyvitamin D3. Cancer Res 1992;52:515–20.
    OpenUrlAbstract/FREE Full Text
  6. 6.↵
    1. Barreto AM,
    2. Schwartz GG,
    3. Woodruff R,
    4. Cramer SD
    . 25-hydroxyvitamin D3, the prohormone of 1,25-dihydroxyvitamin D3, inhibits the proliferation of primary prostatic epithelial cells. Cancer Epidemiol Biomarkers Prev 2000;9:265–70.
    OpenUrlAbstract/FREE Full Text
  7. 7.↵
    1. Peehl DM,
    2. Skowronski RJ,
    3. Leung GK,
    4. Wong ST,
    5. Stamey TA,
    6. Feldman D
    . Antiproliferative effects of 1,25-dihydroxyvitamin D3 on primary cultures of human prostatic cells. Cancer Res 1994;54:805–10.
    OpenUrlAbstract/FREE Full Text
  8. 8.↵
    1. Jensen S,
    2. Madsen M,
    3. Lukas J
    . Inhibitory effects of 1,25-dihydroxyvitamin D2 on the G1-S phase controlling machinery. Mol Endocrinol 2001;15:1370–80.
    OpenUrlCrossRefPubMed
  9. 9.↵
    1. Guzey M,
    2. Kitada S,
    3. Reed JC
    . Apoptosis induction by 1α,25-Dihydroxyvitamin D3 in prostate cancer. Mol Cancer Ther 2002;1:667–77.
    OpenUrlAbstract/FREE Full Text
  10. 10.↵
    1. Bostwick DG,
    2. Burke HB,
    3. Djakiew D,
    4. Euling S,
    5. Ho SM,
    6. Landolph J,
    7. et al.
    Human prostate cancer risk factors. Cancer 2004;101:2371–490.
    OpenUrlCrossRefPubMed
  11. 11.↵
    1. Luscombe CJ,
    2. Freyer AA,
    3. French ME,
    4. Liu S,
    5. Saxby MF,
    6. Jones PW,
    7. et al.
    Exposure to ultraviolet radiation: association with susceptibility and age at presentation with prostate cancer. Lancet 2001;358:641–2.
    OpenUrlCrossRefPubMed
  12. 12.↵
    1. Ahonen MH,
    2. Tenkanen L,
    3. Teppo L,
    4. Hakama M,
    5. Tuohimaa P
    . Prostate cancer risk and prediagnostic serum 25-hydroxyvitamin D levels (Finland). Cancer Causes Control 2000;11:847–52.
    OpenUrlCrossRefPubMed
  13. 13.↵
    1. Shui IM,
    2. Mucci LA,
    3. Kraft P,
    4. Tamimi RM,
    5. Lindstrom S,
    6. Penney KL,
    7. et al.
    Vitamin D-related genetic variation, plasma vitamin D, and risk of lethal prostate cancer: a prospective nested case-control study. J Natl Cancer Inst 2012;104:690–9.
    OpenUrlAbstract/FREE Full Text
  14. 14.↵
    1. Albanes D,
    2. Mondul AM,
    3. Yu K,
    4. Parisi D,
    5. Horst RL,
    6. Virtamo J,
    7. et al.
    Serum 25-hydroxy vitamin D and prostate cancer risk in a large nested case-control study. Cancer Epidemiol Biomarkers Prev 2011;20:1850–60.
    OpenUrlAbstract/FREE Full Text
  15. 15.↵
    1. Meyer HE,
    2. Robsahm TE,
    3. Bjorge T,
    4. Brustad M,
    5. Blomhoff R
    . Vitamin D, season, and risk of prostate cancer: a nested case-control study within Norwegian health studies. Am J Clin Nutr 2013;97:147–54.
    OpenUrlAbstract/FREE Full Text
  16. 16.↵
    1. Brandstedt J,
    2. Almquist M,
    3. Manjer J,
    4. Malm J
    . Vitamin D, PTH, and calcium and the risk of prostate cancer: a prospective nested case-control study. Cancer Causes Control 2012;23:1377–85.
    OpenUrlCrossRefPubMed
  17. 17.↵
    1. Mikhak B,
    2. Hunter DJ,
    3. Spiegelman D,
    4. Platz EA,
    5. Hollis BW,
    6. Giovannucci E
    . Vitamin D receptor (VDR) gene polymorphisms and haplotypes, interactions with plasma 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, and prostate cancer risk. Prostate 2007;67:911–23.
    OpenUrlCrossRefPubMed
  18. 18.↵
    1. Tuohimaa P,
    2. Tenkanen L,
    3. Ahonen M,
    4. Lumme S,
    5. Jellum E,
    6. Hallmans G,
    7. et al.
    Both high and low levels of blood vitamin D are associated with a higher prostate cancer risk: a longitudinal, nested case-control study in the Nordic countries. Int J Cancer 2004;108:104–8.
    OpenUrlCrossRefPubMed
  19. 19.↵
    1. Platz EA,
    2. Leitzmann MF,
    3. Hollis BW,
    4. Willett WC,
    5. Giovannucci E
    . Plasma 1, 25-dihydroxy-and 25-hydroxyvitamin D and subsequent risk of prostate cancer. Cancer Causes Control 2004;15:255–65.
    OpenUrlCrossRefPubMed
  20. 20.↵
    1. Faupel-Badger JM,
    2. Diaw L,
    3. Albanes D,
    4. Virtamo J,
    5. Woodson K,
    6. Tangrea JA
    . Lack of association between serum levels of 25-hydroxyvitamin D and the subsequent risk of prostate cancer in Finnish men. Cancer Epidemiol Biomarkers Prev 2007;16:2784–6.
    OpenUrlFREE Full Text
  21. 21.↵
    1. Gann PH,
    2. Ma J,
    3. Hennekens CH,
    4. Hollis BW,
    5. Haddad JG,
    6. Stampfer MJ
    . Circulating vitamin D metabolites in relation to subsequent development of prostate cancer. Cancer Epidemiol Biomarkers Prev 1996;5:121–6.
    OpenUrlAbstract/FREE Full Text
  22. 22.↵
    1. Ahn J,
    2. Albanes D,
    3. Berndt SI,
    4. Peters U,
    5. Chatterjee N,
    6. Freedman ND,
    7. et al.
    Vitamin D-related genes, serum vitamin D concentrations and prostate cancer risk. Carcinogenesis 2009;30:769–76.
    OpenUrlAbstract/FREE Full Text
  23. 23.↵
    1. Corder EH,
    2. Guess HA,
    3. Hulka BS,
    4. Friedman GD,
    5. Sadler M,
    6. Vollmer RT,
    7. et al.
    Vitamin D and prostate cancer: a prediagnostic study with stored sera. Cancer Epidemiol Biomarkers Prev 1993;2:467–72.
    OpenUrlAbstract
  24. 24.↵
    1. Nomura AMY,
    2. Stemmermann GN,
    3. Lee J,
    4. Kolonel LN,
    5. Chen TC,
    6. Turner A,
    7. et al.
    Serum vitamin D metabolite levels and the subsequent development of prostate cancer (Hawaii, United States). Cancer Causes Control 1998;9:425–32.
    OpenUrlCrossRefPubMed
  25. 25.↵
    1. Barnett CM,
    2. Nielson CM,
    3. Shannon J,
    4. Chan JM,
    5. Shikany JM,
    6. Bauer DC,
    7. et al.
    Serum 25-OH vitamin D levels and risk of developing prostate cancer in older men. Cancer Causes Control 2010;21:1297–303.
    OpenUrlCrossRefPubMed
  26. 26.↵
    1. Travis RC,
    2. Crowe FL,
    3. Allen NE,
    4. Appleby PN,
    5. Roddam AW,
    6. Tjonneland A,
    7. et al.
    Serum vitamin D and risk of prostate cancer in a case-control analysis nested within the European Prospective Investigation into Cancer and Nutrition (EPIC). Am J Epidemiol 2009;169:1223–32.
    OpenUrlAbstract/FREE Full Text
  27. 27.↵
    1. Park SY,
    2. Cooney RV,
    3. Wilkens LR,
    4. Murphy SP,
    5. Henderson BE,
    6. Kolonel LN
    . Plasma 25-hydroxyvitamin D and prostate cancer risk: the multiethnic cohort. Eur J Cancer 2010;46:932–6.
    OpenUrlPubMed
  28. 28.↵
    1. Jacobs ET,
    2. Giuliano AR,
    3. Martinez ME,
    4. Hollis BW,
    5. Reid ME,
    6. Marshall JR
    . Plasma levels of 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D and the risk of prostate cancer. J Steroid Biochem Mol Biol 2004;89–90:533–7.
    OpenUrl
  29. 29.↵
    1. Braun MM,
    2. Helzlsouer KJ,
    3. Hollis BW,
    4. Comstock GW
    . Prostate cancer and prediagnostic levels of serum vitamin D metabolites (Maryland, United States). Cancer Causes Control 1995;6:235–9.
    OpenUrlCrossRefPubMed
  30. 30.↵
    1. Freedman DM,
    2. Looker AC,
    3. Chang SC,
    4. Graubard BI
    . Prospective study of serum vitamin D and cancer mortality in the United States. J Natl Cancer Inst 2007;99:1594–602.
    OpenUrlAbstract/FREE Full Text
  31. 31.↵
    1. Baron JA,
    2. Beach M,
    3. Wallace K,
    4. Grau MV,
    5. Sandler RS,
    6. Mandel JS,
    7. et al.
    Risk of prostate cancer in a randomized clinical trial of calcium supplementation. Cancer Epidemiol Biomarkers Prev 2005;14:586–9.
    OpenUrlAbstract/FREE Full Text
  32. 32.↵
    1. Li H,
    2. Stampfer MJ,
    3. Hollis JB,
    4. Mucci LA,
    5. Gaziano JM,
    6. Hunter D,
    7. et al.
    A prospective study of plasma vitamin D metabolites, vitamin D receptor polymorphisms, and prostate cancer. PLoS Med 2007;4:e103.
    OpenUrlCrossRefPubMed
  33. 33.↵
    1. Kristal AR,
    2. Stanford JL
    . Cruciferous vegetables and prostate cancer risk: confounding by PSA screening. Cancer Epidemiol Biomarkers Prev 2004;13:1265.
    OpenUrlFREE Full Text
  34. 34.↵
    1. Thompson IM,
    2. Goodman PJ,
    3. Tangen CM,
    4. Lucia MS,
    5. Miller GJ,
    6. Ford LG,
    7. et al.
    The influence of finasteride on the development of prostate cancer. N Engl J Med 2003;349:215–24.
    OpenUrlCrossRefPubMed
  35. 35.↵
    1. Thompson IM,
    2. Chi C,
    3. Ankerst DP,
    4. Goodman PJ,
    5. Tangen CM,
    6. Lippman SM,
    7. et al.
    Effect of finasteride on the sensitivity of PSA for detecting prostate cancer. J Natl Cancer Inst 2006;98:1128–33.
    OpenUrlAbstract/FREE Full Text
  36. 36.↵
    1. Neuhouser ML,
    2. Kristal AR,
    3. McLerran D,
    4. Patterson RE,
    5. Atkinson J
    . Validity of short food frequency questionnaires used in cancer chemoprevention trials: Results from the Prostate Cancer Prevention Trial. Cancer Epidemiol Biomarkers Prev 1999;8:721–5.
    OpenUrlAbstract/FREE Full Text
  37. 37.↵
    1. Neuhouser ML,
    2. Kristal AR,
    3. Patterson RE,
    4. Goodman PJ,
    5. Thompson IM
    . Dietary supplement use in the Prostate Cancer Prevention Trial: implications for prevention trials. Nutr Cancer 2001;39:12–8.
    OpenUrlCrossRefPubMed
  38. 38.↵
    1. Boutell T
    . Free Zip Code Latitude and Longitude Database [Internet]. [cited 2012 Oct 12]. Available from: http://www.boutell.com/zipcodes/.
  39. 39.↵
    1. Willett W
    . Nutritional epidemiology. New York: Oxford Universal Press; 1998.
  40. 40.↵
    1. Ross AC,
    2. Manson JE,
    3. Abrams SA,
    4. Aloia JF,
    5. Brannon PM,
    6. Clinton SK,
    7. et al.
    The 2011 Dietary Reference Intakes for Calcium and Vitamin D: what dietetics practitioners need to know. J Am Diet Assoc 2011;111:524–7.
    OpenUrlCrossRefPubMed
  41. 41.↵
    1. Kaeding J,
    2. Belanger J,
    3. Caron P,
    4. Verreault M,
    5. Belanger A,
    6. Barbier O
    . Calcitrol (1 {alpha}, 25-dihydroxyvitamin D3) inhibits androgen glucuronidation in prostate cancer cells. Mol Cancer Ther 2008;7:380–90.
    OpenUrlAbstract/FREE Full Text
  42. 42.↵
    1. Rock CL,
    2. Thornquist M,
    3. Kristal AR,
    4. Patterson RE,
    5. Cooper D,
    6. Neuhouser ML,
    7. et al.
    Demographic, dietary and lifestyle factors differentially explain variability in serum carotenoids and fat-soluble vitamins: baseline results from the Sentinal Site of the Olestra Post-Marketing Surveillance Study. J Nutr 1999;129:855–64.
    OpenUrlAbstract/FREE Full Text
  43. 43.↵
    1. Wortsman J,
    2. Matsuoka LY,
    3. hen TC,
    4. Lu Z,
    5. Holick MF
    . Decreased bioavailability of vitamin D in obesity. Am J Clin Nutr 2000;72:690–3.
    OpenUrlAbstract/FREE Full Text
  44. 44.↵
    1. Greider K
    . Has vitamin D been oversold? [Internet]. [cited 2013 Mar 13]. AARP Bulletin.
  45. 45.↵
    1. Gahche J,
    2. Bailey R,
    3. Burt V,
    4. Hughes J,
    5. Yetley E,
    6. Dwyer J,
    7. et al.
    Dietary supplement use among U.S. adults has increased since NHANES III (1988–1994). NCHS Data Brief 2011;61:1–8.
    OpenUrlPubMed
  46. 46.↵
    1. Patterson RE,
    2. Neuhouser ML,
    3. White E,
    4. Hunt JR,
    5. Kristal AR
    . Cancer-related behavior of vitamin supplement users. Cancer Epidemiol Biomarkers Prev 1998;7:79–81.
    OpenUrlAbstract
  47. 47.↵
    1. Woold SH
    . Screening for prostate cancer with prostate-specific antigen: an examination of the evidence. N Engl J Med 1995;333:1041–5.
    OpenUrl
  48. 48.↵
    1. Leman ES,
    2. Arlotti JA,
    3. Dhir R,
    4. Getzenberg RH
    . Vitamin D and androgen regulation of prostatic growth. J Cell Biochem 2003;90:138–47.
    OpenUrlCrossRefPubMed
  49. 49.↵
    1. Torkko KC,
    2. van Bokhoven A,
    3. Mai P,
    4. Beuten J,
    5. Balic I,
    6. Byers TE,
    7. et al.
    VDR and SRD5A2 polymorphisms combine to increase risk for prostate cancer in both non-Hispanic white and Hispanic white men. Clin Cancer Res 2008;14:3223–9.
    OpenUrlAbstract/FREE Full Text
  50. 50.↵
    1. Ginde AA,
    2. Liu MC,
    3. Camargo CA
    . Demographic differneces and trends of vitamin D in sufficiency in the US population, 1988–2004. Arch Int Med 2009;169:626–32.
    OpenUrlCrossRefPubMed
  51. 51.↵
    1. Gong Z,
    2. Kristal AR,
    3. Schenk JM,
    4. Tangen CM,
    5. Goodman PJ,
    6. Thompson IM
    . Alcohol consumption, finasteride, and prostate cancer risk. Results from the Prostate Cancer Prevention Trial. Cancer 2009;115:3661–9.
    OpenUrlPubMed
  52. 52.↵
    1. Hofmann JN,
    2. Yu K,
    3. Horst RL,
    4. Hayes RB,
    5. Purdue MP
    . Long-term variation in serum 25-hydroxyvitamin D concentration among participants in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Cancer Epidemiol Biomarkers Prev 2010;19:927–31.
    OpenUrlAbstract/FREE Full Text
  53. 53.↵
    1. Harris SS,
    2. Soteriades E,
    3. Coolidge JA,
    4. Mudgal S,
    5. Dawson-Hughes B
    . Vitamin D insufficiency and hyperparathyroidism in a low income, multiracial, elderly population. J Clin Endocrinol Metab 2000;85:4125–30.
    OpenUrlCrossRefPubMed
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Cancer Epidemiology Biomarkers & Prevention: 23 (8)
August 2014
Volume 23, Issue 8

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Serum 25-Hydroxyvitamin D Concentrations and Risk of Prostate Cancer: Results from the Prostate Cancer Prevention Trial
Jeannette M. Schenk, Cathee A. Till, Catherine M. Tangen, Phyllis J. Goodman, Xiaoling Song, Kathleen C. Torkko, Alan R. Kristal, Ulrike Peters and Marian L. Neuhouser
Cancer Epidemiol Biomarkers Prev August 1 2014 (23) (8) 1484-1493; DOI: 10.1158/1055-9965.EPI-13-1340
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