Skip to main content
  • AACR Publications
    • Blood Cancer Discovery
    • Cancer Discovery
    • Cancer Epidemiology, Biomarkers & Prevention
    • Cancer Immunology Research
    • Cancer Prevention Research
    • Cancer Research
    • Clinical Cancer Research
    • Molecular Cancer Research
    • Molecular Cancer Therapeutics

AACR logo

  • Register
  • Log in
  • My Cart
Advertisement

Main menu

  • Home
  • About
    • The Journal
    • AACR Journals
    • Subscriptions
    • Permissions and Reprints
    • Reviewing
  • Articles
    • OnlineFirst
    • Current Issue
    • Past Issues
    • CEBP Focus Archive
    • Meeting Abstracts
    • Progress and Priorities
    • Collections
      • COVID-19 & Cancer Resource Center
      • Disparities Collection
      • Editors' Picks
      • "Best of" Collection
  • For Authors
    • Information for Authors
    • Author Services
    • Best of: Author Profiles
    • Informing Public Health Policy
    • Submit
  • Alerts
    • Table of Contents
    • Editors' Picks
    • OnlineFirst
    • Citation
    • Author/Keyword
    • RSS Feeds
    • My Alert Summary & Preferences
  • News
    • Cancer Discovery News
  • COVID-19
  • Webinars
  • Search More

    Advanced Search

  • AACR Publications
    • Blood Cancer Discovery
    • Cancer Discovery
    • Cancer Epidemiology, Biomarkers & Prevention
    • Cancer Immunology Research
    • Cancer Prevention Research
    • Cancer Research
    • Clinical Cancer Research
    • Molecular Cancer Research
    • Molecular Cancer Therapeutics

User menu

  • Register
  • Log in
  • My Cart

Search

  • Advanced search
Cancer Epidemiology, Biomarkers & Prevention
Cancer Epidemiology, Biomarkers & Prevention
  • Home
  • About
    • The Journal
    • AACR Journals
    • Subscriptions
    • Permissions and Reprints
    • Reviewing
  • Articles
    • OnlineFirst
    • Current Issue
    • Past Issues
    • CEBP Focus Archive
    • Meeting Abstracts
    • Progress and Priorities
    • Collections
      • COVID-19 & Cancer Resource Center
      • Disparities Collection
      • Editors' Picks
      • "Best of" Collection
  • For Authors
    • Information for Authors
    • Author Services
    • Best of: Author Profiles
    • Informing Public Health Policy
    • Submit
  • Alerts
    • Table of Contents
    • Editors' Picks
    • OnlineFirst
    • Citation
    • Author/Keyword
    • RSS Feeds
    • My Alert Summary & Preferences
  • News
    • Cancer Discovery News
  • COVID-19
  • Webinars
  • Search More

    Advanced Search

Hypothesis/Commentary

Vitamin D in Blood and Risk of Prostate Cancer: Lessons from the Selenium and Vitamin E Cancer Prevention Trial and the Prostate Cancer Prevention Trial

Gary G. Schwartz
Gary G. Schwartz
Departments of 1Cancer Biology,
2Urology, and
3Epidemiology and Prevention, Wake Forest University School of Medicine, Winston-Salem, North Carolina
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: gschwart@wakehealth.edu
DOI: 10.1158/1055-9965.EPI-14-0520 Published August 2014
  • Article
  • Info & Metrics
  • PDF
Loading

Abstract

The effects of blood levels of 25-hydroxyvitamin D (25-OHD) on the risk of total, low-, and high-grade prostate cancer were examined in the Selenium and Vitamin E Cancer Prevention Trial (SELECT) and the Prostate Cancer Prevention Trial (PCPT). In the SELECT study, plasma 25-OHD levels were associated with a linear decrease in prostate cancer risk for high-grade cancers in African American men and an apparent “U”-shaped effect in other men. The “U-shaped” curve may reflect detection bias. In the PCPT study, in which detection bias was minimized, serum 25-OHD levels were associated with a linear decrease in the risk of high-grade prostate cancers. The results from these large prevention trials support the hypothesis that circulating levels of 25-OHD decrease the risk of clinically relevant prostate cancers. Cancer Epidemiol Biomarkers Prev; 23(8); 1447–9. ©2014 AACR.

See related articles by Kristal et al., p. 1494, and Schenk et al., p. 1484

The hypothesis that vitamin D, or its major source, sunlight, inhibits prostate cancer has gone from a “dark horse” to a front-runner in the race to understand the epidemiology of prostate cancer. Clinically relevant prostate cancer preferentially afflicts the elderly, Blacks, and residents in northern latitudes (1). Conversely, the prevalence of subclinical prostate cancer (cancer detected in asymptomatic men) increases with age but does not vary by race or geography. In 1990, Schwartz and Hulka noted that the major descriptive risk factors for clinical prostate cancer (age, race, and northern latitudes) are associated with vitamin D deficiency and hypothesized that vitamin D inhibits the development of clinical prostate cancer from the ubiquitous subclinical cancers (2). Bolstered by maps showing that the geographic distribution of prostate cancer mortality is inversely correlated with the geographic distribution of sunlight (3), the hypothesis that vitamin D inhibits prostate cancer galvanized research in many fields. In the laboratory, it ceased to be a hypothesis, as we learned that prostate cells possess the receptor for the vitamin D hormone, 1,25-dihydroxyvitamin D (discovered in 1992; ref. 4), and the enzyme 1α-hydroxylase, which converts the vitamin D pro-hormone, 25-hydroxyvitamin D (25-OHD), into the vitamin D hormone (discovered in 1998; ref. 5). Both the hormone and pro-hormone exert prodifferentiating, antiproliferative, and antimetastatic effects on prostate cells (for reviews see refs. 6–8).

Although the results of experimental studies of vitamin D and prostate cancer have been uniformly positive, the results of observational studies have been mixed. Numerous ecologic studies replicated the inverse correlation of prostate cancer rates with sunlight (9–11). Analytic studies support a protective effect of sunlight exposure in individual men, including an effect for exposure during early life (12–14). However, results from serologic studies of 25-OHD and prostate cancer risk have been inconsistent, with articles reporting negative, null, and positive associations (for review see ref. 15). This inconsistency has several causes. First, if some of the protective effect of 25-OHD is due to a prodifferentiating effect on prostate cells during early life, then studies that measure 25-OHD during later life may not detect it. Second, part of the inconsistency may be due to differences in what is considered prostate “cancer.” For example, consider a car; when it is new, it has no dents. However, virtually all cars accumulate minor dents with time but most do not threaten the working of the car. The prostate also accumulates subclinical lesions with age. Histologically, these lesions are classified as “cancer” yet most are not life-threatening. At diagnosis, approximately half of all newly diagnosed patients with prostate cancer have cancer with a Gleason score ≤ 6 (“low-grade cancer”; ref. 16). For men with low-grade prostate cancers (Gleason 2–6), the risk of death from prostate cancer during 15 years of follow-up is low: 6 to 30 deaths per 1,000 person-years. Conversely, the risk of death from prostate cancer for men with high-grade cancers (Gleason 8–10) is high: 121 deaths per 1,000 person-years. Men with a Gleason 7 cancer have an intermediate risk of death (17).

These concepts are pertinent to two articles in the current issue of Cancer Epidemiology, Biomarkers & Prevention. The article by Kristal and colleagues examines plasma 25-OHD levels in the Selenium and Vitamin E Cancer Prevention Trial (SELECT), a randomized, placebo-controlled trial of selenium and vitamin E on prostate cancer risk (18). Data for this case–cohort analyses included 1,731 cases and 3,203 controls. Kristal and colleagues examined the effects of baseline 25-OHD levels with risk of total, low-, and high-grade prostate cancer. Using quintiles of 25-OHD based on the distribution of 25-OHD in the cohort, the risk of total prostate cancer for non-African American men was U-shaped: compared with the first quintile, the reductions in prostate cancer risk in the second to fifth quintiles were 17%, 26%, 14%, and 2%. Similar findings were observed for Gleason 2–6 cancer and Gleason 7–10 and 8–10 cancer, but were strongest for Gleason 8–10 cancers. Conversely, among the 250 African American cases, the risk of high-grade prostate cancer decreased linearly with increasing levels of 25-OHD.

An important limitation of the SELECT study is that the use of PSA screening and prostate biopsy was not controlled. The use of PSA screening, or the decision to follow-up an elevated PSA with biopsy, may differ between men with low and high vitamin D levels. For example, in the NIH-AARP Diet and Health Study, which studied >295,000 men, high users of multivitamins were more likely to undergo prostate cancer screening by PSA (19). If men in the SELECT study behaved similarly, then men with higher levels of circulating vitamin D would be more likely to undergo biopsy and to be diagnosed with prostate cancer. A related bias may have occurred in the SELECT study. In population-based studies, mean blood levels of 25-OHD decline with age (20, 21). Yet, mean plasma 25-OHD levels in the SELECT study increased with age and were significantly higher among men of ages ≥70 years than among men of ages 50 to 54 years (P < 0.001; see Table 2; ref. 18). If the anomalously high 25-OHD levels in older men resulted from recent vitamin D supplementation (which seems likely), then the (pre-supplementation) association between plasma 25-OHD and prostate cancer risk would be distorted upwards.

In a second study in this issue, Schenk and colleagues examined associations between serum 25-OHD and prostate cancer risk in a case–control trial nested with the Prostate Cancer Prevention Trial (PCPT), a double-blind placebo-controlled trial of finasteride for the primary prevention of prostate cancer (22). This study included 1,695 men with prostate cancer and 1,682 controls. An important advantage of the PCPT study was its ability to minimize detection bias. All men had annual PSA and digital rectal examinations and the absence or presence of prostate cancer was confirmed by biopsy either during (for cases) or at the end of the trial (for all men). The key finding was that among combined treatment arms of this trial, comparing the highest with lowest quartile of serum 25-OHD, 25-OHD levels were associated with a linear decrease in the risk of Gleason 8–10 prostate cancer [OR, 0.55; 95% confidence interval (CI), 0.32–0.94]. There was no evidence of a preventive effect for Gleason 2–6 cancers, which were nonsignificantly increased, or of a “U”-shaped curve.

What is the “take-home” message from these studies? First, both studies support a protective role for circulating 25-OHD on prostate cancer risk. The effect was clearer in the PCPT study, which found that 25-OHD levels were associated with a linear decrease in risk of Gleason 8–10 prostate cancer, than in the SELECT study, which found that 25-OHD was associated with a linear decrease in the risk of high-grade cancers in African Americans and an apparent “U”-shaped curve in other men. Because a “U”-shaped curve was observed in the SELECT study, which was vulnerable to detection bias, but was not observed in the PCPT study, which was largely free from this bias, the “U”-shaped curve in the SELECT study may reflect such bias. Second, both studies show that the protective effect of 25-OHD was associated more strongly with high-grade than with low-grade prostate cancers. This finding is consistent with the hypothesis that vitamin D inhibits the development of clinically relevant, but not subclinical prostate cancer (2). To return to our automotive example, seat belts prevent serious injury and death from automobile collisions; they do not prevent whiplash, a common but non–life-threatening injury (23). Thus, if fatal and nonfatal automobile injuries were combined into the single category, “injuries,” the life-saving effect of seat belts could be missed. This may be relevant to some of the inconsistency in previous reports of circulating 25-OHD and risk of (predominantly low grade) prostate cancer.

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Acknowledgments

The author thanks Bart Frizzell and Christopher Thomas for helpful comments on this commentary.

  • Received May 9, 2014.
  • Accepted May 9, 2014.
  • ©2014 American Association for Cancer Research.

References

  1. 1.↵
    Prostate cancer incidence and mortality trends in 37 European countries: an overview. Eur J Cancer 2010;46:3040–52.
    OpenUrlCrossRefPubMed
  2. 2.↵
    1. Schwartz GG,
    2. Hulka BS
    . Is vitamin D deficiency a risk factor for prostate cancer? (Hypothesis) Anticancer Res 1990;10:1307–11.
    OpenUrlPubMed
  3. 3.↵
    1. Hanchette CL,
    2. Schwartz GG
    . Geographic patterns of prostate cancer mortality: evidence for a protective effect of ultraviolet radiation. Cancer 1992;70:2861–9.
    OpenUrlCrossRefPubMed
  4. 4.↵
    1. Miller GJ,
    2. Stapelton 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 1α25-dihydroxyvitamin D3. Cancer Res 1992;52:515–20.
    OpenUrlAbstract/FREE Full Text
  5. 5.↵
    1. Schwartz GG,
    2. Whitlach LW,
    3. Chen TC,
    4. Lokeshwar B,
    5. Holick MF
    . Human prostate cells synthesize 1,25-dihydroxyvitamin D3 from 25-hydroxyvitamin D3 . Cancer Epidemiol Biomarkers Prev 1998;7:391–5.
    OpenUrlAbstract/FREE Full Text
  6. 6.↵
    1. Krishan AV,
    2. Feldman D
    . Molecular pathways mediating the anti-inflammatory effects of calcitriol: implications for prostate cancer chemoprevention and treatment. Endocr Relat Cancer 2010;17:R19–39.
    OpenUrlAbstract/FREE Full Text
  7. 7.↵
    1. Carlberg C,
    2. Molnar F
    . Current status of vitamin D signaling and its therapeutic implications. Curr Top Med Chem 2012;12:525–47.
    OpenUrl
  8. 8.↵
    1. Deeb KK,
    2. Trump DL,
    3. Johnson CS
    . Vitamin D signaling pathways in cancer: potential for anticancer therapies. Nat Rev Cancer 2007;7:684–700.
    OpenUrlCrossRefPubMed
  9. 9.↵
    1. Grant WB
    . An estimate of premature cancer mortality in the U.S. due to inadequate doses of solar ultraviolet B-radiation. Cancer 2002;94:1867–75.
    OpenUrlCrossRefPubMed
  10. 10.↵
    1. Bosco FP,
    2. Schymura MJ
    . Solar ultraviolet-B exposure and cancer incidence and mortality in the United States, 1993–2002. BMC Cancer 2006;10:264.
    OpenUrl
  11. 11.↵
    1. Schwartz GG,
    2. Hanchette CL
    . UV, latitude, and prostate cancer mortality: all sunlight is not the same (United States). Cancer Cause Control. 2006;17:1091–101.
    OpenUrlCrossRefPubMed
  12. 12.↵
    1. John EM,
    2. Koo J,
    3. Schwartz GG
    . Sun exposure and prostate cancer risk: evidence for a protective effect of early life exposure. Cancer Epidemiol Biomarkers Prev 2007;16:1283–6.
    OpenUrlAbstract/FREE Full Text
  13. 13.↵
    1. Rukin N,
    2. Blagojevic M,
    3. Luscombe CJ,
    4. Liu S,
    5. Saxby MR,
    6. Ramachandran S,
    7. et al.
    Associations between timing of exposure to ultraviolet radiation, T-stage and survival in prostate cancer. Cancer Detect Prev 2007;31:443–9.
    OpenUrlCrossRefPubMed
  14. 14.↵
    1. Lin SH,
    2. Wheller D,
    3. Yikung P,
    4. Cahoon E,
    5. Hollenbeck A,
    6. Freedman D,
    7. et al.
    Prospective study of ultraviolet radiation exposure and risk of cancer in the U.S. Int J Cancer 2012;131:E1015–123.
    OpenUrlCrossRefPubMed
  15. 15.↵
    1. Schwartz GG
    . Vitamin D, sunlight, and the epidemiology of prostate cancer. Anticancer Agents Med Chem 2013;13:45–57.
    OpenUrlPubMed
  16. 16.↵
    1. Carter HB,
    2. Partin AW,
    3. Walsh PC,
    4. Trock BJ,
    5. Veltri RW,
    6. Nelson WG,
    7. et al.
    Gleason Score 6 adenocarcinoma: should it be labeled as cancer? J Clin Oncol 2012;30:4294–6.
    OpenUrlFREE Full Text
  17. 17.↵
    1. Albertsen PC,
    2. Hanley JA,
    3. Fine J
    . 20-year outcomes following conservative management of clinically localized prostate cancer. JAMA 2005;293:2095–101.
    OpenUrlCrossRefPubMed
  18. 18.↵
    1. Kristal AR,
    2. Till C,
    3. Song X,
    4. Tangen CM,
    5. Goodman PJ,
    6. Neuhauser ML,
    7. et al.
    Plasma vitamin D and prostate cancer risk: results from the Selenium and Vitamin E Cancer Prevention Trial. Cancer Epidemiol Biomarkers Prev 2014;23:1494–504.
    OpenUrlAbstract/FREE Full Text
  19. 19.↵
    1. Lawson KA,
    2. Wright ME,
    3. Subar A,
    4. Hollenbeck A,
    5. Sahtzkin A,
    6. Leitzman MF
    . Multivitamin use and risk of prostate cancer in the National Institutes of Health AARP Diet and Health Study. J Natl Cancer Inst 2007;99:754–64.
    OpenUrlAbstract/FREE Full Text
  20. 20.↵
    1. Ginde AA,
    2. Liu MC,
    3. Camargo CA Jr.
    . Demographic differences and trends of vitamin D insufficiency in the US population, 1988–2004. Arch Intern Med 2009;169:626–32.
    OpenUrlCrossRefPubMed
  21. 21.↵
    1. Zadshir A,
    2. Tareen N,
    3. Pan D,
    4. Norris K,
    5. Martins D
    . The prevalence of hypovitaminosis D among US adults: data from the NHANES III. Ethn Dis 2005;15(4 Suppl 5):S5-91–101.
    OpenUrl
  22. 22.↵
    1. Schenk JM,
    2. Till CA,
    3. Tangen CM,
    4. Goodman PJ,
    5. Song X,
    6. Torkko KC,
    7. et al.
    Serum 25-hydroxyvitamin D concentrations and risk of prostate cancer: results from the Prostate Cancer Prevention Trial. Cancer Epidemiol Biomarkers Prev 2014;23:1484–93.
    OpenUrlAbstract/FREE Full Text
  23. 23.↵
    1. Richter M,
    2. Otte D,
    3. Pohlemann T,
    4. Krettek C,
    5. Blauth M
    . Whiplash-type neck distortion in restrained car drivers: frequency, causes and long-term results. Eur Spine J 2000;9:109–17.
    OpenUrlCrossRefPubMed
View Abstract
PreviousNext
Back to top
Cancer Epidemiology Biomarkers & Prevention: 23 (8)
August 2014
Volume 23, Issue 8
  • Table of Contents
  • Table of Contents (PDF)

Sign up for alerts

View this article with LENS

Open full page PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for sharing this Cancer Epidemiology, Biomarkers & Prevention article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
Vitamin D in Blood and Risk of Prostate Cancer: Lessons from the Selenium and Vitamin E Cancer Prevention Trial and the Prostate Cancer Prevention Trial
(Your Name) has forwarded a page to you from Cancer Epidemiology, Biomarkers & Prevention
(Your Name) thought you would be interested in this article in Cancer Epidemiology, Biomarkers & Prevention.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Vitamin D in Blood and Risk of Prostate Cancer: Lessons from the Selenium and Vitamin E Cancer Prevention Trial and the Prostate Cancer Prevention Trial
Gary G. Schwartz
Cancer Epidemiol Biomarkers Prev August 1 2014 (23) (8) 1447-1449; DOI: 10.1158/1055-9965.EPI-14-0520

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Share
Vitamin D in Blood and Risk of Prostate Cancer: Lessons from the Selenium and Vitamin E Cancer Prevention Trial and the Prostate Cancer Prevention Trial
Gary G. Schwartz
Cancer Epidemiol Biomarkers Prev August 1 2014 (23) (8) 1447-1449; DOI: 10.1158/1055-9965.EPI-14-0520
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • Disclosure of Potential Conflicts of Interest
    • Acknowledgments
    • References
  • Info & Metrics
  • PDF
Advertisement

Related Articles

Cited By...

More in this TOC Section

  • The Evolving Scale and Profile of Cancer
  • Physicians and HPV Vaccination
  • HPV Genotyping as Triage Marker
Show more Hypothesis/Commentary
  • Home
  • Alerts
  • Feedback
  • Privacy Policy
Facebook   Twitter   LinkedIn   YouTube   RSS

Articles

  • Online First
  • Current Issue
  • Past Issues

Info for

  • Authors
  • Subscribers
  • Advertisers
  • Librarians

About Cancer Epidemiology, Biomarkers & Prevention

  • About the Journal
  • Editorial Board
  • Permissions
  • Submit a Manuscript
AACR logo

Copyright © 2021 by the American Association for Cancer Research.

Cancer Epidemiology, Biomarkers & Prevention
eISSN: 1538-7755
ISSN: 1055-9965

Advertisement