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Background and aims
Knowledge about potentially effective interventions for the primary (prevention of disease occurrence) or tertiary (halting or slowing disease progression and recurrence) prevention of prostate cancer is limited. It has been suggested that men with higher intakes or circulating levels of vitamin D may have a reduced risk of prostate cancer, but the evidence-base is limited and inconclusive.
Previous studies have typically been small, relied on retrospective recall of diet and case or control selection has not been standardised or population-based, so may be prone to selection bias (e.g. latent cancers are often not excluded amongst control men, or associations of risk factors with prostate cancer may reflect factors associated with referral for biopsy). Few studies have investigated associations of circulating vitamin D or measures of sun exposure, the most important determinant of vitamin D status, with prostate cancer prevalence or progression.
Thus the potential effects of modifying circulating 25-hydroxyvitamin D (25(OH)D) and 1,25-dihydroxyvitamin D (1,25(OH)2D) levels via sun exposure, supplements or changes in diet are uncertain. Robust evidence indicating whether vitamin D really lowers prostate cancer risk could inform the development of interventions aimed at primary or tertiary prevention.
This project investigated whether measures of life-course sun exposure, circulating 25(OH)D and circulating 1,25(OH)2D are inversely associated with prostate cancer and, in particular, with more aggressive prostate cancers.
To set our findings within the context of the current body of evidence we conducted systematic reviews and meta-analyses examining associations of prostate cancer with four indicators of vitamin D status: circulating 25(OH)D; circulating 1,25(OH)2D; sun exposure; and dietary intake. We then conducted a population-based nested case-control study in men who received prostate specific antigen (PSA) tests within a randomised controlled trial of treatments for prostate cancer.
We investigated associations of life-course sun exposure (n=1,020 prostate cancer cases; 5,044 healthy controls), circulating 25(OH)D (n=1,447 cases; 1,449 controls) and 1,25(OH)2D (n=1282 cases; 1290 controls) with prostate cancer risk.
We investigated associations of 25(OH)D and 1,25(OH)2D with PSA-defined progression in men undergoing active monitoring for localised prostate cancer (n=490).
We additionally investigated whether single nucleotide polymorphisms (SNPs) involved in the vitamin D pathway are associated with an increased risk of prostate cancer, and whether SNPs that predict pigmentation traits reflecting sun exposure (tanning, skin colour, freckling) are associated with prostate cancer risk.
Associations were quantified by stage (advanced vs localised) and Gleason grade (high-grade (≥7) vs. low-grade (<7).
- Systematic reviews and meta-analyses found limited evidence for an association between vitamin D and prostate cancer. There was weak evidence that men with the lowest (versus highest) sunlight exposure had an increased risk of prostate cancer (3 studies; OR= 1.18; 95% CI: 1.04,1.34) and more aggressive cancers (5 studies; OR=1.17; 95% CI: 1.03 to 1.32). A potentially important protective effect of 1,25(OH)2D against aggressive cancer could not be excluded (2 studies; OR=0.86, 95% CI: 0.72, 1.02).
- The ProtecT nested case-control study indicated that men with the lowest (versus the highest) levels of sun exposure had an increased prostate cancer risk (OR=1.24; 95% CI: 1.03,1.50). However, the lowest levels of sun exposure were associated with a reduced risk of advanced compared to localised prostate cancer (OR=0.49; 95% CI: 0.27,0.89). This unexpected finding was not replicated when investigating associations with 25(OH)D levels.
- There was no evidence that men with the lowest 25(OH)D or 1,25(OH)2D had an increased overall prostate cancer risk. There was evidence that men with the lowest concentrations of 25(OH)D had a two-fold increased risk of more aggressive prostate cancer (OR of deficient vs adequate 25(OH)D=2.30, 95% CI: 1.27,4.19).
- There was no evidence that men with the lowest 1,25(OH)2D had an increased risk of more aggressive prostate cancer.
- Circulating 25(OH)D and 1,25(OH)2D levels were not associated with PSA-defined progression.
- There was evidence that SNPs in the vitamin D receptor gene were associated with prostate cancer in men deficient in circulating vitamin D.
- Men with a genetic tendency to burn (rather than tan) were more likely to have lower circulating vitamin D and to have prostate cancer.
- Proxies for vitamin D status, including sun exposure and dietary intake, did not strongly predict circulating concentrations of 25(OH)D.
These results strengthen the evidence that high 25(OH)D may protect against more aggressive prostate cancer. There was no evidence of an association with overall prostate cancer risk, or of an effect of 1,25(OH)2D. The observed association between vitamin D and more aggressive cancers indicates the potential role for vitamin D manipulation to control the progression of prostate cancer.