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Previous prospective studies assessing the relationship between circulating concentrations of vitamin D and prostate cancer risk have shown inconclusive results, particularly for risk of aggressive disease. In this study, we examine the association between prediagnostic concentrations of 25-hydroxyvitamin D [25(OH)D] and 1,25-dihydroxyvitamin D [1,25(OH) 2 D] and the risk of prostate cancer overall and by tumor characteristics. Principal investigators of 19 prospective studies provided individual participant data on circulating 25(OH)D and 1,25(OH) 2 D for up to 13,462 men with incident prostate cancer and 20,261 control participants. ORs for prostate cancer by study-specific fifths of season-standardized vitamin D concentration were estimated using multivariable-adjusted conditional logistic regression. 25(OH)D concentration was positively associated with risk for total prostate cancer (multivariable-adjusted OR comparing highest vs. lowest study-specific fifth was 1.22; 95% confidence interval, 1.13-1.31; P trend < 0.001). However, this association varied by disease aggressiveness ( P heterogeneity D concentration was not associated with risk for prostate cancer overall or by tumor characteristics. The absence of an association of vitamin D with aggressive disease does not support the hypothesis that vitamin D deficiency increases prostate cancer risk. Rather, the association of high circulating 25(OH)D concentration with a higher risk of nonaggressive prostate cancer may be influenced by detection bias. SIGNIFICANCE: This international collaboration comprises the largest prospective study on blood vitamin D and prostate cancer risk and shows no association with aggressive disease but some evidence of a higher risk of nonaggressive disease.2 D concentration was not associated with risk for prostate cancer overall or by tumor characteristics. The absence of an association of vitamin D with aggressive disease does not support the hypothesis that vitamin D deficiency increases prostate cancer risk. Rather, the association of high circulating 25(OH)D concentration with a higher risk of nonaggressive prostate cancer may be influenced by detection bias. SIGNIFICANCE: This international collaboration comprises the largest prospective study on blood vitamin D and prostate cancer risk and shows no association with aggressive disease but some evidence of a higher risk of nonaggressive disease., (©2018 American Association for Cancer Research.)

Cancer is a broad term for many disparate diseases with different etiologies, commonly classified by affected organ site. This review summarizes the published evidence from prospective cohort studies examining the associations between vitamin D, measured as serum 25-hydroxyvitamin D (25OHD) concentrations, and the risk of rarer cancer sites including pancreatic, non-Hodgkin lymphoma, ovarian, endometrial, kidney, gastric and esophageal cancer. Overall, evidence from prospective cohort studies provides little support for a protective association between adequate or higher serum 25OHD concentrations and risk of these rarer cancer sites. Additionally, controversy persists concerning a potential increased risk of pancreatic cancer associated with serum 25OHD levels > 100 nmol/L due to conflicting results reported by two large prospective pooling projects.

This study compared type, severity and location of musculoskeletal symptoms and associations with 25-hydroxyvitamin D (25(OH)D) and C-reactive protein (CRP) concentrations between women initiating aromatase inhibitor (AI) therapy and an unexposed comparison group. A 6-month prospective cohort study was conducted, enrolling 100 breast cancer patients prior to initiating AI treatment and an unexposed comparison group of 200 postmenopausal women. Multivariate associations were assessed with generalized linear models. At baseline, 55% of breast cancer patients and 63% of the comparison group reported any musculoskeletal symptoms. Among the unexposed group, prevalence and severity of symptoms remained constant with no statistically significant change over 6 months. Among breast cancer patients, but not unexposed women, the pain severity score significantly increased over the 6 month period for joint (P (trend) < 0.001), muscle (P (trend) = 0.004), and bone pain (P (trend) = 0.01). Women treated with AIs were more likely to report pain in wrists/palms (63% at 6 months) compared to unexposed women (31% at 6 months) (P < 0.001). 25(OH)D concentrations increased over the study period among breast cancer patients (P (trend) = 0.004). An increase in pain severity and prevalence was observed among breast cancer patients despite an increase in 25 (OH)D concentration. CRP concentrations were not associated with symptoms. Musculoskeletal symptoms are common among postmenopausal women. Breast cancer patients initiating AI treatment were at increased risk for developing new onset and more severe joint, muscle and bone pain compared to unexposed women, with a distinct distribution. AI-associated symptoms were not associated with 25(OH)D or CRP concentrations.

The Cohort Consortium Vitamin D Pooling Project of Rarer Cancers (VDPP), a consortium of 10 prospective cohort studies from the United States, Finland, and China, was formed to examine the associations between circulating 25-hydroxyvitamin D (25(OH)D) concentrations and the risk of rarer cancers. Cases (total n = 5,491) included incident primary endometrial (n = 830), kidney (n = 775), ovarian (n = 516), pancreatic (n = 952), and upper gastrointestinal tract (n = 1,065) cancers and non-Hodgkin lymphoma (n = 1,353) diagnosed in the participating cohorts. At least 1 control was matched to each case on age, date of blood collection (1974-2006), sex, and race/ethnicity (n = 6,714). Covariate data were obtained from each cohort in a standardized manner. The majority of the serum or plasma samples were assayed in a central laboratory using a direct, competitive chemiluminescence immunoassay on the DiaSorin LIAISON platform (DiaSorin, Inc., Stillwater, Minnesota). Masked quality control samples included serum standards from the US National Institute of Standards and Technology. Conditional logistic regression analyses were conducted using clinically defined cutpoints, with 50-<75 nmol/L as the reference category. Meta-analyses were also conducted using inverse-variance weights in random-effects models. This consortium approach permits estimation of the association between 25(OH)D and several rarer cancers with high accuracy and precision across a wide range of 25(OH)D concentrations.

A role for vitamin D in ovarian cancer etiology is supported by ecologic studies of sunlight exposure, experimental mechanism studies, and some studies of dietary vitamin D intake and genetic polymorphisms in the vitamin D receptor. However, few studies have examined the association of circulating 25-hydroxyvitamin D (25(OH)D), an integrated measure of vitamin D status, with ovarian cancer risk. A nested case-control study was conducted among 7 prospective studies to evaluate the circulating 25(OH)D concentration in relation to epithelial ovarian cancer risk. Logistic regression models were used to estimate odds ratios and 95% confidence intervals among 516 cases and 770 matched controls. Compared with 25(OH)D concentrations of 50-<75 nmol/L, no statistically significant associations were observed for <37.5 (odds ratio (OR) = 1.21, 95% confidence interval (CI): 0.87, 1.70), 37.5-<50 (OR = 1.03, 95% CI: 0.75, 1.41), or > or =75 (OR = 1.11, 95% CI: 0.79, 1.55) nmol/L. Analyses stratified by tumor subtype, age, body mass index, and other variables were generally null but suggested an inverse association between 25(OH)D and ovarian cancer risk among women with a body mass index of > or =25 kg/m(2) (P(interaction) < 0.01). In conclusion, this large pooled analysis did not support an overall association between circulating 25(OH)D and ovarian cancer risk, except possibly among overweight women.

A nested case-control study, including 830 cases and 992 controls from 7 cohorts, was conducted to evaluate the association of circulating 25-hydroxyvitamin D (25(OH)D), the best indicator of vitamin D status, with risk of endometrial cancer. Matching factors included age at blood donation, date of blood donation, and race. Conditional logistic regression was used in the main analysis. The median concentration of 25(OH)D was slightly lower in cases (49.4 nmol/L) than in controls (50.8 nmol/L) (P = 0.08). However, there was no association between 25(OH)D concentration and disease risk, after adjustment for body mass index. Compared with the 50-<75 nmol/L 25(OH)D category, the body mass index-adjusted odds ratios and 95% confidence intervals were 1.08 (95% confidence interval: 0.73, 1.57) for the <25 nmol/L category and 0.90 (95% confidence interval: 0.51, 1.58) for the > or =100 nmol/L category (P(trend) = 0.99). Similarly null results were observed after further adjustment for other known risk factors and in stratified analyses. Although an effect of circulating 25(OH)D at high concentrations cannot be ruled out (the highest category of 25(OH)D was > or =100 nmol/L, and for stratified analyses, > or =75 nmol/L), these results do not support a protective role of vitamin D against endometrial cancer.

Case-control studies generally suggesting an inverse association between sun exposure and non-Hodgkin lymphoma (NHL) have led to speculation that vitamin D may protect against lymphomagenesis. To examine this hypothesis, the authors conducted a pooled investigation of circulating 25-hydroxyvitamin D (25(OH)D) and subsequent NHL risk within 10 cohorts participating in the Cohort Consortium Vitamin D Pooling Project of Rarer Cancers. The authors analyzed measurements from 1,353 cases and 1,778 controls using conditional logistic regression and other methods to estimate the association of 25(OH)D with NHL. No clear evidence of association between categories of 25(OH)D concentration and NHL was observed overall (P(trend) = 0.68) or by sex (men, P(trend) = 0.50; women, P(trend) = 0.16). Findings for other measures (continuous log(25(OH)D), categories of 25(OH)D using sex-/cohort-/season-specific quartiles as cutpoints, categories of season-adjusted residuals of predicted 25(OH)D using quartiles as cutpoints) were generally null, although some measures of increasing 25(OH)D were suggestive of an increased risk for women. Results from stratified analyses and investigations of histologic subtypes of NHL were also null. These findings do not support the hypothesis that elevated circulating 25(OH)D concentration is associated with a reduced risk of NHL. Future research investigating the biologic basis for the sunlight-NHL association should consider alternative mechanisms, such as immunologic effects.

Although the kidney is a major organ for vitamin D metabolism, activity, and calcium-related homeostasis, little is known about whether this nutrient plays a role in the development or the inhibition of kidney cancer. To address this gap in knowledge, the authors examined the association between circulating 25-hydroxyvitamin D (25(OH)D) and kidney cancer within a large, nested case-control study developed as part of the Cohort Consortium Vitamin D Pooling Project of Rarer Cancers. Concentrations of 25(OH)D were measured from 775 kidney cancer cases and 775 age-, sex-, race-, and season-matched controls from 8 prospective cohort studies. Overall, neither low nor high concentrations of circulating 25(OH)D were significantly associated with kidney cancer risk. Although the data showed a statistically significant decreased risk for females (odds ratio = 0.31, 95% confidence interval: 0.12, 0.85) with 25(OH)D concentrations of > or =75 nmol/L, the linear trend was not statistically significant and the number of cases in this category was small (n = 14). The findings from this consortium-based study do not support the hypothesis that vitamin D is inversely associated with the risk of kidney cancer overall or with renal cell carcinoma specifically.

The Cohort Consortium Vitamin D Pooling Project of Rarer Cancers (VDPP) brought together 10 cohorts to conduct a prospective study of the association between vitamin D status, measured as serum concentrations of 25-hydroxyvitamin D (25(OH)D), and the development of 7 rarer cancer sites: endometrial, esophageal, gastric, kidney, non-Hodgkin lymphoma, ovarian, and pancreatic cancers. The cohorts come from 3 continents, with participants from a wide range of latitude who are racially diverse. Across each cancer site, there was no evidence of a protective association between higher concentrations of 25-hydroxyvitamin D (>75 nmol/L) and cancer outcome. An increased risk at very high levels (> or =100 nmol/L) was noted for pancreatic cancer, confirming previous reports. The articles included in this issue detail the overall design and governance of the project, correlates of vitamin D status, and results from the cancer site-specific investigations. The Vitamin D Pooling Project realizes a major goal of consortium efforts, namely, to rigorously test hypotheses for rarer cancer outcomes that may not be adequately addressed in any one prospective cohort study. The results of this study have application for the planning and conduct of intervention trials, especially in determining potential risks.

Upper gastrointestinal (GI) cancers of the stomach and esophagus have high incidence and mortality worldwide, but they are uncommon in Western countries. Little information exists on the association between vitamin D and risk of upper GI cancers. This study examined the association between circulating 25-hydroxyvitamin D (25(OH)D) and upper GI cancer risk in the Cohort Consortium Vitamin D Pooling Project of Rarer Cancers. Concentrations of 25(OH)D were measured from 1,065 upper GI cancer cases and 1,066 age-, sex-, race-, and season-of blood draw-matched controls from 8 prospective cohort studies. In multivariate-adjusted models, circulating 25(OH)D concentration was not significantly associated with upper GI cancer risk. Subgroup analysis by race showed that among Asians, but not Caucasians, lower concentrations of 25(OH)D (<25 nmol/L) were associated with a statistically significant decreased risk of upper GI cancer (reference: 50-<75 nmol/L) (odds ratio = 0.53, 95% confidence interval: 0.31, 0.91; P trend = 0.003). Never smokers with concentrations of <25 nmol/L showed a lower risk of upper GI cancers (odds ratio = 0.55, 95% confidence interval: 0.31, 0.96). Subgroup analyses by alcohol consumption produced opposing trends. Results do not support the hypothesis that interventions aimed at increasing vitamin D status would lead to a lower risk of these highly fatal cancers.

Results from epidemiologic studies examining pancreatic cancer risk and vitamin D intake or 25-hydroxyvitamin D (25(OH)D) concentrations (the best indicator of vitamin D derived from diet and sun) have been inconsistent. Therefore, the authors conducted a pooled nested case-control study of participants from 8 cohorts within the Cohort Consortium Vitamin D Pooling Project of Rarer Cancers (VDPP) (1974-2006) to evaluate whether prediagnostic circulating 25(OH)D concentrations were associated with the development of pancreatic cancer. In total, 952 incident pancreatic adenocarcinoma cases occurred among participants (median follow-up, 6.5 years). Controls (n = 1,333) were matched to each case by cohort, age, sex, race/ethnicity, date of blood draw, and follow-up time. Conditional logistic regression analysis was used to calculate smoking-, body mass index-, and diabetes-adjusted odds ratios and 95% confidence intervals for pancreatic cancer. Clinically relevant 25(OH)D cutpoints were compared with a referent category of 50-<75 nmol/L. No significant associations were observed for participants with lower 25(OH)D status. However, a high 25(OH)D concentration (> or =100 nmol/L) was associated with a statistically significant 2-fold increase in pancreatic cancer risk overall (odds ratio = 2.12, 95% confidence interval: 1.23, 3.64). Given this result, recommendations to increase vitamin D concentrations in healthy persons for the prevention of cancer should be carefully considered.

A letter to the editor is presented in response to an article about the Vitamin D Pooling Project of Rarer Cancers (VDPP).