Prediagnostic 25-hydroxyvitamin Research Articles

Prediagnostic 25-Hydroxyvitamin D in Association with Cancer-specific and All-cause Mortality among Low-income, Non-Hispanic Black Americans with Colorectal Cancer.

Observational studies show high prediagnosis 25-hydroxyvitamin D is associated with lower mortality after colorectal cancer diagnosis. Results from clinical trials suggest vitamin D supplementation may improve outcomes among patients with colorectal cancer. Most studies included few Black Americans, who typically have lower 25-hydroxyvitamin D. We evaluated associations between serum 25-hydroxyvitamin D and mortality after colorectal cancer diagnosis among Black American cases. Data arose from 218 Black Americans from the Southern Community Cohort Study diagnosed with colorectal cancer during follow-up (age 40-79 at enrollment). Prediagnostic 25-hydroxyvitamin D was measured at enrollment and categorized as deficient (<12 ng/mL), insufficient (12-19.9 ng/mL), or sufficient (≥20 ng/mL). Mortality was determined from the National Death Index. Cox proportional hazards were used to estimate HRs and 95% confidence intervals (CI) for associations between 25-hydroxyvitamin D and mortality. As a continuous exposure, higher 25-hydroxyvitamin D was associated with overall mortality [HR = 0.79 (0.65-0.96) per-SD increase, Ptrend = 0.02] and colorectal cancer-specific mortality [HR = 0.83 (0.64-1.08), Ptrend = 0.16]. For overall mortality, associations were strongest among females [HR = 0.65 (0.42-0.92)], current smokers [HR = 0.61 (0.38-0.98)], and obese participants [HR = 0.47 (0.29-0.77)]. Compared with those with deficiency, participants with sufficient 25-hydroxyvitamin D had lower overall mortality after multivariable adjustment [HR: 0.61 (0.37-1.01)]. Prediagnosis 25-hydroxyvitamin D is inversely associated with overall and colorectal cancer-specific mortality among Black Americans with colorectal cancer. Correcting vitamin D deficiency may improve survival of these patients, particularly for obese individuals and smokers. Our results support including more Black Americans in trials of vitamin D supplementations to improve colorectal cancer outcomes.

Prediagnostic 25-Hydroxyvitamin D Concentrations in Relation to Tumor Molecular Alterations and Risk of Breast Cancer Recurrence.

Although vitamin D inhibits breast tumor growth in experimental settings, the findings from population-based studies remain inconclusive. Our goals were to investigate the association between prediagnostic plasma 25-hydroxyvitamin D [25(OH)D] concentration and breast cancer recurrence in prospective epidemiologic studies and to explore the molecular underpinnings linking 25(OH)D to slower progression of breast cancer in the Nurses' Health Studies (NHS, N = 659). Plasma 25(OH)D was measured with a high-affinity protein-binding assay and a radioimmunoassay. We profiled transcriptome-wide gene expression in breast tumors using microarrays. Hazard ratios (HR) of breast cancer recurrence were estimated from covariate-adjusted Cox regressions. We examined differential gene expression in association with 25(OH)D and employed pathway analysis. We derived a gene expression score for 25(OH)D, and assessed associations between the score and cancer recurrence. Although 25(OH)D was not associated with breast cancer recurrence overall [HR = 0.97; 95% confidence interval (CI), 0.88-1.08], the association varied by estrogen-receptor (ER) status (P interaction = 0.005). Importantly, among ER-positive stage I to III cancers, every 5 ng/mL increase in 25(OH)D was associated with a 13% lower risk of recurrence (HR = 0.87; 95% CI, 0.76-0.99). A null association was observed for ER-negative cancers (HR = 1.07; 95% CI, 0.91-1.27). Pathway analysis identified multiple gene sets that were significantly (FDR < 5%) downregulated in ER-positive tumors of women with high 25(OH)D (≥30 ng/mL), compared with those with low levels (<30 ng/mL). These gene sets are primarily involved in tumor proliferation, migration, and inflammation. 25(OH)D score derived from these gene sets was marginally associated with reduced risk of recurrence in ER-positive diseases (HR = 0.77; 95% CI, 0.59-1.01) in the NHS studies; however no association was noted in METABRIC, suggesting that further refinement is need to improve the generalizability of the score. Our findings support an intriguing line of research for studies to better understand the mechanisms underlying the role of vitamin D in breast tumor progression, particularly for the ER-positive subtype. Vitamin D may present a personal-level secondary-prevention strategy for ER-positive breast cancer.

Abstract A85: Prediagnostic 25-hydroxyvitamin D concentrations in relation to tumor molecular alterations and risk of breast cancer recurrence

Abstract Although vitamin D inhibits breast tumor growth and development in experimental settings, the findings from population-based studies remain inconclusive. Our goals were to investigate the association between prediagnostic plasma 25-hydroxyvitamin D [25(OH)D] concentration and breast cancer recurrence in prospective epidemiologic studies and to explore the molecular underpinnings linking 25(OH)D to slower progression of breast cancer. Our study included 659 women with invasive breast cancer from the Nurses’ Health Studies (NHS) diagnosed from 1989 to 2010. Plasma 25(OH)D was measured with a high-affinity protein binding assay or a radioimmunoassay. We profiled transcriptome-wide gene expression in breast tumors using microarrays. Hazard ratios (HRs) of breast cancer recurrence were estimated from covariate-adjusted Cox proportional hazards models. We examined differential gene expression regulation in association with 25(OH)D with covariate-adjusted linear regression and employed pathway analysis. We derived a gene expression score for 25(OH)D, and further assessed associations between the standardized score and breast cancer recurrence. Although 25(OH)D was not associated with breast cancer recurrence overall (hazard ratio (HR)=0.96; 95% confidence interval (CI): 0.86, 1.08) (median follow-up=12.8 years), the association varied by estrogen receptor (ER) status (p for interaction=0.005). Importantly, among ER-positive stage I to III cancers, every 5 ng/ml increase in prediagnostic plasma 25(OH)D was associated with a 13% lowered risk of recurrence (HR=0.87; 95% CI: 0.76; 0.99). No association was observed in women with stage I to III ER-negative cancers (HR=1.07; 95% CI: 0.91; 1.27). Pathway analysis identified multiple gene sets that were significantly (FDR&amp;lt;5%) downregulated in ER-positive breast tumors of women with high prediagnostic 25(OH)D (≥30 ng/ml), compared to those with low levels (&amp;lt;30 ng/ml). These gene sets are primarily involved in tumor proliferation, apoptosis, migration and invasion, inflammation, and cancer cell metabolism. The standardized score of 25(OH)D signatures derived from these gene sets was marginally significantly associated with reduced risk of recurrence in ER-positive diseases (HR=0.77; 95% CI: 0.59, 1.01). Using TIMER, a mathematical algorithm to deconvolute tumor cellular heterogeneity, we found more infiltrated CD8+ T cells in ER-negative tumors as compared to ER-positive tumors, and this higher immune infiltration in ER-negative tumors may contribute to the observed heterogeneous response. Our findings support an intriguing line of research for future studies to better understand the biologic mechanisms underlying the role of vitamin D in breast tumor progression, particularly for the ER-positive subtype. Citation Format: Yujing Heng, Donghao Lu, Natalie DuPre, Kimberly Glass, Peter Kraft, David Feldman, Susan Hankinson, Kathryn Rexrode, Heather Eliassen, Rulla Tamimi, Cheng Peng. Prediagnostic 25-hydroxyvitamin D concentrations in relation to tumor molecular alterations and risk of breast cancer recurrence [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr A85.

Highlights of This Issue

Urban–rural disparities in treatment are often attributed to the longer distances rural patients must travel to receive care. However, recent evidence suggests that distance to care has a differential effect on urban and rural patients. Spees and colleagues examined the influence of distance on the timely treatment initiation and completion in women with cervical cancer. In urban areas, living further away from care was associated with a lower likelihood of initiating treatment. However, rural women with advanced cervical cancer residing farther from care were more likely to complete timely treatment. Distance was not associated with timely treatment completion among urban women. Distance is an access barrier for cervical cancer patients in urban areas whereas rural patients may require more intensive support, even among those living closer to treatment.The role of vitamin D in cancer risk is contentious and data on associations with tumor subtypes are limited. Heath and colleagues investigated the association between prediagnostic 25-hydroxyvitamin D (25(OH)D) concentration and risk of incident colorectal, breast, and prostate cancers and subtypes of these cancers in a cohort of middle-aged Australians. Circulating 25(OH)D was not associated with risk of breast cancer or prostate cancer, whereas higher 25(OH)D was associated with a lower risk of colorectal cancer in women and BRAF V600E-mutant colorectal cancer. Vitamin D might be important for preventing some colorectal cancer in women and specifically BRAF-mutant tumors.Ascha and colleagues describe incidence proportions (IP) of both synchronous (SBM) and lifetime brain metastases (LBM) for primary lung, breast, and skin cancers, validating their Medicare-derived estimates of lifetime incidence by comparison with cancer registry data. The SBM IP was highest in lung (specifically for non–small cell lung cancer) followed by breast and melanoma cancers; the LBM IP was also highest in lung (specifically for small-cell lung cancer), followed by breast and melanoma cancers. Large population-based datasets such as SEER-Medicare allow for accurate estimates of both SBM and LBM for an elderly U.S. population.Palazzo and colleagues analyzed cancer registry data to identify patient factors associated with the utilization of genetic testing and treatment with erlotinib, a targeted therapy drug for metastatic non–small cell lung cancer, and to examine how these associations changed over time. Patient age was found to be associated with genetic testing; race, gender, and income level were associated with erlotinib treatment. Some of these disparities decreased in magnitude over time, while others remained stable or grew. This study highlights the need to reduce disparities as precision cancer treatments continue to be developed.

Pre-diagnostic 25-hydroxyvitamin D levels and survival in cancer patients

Our main aim was to explore whether pre-diagnostic circulating levels of 25-hydroxyvitamin D (25(OH)D) among older individuals with cancer were associated with overall and cancer-specific survival after diagnosis. We used data from the Reykjavik-AGES Study on participants (n = 4,619) without cancer at entry, when blood samples were taken for 25(OH)D standardized measurements. The association with cancer risk, all-cause- and cancer-specific mortality was assessed among those later diagnosed with cancer, comparing four 25(OH)D categories, using 50-69.9nmol/L as the reference category. Cancer was diagnosed in 919 participants on average 8.3years after blood draw. No association was observed between the reference group and other 25(OH)D groups and total cancer incidence. Mean age at diagnosis was 80.9 (± 5.7)years. Of those diagnosed, 552 died during follow-up, 67% from cancer. Low pre-diagnostic levels of 25(OH)D < 30nmol/L were significantly associated with increased total mortality (HR: 1.39, 95% CI 1.03, 1.88) and non-significantly with cancer-specific mortality (HR: 1.33, 95% CI 0.93, 1.90). Among patients surviving more than 2years after diagnosis, higher pre-diagnostic 25(OH)D levels (≥ 70nmol/L) were associated with lower risk of overall (HR: 0.68, 95% CI 0.46, 0.99) and cancer-specific mortality (HR: 0.47, 95% CI 0.26, 0.99). Among elderly cancer patients, low pre-diagnostic serum 25(OH)D levels (< 30nmol/L) were associated with increased overall mortality.

Vitamin D–Related Genetic Variation, Plasma Vitamin D, and Risk of Lethal Prostate Cancer: A Prospective Nested Case–Control Study

The association of vitamin D status with prostate cancer is controversial; no association has been observed for overall incidence, but there is a potential link with lethal disease. We assessed prediagnostic 25-hydroxyvitamin D [25(OH)D] levels in plasma, variation in vitamin D-related genes, and risk of lethal prostate cancer using a prospective case-control study nested within the Health Professionals Follow-up Study. We included 1260 men who were diagnosed with prostate cancer after providing a blood sample in 1993-1995 and 1331 control subjects. Men with prostate cancer were followed through March 2011 for lethal outcomes (n = 114). We selected 97 single-nucleotide polymorphisms (SNPs) in genomic regions with high linkage disequilibrium (tagSNPs) to represent common genetic variation among seven vitamin D-related genes (CYP27A1, CYP2R1, CYP27B1, GC, CYP24A1, RXRA, and VDR). We used a logistic kernel machine test to assess whether multimarker SNP sets in seven vitamin D pathway-related genes were collectively associated with prostate cancer. Tests for statistical significance were two-sided. Higher 25(OH)D levels were associated with a 57% reduction in the risk of lethal prostate cancer (highest vs lowest quartile: odds ratio = 0.43, 95% confidence interval = 0.24 to 0.76). This finding did not vary by time from blood collection to diagnosis. We found no statistically significant association of plasma 25(OH)D levels with overall prostate cancer. Pathway analyses found that the set of SNPs that included all seven genes (P = .008) as well as sets of SNPs that included VDR (P = .01) and CYP27A1 (P = .02) were associated with risk of lethal prostate cancer. In this prospective study, plasma 25(OH)D levels and common variation among several vitamin D-related genes were associated with lethal prostate cancer risk, suggesting that vitamin D is relevant for lethal prostate cancer.

Prediagnostic 25-Hydroxyvitamin D,VDRandCASRPolymorphisms, and Survival in Patients with Colorectal Cancer in Western European Populations

Individuals with higher blood 25-hydroxyvitamin D [25(OH)D] levels have a lower risk of developing colorectal cancer (CRC), but the influence of 25(OH)D on mortality after CRC diagnosis is unknown. The association between prediagnostic 25(OH)D levels and CRC-specific (N = 444) and overall mortality (N = 541) was prospectively examined among 1,202 participants diagnosed with CRC between 1992 and 2003 in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Multivariable Cox proportional hazards models were used to calculate HRs and corresponding 95% CIs according to 25(OH)D quintiles and genetic variation within the VDR and CASR genes. Potential dietary, lifestyle, and metabolic effect modifiers were also investigated. There were 541 deaths, 444 (82%) due to CRC. Mean follow-up was 73 months. In multivariable analysis, higher 25(OH)D levels were associated with a statistically significant reduction in CRC-specific (P(trend) = 0.04) and overall mortality (P(trend) = 0.01). Participants with 25(OH)D levels in the highest quintile had an adjusted HR of 0.69 (95% CI: 0.50-0.93) for CRC-specific mortality and 0.67 (95% CI: 0.50-0.88) for overall mortality, compared with the lowest quintile. Except for a possible interaction by prediagnostic dietary calcium intake (P(interaction) = 0.01), no other potential modifying factors related to CRC survival were noted. The VDR (FokI and BsmI) and CASR (rs1801725) genotypes were not associated with survival. High prediagnostic 25(OH)D levels are associated with improved survival of patients with CRC. Our findings may stimulate further research directed at investigating the effects of blood vitamin D levels before, at, and after CRC diagnosis on outcomes in CRC patients.

Reduced Prediagnostic 25-Hydroxyvitamin D Levels in Women with Breast Cancer: A Nested Case-Control Study

Vitamin D status may affect risk of cancer. In a cross-sectional study with a nested case-control analysis, we determined whether risk of breast cancer is associated with prediagnostic plasma 25-hydroxyvitamin D (25OHD) levels and the effects of lifestyle characteristics known to influence vitamin D status on risk of breast cancer. We studied women without a prior history of breast cancer referred to a diagnostic mammography examination (n = 2,465). Cases were women diagnosed with an incident breast cancer (n = 142). Controls were women not diagnosed with a breast cancer matched to cases on age, menopausal status, and time of year of blood sampling (n = 420). Characteristics of cases and controls were assessed by a self-administrated questionnaire. Blood samples were collected prior to the diagnostic mammography examination. Cases had lower plasma 25OHD levels than controls. Compared with the lowest tertile of 25OHD levels, risk of breast cancer was significantly reduced among women in the highest tertile (relative risk, 0.52; 95% confidence interval, 0.32-0.85). Risk estimates were similar in women with an estrogen receptor-positive and estrogen receptor-negative breast cancer. Use of vitamin D supplements, sunbathing frequency, and fish intake was associated with 25OHD levels, but did not affect the risk of breast cancer. Accordingly, risk of breast cancer was inversely associated with 25OHD levels. Randomized controlled trials are warranted in order to assess whether a causal relationship exists.

Reduced pre-diagnostic 25-hydroxyvitamin D levels in women with breast cancer

Reduced pre-diagnostic 25-hydroxyvitamin D levels in women with breast cancer