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Vitamin D insufficiency in a multiethnic cohort of breast cancer survivors^1,2,3

¹ From the Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, WA (MLN, BS, CMU, and AM); the Department of Pediatrics, Medical University of South Carolina, Charleston, SC (BWH); the Applied Research Program, Division of Cancer Control and Population Sciences, National Cancer Institute, Bethesda, MD (AA and RB-B); the Department of Preventive Medicine and Norris the Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA (LB and FG); the Division of Population Sciences, City of Hope Cancer National Medical Center, Duarte, CA (LB); the New Mexico Tumor Registry, University of New Mexico, Albuquerque, NM (SW); and the Department of Epidemiology and Population Health, School of Public Health and Information Sciences, University of Louisville, Louisville, KY (KB and RB)

² Supported by the National Cancer Institute (contracts N01-CN-75036-20, N01-CN-05228, N01-PC-67010/N01-PC-35139, N01-PC-67007/N01-PC-35138, and N01-PC-67009/N01-PC-35142) and the National Institutes of Health (training grant T32 CA09661). A portion of this work was conducted through the Clinical Research Center at the University of Washington and supported by the National Institutes of Health (grant M01-RR-00037). Data collection for the Women's Contraceptive and Reproductive Experiences Study (CARE) at the University of Southern California was supported by the National Institute of Child Health and Human Development (contract N01-HD-3-3175). Patient identification was supported in part by the California Department of Health Services (grant 050Q-8709-S1528).

³ Address reprint requests to ML Neuhouser, Cancer Prevention Program, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, M4-B402, PO Box 19024, Seattle, WA 98109-1024. E-mail: mneuhous{at}fhcrc.org.

	ABSTRACT

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Background:Little is known about vitamin D status in breast cancer survivors. This issue is important because vitamin D influences pathways related to carcinogenesis.

Objective:The objective of this report was to describe and understand vitamin D status in a breast cancer survivor cohort.

Design:Data are from the Health, Eating, Activity, and Lifestyle study. With the use of a cross-sectional design, we examined serum concentrations of 25-hydroxyvitamin D [25(OH)D] in 790 breast cancer survivors from western Washington state, New Mexico, and Los Angeles County. Cancer treatment data were obtained from Surveillance, Epidemiology, and End Results registries and medical records. Fasting blood, anthropometry, and lifestyle habits were collected after diagnosis and treatment. We examined distributions of 25(OH)D by race-ethnicity, season, geography, and clinical characteristics. Multivariate regression tested associations between 25(OH)D and stage of disease.

Results:Five hundred ninety-seven (75.6%) of the women had low serum 25(OH)D, suggesting vitamin D insufficiency or frank deficiency. The overall mean (±SD) was 24.8 ± 10.4 ng/mL, but it was lower for African Americans (18.1 ± 8.7 ng/mL) and Hispanics (22.1 ± 9.2 ng/mL). Women with localized (n = 424) or regional (n = 182) breast cancer had lower serum 25(OH)D than did women with in situ disease (n = 184) (P = 0.05 and P = 0.03, respectively). Multivariate regression models controlled for age, body mass index (in kg/m²), race-ethnicity, geography, season, physical activity, diet, and cancer treatments showed that stage of disease independently predicted serum 25(OH)D (P = 0.02).

Conclusions:In these breast cancer survivors, the prevalence of vitamin D insufficiency was high. Clinicians might consider monitoring vitamin D status in breast cancer patients, together with appropriate treatments, if necessary.

	INTRODUCTION

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Vitamin D is an essential nutrient for humans and has been primarily recognized for its role in the prevention of bone diseases, such as vitamin D–related rickets, osteomalacia, and age-related fractures (1). More recently, carcinogenesis-related functions were identified for vitamin D, including cellular differentiation, T cell–mediated immunity, cell-cycle arrest, and apoptosis (2–5). The vitamin D receptor, which is activated by 1,25-dihydroxyvitamin D [1,25(OH)D], is found in nearly all tissues and organs in the human body and is responsible for the transcription of numerous genes related to cell-cycle control, apoptosis, and metastatic potential (6, 7). Thus, vitamin D is of considerable interest in relation to many cancers, including breast cancer. In addition to direct influences on the cell cycle and apoptosis, vitamin D may also exert its protective effect by influencing sex hormones and other crucial peptides (8–11). For example, although not completely understood, vitamin D analogues successfully inhibit the growth of mammary tumors (9, 11), and an estrogen-independent mechanism exists whereby vitamin D may reduce the proliferative effects of insulin-like growth factor I, which is a potent mitogen (8, 12, 13). One animal model has shown that a vitamin D analogue enhances the action of tamoxifen in mammary carcinoma (9).

Accumulating evidence from human observational studies suggests that both dietary and blood measures of vitamin D are inversely associated with incident breast cancer risk (14–17). A pooled analysis of serum 25-hydroxyvitamin D [25(OH)D] across 2 case-control studies (701 cases and 724 controls in one study and 179 cases and controls in the other study) showed that the pooled odds ratio for breast cancer was 0.50 (P for trend < 0.001) for the highest compared with the lowest quintile of the biomarker (18). A comprehensive review evaluated publications on dietary and supplemental sources of vitamin D and related foods and nutrients, biomarkers of vitamin D, and genetic variation in the vitamin D receptor gene, all in relation to breast cancer risk (19). The review concluded that, despite some inconsistencies, increasing vitamin D concentrations were associated with decreasing breast cancer risk (19). Although these important findings have implications for primary breast cancer prevention, little is known about vitamin D status among breast cancer survivors. Understanding vitamin D status among cancer patients is critical because vitamin D influences important cellular events related to prognosis and survival (eg, apoptosis, cell-cycle regulation) (4, 6, 19). Here, we report on vitamin D status, assessed by circulating 25(OH)D concentrations, in a breast cancer survivor cohort. We also examine the relevance of breast cancer clinical characteristics and whether tamoxifen, which is used by many breast cancer patients, influences circulating concentrations of 25(OH)D (9, 20).

	SUBJECTS AND METHODS

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Study design, population, and recruitment
The Health, Eating, Activity, and Lifestyle (HEAL) study is a population-based, multicenter, multiethnic prospective cohort study of 1183 breast cancer patients that investigated whether weight, physical activity, diet, hormones, and other exposures affect breast cancer prognosis and survival. Details of the study design and procedures are published (21). Briefly, we used the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) registries in New Mexico, Los Angeles County (CA), and western Washington state for study recruitment. In New Mexico, we recruited 615 women, aged 18 y, diagnosed with in situ to stage IIIA breast cancer between July 1996 and March 1999. In Western Washington, we recruited 202 women, aged 40–64 y, diagnosed with in situ to stage IIIA breast cancer between September 1997 and September 1998. In Los Angeles County, we recruited 366 African American women with stage 0–IIIA primary breast cancer who had previously participated in the Los Angeles portion of the Women's Contraceptive and Reproductive Experiences study or who had participated in a parallel case-control study of in situ breast cancer. Thus, the Los Angeles participants were a subset of women diagnosed with breast cancer between May 1995 and May 1998, aged 35–64 y at diagnosis, English speaking, and born in the United States. Procedures were approved by the institutional review boards of the participating centers, in accord with an assurance filed with and approved by the US Department of Health and Human Services; all participants gave written informed consent.

The HEAL participants completed extensive interviews within their first year after diagnosis (on average 7.5 mo after diagnosis) and 24 mo later (within their third year after diagnosis; on average 31.5 mo after diagnosis). Of the 1223 women initially enrolled in the study at baseline, 39 (3.2%) were later found to have had a prior breast cancer diagnosis (suggesting that the current diagnosis was either a recurrence or a second primary tumor) and 1 woman (<1.0%) was found to have metastatic disease at initial diagnosis. Because the women with recurrent or metastatic disease no longer met the HEAL eligibility criteria, they were subsequently excluded. Of the remaining 1183 women, 239 (20.2%) women did not return for the 24-mo visit. Reasons for not participating were death (n = 44), illness (n = 2), refusal (n = 105), moved (n = 16), and unable to contact or locate (n = 72). Nine hundred forty-four women completed the 24-mo follow-up questionnaires, which included detailed questions on health, menopausal status, diet, physical activity, and alcohol and tobacco use. Staff members also measured height and weight and collected a fasting blood specimen from all participants. We used the data and specimens collected at the 24-mo interview for this report, but we excluded those participants with no archived blood specimen (n = 790 available for analysis).

Breast cancer stage of disease and cancer treatment
Data on breast cancer stage of disease at diagnosis were obtained from the SEER registries. Participants were classified as having in situ, stage I, or stage II–IIIA breast cancer based on American Joint Committee on Cancer stage of disease classification. Treatment data were obtained during a review of medical records that provided more detailed information on chemotherapy, radiation, and hormonal therapy than that maintained by the registries. Adjuvant treatment was categorized into 4 mutually exclusive groups: 1) surgery only, 2) surgery and radiation, 3) surgery and chemotherapy, and 4) radiation and chemotherapy. Tamoxifen use was defined as self-reported current use at the 24-mo interview and blood draw.

Blood collection and 25(OH)D analysis
Fasting blood specimens were processed within 3 h of collection and stored at –70 to –80 °C until analysis. The biologically active form of vitamin D is 1,25(OH)D, but it is not a good biomarker because of its short half-life and tight homeostatic control (1, 22). Serum 25(OH)D is an excellent biomarker of vitamin D status, representing both cutaneous synthesis and dietary intake (1, 22). Serum 25(OH)D was assayed with the use of a radioimmunoabsorbant assay (DiaSorin Inc, Sillwater, MN). We included blinded duplicates in each assay, and the within- and between-assay CV was 3.7%.

Dietary assessment
Diet was assessed with the use of a validated self-administered food-frequency questionnaire that was designed for use in multiethnic postmenopausal women (23) This food-frequency questionnaire included 122 line items, 19 adjustment questions, and 4 summary questions. The database used to convert food information into nutrients is derived from the University of Minnesota's Nutrition Data Systems for Research (NDS-R, version 2005) and includes recent analytic food values for vitamin D. Information on vitamin D–containing dietary supplements was obtained by 1) close-ended questions on the use of specific single supplements, including vitamin D and 2) open-ended questions (New Mexico and Washington only) on the use of any other dietary supplements used at least weekly. We defined vitamin D–containing supplements as either single supplements or combination supplements (eg, vitamin D and calcium–type mixtures). Multivitamins were not included because we had no information on specific brands or formulations. However, because a high proportion of women reported use of multivitamins (72.9%), additional adjustments would not likely provide meaningful information.

Anthropometry
Participants wore light clothing without shoes, and weight was measured to the nearest 0.1 kg with the use of a balance-beam laboratory scale (New Mexico and Washington) or portable scale (Los Angeles). Height was measured without shoes to the nearest 0.1 cm with the use of a stadiometer or measuring tape affixed to a wall. All measurements were performed and recorded twice, then averaged for a final value. Body mass index (BMI; in kg/m²) was computed. We used the World Health Organization–National Institutes of Health categorizations of normal weight and obesity based on BMI: normal, <25.0; overweight, 25.0–29.9; and obese, 30.0 (24).

Other data
Standardized information was collected on medical history, family history of breast and other cancers, smoking, physical activity, and demographic data. Geographic locale serves as a surrogate of ultraviolet B (UV-B) exposure because both latitude and altitude influence UV-B exposure (1, 25).

Statistical analysis
We used descriptive statistics to characterize the study sample and to examine the distributions of serum concentrations of 25(OH)D by race-ethnicity, geography, and season. Multivariate linear regression determined the breast cancer clinical characteristics that independently predicted serum 25(OH)D after adjustment for other variables. Covariates included in the models were selected from known or suspected a priori predictors of vitamin D from the published literature, such as BMI and physical activity (22, 26, 27). Variables were only retained in the multivariate models if the effect of the variable changed the serum 25(OH)D by >10% (a standard analytic approach). Variables that were examined, but not retained in the final models, included smoking, menopausal status, and alcohol intake. Because those variables were neither statistically significant nor influential on the outcome of interest, they were not retained in the model. All analyses were completed with SAS (version 9.1; SAS Institute Inc, Cary, NC).

Standard clinical cutoffs of serum 25(OH)D concentrations were used to define frank deficiency (<10 ng/mL), insufficiency (10 to <32 ng/mL), and sufficiency (32 ng/mL) (1, 22, 28). Season was classified as winter (December–February), spring (March–May), summer (June–August), or fall (September–November).

	RESULTS

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Demographic and breast cancer clinical characteristics of the 790 HEAL participants are presented in Table 1. The mean age was 57.3 y, and 62.3% were overweight (BMI: 25.0–29.0) or obese (BMI 30). More than half (59.4%) of the participants were non-Hispanic white, 26.5% were African American, and 11.4% were Hispanic. Participants were well educated (73.7% with at least some college); 11.9% were smokers. No differences were observed in age or smoking status between participants who did complete the 24-mo interview and those who did not. However, differences were observed between participants who did return for the 24-mo interview than those who did not with regard to the proportion of patients from Los Angeles (African American), income, and education (P < 0.001) (data not shown).

Few of these breast cancer survivors had serum 25(OH)D considered optimal for health (Figure 1) (1, 22), and concentrations differed across racial-ethnic groups by geography but less so by season. The mean concentration of 25(OH)D for African American women in Los Angeles (n = 208) was 18.1 ng/mL with little seasonal variation. For Hispanic women in New Mexico (n = 88), the mean was 22.1 ng/mL but ranged from 18.8 ng/mL in winter and spring to 27.0 ng/mL in summer and fall. The mean concentration of 25(OH)D for all non-Hispanic white women was 28.4 ng/mL and ranged from 27.0 to 32.7 ng/mL across the seasons for women in New Mexico, whereas in Washington the low to high range was 23.6 ng/mL for summer and 25.8 ng/mL for autumn. Forty-nine women (6.2%) had frank 25(OH)D deficiency (<10.0 ng/mL) and 548 women (69.4%) had insufficient serum 25(OH)D (10–32 ng/mL) (data not shown).

View larger version (19K): [in this window] [in a new window]   FIGURE 1. Vitamin D [25(OH)D] sufficiency, insufficiency, and frank deficiency by race-ethnicity, geography, and season in a cohort of breast cancer survivors. One African American and 2 Hispanics at the Seattle site are not included because numbers would be too small for meaningful display by geographic locale. FHCRC, Fred Hutchinson Cancer Research Center, Seattle, WA; UNM, University of New Mexico, Albuquerque, NM; USC, University of Southern California, Los Angeles, CA.

Table 2

Table 3

Table 4

	DISCUSSION

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The women in the HEAL study with local or regional stage breast cancer had significantly lower circulating concentrations of 25(OH)D than did the women with in situ disease. One explanation is that, if a woman was vitamin D deficient before the diagnosis, the deficiency could have reduced the ability of vitamin D to suppress proliferation and metastasis. Under this scenario, early noninvasive lesions could possibly advance in the presence of a vitamin D deficiency. This mechanism is supported by in vitro (35) and experimental animal (36) studies. However, we are unable to directly test this mechanism in the HEAL study because enrollment in this survivor cohort occurred after diagnosis. It is also possible that women with more advanced disease experience greater fatigue and malaise, which could limit outdoor physical activity and sun exposure, thus lowering serum 25(OH)D. Similarly, patients with more advanced disease may have poor dietary intake secondary to chemotherapy-related emesis. However, because this study assayed blood specimens collected, on average, 31.5 mo after diagnosis, it is unlikely that active treatment-related side effects influenced these results. In addition, the parameter estimates for treatment in Table 4 were not statistically significant (P > 0.05 for all treatments), suggesting that completed treatment itself is not as influential as is stage of disease at diagnosis. The possibility that stage of disease is independently associated with 25(OH)D deserves further investigation, particularly if serum 25(OH)D is confirmed as a reliable prognostic indicator for breast cancer, as was suggested for other cancers (30, 32).

Our findings suggested that results differed slightly according to patient use of tamoxifen. We are aware of only one animal model study showing that a vitamin D analogue enhanced the efficacy of tamoxifen in a mammary cancer model. The vitamin D analogue plus tamoxifen was 10–100 times more effective than the analogue alone (9).

Vitamin D therapy could be a useful, cost-effective treatment for breast cancer patients. Giovannucci et al (32) predicted that every increase of 25 nmol/L (10 ng/mL) in serum 25(OH)D was associated with a 29% reduction in the total cancer mortality in men. An increase in serum 25(OH)D of this magnitude (10 ng/mL) can be achieved through dietary supplements or modest sun exposure (22, 28). Scientists and clinicians are currently considering how improvements in vitamin D status might enhance survivorship from colon, prostate, and other cancers (37, 38). Our results suggest that breast cancer might be included in these discussions.

There are several strengths to this investigation. The HEAL study is a population-based prospective cohort study that includes breast cancer patients across varied race-ethnic groups and geographic locations. Because we conducted a medical records review, we have more detailed data on medical and hormonal treatments for breast cancer than would be obtained through the SEER registries alone or by self-report. We used standardized questions on diet and lifestyle factors and used measured height and weight. Our primary assessment of vitamin D status was a reliable biomarker, serum 25(OH)D, and the laboratory CVs from blinded duplicate samples was excellent (3.7%). Vitamin D metabolites are stable for long periods of time at –80 °C and are unaffected by freeze-thaw cycles (39, 40). Although the blood specimens were drawn 24 mo after enrollment, breast cancer treatments (other than tamoxifen) were completed by the blood draw date, so confounding by treatment should be minimized.

There are also limitations. First, although the HEAL study included African American and Hispanic women, the study sample was still mostly non-Hispanic white women. Second, we did not collect data on sun exposure, sunscreen use, or time spent out of doors, so we are unable to assess UV-B exposure; instead, geographic location is a proxy for sunlight exposure (1, 25, 41). Third, we had missing ER status on approximately one-third of the HEAL study participants, so we had insufficient statistical power to test whether these tumor characteristics were associated with vitamin D status. Further, there are limitations to assessing dietary vitamin D because of the limited food sources, as well as to overall limitations in self-reported diet (42). Finally, because we only had blood specimens collected after breast cancer diagnosis, we were unable to definitively establish the temporal relation between vitamin D status and any clinical characteristics of breast cancer.

In conclusion, in this multiethnic cohort of breast cancer survivors, most women had low serum concentrations of 25(OH)D, the primary biomarker used to assess vitamin D status. Although insufficient vitamin D status is a concern in the general US population (43, 44), particularly among the elderly (45) and African Americans (43, 46), the findings from this study show that breast cancer survivors may be at particular risk of vitamin D deficiency. It is unknown whether vitamin D status predicts prognosis; further investigations are needed to examine this critical issue. In the meantime, clinicians may want to consider testing their breast cancer patients for serum 25(OH)D and to offer appropriate recommendations, if necessary, to improve vitamin D status.

	ACKNOWLEDGMENTS

 
The authors' responsibilities were as follows—MLN: designed the study and analyzed and drafted the manuscript; BS: was the study statistician and conducted all statistical analyses; BWH: conducted the 25(OH)D assays and contributed to the interpretation of results and manuscript writing; AA, AM, LB, FG, KB, and RB: secured funding, recruited participants, and collected data; SW and CMU: contributed to the drafting of the manuscript; RB-B: provided overall leadership to the HEAL study, including securing of funding and participation in all decisions related to analyses and manuscript preparation; all authors contributed to the interpretation of results and to the writing of the manuscript and reviewed and accepted the final version. None of the authors had a personal or financial conflict of interest.

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