Vitamin D intake and breast cancer risk: a case control study in Italy

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1 Annals of Oncology 20: , 2009 doi: /annonc/mdn550 Published online 18 August 2008 original article Vitamin D intake and breast cancer risk: a case control study in Italy M. Rossi 1 *, J. K. McLaughlin 2,5, P. Lagiou 3, C. Bosetti 1, R. Talamini 4, L. Lipworth 2,5, A. Giacosa 6, M. Montella 7, S. Franceschi 8, E. Negri 1 & C. La Vecchia 1,9 1 Department of Epidemiology, Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy; 2 Department of Epidemiology, International Epidemiology Institute, Rockville, USA; 3 Department of Hygiene and Epidemiology, University of Athens Medical School, Athens, Greece; 4 Department of Epidemiology, Centro di Riferimento Oncologico, Aviano, Italy; 5 Department of Medicine, Vanderbilt University Medical Center and Vanderbilt Ingram Cancer Center, Nashville, USA; 6 Department of Epidemiology, Policlinico di Monza, Monza; 7 Department of Epidemiology, Fondazione Pascale, Naples, Italy; 8 Department of Epidemiology and Biology, International Agency for Research on Cancer, Lyon Cedex, France; 9 Department of Epidemiology, Istituto di Statistica Medica e Biometria G. A. Maccacaro, Universita` degli Studi di Milano, Milan, Italy Received 30 October 2007; revised 5 May 2008; accepted 9 July 2008 Background: Vitamin D has been suggested to play a protective role against several cancers, including breast cancer. Patients and methods: We used data from a case control study conducted in Italy from 1991 to 1994 to study the relation between dietary intake of vitamin D and breast cancer risk. Subjects were 2569 women with incident, histologically confirmed breast cancer and 2588 hospital controls. Odds ratios (ORs) and 95% confidence intervals (CIs) according to deciles of vitamin D intake were estimated by multiple logistic regression models. Results: After allowance for major risk factors for breast cancer and dietary covariates including calcium and energy intake, there was no association with vitamin D up to the seventh decile. Thereafter, the OR declined, so that the overall trend was statistically significantly inverse. The OR for subjects in the three highest deciles of consumption compared with those in the lowest ones combined was 0.79 (95% CI ). Intake of vitamin D >3.57 lg or 143 IU appeared to have a protective effect against breast cancer. The inverse association was consistent across strata of menopausal status. Conclusions: This study adds to the existing evidence that vitamin D intake in inversely associated with breast cancer risk. Key words: breast cancer, case control study, risk factors, vitamin D introduction The hypothesis that vitamin D has a favorable effect on cancer risk was proposed in the early 1980s [1], but vitamin D started to be intensively studied in relation to cancer only in the 1990s [2]. Inverse associations have also been reported between vitamin D and risk of colorectal and prostate cancer, while the relations with other cancers have been less extensively studied [3]. With respect to breast cancer, at least four studies have considered serum or plasma vitamin D levels [4 7], with inconsistent results. Results from a pooled analysis of two studies reporting data on serum 25(OH)D and breast cancer, one from the UK [7] and one from the United States [6], indicated that subjects with serum 25(OH)D >50 ng/ml had a significant 50% lower risk of breast cancer compared with women having serum values <13 ng/ml [8]. *Correspondence to: Dr M. Rossi, Department of Epidemiology, Istituto di Ricerche Farmacologiche Mario Negri, Via G. La Masa 19, Milan, Italy. Tel: ; Fax: ; mrossi@marionegri.it At least six case control studies [9 14] and six cohort studies [15 20] have reported data on various measures of dietary or supplemental intake of vitamin D and breast cancer risk. Of these, eight studies reported relative risks (RRs) below unity (significant for three cohort studies [16, 19, 20] and one case control study [14]), two no association, and one a nonsignificant excess risk [11]. A randomized trial of supplemental calcium plus 1100 IU vitamin D 3, which included 1179 postmenopausal women, reported a RR of 0.5, of borderline significance, for cancer incidence overall after 4 years, but the number of breast cancer cases was small (15 in the placebo, nine in the calcium and vitamin D group), and subjects that received calcium only had a similar reduction in breast cancer risk as those receiving calcium plus vitamin D [21]. To provide further information on the issue, we considered data on dietary vitamin D and breast cancer risk from a large multicenter case control study in Italy. Findings on other micronutrients from the same dataset have been reported previously [22]. ª The Author Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please journals.permissions@oxfordjournals.org

2 Annals of Oncology original article patients and methods We conducted a multicentric case control study of breast cancer from June 1991 to April 1994 in six Italian areas: the provinces of Pordenone and Gorizia, the greater Milan area, the urban area of Genoa, the province of Forli, the province of Latina, and the urban area of Naples [23]. Cases were 2569 women with incident, histologically confirmed breast cancer (median age 55, range years) admitted to major teaching and general hospitals of the study areas. Controls were 2588 women (median age 56, range years) with no history of cancer admitted to the same hospitals for acute, non-neoplastic, nongynecological conditions, unrelated to hormonal or digestive tract diseases or to conditions linked to diet. Among controls, 22% had traumas, 33% other orthopedic diseases such as low back pain or strains, 15% acute surgical conditions, 18% eye diseases, and 12% other miscellaneous diseases. Less than 4% of cases and controls approached for interview did not consent to participate. Cases and controls were interviewed in the hospital by centrally trained interviewers, using a standard structured questionnaire. This included information on sociodemographic factors, anthropometric variables, lifestyle habits, including tobacco smoking and alcohol drinking, as well as obstetric, gynecologic, and general medical history. A reproducible and valid [24, 25] food frequency questionnaire (FFQ) was used to assess the patients usual diet in the previous 2 years. The questionnaire included 78 foods or food groups, plus questions aimed at assessing fat intake and general dietary habits. Subjects were asked to indicate their average weekly consumption of single food items or food groups. Intakes lower than once a week, but at least once per month, were coded as 0.5/week. To compute energy and nutrient intakes, including vitamin D intake, an Italian food composition database as well as information from additional sources were used [22, 26, 27]. Use of vitamin supplements was uncommon in the early 90s in this population [22]. Odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) were estimated by modeling the data through logistic regression [28]. A core model was used that included age (quinquennia, categorically), study center (categorically), years of education (<7, 7 11, 12, categorically), age at menarche (in years, continuously), parity (0, 1, 2, 3, orderly), menopausal status (post- versus pre/perimenopausal), combined vegetable and fruit consumption (quintiles, orderly), calcium, b-carotene, vitamin E, flavone, flavonol, and total energy intake (quintiles, orderly). Additional analyses were done separately for Southern/Northern Italy and pre/ perimenopausal women, adjusting also for body mass index (BMI) (quintiles, orderly) and oral contraceptive use (ever versus never use), as well as for postmenopausal women, adjusting also for BMI (quintiles, orderly), age at menopause (in years, continuously), and hormone replacement therapy (ever versus never). In order to provide more detailed analyses of the levels of vitamin D intake, vitamin D was entered in the models as deciles of intake (on the basis of case and control combined distribution) [29], or as a continuous variable, with the increment set at 1 standard deviation of the overall distribution. Tests for trends for deciles of vitamin D were on the basis of a likelihood ratio test between the models with and without a linear term for the vitamin D deciles. results Table 1 shows multiple logistic regression-derived ORs and corresponding 95% CIs for breast cancer according to intake (deciles) of vitamin D for three different models. In all models, no trend is noted up to the seventh decile. Thereafter, however, the OR declines, so that in models II and III, which generate more valid estimates for vitamin D intake in relation to breast cancer risk, the inverse trend over all deciles becomes statistically significant or borderline so. Since only intake of Table 1. Multiple logistic regression-derived OR and corresponding 95% CI for 2569 cases of breast cancer and 2588 controls, according to intake deciles of vitamin D (Italy, ) Continuous OR b Vitamin D Deciles of intake, a OR (95% CI) v 2 trend 1 c (P value) Upper cut points (lg) Cases Controls Model I d ( ) 1.06 ( ) 1.16 ( ) 1.37 ( ) 1.05 ( ) 1.37 ( ) 1.00 ( ) 0.97 ( ) 0.84 ( ) 1.50 (0.22) 0.95 ( ) Model II e ( ) 1.02 ( ) 1.07 ( ) 1.26 ( ) 0.94 ( ) 1.21 ( ) 0.87 ( ) 0.85 ( ) 0.70 ( ) 8.07 (0.005) 0.90 ( ) Model III f ( ) 1.02 ( ) 1.08 ( ) 1.26 ( ) 0.96 ( ) 1.27 ( ) 0.92 ( ) 0.91 ( ) 0.76 ( ) 3.67 (0.056) 0.92 ( ) a Deciles among cases and controls combined. b Estimated for an increment of intake equal to 1 standard deviation among cases and controls (=1.34 lg). c Reference category. d Adjusted for age, study center, and education. e Adjusted as in model I, controlling also for parity, age at menarche, menopausal status, and total energy intake. f Adjusted as in model II, controlling also for vegetable and fruit consumption, calcium, b-carotene, vitamin E, flavones, and flavonol intake. OR, odds ratio; CI, confidence interval. Volume 20 No. 2 February 2009 doi: /annonc/mdn

3 Annals of Oncology vitamin D after the seventh decile (>3.57 lg or 143 IU) appears to have a favourable effect against breast cancer, which is significant above the ninth decile (>4.76 lg or 188 IU), indicating a threshold effect, we have also computed the ORs for subjects in the three upper deciles of consumption compared with those in the seven lower ones combined. The ORs from models II and III were, respectively, 0.75 (95% CI ) and 0.79 (95% CI ). In Table 2, the relation between vitamin D and breast cancer risk is presented in strata of menopausal status (adjusting also for BMI and some reproductive factors, as appropriate) and geographical area of origin. The inverse association between vitamin D intake and breast cancer risk is apparently more evident among women from Southern Italy compared with women from the North. However, when vitamin D was assessed as a continuous variable for all women, the P value for the interaction of vitamin D and geographical area of origin was No substantial differences were observed across strata of menopausal status. In order to provide more stable estimates, we have also reported a comparison between deciles 8 10 combined and deciles 1 7 among these strata. The ORs were 0.80 (95% CI ) and 0.78 (95% CI ) among pre/peri- and postmenopausal women, respectively, and 0.82 (95% CI ) and 0.64 (95% CI ) among women from Northern and Southern Italy, respectively. discussion In this large multicenter case control study, dietary intake of vitamin D was inversely associated with breast cancer risk, after allowance for major recognized risk factors for breast cancer and several dietary covariates including energy intake. The inverse relation appeared to be restricted to the three highest deciles of vitamin D. The present study results support the existing evidence that increased levels of dietary intake of vitamin D are associated with decreased breast cancer risk [3, 8, 14, 30]. We collected information only on dietary sources of vitamin D. Our FFQ was tested for reproducibility [31] and validity [25]. Although at that time we had no information on vitamin D, the Pearson correlation coefficients for most micronutrients ranged between 0.6 and 0.7 for reproducibility and 0.4 and 0.5 for validity. The absence of data on supplement use is not a major problem, given the low frequency of supplement use by this Italian population in the early 90s [22]. Skin synthesis is, however, a major source of vitamin D [32]. Consequently, the absence of information on sun exposure or serum level of 25(OH)D is a limitation of the study. However, sun exposure is limited in winter, particularly among the elderly. In a study of plasma vitamin D and colorectal cancer risk, average UV sunlight exposure was less strongly correlated with 25(OH)D concentrations than vitamin D from nutrition and dietary sources [33]. Among the strengths of this study are the large dataset, the use of a reproducible and valid FFQ [24, 25], and the virtually complete participation of cases and controls. With reference to confounding, we were able to adjust for major recognized risk factors for breast cancer, and the study has generated results on other breast cancer risk factors that were consistent with earlier and subsequent investigations, providing assurance that major biases were not operating during implementation of the study. Allowance for intake of other micronutrients that were inversely associated with breast cancer in this dataset [22] did not change the association with vitamin D. The main dietary sources of vitamin D in this population were fish (55.0%), meat (23.5%), cheese (6.8%), and eggs (5.6%). Of these, fish was found to have an inverse association with breast cancer in our data, while some varieties of meat were positively associated [23]; no association was found with cheese and eggs. The inverse association between vitamin D and breast cancer was consistent among strata of menopausal status and geographical area of origin, although appeared more pronounced in Southern compared with Northern Italy. This could be due to chance given the low number of subjects from Southern Italy, and the absence of significant Table 2. Multiple logistic regression-derived OR a and corresponding 95% CI for 2569 cases of breast cancer and 2588 controls, according to intake deciles of vitamin D across strata of menopausal status and geographical area (Italy, ) Vitamin D Cases : Controls e Decile of intake, OR (95% CI) versus the lowest decile of intake b Continuous OR (95% CI) c Menopausal status Pre/perimenopause 987 : ( ) 0.85 ( ) 0.78 ( ) 0.95 ( ) Postmenopause 1579 : ( ) 0.94 ( ) 0.70 ( ) 0.91 ( ) Geographical area Northern 2024 : ( ) 1.08 ( ) 0.86 ( ) 0.93 ( ) d Southern 543 : ( ) 0.41 ( ) 0.36 ( ) 0.80 ( ) d a Adjusted for age, study center, education, parity, age at menarche, body mass index, oral contraceptive use (only pre/perimenopausal), age at menopause (only postmenopausal), hormone replacement therapy (only postmenopausal), vegetable and fruit consumption, calcium, b-carotene, vitamin E, flavone, flavonol, and total energy intake. b Deciles among cases and controls combined. c Estimated for an increment of intake equal to 1 standard deviation (1.34 lg). d v 2 1 for interaction = 2.05 (P value = 0.15). OR, odds ratio; CI, confidence interval. e Strata do not add up to the total because of missing values. 376 Rossi et al. Volume 20 No. 2 February 2009

4 Annals of Oncology heterogeneity. When the OR estimates were computed in the three upper deciles of consumption compared with those in the seven lowest ones combined, the difference was attenuated. Furthermore, the geographic area of residence (Northern versus Southern Italy) may not be an optimal surrogate for UV-B radiation exposure. A recent study in Australia reported a relatively high prevalence of vitamin D insufficiency in winter and spring across a wide range of latitudes and suggested that season may be more important than latitudes in predicting variation in 25(OH)D levels, although both accounted for less than one-fifth of the variation [34]. Several mechanisms of action of vitamin D on breast carcinogenesis have been suggested. The 25(OH)D can inhibit cell proliferation, induce differentiation and apoptosis, and reduce angiogenesis as suggested by in vitro and animal studies [3, 35 38]. It has also been reported that seasonal variation of 25(OH)D may also be related to changes in mammographic density, a recognized indicator of breast cancer [39]. The observation that reduced risk is restricted to the highest levels of vitamin D intake can be explained in term of a threshold effect on substrate availability of 25(OH)D to the terminal ductal lobular unit of the breast [8]. Differences in dietary patterns associated with differences in vitamin D intakes may at least in part account for the inverse association observed. In this dataset, the animal and fish products and unsaturated fat and fiber were inversely related to breast cancer risk, while the starch-rich pattern was directly associated with it. [40] These uncertainties and cautions notwithstanding the observation that vitamin D is inversely related to breast cancer risk are consistent with the long recognized geographic patterns of breast cancer in Italy, which shows higher rates in the North and lower in the South where sun exposure, together with selected aspects of diet, contributes to higher availability of vitamin D [1, 41]. acknowledgements This work was conducted with the contribution of the Italian Association for Cancer Research and the Italian League Against Cancer. The work in this paper was undertaken while CLV was a Senior Fellow at the International Agency for Research on Cancer. The authors thank Ms I. Garimoldi and Ms M. P. Bonifacino for editorial assistance. references 1. Garland CF, Garland FC. Do sunlight and vitamin D reduce the likelihood of colon cancer? Int J Epidemiol 1980; 9: Garland CF, Garland FC, Gorham ED. Calcium and vitamin D. Their potential roles in colon and breast cancer prevention. Ann N Y Acad Sci 1999; 889: Giovannucci E. The epidemiology of vitamin D and cancer incidence and mortality: a review (United States). Cancer Causes Control 2005; 16: Hiatt RA, Krieger N, Lobaugh B et al. Prediagnostic serum vitamin D and breast cancer. J Natl Cancer Inst 1998; 90: Janowsky EC, Lester GE, Weinberg CR et al. Association between low levels of 1,25-dihydroxyvitamin D and breast cancer risk. Public Health Nutr 1999; 2: Bertone-Johnson ER, Chen WY, Holick MF et al. Plasma 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D and risk of breast cancer. Cancer Epidemiol Biomarkers Prev 2005; 14: original article 7. Lowe LC, Guy M, Mansi JL et al. Plasma 25-hydroxy vitamin D concentrations, vitamin D receptor genotype and breast cancer risk in a UK Caucasian population. Eur J Cancer 2005; 41: Garland CF, Gorham ED, Mohr SB et al. Vitamin D and prevention of breast cancer: pooled analysis. J Steroid Biochem Mol Biol 2007; 103: Simard A, Vobecky J, Vobecky JS. Vitamin D deficiency and cancer of the breast: an unprovocative ecological hypothesis. Can J Public Health 1991; 82: Witte JS, Ursin G, Siemiatycki J et al. Diet and premenopausal bilateral breast cancer: a case-control study. Breast Cancer Res Treat 1997; 42: Levi F, Pasche C, Lucchini F, La Vecchia C. Dietary intake of selected micronutrients and breast-cancer risk. Int J Cancer 2001; 91: Frazier AL, Ryan CT, Rockett H et al. Adolescent diet and risk of breast cancer. Breast Cancer Res 2003; 5: R59 R Knight JA, Lesosky M, Barnett H et al. Vitamin D and reduced risk of breast cancer: a population-based case-control study. Cancer Epidemiol Biomarkers Prev 2007; 16: Abbas S, Linseisen J, Chang-Claude J. Dietary vitamin D and calcium intake and premenopausal breast cancer risk in a German case-control study. Nutr Cancer 2007; 59: John EM, Schwartz GG, Dreon DM, Koo J. Vitamin D and breast cancer risk: the NHANES I epidemiologic follow-up study, to National Health and Nutrition Examination Survey. Cancer Epidemiol Biomarkers Prev 1999; 8: Shin MH, Holmes MD, Hankinson SE et al. Intake of dairy products, calcium, and vitamin D and risk of breast cancer. J Natl Cancer Inst 2002; 94: Frazier AL, Li L, Cho E et al. Adolescent diet and risk of breast cancer. Cancer Causes Control 2004; 15: McCullough ML, Rodriguez C, Diver WR et al. Dairy, calcium, and vitamin D intake and postmenopausal breast cancer risk in the Cancer Prevention Study II Nutrition Cohort. Cancer Epidemiol Biomarkers Prev 2005; 14: Robien K, Cutler GJ, Lazovich D. Vitamin D intake and breast cancer risk in postmenopausal women: the Iowa Women s Health Study. Cancer Causes Control 2007; 18: Lin J, Manson JE, Lee IM et al. Intakes of calcium and vitamin D and breast cancer risk in women. Arch Intern Med 2007; 167: Lappe JM, Travers-Gustafson D, Davies KM et al. Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial. Am J Clin Nutr 2007; 85: Negri E, La Vecchia C, Franceschi S et al. Intake of selected micronutrients and the risk of breast cancer. Int J Cancer 1996; 65: Franceschi S, Favero A, La Vecchia C et al. Influence of food groups and food diversity on breast cancer risk in Italy. Int J Cancer 1995; 63: Franceschi S, Negri E, Salvini S et al. Reproducibility of an Italian food frequency questionnaire for cancer studies: results for specific food items. Eur J Cancer 1993; 29A: Decarli A, Franceschi S, Ferraroni M et al. Validation of a food-frequency questionnaire to assess dietary intakes in cancer studies in Italy. Results for specific nutrients. Ann Epidemiol 1996; 6: Salvini S, Gnagnarella P, Parpinel MT et al. The food composition database for an Italian food frequency questionnaire. J Food Compost Anal 1996; 9: U.S. Department of Agriculture. USDA Database for the Flavonoid Content of Selected Foods. Beltsville, MD: USDA Breslow NE, Day NE. Statistical methods in cancer research. Vol. 1. The Analysis of Case Control studies. IARC Sci Publ no. 32. Lyon, France: IARC Hsieh CC, Maisonneuve P, Boyle P et al. Analysis of quantitative data by quantiles in epidemiologic studies: classification according to cases, noncases, or all subjects? Epidemiology 1991; 2: Cui Y, Rohan TE, Vitamin D. calcium. breast cancer risk: a review. Cancer Epidemiol Biomarkers Prev 2006; 15: Franceschi S, Barbone F, Negri E et al. Reproducibility of an Italian food frequency questionnaire for cancer studies. Results for specific nutrients. Ann Epidemiol 1995; 5: Millen AE, Bodnar LM. Vitamin D assessment in population-based studies: a review of the issues. Am J Clin Nutr 2008; 87: 1102S 1105S. Volume 20 No. 2 February 2009 doi: /annonc/mdn

5 33. Feskanich D, Ma J, Fuchs CS et al. Plasma vitamin D metabolites and risk of colorectal cancer in women. Cancer Epidemiol Biomarkers Prev 2004; 13: Van der Mei IAF, Ponsonby AL, Engelsen O et al. The high prevalence of vitamin D insufficiency across Australian populations is only partly explained by season and latitude. Environ Health Perspect 2007; 115: Colston KW, Berger U, Coombes RC. Possible role for vitamin D in controlling breast cancer cell proliferation. Lancet 1989; 1: Saez S, Falette N, Guillot C et al. William L. McGuire Memorial Symposium. 1,25(OH)2D3 modulation of mammary tumor cell growth in vitro and in vivo. Breast Cancer Res Treat 1993; 27: Annals of Oncology 37. Mantell DJ, Owens PE, Bundred NJ et al. 1 alpha,25-dihydroxyvitamin D(3) inhibits angiogenesis in vitro and in vivo. Circ Res 2000; 87: Welsh J. Vitamin D and breast cancer: insights from animal models. Am J Clin Nutr 2004; 80: 1721S 1724S. 39. Brisson J, Berube S, Diorio C et al. Synchronized seasonal variations of mammographic breast density and plasma 25-hydroxyvitamin D. Cancer Epidemiol Biomarkers Prev 2007; 16: Edefonti V, Decarli A, La Vecchia C et al. Nutrient dietary patterns and the risk of breast and ovarian cancers. Int J Cancer 2008; 122: Facchini U, Camnasio M, Cantaboni A et al. Geographical variation of cancer mortality in Italy. Int J Epidemiol 1985; 14: Rossi et al. Volume 20 No. 2 February 2009