Incident Invasive Breast Cancer, Geographic Location of Residence, and Reported Average Time Spent Outside Amy E. Millen, 1 Mary Pettinger, 2 Jo L. Freudenheim, 1 Robert D. Langer, 3 Carol A. Rosenberg, 4 Yasmin Mossavar-Rahmani, 5 Christine M. Duffy, 6 Dorothy S. Lane, 7 Anne McTiernan, 8 Lewis H. Kuller, 9 Ana Maria Lopez, 10 and Jean Wactawski-Wende 1 1 Department of Social and Preventive Medicine, School of Public Health and Health Professions, University at Buffalo, Buffalo, New York; 2 Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington; 3 Outcomes Research Institute, Center for Health Research, Geisinger Health System, Danville, Pennsylvania; 4 Department of Medicine, Evanston Northwestern Healthcare, Evanston Illinois; 5 Division of Behavioral & Nutritional Research, Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York; 6 Division of General Internal Medicine, Brown University School of Medicine, Providence, Rhode Island; 7 Department of Preventive Medicine, Stony Brook University School of Medicine, Stony Brook, New York; 8 Prevention Center, Fred Hutchinson Cancer Research Center, Seattle, Washington; 9 Department of Epidemiology, University of Pittsburgh, Pittsburgh, Pennsylvania; and 10 Clinical Medicine and Pathology, Arizona Telemedicine Program, Arizona Cancer Center, University of Arizona, Tucson, Arizona Abstract There have been reports of greater breast cancer incidence and mortality at northern compared with southern latitudes postulated to be related to vitamin D exposure. Among 71,662 participants in the Women’s Health Initiative Observational Study (WHIOS) free of cancer at baseline (1993-1998), associations were ex- plored between incident invasive postmenopausal breast cancer (n = 2,535), over f8.6 years follow-up, and the following: (a ) region of residence at birth, age 15 years, age 35 years; (b ) region of residence at WHIOS baseline; and (c ) clinic center solar irradiance. Hazard ratios and 95% confidence intervals (CI) for breast cancer were estimated after adjustment for individual level confounders. There was no difference in breast cancer risk by region of earlier life, baseline residence, or solar irradiance measured in Langelys (gm-cal) per cm 2 . There was an observed 15% decreased risk among women residing in areas of low versus high solar irradiance measured in Watts per m 2 (95% CI, 2-26%). However, the associated P trend of 0.20 was not signif- icant. Conversely, women who reported spending on average <30 minutes versus >2 hours outside in daylight year round at WHIOS year 4 follow-up (n = 46,926), had a 20% (95% CI, 2-41%; P trend = 0.001) increased risk of breast cancer. In conclusion, region of residence and geographic solar irradiance are not consistently related to risk of breast cancer and may not be sufficient proxy measures for sunlight/vitamin D exposure. The ob- served association between time spent outside and breast cancer risk support the hypothesis that vitamin D may protect against breast cancer. (Cancer Epidemiol Biomarkers Prev 2009;18(2):495–507) Introduction Breast cancer mortality and incidence rates have been found to be higher among U.S. postmenopausal women living at northern compared with those living in southern latitudes (1-3) and inversely associated in U.S. women with increasing levels of total average sunlight energy striking the ground (4-6). Similar results have also been observed in other countries (7, 8). It has been suggested that the association between breast cancer and geographic variation may be explained, at least in part, by exposure to vitamin D (4, 8). Lower latitude means greater potential for sunlight exposure and thus synthe- sis of vitamin D. Humans can synthesize vitamin D from a cholesterol precursor in the skin; the majority of circulating vitamin D in most people is obtained through sunlight exposure (reviewed in ref. 9), less from diet and supplements. However, diet and supplements may contribute more significantly in Northern climates. Interest in vitamin D as a protective agent against cancercamefromresearchshowingthattheactiveformof vitamin D, 1,25 dihydroxyvitamin D, has an antiprolifer- ative effect on cultured human cancer cells (10, 11). Research in humans and in animals supports a potential role for vitamin D in breast cancer prevention, as previously reviewed (12, 13). However, few studies that have investigated relation- ships between region of residence and breast cancer risk have used incidence data (6, 8, 14, 15). Most previous studies focused on mortality from breast cancer (1-5, 7, 16, 17),andwereoftenassessedatthepopulationlevel(1,4,5, 7, 17); adjusted for risk factors assessed at the regional, not individual level (1, 2, 4-8, 16, 17); and were unable, or did not, explore associations by race or ethnicity. Furthermore, there has been little exploration of differ- ences in effect of exposures at different periods of life. Migration of individuals could affect our understanding of the effect of sunlight exposure on risk. Cancer Epidemiol Biomarkers Prev 2009;18(2). February 2009 Received 7/18/08; revised 10/23/08; accepted 11/25/08; published OnlineFirst 02/03/2009. Requests for reprints: Amy E. Millen, Department of Social and Preventive Medicine, School of Public Health and Health Professions, University at Buffalo, 270 Farber Hall, Buffalo, NY 14214-8001. Phone: 716-829-5377; Fax: 716-829-2979. E-mail: aemillen@buffalo.edu Copyright D 2009 American Association for Cancer Research. doi:10.1158/1055-9965.EPI-08-0652 495 Published Online First on February 3, 2009 as 10.1158/1055-9965.EPI-08-0652