1. Long Island Long Island residents concerned about : –DDT for control of gypsy moths and mosquitoes –Other pesticides used on farmlands –Groundwater contamination –Air pollution (major roads, airports) –Electromagnetic fields –Chemical waste

2. Long Island Breast Cancer Rates (per 100,000 women, age-standardized to1970 U.S. population) 1997 1992-1996 SEERNassauSuffolk Incidence109.5117.8113.6 Mortality 27.2 30.6 31.1 Source: http://www.health.state.ny.us/nysdoh/cancer/volume1.htm SEER - Surveillance, Epidemiologu and End Results ~15% of US population

3. Long Island Breast Cancer Study Project NCI and NIEHS sponsored group of ten studies undertaken in response to federal legislation (Public Law 103-43) The cornerstone project, LIBCSP, is a large population-based study of 3000 women

4. LIBCSP Primary Aims Determine whether breast cancer is associated with: Organochlorine compounds (DDT/DDE, PCBs, chlordane, dieldrin) as measured in blood Polycyclic aromatic hydrocarbon (PAH)-DNA adducts

5. LIBCSP Other Aims Whether breast cancer is associated with: Lifestyle –alcohol, body size, recreational physical activity, occupational physical activity Diet –PAH-related foods, alcohol, isoflavones, estrogen-metabolite related foods, folate, phytoestrogens, insulin-related foods, brassica veggies Early life exposures –DES, preeclampsia HRT and other factors among the elderly Family History of Cancer Medical History –NSAIDS

6. LIBCSP Additional Environmental Study Aims Questionnaire-assessed exposures –self-reported pesticide use –environmental tobacco smoke (ETS) –home appliance exposure to electromagnetic fields (EMF) –occupation –medical ionizing radiation Historical exposures assessed by geographic modeling –long-term PAH exposure Model validated against soil sample measures taken from the home Exposure assessment based on home samples –in-home exposure to PAH and organochlorines in dust samples –chlorinated and carbamated pesticides, and metals in drinking water Biologic samples –urinary estrogen metabolites ratio of 16alpha-hydroxyestrone to 2-hydroestrone

7. Population-Based Breast Cancer Cases Eligibility criteria –newly diagnosed 1996-1997 –resident of Nassau or Suffolk county –no age restrictions –speaks English Identification protocol –daily contact with 33 hospitals on LI and NYC –diagnosis confirmed by MD N = 1508 –82% completed interviews –Response varied by age:< 65yrs = 89%,  65yrs = 72%

8. Population-Based Controls Eligibility criteria –resident of Nassau or Suffolk county –no personal history of breast cancer –speaks English –frequency-matched on age to expected distribution of cases Identification protocol –Random digit dialing among women under age 65 years –Health Care Financing and Administration for >65 years N = 1556 –63% completed interviews –Response varied by age:< 65 yrs=76%,  65 yrs=43%

9. LIBCSP Case-Control Study Random sample of long-term (15 yr) residents: Interview-home samples CasesControls Dust 84%83% Water 94%94% Soil 94%94%

10. LIBCSP Molecular Epidemiology Studies Biologic Specimens Available: Urine (n = 1400 cases and 1300 controls) Blood (n = 1100 cases and 1100 controls) DNA isolated from blood donations (n = 1100 cases and 1100 controls) Archived tumor blocks (n = 975 cases)

11. Results of LIBCSP in Relation to Known Risk Factors Protective Beginning menstruating at an older age Having children Increases with number of children Having a first child at a younger age Breast feeding Risk Factor Higher body mass index is a risk factor Smoking and alcohol consumption are not significant Breast Cancer Res Treat 74: 235, 2002

12. Environmental Chemicals and Risk for Breast Cancer in the LIBCSP No relationship with blood levels of organochlorine compounds measured - DDE, DDT, PCBs, dieldrin, chlordane High PAH-DNA damage in blood cells indicated small (50%) but statistically significant increase in risk-but no dose-response [Results duplicated in remaining samples]

13. Immunohistochemical Detection of 4- ABP-DNA in Breast Adjacent Nontumor Tissues 4ABP-DNA higher in smokers compared to nonsmokers

14. 4-ABP-DNA (log transformed staining intensity) in Tumor and Normal Adjacent Tissue Active smokingAdjacent TissueTumor Tissue Never5.77  0.60205.33  0.71 57 Past/former5.95  0.50255.43  0.83 65 Current6.20  0.43105.37  0.80 26 p=0.04 a p=0.68 a Passive smoking Never5.52  0.83 55.64  0.71 15 Past/former5.97  0.50435.37  0.77108 Current6.03  0.49 65.28  0.86 23 p=0.14 a p=0.19 a Active and passive smoking Never either4.63  0.14 25.24  0.58 7 Ever passive only5.90  0.48185.34  0.73 50 Ever active only6.11  0.25 35.99  0.66 8 Ever both6.02  0.51315.36  0.82 81 p=0.03 a p=0.84 a a p value for linear trend

15. Genes Environment Interindividual Variation Cancer Carcinogen metabolism Chemicals Estrogen metabolism Radiation DNA Repair Viruses

16. Exon 23 Polymorphism in XPD and Breast Cancer Risk GenotypeCasesControlsOR(95%CI)N(%) Lys/Lys (AA)3874531 Lys/Gln (AC)5134981.22(1.01-1.46) Gln/Gln (CC)1531511.18(0.91-1.53) Lys/Gln+Gln/Gln6666491.21(1.01-1.44)

17. Multivariate-adjusted ORs for Risk Factors Stratified by XPD Status Genotype PAH-DNA Nondetect Median AA111 AC1.25(0.83-1.86)1.01(0.71-1.44)1.22(0.85-1.76) CC0.91(0.52-1.62)1.05(0.64-1.74)1.61(0.99-2.63)

18. Multivariate-adjusted ORs for Risk Factors Stratified by XPD Status Active Smoking Never FormerCurrent AA1 1 1 AC 0.89(0.67-1.19) 1.56(1.12-2.16) 1.25(0.80-1.97) CC 0.87(0.57-1.32) 1.16(0.75-1.81) 1.97(1.02-3.81)

19. Myeloperoxidase Genotype, Dietary Antioxidants and Breast Cancer Risk G463A variant-in promoter region-G allele higher transcriptional activation Among premenopausal women GG1 GA 0.92(0.63-1.33) AA 0.42(0.21-0.84) GA+AA+high fruits/veg0.33(0.13-0.88) Ahn, Ambrosone et al

20. LIBCSP Molecular Epidemiology Studies (projects as of 10/03) Urinary Markers: –Estrogen metabolites, isoprostanes,isothiocyanates Blood Markers: –Exposure Markers PAH-DNA adducts, oxidative DNA damage, organochlorine compounds, insulin (among controls) –Genetic Markers polymorphisms in estrogen,folate and carcinogen metabolism,DNA repair, oxidative stress, estrogen receptor alpha and beta genes, IGF, cyclin D Tumor Markers: –Tissue - PAH-DNA, 4-ABP-DNA, p53 protein expression, p53 mutations, cyclin D1 and HER-2/neu overexpression –Blood - antibodies to p53, HER-2/neu protein

21. LIBCSP Follow-Up Breast Cancer Cases Determine case vital status, change of address Primary exposures of interest are measures : –assessed at baseline case-control study, and –during the follow-up interview Re-interview case participants or proxy at 5-year follow-up –One-hour telephone interview to determine medical treatment for initial cancer, and changes in: residence, occupation, use of pesticides and other contaminants, appliance use, alcohol use, passive and active smoking, body size, physical activity, medical hx, hormone use, complementary and alternative medicine (CAM) use –Self-administered FFQ Collect medical records Determine outcome status –NYS Tumor Registry, NDI, respondent, medical record

22. LIBCSP: Companion Projects Geographic Information System (GIS) –National Cancer Institute –Mapped layers of historical exposure data from multiple sources (EPA) –-Mapped cancer data from NYS Tumor registry, conserving patient privacy –Use as an estimate of historical exposures, particularly for compounds for which biomarkers are not currently feasible –May be useful for exploratory or hypothesis- generating analyses –Access on line lay public vs. scientific researchers

23. LIBCSP: Companion Projects Electromagnetic Fields (EMF) –SUNY at Stony Brook (PI: C Leske) Recontacted long-term residents of case- control interview –More detailed interview on occupational and residential EMF exposures –In-home spot and 24-hour measures with EMDEX meter –Wire Coding –May affect production of melatonin inversely related to biologically available endogenous estrogen levels

24. LIBCSP Collaborators UNC:MD Gammon (PI), P Abrahamson, R Cleveland, S White, K McCullough, M Gaudet, K Conway, R Millikan,S Steck-Scott Columbia:RM Santella, AI Neugut, S Stellman, MB Terry, R Senie, B Levin, J Jacobson, H Hibshoosh Mt. Sinai: MS Wolf, M Hatch, SL Teitelbaum, JA Britton, J Chen, C Ambrosone Stonybrook: G Kabat, E O’Leary NIH:Obrams (NCI), G Coleman (NIEHS), E Heineman (NCI) Westat:C Maffeo, P Montalvan