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

Long Island

Breast Cancer Rates (per 100,000 women, age-standardized to1970 U.S. population)

1997 1992-1996SEER Nassau Suffolk

Incidence 109.5 117.8 113.6Mortality 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

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

LIBCSPPrimary 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

LIBCSP Other AimsWhether 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

LIBCSPAdditional 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

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%

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%

LIBCSP Case-Control Study

Random sample of long-term (15 yr) residents:Interview-home samples

Cases Controls

Dust 84% 83%

Water 94% 94%

Soil 94% 94%

LIBCSP Molecular Epidemiology StudiesBiologic 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)

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 significantBreast Cancer Res Treat 74: 235, 2002

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]

Immunohistochemical Detection of 4-ABP-DNA in Breast Adjacent Nontumor

Tissues

4ABP-DNA higher in smokers compared to nonsmokers

4-ABP-DNA (log transformed staining intensity) in Tumor and Normal Adjacent Tissue

Active smoking Adjacent Tissue Tumor Tissue

Never 5.770.60 20 5.330.71 57 Past/former 5.950.50 25 5.430.83 65 Current 6.200.43 10 5.370.80 26

p=0.04a p=0.68a

Passive smoking Never 5.520.83 5 5.640.71 15 Past/former 5.970.50 43 5.370.77 108 Current 6.030.49 6 5.280.86 23

p=0.14a p=0.19a

Active and passive smoking Never either 4.630.14 2 5.240.58 7 Ever passive only 5.900.48 18 5.340.73 50 Ever active only 6.110.25 3 5.990.66 8 Ever both 6.020.51 31 5.360.82 81

p=0.03a p=0.84a

a p value for linear trend

Genes Environment

Interindividual Variation

Cancer

Carcinogen metabolism Chemicals

Estrogen metabolism Radiation

DNA Repair Viruses

Exon 23 Polymorphism in XPD and Breast Cancer Risk

Genotype Cases Controls OR(95%CI)

N(%) N(%)

Lys/Lys (AA) 387 453 1

Lys/Gln (AC) 513 498 1.22(1.01-1.46)

Gln/Gln (CC) 153 151 1.18(0.91-1.53)

Lys/Gln+Gln/Gln 666 649 1.21(1.01-1.44)

Multivariate-adjusted ORs for Risk Factors Stratified by XPD Status

Genotype PAH-DNA

Nondetect <Median >Median

AA 1 1 1

AC 1.25(0.83-1.86) 1.01(0.71-1.44) 1.22(0.85-1.76)

CC 0.91(0.52-1.62) 1.05(0.64-1.74) 1.61(0.99-2.63)

Multivariate-adjusted ORs for Risk Factors Stratified by XPD Status

Active Smoking

Never Former Current

AA 1 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)

Myeloperoxidase Genotype, Dietary Antioxidants and Breast Cancer Risk

G463A variant-in promoter region-G allele higher transcriptional activation

Among premenopausal women

GG 1

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

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

LIBCSP Follow-UpBreast 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

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

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

LIBCSP

CollaboratorsUNC: MD Gammon (PI), P Abrahamson, R Cleveland,

S White, K McCullough, M Gaudet, K Conway, R Millikan,S Steck-ScottColumbia: 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 AmbrosoneStonybrook: G Kabat, E O’LearyNIH: Obrams (NCI), G Coleman (NIEHS), E

Heineman (NCI)Westat: C Maffeo, P Montalvan