Community Participation in Cancer Discovery Research: Linking Biology,

Cancer Disparities, and Dissemination

Robert A. Hiatt

UCSF Helen Diller FamilyComprehensive Cancer Center

July 13, 2011Bethesda, MD

Question?

• How can basic research on the origins of cancer disparities be 1) better understood by the public and 2) better disseminated to the people who are intended to benefit from the results?

Community Participation

• Community Based Participatory Research (CBPR) is not new, but its application to discovery research is unusual.

• For cancer disparities research that takes a transdisciplinary approach and seeks to integrate basic biologic understanding into a fuller picture of its origins, dissemination can be a challenge.

Community Participation

• How can community participation be integrated into cancer disparities research for the benefit of science and the public health?

• An example from the Breast Cancer and the Environment Research Centers, an NCI/NIEHS sponsored national network.

The Breast Cancer and the Environment Research Centers

Research Question

Do environmental factors contribute to the etiology of breast cancer in humans?

What evidence motivates this question?

Female Breast Cancer Incidence Ratesage-standardized rates, 1988-1992

From Parkin, et al., IARC, 1997

Cases/100,000 p-yrs

Variation in Breast Cancer Rates, Japaneseage-standardized incidence rates, 1988-1992

From Parkin, et al., IARC, 1997

Cases/100,000 p-yrs

Research Approaches

• Mechanistic

• Animal studies

• Epidemiology

.

Epidemiologic Studies

• Most have been performed in adults

• Study designs have followed case-control or cohort approaches.

• Some natural experiments

Selected Factors Known to Influence Breast Cancer

Risk Factor Comparison RR 95% CIAge at menarche ≥15 vs. <12 y 0.72 (0.62-0.82)Parity ≥3 vs. none 0.72 (0.61-0.86)Age at First Birth >30 vs. ≤20 y 1.46 (1.22-1.75)Education >HS vs. <HS 1.08 (0.90-1.29)BBD Yes vs. No 1.53 (1.41-1.65)Maternal History Yes vs. No 1.38 (1.14-1.67)Sister History Yes vs. No 1.47 (1.27-1.70)From Hunter DJ, et al. Cancer Causes Control 1997;8:49-56. Analysis includes 322,647 women followed for 5-7 years, with 4,827 incident cases of breast cancer.

Seasons of Life & Breast Cancer Risk

• In utero: birthweight; in utero exposures?

• Infancy: infant feeding practices?

• Early childhood: growth patterns?

• Adolescence: earlier age at menarche increases risk

• Young adulthood: late age at first birth increases risk

• Childbearing years: greater parity decreases risk; breastfeeding decreases risk

• Menopausal transition: late menopause increases risk; use of HRT increases risk

• Postmenopausal years: lifetime body weight patterns influence risk

Has led to more interest in “windows of susceptibility”

Puberty

Reasons for interest as a window of susceptibility:

• Time of rapid development of both epithelial cells and stroma.

• Period of rapid growth in height.

• Age of menarche highly variable internationally

• Age of menarche dropping over last century with industrialization

The Changing Age of Puberty Over Time

International Trends in Age at Menarche

Korean example

Cho GJ et al. Eur J Pediatrics 2010

Prevalence of Breast Developmentat Tanner Stage 2 or Greater by Age and Race

Herman-Giddens et al., Pediatrics, 1997

Height & Breast CancerPooled Analysis, Cohort Studies of Diet & Breast Cancer

Cohort

Rela

tive

Ris

k,H

eigh

t (m

) ≥1

.68

vs <

1.6

Pooled RR = 1.25 (1.14-1.37)

from van den Brandt, et al., Am J Epidemiol, 2000

Median Age at Maturation MilestonesNHLBI Growth and Health Study, Biro et al., Pediatrics, 2006

New Approach

• Age at menarche an established risk factor

• Puberty a time of rapid breast development

• Changing age for initiation of puberty -likely due to environmental factors

• So…

• Take a life-course approach

• Focus on early development

Bay Area Breast Cancer & Environment Research Center

Project 1: Environmental Effects on the Molecular Architecture and Function of the Mammary Gland across the Lifespan.PI: Zena Werb, PhD, UCSF

Project 2:

COTC:

Environmental and Genetic Determinants of PubertyPI: Lawrence Kushi, ScD, KP/DOR

PI: Robert A. Hiatt, MD, PhD, UCSF CCC

Community Outreach and Translation CorePI: Janice Barlow, RN, Zero Breast Cancer

Breast Cancer and the Environment Research Centers (BCERCs)

Cincinnati Children’s HospitalUCSFLBNL

Michigan State University

University of Cincinnati

Mount SinaiSchool of Medicine

Fox Chase Cancer Center

Kaiser Permanente

University of Alabama

NIEHS

NCI

Zero BreastCancer

Funding Agencies

BCERC Prime Institutions

Collaborating Institutions

Roswell ParkCancer Institute

University of MichiganCalifornia Departmentof Health Services

Marin County DHHS

Project 1 - Specific Aims

Specific Aim 1: Determine the alterations in the mammary microenvironment andthe mammary cells in normal and cancer prone mice in vivo during prenataldevelopment, pubertal branching morphogenesis, pregnancy and aging.

Specific Aim 2: Determine the effects of exposure to prototypical environmentalstressors during prenatal development, pubertal branching morphogenesis,pregnancy and aging on the mammary gland in normal and cancer prone mice invivo

Specific Aim 3: Determine the effects of environmental agents implicated fromstudies in Project 2 on regulating the mammary microenvironment of mammarycells during branching morphogenesis

Specific Aim 4: Validate the animal experiments by determining how these environmental stressors affect human mammary epithelial cells in culture through the telomere crisis, comparing the critical endpoints derived from the animal.

Distinct mechanisms pattern the mammary gland

Adapted from Wiseman & Werb (2002) Science 296 1046

Lateral branching TEB invasionDichotomous branching

Mammary Development

3 wks 5 wks 11 wksnipple

lymph node

nipple

Luminal (Keratin 8/18)Myoepithelial (Keratin 5/14)

Mature Duct Terminal End Bud

Body cells

Cap cells

BCERC Epidemiology Study Populations

• Healthy girls age 6-8 yrs at time of recruitment

• California:– Bay area KPNC members

– Larry Kushi, PI, Division of Research, Kaiser Permanente Northern California

• Ohio:– Cincinnati-area school districts

– Frank Biro, PI, Cincinnati Children’s Hospital

• New York:– East Harlem neighborhood clinics

– Mary Wolff, PI, Mount Sinai School of Medicine

Methods• Food intake

• Physical activity

• Environmental exposures

• Medical and related history

• Psychosocial measures

• Demographics

• Anthropometry

• Biospecimens

• Tanner Staging

Puberty – Tanner Staging

Tempo (Pace, B2 → Menarche)

Tempo

3 y

2 y

3 y

Menarche12 y 13 y

Age (years)

9 10 11 12 13 14

B29 y 10 y

Cohort study of Young Girls’ Nutrition,

Environment & Transitions

A Project of the Bay Area Breast Cancer

and the Environment Research Center

CYGNET Study Population

• Born in and currently a member of Kaiser Permanente

• Resident at birth and currently of Marin County, San Francisco, and selected East Bay communities (e.g.,Richmond, El Cerrito, Berkeley, Oakland) in western Contra Costa and Alameda Counties

• Age 6 or 7 yrs at time of recruitment

KP San Francisco

KP San Rafael

KP DOR

Results to Date

Breast Maturation Status, age 7 yearsBCERP Puberty Studies, Biro et al., Pediatrics, 2010

GroupMSSM Cincinnati KPNC Total

B1 B2+ (%) B1 B2+ (%) B1 B2+ (%) B1 B2+ (%)

Black 77 31 (28.7) 75 34 (31.3) 75 26 (25.7) 233 71 (23.4)

Hispanic 117 25 (17.6) 10 1 (9.1) 79 10 (11.2) 206 36 (14.9)

Asian 4 0 (0.0) 40 1 (2.4) 44 1 (2.2)

White 184 29 (13.6) 179 13 (6.8) 363 42 (10.4)

Breast Maturation Status, age 8 yearsBCERP Puberty Studies, Biro et al., Pediatrics, 2010

GroupMSSM Cincinnati KPNC Total

B1 B2+ (%) B1 B2+ (%) B1 B2+ (%) B1 B2+ (%)

Black 83 11 (11.7) 54 58 (51.8) 55 24 (30.4) 109 82 (42.9)

Hispanic 97 60 (38.2) 8 4 (33.3) 78 18 (18.8) 283 82 (30.9)

Asian 4 0 (0.0) 34 6 (15.0) 38 6 (13.6)

White 156 57 (26.7) 152 12 (7.3) 308 69 (18.3)

Breast Development in the BCERP Puberty Studies (Biro, 2010) and PROS (Herman-Giddens, 1997)

Age 7 y Age 8 y

Father absence and breast development adjusted for BMI

Deardorff, et al., J Adol Health 2011

Income categoryB2 onset

AllRR (95% CI)

PH2 onset -AA

RR (95% CI)

Higher income, ≥$75,000/year 2.4 (1.2 – 4.9) 4.6(1.6-12.7)

Lower income, <$75,000/year 0.8 (0.5 – 1.2) 1.1(.5-2.6)

A Transdisciplinary Approach

METABOLOME

PROTEOME

TRANSCRIPTOME

GENOME

Policy

Neighborhoods

Workplace

Exercise

Smoking

Diet

TDS Conceptual Model

• Life-course approach• Multiple levels of analysis (social ecologic

model)• Stages of carcinogenesis• Must incorporate aims of constituent

investigators and collaborators• Demonstrate hypotheses• Predictive value

Life-course Approach

• Pre-natal

• Early childhood

• Pre-puberty

• Pregnancy

• Pre-menopause

• Menopause

• Post-menopause

Levels of Analysis

• Gene

• Cell

• Tissue/Organ

• Individual

• Family

• Neighborhood/City

• Society

Dissemination Activities

• Community meetings - bidirectional exchange (e.g., Town Halls, Tea Talks)

• Fact sheets on chemical exposures and puberty

• Communication (e.g., videos)

• Recruitment and retention

• Evaluation

• Hands-on Laboratory Training for Advocates

• Modeling Breast Cancer and the Environment Report

• DVD “Of Mice and Women”

• DVD “The Breast Biologues”

COTC Collaborations with Biology

Of Mice and Women: Modeling Breast Cancer and the Environment

An innovative educational tool to engage the community on why mouse models are used in breast cancer research

Developed by the Bay Area Breast Cancer and Environment Research Center, Community Outreach and Translation Core in partnership with Dr. Mary Helen Barcellos-Hoff, PhD, co-investigator, Project 1

The Breast Biologues: A biology dialogue about breast cancer and the environment

A new education kit that explains how the breast develops and how exposures to potential cancer-causing chemicals at specific times during development might influence future breast cancer risk.

Developed by the Bay Area Breast Cancer and Environment Research Center, Community Outreach and Translation Core in partnership with Lori Schkufza, an animation consultant; the BABCERC basic science researchers: Dr. Zena Werb at University of California San Francisco, Dr. Paul Yaswen at Lawrence Berkeley National Laboratory, and Dr. Mary Helen Barcellos-Hoff at New York University Langone School of Medicine.

Target Populations1. Study Participants

– Recruitment and Retention • Newsletters, Community Meetings

– Returning Individual Level Results

COTC Collaborations with Epidemiology

2. Pediatricians– PARDNER grant: Partnerships for the Dissemination of

New Results.

COTC Collaborations with Epidemiology

3. Lay Public– Community

Participation• Town Hall

Meetings

• Resource Tables

• Presentations

– Public Health Messages

COTC Collaborations with Epidemiology

How can we create effective messages/tools/interventions that integrate

findings from genetic, cellular, animal and human studies?

Purpose:• To synthesize the BCERC biological, toxicologic, and

epidemiologic research results into integrated messages at appropriate education levels that can be broadly disseminated to affected communities

• To identify key messages integrating the body of peer reviewed research derived from the BCERC network

• To identify strategies for developing key messages for affected communities

• To develop a well designed dissemination plan for the key messages developed

Public Health Messages

Challenges:• Are findings from the laboratory relevant for human

populations?

• When are findings consistent enough to warrant dissemination?

• How can we evaluate the impact of the findings on “final” endpoints ?

• What messages do we want to prioritize for the lay public?

• How do findings translate so they have utility for members of the lay public?

Public Health Messages

FIN