Basic Center Requirements DOD

1
Basic Center Requirements (DOD)

• Focus on the solution of a critical question in
  breast cancer research
• using research strategies that optimize the
  Breast Cancer Center of Excellence
• Awards comprehensive array of personnel and
  resources
• Integrate a team of preeminent investigators
  from appropriate disciplines and
• institutions
• Incorporate breast cancer consumer/survivor
  groups into every aspect of the
• proposed consortium
• Optimize, facilitate, and accelerate research
  progress through real-time
• communication
• Provide an effective, coordinated administrative
  management plan that
• integrates and optimizes the research and
  collaboration

2
Review Criteria (DOD)

• Disease Relevance and Impact
• Innovation
• Research Strategy
• Center Structure
• Personnel
• Consumer Participation
• Environment
• Budget
• up to 10 million for 5 years total
• direct 6 million
• 1.2 million/yr

3
Our Proposed Center Structure

• Principal Investigator
• External Advisory Committee
• Internal Oversight Committee
• Consumer Advisory Committee
• Team Leaders
• Administrative Unit (like a core)
• Research
• aligned in themes (currently two)
• defined in specific aims
• supported by teams of experts

4
Obesity and Breast Cancer
5
U54 Nutrition Center
PROJECTS
Mechanisms mediating the effects of dietary fats
and plant estrogens on the breast issue of
timing Leena Hilakivi-Clarke
Early life exposure to phytoestrogens Sari
Makela
Timing of vitamin A and D exposures Stephen
Byers
Inherited breast cancer and body weight at birth,
puberty, and pregnancy Claudine Isaacs, Celia
Byrne

PILOT PROJECTS
Dietary intervention during pregnancy and
pregnancy weight gain Riitta Luoto
Prepubertal exposure to selenium and breast
cancer Mary Beth Martin
CORES
Administrative L. Hilakivi-Clarke Statistics
and Microarray R. Clarke Bioresources M.B.
Martin
6
Trends in Obesity Prevalence (), By Gender,
Adults Aged 20 to 74, US, 1960-2000
Obesity is defined as a body mass index of 30
kg/m2 or greater. Source National Health
Examination Survey 1960-1962, National Health and
Nutrition Examination Survey, 1971-1974,
1976-1980, 1988-1994, 1999-2000, National Center
for Health Statistics, Centers for Disease
Control and Prevention, 2002.
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Lifetime Probability of Developing Cancer, by
Site, Women, US, 1998-2000
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Cancer Sites in Which African-American Death
Rates Exceed White Death Rates for Women, US,
1996-2000
Ratio of African American/White
White
African American

• All sites 198.6 166.9 1.2
• Myeloma 6.6 2.9 2.3
• Stomach 6.5 2.9 2.2
• Uterine cervix 5.9 2.7 2.2
• Esophagus 3.4 1.7 2.0
• Uterine corpus, NOS 7.0 3.8 1.8
• Larynx 0.9 0.5 1.8
• Liver intrahepatic bile duct 3.0 1.9 1.6
• Pancreas 12.9 8.9 1.5
• Colon rectum 24.6 17.5 1.4
• Breast 35.9 27.2 1.3
• Urinary bladder 3.0 2.3 1.3
• Soft tissue, including heart 1.7 1.3 1.3

Per 100,000, age-adjusted to the 2000 US
standard population. Source Surveillance,
Epidemiology, and End Results Program, 1975-2000,
Division of Cancer Control and Population
Sciences, National Cancer Institute, 2003.
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Obesity and Breast Cancer
"Focus on the solution of a critical question in
breast cancer research"

• Obesity
• 20 of adults in more than 50 of states in US
  are obese
• 60 of Americans are overweight
• Breast Cancer
• most common cancer among women
• risk of mortality is greater in African American
  women
• What are the roles of obesity in affecting
  breast cancer risk
• and mortality
• breast cancer risk is increased in obese
  postmenopausal women
• breast cancer mortality is higher in obese women
• greatest increase in mortality is seen in
  postmenopausal women
• with ER tumors (RR3.3 CI1.1-10.4)

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Timing of Obesity and Breast Cancer Risk

• Body weight/BMI is associated with breast cancer
  risk throughout a womans life
• However, the direction of effects depend on when
  during a womans life-cycle her body weight is
  elevated
• Birth weight (high - increased risk)
• BMI during childhood (high - reduced risk)
• Premenopausal BMI (high - reduced risk)
• Pregnancy weight gain (excessive increased
  risk)
• Postmenopausal weight (obesity - increased risk)

"The effects of obesity on breast cancer
risk/mortality represent a critical intersection
between two of the most important problems facing
women living in the U.S."
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Obesity and Breast Cancer Theme 1
Premenopausal vs. postmenopausal obesity and
breast cancer risk

• Hypothesis pubertal body mass index determines
  adult breast density
• (women who were obese at puberty have low
  breast density)
• Hypothesis women who become obese after puberty
  exhibit a reduced
• premenopausal and then increased postmenopausal
  breast cancer risk,
• (risk is independent of an association between
  obesity and breast density)
• Hypothesis the ability of obesity to modify the
  risks of developing
• primary breast cancer, recurrent disease,
  and/or mortality are partly
• contributed by, and/or can be accurately
  predicted from, the presence of
• polymorphisms in genes associated with the
  etiology of both breast cancer
• and obesity

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Obesity and Breast Cancer Theme 1
Premenopausal vs. postmenopausal obesity and
breast cancer risk

• Aim 1 what structural and molecular changes in
  the mammary gland that
• are caused by obesity at puberty, premenopause,
  and postmenopause,
• and that might explain the effects of timing of
  obesity on breast cancer risk
• use a rat model and genetically modified mice,
  e.g., existing mouse
• models of leptin, adiponectin, and PPAR?
  knockout
• Aim 2 how does obesity in pubertal,
  premenopausal, and
• postmenopausal women affect breast density in
  African American and
• Caucasian women
• relationships among obesity, hormones and growth
  factors, and
• polymorphisms related to breast density will
  be studied
• breast density will be used as an outcome and
  surrogate marker for risk

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Obesity and Breast Cancer Theme 1
Premenopausal vs. postmenopausal obesity and
breast cancer risk

• Aim 3 do polymorphisms in genes associated with
  obesity modify the
• effect of obesity on pre- and/or postmenopausal
  breast cancer risk
• and disease outcome
• adiponectin, PPAR-gamma, leptin, AIB1, PgR
• 3,000 cases diagnosed from 1993-1995 and 3,000
  controls in Stockholm
• 1,000 cases and 2,000 controls in two counties
  of New York State

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Obesity and Breast Cancer Theme 2
Obesity and breast cancer prognosis

• Hypothesis obesity modifies the transcriptome
  of breast tumors such
• that the tumors exhibit a more aggressive
  phenotype and increased
• likelihood of recurrence and death
• Aim 4 effects of obesity on the molecular
  profile of breast tumors
• use cases from an ongoing prognostic molecular
  profiling study of
• recurrent and non-recurrent breast cancers
• analysis (stratified by obese vs. non-obese)
• validate molecular profiles in cases from the
  control arm of the Scottish
• Adjuvant Tamoxifen Trial (or from cases in
  Sweden)

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Teams

• Team 1 Nutrition and Epidemiology
• Lucile Adams-Campbell (Howard) Leena
  Hilakivi-Clarke
• Celia Byrne
• Robert Clarke
• Jo Freudenheim (SUNY)
• Per Hall (Karolinska)
• Peter Shields
• Kate Taylor
• Team 2 Biostatistics and Bioinformatics
• Ed Gehan Joseph Wang (VA Tech)
• Robert Clarke
• Matthew Freedman
• Stan Fricke
• Arnie Miles
• Antai Wang
• Cathy Wu
• Jason Xuan (CUA)

16
Teams

• Team 3 Molecular Endocrinology/Biology and
  Oncology
• Robert Clarke Leena Hilakivi-Clarke
• Mike Dixon (Edinburgh)
• Matthew Freedman
• Bassem Haddad
• Per Hall (Karolinska)
• Minetta Liu
• Mary Beth Martin
• Bill Miller (Edinburgh)
• Andrew Quong
• Baljit Singh
• Peter Shields
• Team 4 Consumers/Advocates
• Kate Taylor (Lombardi)
• Sharon Goodrich (National Breast Cancer
  Coalition)
• Margaret Borwhat (Women's Cancer Advocacy
  Network)
• we need to recruit 8-10 other survivors ASAP!

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Current Collaborating Institutions

• Howard University (subcontractor)
• Virginia Tech (Arlington)
• Catholic University (DC)
• SUNY (Buffalo, NY)
• University of Edinburgh, Scotland
• Karolinska Institute, Sweden

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Expertise and Technologies

• Expertise
• nutritionists and nutritional epidemiologists
• endocrinologists
• molecular biologists
• radiologists
• biostatisticians
• engineers
• medical oncologists
• computer scientists
• pathologists
• epidemiologists
• behavioral scientists
• Technologies
• high throughput genotyping
• molecular profiling (Affymetrix)
• tissue arrays
• digital mammography
• magnetic resonance imaging