Download Racial Differences in Prostate Cancer

Past, Present and Future
By Leila Family and Katie O’Brien
October 31, 2008
Study Purpose: Phase I
• Dr. Beth Newman, Dr. Robert Millikan and other UNC
investigators saw need for a population-based, casecontrol study of breast cancer
• Environmental, genetic, and lifestyle risk factors
• Traditionally underserved populations
– Younger women (under age 50)
– Black women
– Rural populations
Breast Cancer Incidence by Race,
1973-1993
Age <50
Age >50
Breast Cancer Mortality by Race,
1969-1993
Age <50
Age >50
Eligibility Criteria:
Phase I Cases
Between ages
20 and 74
Living in 24
county
study area
First diagnosis of
invasive breast cancer
between 1993 and 1996
N = 861 (335 AA, 526 non-AA)
Eligibility Criteria:
Phase I Controls
Division of Motor
Vehicle Records
Medicare
Records
Women under age 65
Women age 65 to 74
Women living in same geographic region
without breast cancer, N = 790 (332 AA, 458 non AA)
Study Procedure
•
•
•
•
Identified via NCCCR RCA
Physician permission
Telephone contact
Interview with trained nurse
– Consent, medical record and tissue sample release
– Questionnaire
– Anthropometric measurements and blood sample
Possible Risk Factors
Sociobehavioral and Environmental
• Adolescent Reproductive Events: Early age at menarche, Time
until regular cycle, Pregnancy, and Oral contraceptive use
• Parity and Breast-feeding
• Lifestyle factors in adolescence: Physical activity, Smoking and
alcohol initiation
• Adult Lifestyle Factors: Alcohol use, Obesity and Nutrition
• Pesticides
• Hormone Use (HRT and OC)
• Electromagnetic Fields
Adolescent Reproductive Events
Age at menarche, time to regular cycling, and breast cancer
Rockhill, Moorman, and Newman (1998)
• Modest association with early menarche
Age at Menarche
OR, 95% CI
14 or older
1.00
13
1.3 (1.0, 1.7)
12
1.2 (0.9, 1.6)
11
1.3 (1.0, 1.9)
10 or younger
1.4 (0.9, 2.1)
• No association with time to regular cycling
• No difference by race
Adolescent Reproductive Events
Adolescent Reproductive Events and Subsequent Breast Cancer
Marcus, Baird, Millikan, Moorman, Qaqish, and Newman (1999)
Associated with breast cancer risk:
• Breast-feeding before age 20
• Use of oral contraceptives (A-A women)
OR= 0.2 (0.1, 0.6)
OR= 2.0 (1.0, 4.3)
No effect on risk of breast cancer:
• Having a full-term pregnancy before 18 (versus 20-29)
• Miscarriage or induced abortion before age 20
• Oral contraceptives (white women)
Breast-Feeding
Lactation and breast cancer risk
Furberg, Newman, Moorman, and Millikan (1999)
• Inverse association with breast-feeding across all
ages
OR = 0.7, 95% CI: (0.5, 0.8)
• Number of children, age at first or last child, and
duration of lactation did not alter protective
relationship
Lifestyle factors in adolescence:
Physical Activity
Physical Activity at age 12 and adult breast cancer risk
Marcus, Newman, Moorman, Millikan, Baird, Qaquish and Sternfeld (1999)
• Any physical activity at age 12 versus no activity
OR= 0.8, 95% CI = (0.6, 1.0)
• High activity at age 12
later menarche
more physical activity as adult
• Association not affected by age, race, menopausal status or
comparative body size (age 10)
Lifestyle factors in adolescence: Smoking,
Alcohol and Radiation
The associations of adolescent cigarette smoking, alcoholic beverage
consumption, environmental tobacco smoke, and ionizing radiation with
subsequent breast cancer risk
Marcus, Newman, Millikan, Moorman, Baird, and Qaquish (2000)
• Beginning smoking between age 10-14
OR=1.5 (0.9, 2.5)
• Exposed to ionizing radiation between age 10-19
OR=1.6 (0.4, 7.8)
• No effect of ETS age <18 or alcoholic beverage
consumption age 10-15
Adult Lifestyle factors: Alcohol
Consumption
Alcohol consumption and breast cancer among black and white women in
North Carolina
Kinney, Millikan, Lin, Moorman, Newman (2000)
• Slight association for moderate drinkers (91181.9 g/ week), OR= 1.3 (0.9- 2.1)
• No association between for heavy drinking,
lifetime drinking, binge drinking and alcohol
type did not matter
• Association with ER+ status?
Adult Lifestyle factors: Obesity
Body Size and Breast Cancer Risk in Black Women and White Women
Hall, Newman, Millikan, and Moorman (2000)
Race, Anthropometric Factors, and Stage at Diagnosis of Breast Cancer
Moorman, Jones, Millikan, Hall, and Newman (2001)
• High BMI slightly protective in some groups, but little
effect overall
• Positive dose-response relationship for WHR in all
race/age groups, with adjustment for BMI
• Association between severe obesity and later stage at
diagnosis using either BMI or WHR
• No difference by menopausal status, ER status, or
mammogram history
Adult Lifestyle factors: Nutrition
Vitamin supplement use and breast cancer in a North Carolina population
Moorman, Ricciuti, Millikan, and Newman (2001)
• Lower weekly fruit and vegetable servings increases risk among black
women (<20 vs. >30 servings per week)
OR= 1.51 (1.05, 2.17)
• No association with vitamin use in either race
Vitamin use
OR, Black women
OR, White women
Any multivitamin
1.04 (0.74, 1.56)
0.91 (0.67, 1.25)
Vitamin C
0.92 (0.51, 1.67)
0.85 (0.59, 1.24)
Vitamin E
1.12 (0.60, 2.10)
0.85 (0.57, 1.28)
Vitamin A
2.65 (0.83, 8.40)
1.49 (0.68, 3.25)
-carotene
0.93 (0.23, 3.68)
1.62 (0.78, 3.38)
Pesticides
A Population-Based Case-Control Study of Farming and Breast Cancer in North Carolina
Duell, Millikan, Savitz, Newman, Smith, Schell, and Sandler (2000)
Dichlorodiphenyldichloroethene, Polychlorinated Biphenyls, and Breast Cancer among
African-American and White Women in North Carolina
Millikan, DeVoto, Duell, Tse, Savitz, Beach, Edmiston, and Newman
• Increased duration of farming decreases risk
• Risk increased if mixed or applied pesticides
OR = 0.6 (0.4, 0.9)
OR= 1.8 (1.1, 2.8)
• No clear association with DDE
• Highest vs. lowest PCB levels, AA only
• Total PCBs for obese vs. non-obese, AA only
OR=1.7 (1.0, 3.0)
OR=4.9 (1.6, 14.8)
Hormone Use
Menopausal Hormones and Breast Cancer in a Biracial Population
Moorman, Kuwabara, Millikan, and Newman (2000)
Oral Contraceptives and Breast Cancer among African-American and White Women
Moorman, Millikan, and Newman (2001)
• Ever-HRT use did not increase risk
ORW= 0.8 (0.5, 1.2) ORAA= 0.7 (0.4, 1.2)
• Ever-OC use did not increase risk
ORW= 1.3 (0.8, 2.1) ORAA= 1.4 (0.8, 2.4)
Electromagnetic Fields
Population-Based Case-Control Study of Occupational Exposure to
Electromagnetic Fields and Breast Cancer
Wijngaarden, Nylander-French, Millikan, Savitz, and Loomis (2001)
• Office workers and industrial workers only
• No evidence of increased risk
• Some evidence of modification by ER status
– ER+, premenopausal women had increased risk
Study Purpose: Phase II
• Enrolled 1996-2001
• Increase sample size
• Include some in situ cases and controls
• New exposures- NSAIDs, anti-depressants, dietary questions
• More information about breast cancer subtypes and their
specific risk factors
Phase II Participants
Between ages
20 and 74
Living in 24
county
study area
First diagnosis of
invasive breast cancer
between 1993 and 2001
N = 1808
(788 AA, 1020 non AA)
First diagnosis of
in-situ breast carcinoma
between 1996 and 2001
N = 503
(70 AA, 388 non AA)
NSAIDs and antidepressants
Antidepressant Medications and Their Association with Invasive Breast Cancer and
Carcinoma in situ of the Breast
Moorman, Grubber, Millkan, and Newman (2003)
Association Between Non-Steroidal and Anti-inflammatory drugs (NSAIDs) and
Invasive Breast Cancer and Carcinoma in situ of the Breast
Moorman, Grubber, Millikan and Newman (2003)
Anti-depressants
• No effect on invasive BC
• Decreased risk of CIS
OR= 1.0 (0.7, 1.2)
OR= 0.6 (0.4, 0.8)
NSAIDs
• Decreased risk of invasive BC
• Slightly decreased risk for CIS
OR= 0.5 (0.3, 0.7)
OR= 0.7 (0.4, 1.1)
Known Risk Factors
Sociobehavioral and Environmental
•
•
•
•
•
•
•
•
•
Early Menarche
Lack of Breast-feeding
Lack of Physical Activity (during adolescence)
Early Smoking Initiation
Exposure to Radiation (during adolescence)
High Waist-Hip Ratio
Low Fruit/Vegetable Intake
Direct Pesticide Exposure
No NSAIDs Use
Risk Factors by Subtype
Hormone-related factors and risk of breast cancer by estrogen and progesterone
receptor status.
Huang, Newman, Millkan, Schell, Hulka, Moorman (2000)
ER+PR+ breast cancer (53%):
Early age at menarche
High WHR
Ever Breast-fed
OC use
OR=1.5 (1.1, 2.0)
OR= 1.4 (1.0, 1.9)
OR= 0.7 (0.5, 1.0)
OR= 1.4 (1.0, 2.0)
ER-PR- breast cancer (28%):
OC use
First degree relative with breast/ovarian cancer
OR= 1.4 (1.0, 2.0)
OR= 1.8 (1.2, 2.7)
ER+PR- breast cancer (11%):
Ever Breast-fed
Ever abortion of miscarriage
OR= 0.4 (0.2, 0.8)
OR= 0.5 (0.3, 0.9)
Risk Factors by Race
Tumor Characteristics in African American and White Women
Furberg, Millikan, Dressler, Newman, and Geradts (2001)
African-American women were more likely to have:
• More advanced stage disease
– Larger tumors at diagnosis
– More frequent lymph node involvement
• More ER- /PR- tumors
• Higher grade tumors
Young African-American women are more likely than young
White women to have:
• ER-/PR- tumors
• Stage II, III or IV tumors
Risk Factors by Race
Comparative Analysis of Breast Cancer Risk among African-American Women
and White Women
Hall, Moorman, Millikan and Newman (2005)
Risk factors for young, African-American women:
Early Menarche (< age 11)
OR= 1.6 (1.0, 2.4)
Ever Breast-Fed
OR= 0.6 (0.4, 0.8)
Family History of Breast Cancer
OR= 2.2 (1.3, 3.5)
High Waist-Hip Ratio
OR= 1.4 (1.0, 1.9)
Former Smoker
OR= 1.8 (1.2, 2.7)
Risk factors for young, White women:
Early Menarche (< age 11)
Family History of Breast Cancer
High BMI
High Waist-Hip Ratio
Current Smoker
OR= 1.7 (1.1, 2.6)
OR= 1.7 (1.1, 2.5)
OR= 0.7 (0.5, 0.9)
OR= 1.4 (1.0, 2.0)
OR= 0.7 (0.5, 1.0)
Risk Factors by Race
Comparative Analysis of Breast Cancer Risk among African-American Women and White Women
Hall, Moorman, Millikan and Newman (2005)
Risk factors for older, African-American women:
Late menopause (> 50 years)
OR= 2.2 (1.2, 4.0)
Nulliparity
OR= 2.0 (1.1, 3.6)
High Waist-Hip Ratio
OR= 1.5 (1.0, 3.0)
Had HRT
OR= 0.6 (0.4, 0.8)
Risk factors for older, White women:
Late menopause (> 50 years)
Family History of Breast Cancer
Former Smoker
OR= 2.2 (1.3, 3.8)
OR= 1.5 (1.0, 2.2)
OR= 1.4 (1.0, 1.9)
Breast Cancer Subtypes
Race, Subtypes and Survival
Race, Breast Cancer Subtypes, and Survival in the Carolina Breast Cancer Study
Carey, Perou, Livasy, Dressler, Cowan, Karaca, Troester, Tse, Edmiston, Deming,
Geradts, Cheang, Nieldson, Moorman, Earp and Millikan (2006)
Subtype
Percent of CBCS cases
Luminal A
(ER+ PR+ HER2-)
51%
Luminal B
(ER+ PR+ HER2+)
16%
Basal-like
(ER- PR- HER2- ck5/6+ and/or HER1+)
20%
HER2+, ER(HER2+,ER-, PR-)
7%
Unclassified
(negative for all five IHC markers)
6%
Race, Subtypes and Survival
Race, Breast Cancer Subtypes, and Survival in the Carolina Breast Cancer Study
Carey, Perou, Livasy, Dressler, Cowan, Karaca, Troester, Tse, Edmiston, Deming,
Geradts, Cheang, Nieldson, Moorman, Earp and Millikan (2006)
Race, Subtypes and Survival
Race, Breast Cancer Subtypes, and Survival in the Carolina Breast Cancer Study
Carey, Perou, Livasy, Dressler, Cowan, Karaca, Troester, Tse, Edmiston, Deming,
Geradts, Cheang, Nieldson, Moorman, Earp and Millikan (2006)
Luminal A or B patients older than other patients, Basal-like are
younger
HER2+/ER- patients had more positive lymph nodes
Basal-like patients more likely to be:
•
•
•
•
African-American
Pre-menopausal
Higher grade tumors
Unfavorable histology
Race, Subtypes and Survival
Race, Breast Cancer Subtypes, and Survival in the Carolina Breast Cancer Study
Carey, Perou, Livasy, Dressler, Cowan, Karaca, Troester, Tse, Edmiston, Deming,
Geradts, Cheang, Nieldson, Moorman, Earp and Millikan (2006)
Basal-like Breast Cancer
Epidemiology of Basal-like Breast Cancer
Millikan, Newman, Tse, Moorman, Conway, Smith, Labbok, Geradts, Bensen,
Jackson, Nyante, Livasy, Carey, Earp and Perou (2008)
Basal-like is much more common in young, African-American women and
has one of lowest survival rates
Risk factors for Basal-like tumors (versus Luminal A):
Younger age at menarche (<13)
OR= 1.4 (1.1, 1.9)
Parity (> 3 children)
OR= 1.9 (1.1, 3.3)
Age at first full term pregnancy (< 26)
OR= 1.9 (1.2, 3.2)
Breast-feeding
OR= 0.7 (0.4, 0.9)
Lactation suppressant use
OR= 1.5 (1.1, 2.0)
High Waist-Hip Ratio
OR= 2.3 (1.4, 3.6)
Integrating population-based
epidemiology and molecular biology
Newman B, Moorman PG, Millikan RC, et al. 1995
• Most environmental and sociobehavorial risk factors only
have modest associations
– Use molecular biology to define subtypes
– Look at how genetic susceptibility modifies the effects of
environmental risk factors on breast cancer
Gene Variant
i.e. DNA repair gene polymorphism
Environment Risk Factor
i.e. smoking
Breast Cancer
Integrating population-based
epidemiology and molecular biology
Newman B, Moorman PG, Millikan RC, et al. 1995
Biologic samples:
-collection of blood samples
-DNA from formalin-fixed paraffin embedded tumor
specimens
Lab Techniques:
-PCR (polymerase chain reaction)
-IHC (immunohistochemistry)
-genotyping via Taqman assay
Associations with genetic mutations
and expression
-BRCA1 mutation (inherited)
-p53 mutation (somatic)
-Estrogen receptor alpha A908G mutation
(somatic)
-Focal adhesion kinase expression
Frequency of BRCA1 mutation in
CBCS I
Newman B, Mu H, Butler LM, et al. 1998
Prevalence of BRCA1 mutation (N=211):
• 3.3% in white women
• 0% in African American women
• In white women:
– 23% of cases with family history of ovarian cancer
– 13% of cases with family history of breast cancer
p53 mutations and smoking in breast
cancer
Conway K, Edmiston SN, Cui L, et al. 1995
• Found 108 mutations in 456 invasive tumors
-71% point mutations
-29% deletions or insertions
P53 mutation
Prevalence
OR, 95% CI
Never
23.6%
1.00
Former
16.2%
0.6 (0.4,1.2)
Current
36.5%
2.1 (1.2, 3.8)
Smoking status
• Cigarette smoking modifies the prevalence and
spectrum of p53 mutations
Reproductive factors in relation to
breast cancer characterized by p53
protein expression
Furberg H, Millikan RC, Geradts J, et al 2003
• 296/638 or 46% cases classified as p53+
•
No difference between p53+ and p53- breast cancer
– Except for:
• Prolonged OC use more strongly associated with p53+
(OR=3.1, 95% CI: 1.2-8.1) among younger women only
• A first degree family history of breast cancer was associated
with p53+ for younger women (OR=1.5 95% CI: 1.0-2.2) and
(OR=1.4 95% CI: 0.9-2.3) for older women
The estrogen receptor alpha A908G
(K303R) mutation and breast cancer
risk
Conway K, Parrish E, Edminston, et al. 2005
• Estrogen is important in breast development.
– Point mutation in alpha receptor has been reported to be
hypersensitive to estrogen.
• Detected somatic mutations in 37/653 (5.7%)
• Mutation found more frequently in:
– high grade tumors (OR=2.83, 95% CI: 1.09-7.34)
– mixed lobular/ductal tumors (OR=2.10, 95% CI: 0.86,
5.12)
Risk factors for breast cancer
characterized by the estrogen receptor
alpha A908G (K303R) mutation
Conway K, Parrish E, Edmiston SN, et al. 2007
• ESR1 A908G positive mutation:
– Associated with first degree family history of breast cancer
(OR=2.69, 95% CI: 1.15, 6.28).
– Associated with longer duration and recent OC use
• ESR1 A908G negative mutation:
– Inversely correlated with HRT
High focal adhesion kinase expression in
invasive breast carcinomas is associated
with an aggressive phenotype
Lark AL, Livasy CA, Dressler L, et al. 2005
• FAK is protein tyrosine kinase expressed in early stage
invasive tumors
• N=629/861 (73%) paraffin-embedded tissues had high
expression defined as 3+ or 4+ intensity or 90% positive
cells using IHC
• High FAK expression associated with:
– high mitotic index, nuclear grade 3
– estrogen and progesterone negative
– HER-2/neu overexpression
Association with SNPs*
•
•
•
•
Glutathione S-Transferases (GSTM1, GSTT1, GSTP1)
HER2 codon 655
Manganese superoxide dismutase Ala-9Val
Uridine Diphospho-Glucuronosyltransferase 1A1
(UGT1A1)
• DNA repair polymorphisms (XRCC1, XRCC3, NER)
• CYP1A1
• Mitochondrial DNA G10398A
*SNP=single nucleotide polymorphism= DNA sequence variation that occurs
when a single nucleotide (A,T,C, or G) is changed (in at least 1% of
population)
Glutathione S-Transferases M1, T1,
and P1 and Breast Cancer
Millikan RC, Pittman G, Tse C-K, et al. 2000
• GSTs are involved in detoxification of tobacco smoke
carcinogens
– Null genotype indicates lack of enzymatic activity, increased risk
• No significant case-control differences in genotype
frequencies for all GST loci for both African-American
and white women
• For women with a first degree family history:
– Positive association for GSTM1 null (OR=2.1; 95% CI: 1.0-4.2)
– Positive association for GSTT1 null (OR=1.9; 95% CI: 0.8-4.6)
HER2 codon 655 polymorphism and
breast cancer
Millikan RC, Eaton A, Worley K, et al. 2003
HER2 receptor involved in signal transduction and cell proliferation
Mutations lead to tyrosine phosphorylation amplification and/or overexpression
of HER2 receptor protein
No overall association between HER2 genotype and breast cancer.
Family history, age
at diagnoses
Ile/Ile
Ile/Val
Val/Val
Ile/Val +
Val/Val
Yes, <45
ref
2.0 (0.9, 4.5)
ND
2.3 (1.0, 5.3)
Yes, >45
ref
1.0 (0.6, 1.7)
0.9 (0.3, 2.4)
1.0 (0.6, 1.6)
No, <45
ref
1.1 (0.8, 1.5)
1.3 (0.7, 2.6)
1.1 (0.6, 1.5)
No, >45
ref
0.9 (0.7, 1.1)
1.0 (0.6, 1.5)
0.9 (0.7, 1.1)
HER2 codon 655 polymorphism and
breast cancer
Millikan RC, Hummer AJ, Wolff MS, et al. 2005
Kin cohort study design: genotype of first degree relatives
are inferred based upon measured genotypes in study
participants
• Overall no significant association, increased lifetime risk
for subset of women diagnosed <40 years with Val/Val
genotype
• Results provide additional evidence that HER2 codon 655
may predispose to early-onset breast cancer
Manganese superoxide dismutase Ala-9Val
polymorphism and risk of breast cancer
Millikan RC, Player J, de Cotret AR, et al. 2004
•
MnSOD enzyme counteracts oxidative damage to DNA
• The odds ratio for MnSOD Ala/Ala vs. any Val genotype
was not elevated in African Americans or whites.
Risk factors for Ala/Ala (versus Val/Val or Val/Ala):
OR (95% CI)
Smoking (>20 years)
1. 5 (1.0-2.2)
Radiation to the chest
2.3 (1.3-4.1)
Occupational exposure to ionizing radiation 1.6 (0.8-3.1)
Long term NSAID use
0.4 (0.2-0.7)
Polymorphism in Uridine DiphosphoGlucuronosyltransferase 1A1 and
breast cancer in African-Americans
Guillemente C, Millikan RC, Newman B, et al. 2000
-UGT1A1 enzyme is involved in estradiol metabolism
-RT-PCR analysis showed expression of UGT1A1 in
11/12 breast cancer lines tested
-possible interaction between UGT and hormones
(OR=1.8; 95% CI: 1.0-3.1 in premenopausal women)
-Associated with ER- tumors (OR=2.1; 95% CI: 1.0-4.2)
DNA repair gene XRCC1
polymorphism and breast cancer
Duell E, Millikan RC, Pittman, et al. 2001
• XRCC1 encodes a protein involved in base excision repair
• Looked at 2 XRCC1 polymorphisms (codon 194 and 399)
– No association for codon 194 genotype
– Positive association between codon 399 Arg/Arg
genotype among:
• African-Americans: (OR=1.7; 95% CI: 1.1-2.4)
• Whites: (OR=1.00; 95% CI: 0.8-1.4)
– ORs for duration of smoking were elevated
– ORs for occupational exposure to ionizing radiation were stronger
for both African American and white women
XRCC1 genotype and breast cancer: functional
studies and epidemiologic data show interactions
between XRCC1 codon 280 His and smoking.
Pachkowski F, Winkel S, Kubota Y, et al. 2006
• Study Design: combination of lab and epidemiologic
• Looked at SS break repair capacity of isogenic Chinese hamster ovary
cells expressing human forms of XRCC1 after exposure to toxins
– Indicated that XRCC1 280 His variant is detrimental
• Also looked at potential associations with XRCC1 codon 194, 280, and
399 genotypes, breast cancer and smoking
– Former smokers with Arg/Arg genotype have increased risk
(OR=1.4, 95% CI: 1.1-1.7)
– OR for smoking and breast cancer were stronger for codon 280 His
vs. codon 194 Arg/Arg or 399 Arg/Arg.
Polymorphisms in DNA repair genes,
medical exposure to ionizing radiation,
and breast cancer risk.
Millikan RC, Player JS, deCotret AR, et al. 2005
• Polymorphisms in 4 DNA repair genes:
–
(XRCC3 codon 241Thr/Met, NBS1 codon 185 Glu/Gln, XRCC2 codon 188
ArgHis and BRCH2 codon 372 Asn/His )
• No association for 0 or 1 variants
• Combining women with 2, 3, or 4 variant genotypes, a
positive association was observed between breast cancer
and number of lifetime mammograms
• Limitation:
– inability to distinguish between diagnostic and screening
mammograms
Polymorphisms in nucleotide excision repair
genes, smoking and breast cancer
Mechanic LE, Millikan RC, Player J, et al.2006
• Nucleotide excision repair pathway is the principal pathway for
removing smoking-induced DNA damage
–
ORs calculated for 9 polymorphisms in NER genes: (XPD codon 312, XPD codon 751,
RAD23B codon 249, XPG codon 1104, XPC codon 939, XPF codon 415, XPF codon 662,
ERCC6 1213, and ERCC6 1230)
• Smoking was more strongly associated with African American
compared to white women
For African-American women:
Multiplicative interaction found between combined NER genotypes:
Smoking dose
Duration
Time since cessation
Age at initiation
Former smoking
p=0.06
p=0.09
p=0.02
p=0.04
p=0.03
Cigarette smoking, cytochrome
P4501A1 polymorphisms, and breast
cancer
Li Y, Millikan R, Bell DA, et al. 2004
-CYP1A1 is involved in metabolism of PAHs from
tobacco smoke
-No associations were observed from 4 CYP1A1 variants
(M1-M4) alleles and breast cancer
• Cigarette smoking increases breast cancer risk:
– in women with CYP1A1 M1 variant genotypes
(OR=2.1, 95% CI 1.2-3.5)
– in African American women with CYP1A1 M3 variant genotypes
(OR=1.3 95% CI: 0.8, 2.2)
Polychlorinated biphenyls, P450
CYP1A1 polymorphisms and breast
cancer risk
Li Y, Millikan RC, Bell DA, et al. 2004
•PCBs are metabolized by cytochrome P450 enzymes, activate
CYP1A1, and produce oxidative DNA damage.
•Weak positive association between high levels of PCBs and
breast cancer for premenopausal AA women
Joint effect for PCBs
and CYP1A1 genotype
White
M1
ICR=0.4 (-0.2, 0.9)
M2
ICR=0.8 (0.1, 1.6)
M3
African-American
ICR=0.0 (-0.9, 0.9)
ICR=0.8 (-0.3, 1.9)
Mitochondrial DNA G10398A polymorphism
and invasive breast cancer
Canter JA, Kallianpur AR, Parl FF, et al. 2005
• Mitochondria increase free radical generation 
damage to mitochondrial and nuclear DNA  somatic
mutation carcinogenesis
• African mitochondria harbor polymorphism less frequently
that white mitochondria (~5% vs. 80%)
Results for G10398A polymorphism:
Vanderbilt: OR=2.90; 95% CI: 0.6-18.3
(7 cases, 3 controls)
CBCS:
OR=1.60; 95% CI: 1.10-2.31
(654 cases, 605 controls)
Known Risk Factors
Genetic
•
•
Low prevalence of BRCA1 mutation in CBCS
P53 mutation: High prevalence of p53 for current smokers,
–
•
•
•
•
•
•
•
•
•
•
Prolonged OC use and family history associated with p53+
Estrogen receptor alpha mutation: found in high grade tumors and mixed
lobular/ductal tumors, and associated with family history and OC use
FAK: associated with aggressive tumors and HER-2/neu overexpression
Glutathione S- Transferases: positive associations for GSTM1 and GSTT1 null
for women with family history
HER 2 codon 655: Positive association in women age 45 or younger with family
history with Val/Val genotype
MnSOD: Positive association for Ala/Ala genotype and smoking, and ionizing
radiation, and use of NSAIDs
UDT1A1: Association for premenopausal AA women only and ER- tumors
XRCC1: association with 399 Arg/Arg for AA only
NER: interaction with polymorphisms, breast cancer, smoking only for AA
CYP1A1: Smoking increases risk in women with M1 genotype, and African
American women with M3 genotype
G10398A polymorphism: Increased risk for AA women
Summary of Null Results
Cyclooxygenase 2 polymorphism (Val 511 Ala),
nonsteroidal anti-inflammatory drug use and breast cancer in African
American women, Moorman PG, Sesay J, Nwosu V, et al. 2005
Cigarette smoking, N-acetyltransferases 1 and 2 and breast cancer
risk, Millikan RC, Pittman GS, Newman B, et al. 1998
P57 (KIP2) polymorphisms and breast cancer risk, Li Y, Millikan RC,
Newman B 1999
MDM2-309 T/G promoter polymorphism and breast cancer, Millikan
RC, Heard K, Winkel S, et al. 2006
Catecho-O-methyltransfersase and breast cancer risk, Millikan RC,
Pittman GS, Tse C-K J, et al. 1998
Risk of breast cancer and HER2/neu oncogene amplification, Huang
W-Y, Newman B, Millikan RC, et al. 2000
Take-home messages
• Heterogeneous disease
– 5 “intrinsic” subtypes exhibit distinct clinical behavior
– Implications for treatment and etiology
• Multi-factor Etiology
– Gene-Environment Interaction
• Racial Disparities
– Subtypes by race
• Younger African Americans more likely to be
diagnosed with basal-like subtype.
What’s left?
• Update on survival by subtype using Phase II
participants
• More SNPs (N=1536)
• Ancestry Informative Markers
• Genome Wide Association Studies (GWAS)
• Geocoding/ Access to Care
Senator Jeanne Hopkins Lucas
(1934 - 2007)
Advocacy in CBCS
Phase III
• 2000 new invasive cases
– 500 of each race/age category
• Changes from Phase I and II:
– Added more counties (now 44 total)
– Revised exposure assessment
– Treatment information
• Which treatments offered/received and why
– Quality of Life survey
– Removed dietary questions
– Follow-up calls, every 6 months for 2 years
• Enrolling now through 2013
Phase III Study Map
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
Newman B, Moorman PG, Millikan. R, Qaqish BF, Geradts J, Aldrich TE, Lui ET. The Carolina Breast Cancer
Study: Integrating population-based epidemiology and molecular biology. Breast Cancer Research and Treatment
35: 51-60, 1995.
Millikan R, DeVoto E, Newman B, Savitz D. Studying environment influences and breast cancer risk: Suggestions
for an integrated population-based approach. Breast Cancer Research and Treatment 35: 70-89, 1995.
Rockhill B, Newman B, Weinberg C. Uses and abuses of population attributable fraction. American Journal of
Public Health 88: 15-19, 1998.
Newman B, Mu H, Butler LM, Millikan RC, Moorman PG, King M-C. Frequency of breast cancer attributable to
BRCA1 in a population-based series of American women. JAMA 279: 915-921, 1998.
Millikan RC, Pittman GS, Newman B, Tse C-KJ, Selmin O, Rockhill B, Savitz D, Moorman PG, Bell DA. Cigarette
smoking, N-acetyltransferases 1 and 2 and breast cancer risk. Cancer Epidemiology, Biomarkers and Prevention 7:
826-833, 1998.
Rockhill B, Moorman PG, Newman B. Age at menarche, time to regular cycling, and risk of breast cancer. Cancer
Causes and Control: 447-53, 1998.
Millikan RC, Pittman GS, Tse CKJ, Duell E, Newman B, Savitz D, Moorman PG, Boissy RJ, Bell DA. Catechol-Omethyltransferase (COMT) and breast cancer risk. Carcinogenesis 19: 1943-47, 1998.
Li Y, Millikan R, Tse C-KJ, Newman B, Conway K, Liu ET. Germline P57 polymorphisms and risk of breast cancer.
Human Genetics 104: 83-88, 1999.
Furberg H, Newman B, Moorman P, Millikan R. Lactation and breast cancer risk. International Journal of
Epidemiology 28: 396-402, 1999.
Marcus P, Baird D, Millikan R, Moorman P, Qaqish B, Newman B. Adolescent reproductive events and subsequent
breast cancer risk. American Journal of Public Health 89: 1244-47, 1999.
Marcus P, Newman B, Moorman B, Millikan R, Baird D, Qaqish B, Sternfeld B. Physical activity at age 12 and
adult breast cancer risk (United States). Cancer Causes and Control: 10(4): 293-302, 1999.
Schildkraut J, Demark-Wahnefried DeVoto E, Hughes C, Laseter J, Newman B. Environmental contaminants and
body fat distribution. Cancer Epidemiology, Biomarkers and Prevention 8: 179-83, 1999.
References
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
Marcus P, Newman B, Moorman P, Millikan R, Baird D, Qaqish B. The associations of adolescent cigarette smoking,
alcoholic beverage consumption and environmental tobacco smoke, and ionizing radiation with subsequent breast cancer
risk (United States). 151(7) 703-14, 2000.
Kinney AY, Millikan RC, Lin YH, Moorman PG, Newman B. Alcohol consumption and breast cancer among black and
white women in North Carolina. Cancer Causes and Control (Netherlands) 11(4): 345-357, 2000.
Huang W-Y, Newman B, Millikan R, Schell M, Hulka B, Moorman P. Hormone-related factors and risk of breast cancer
by estrogen receptor and progesterone receptor status. American Journal of Epidemiology (US) 151(7): 703-714, 2000.
Huang W-Y, Newman B, Millikan R, Conway K, Hulka B, Schell M, Liu E. Risk of breast cancer according to the status
of Her-2/neu oncogene amplification. Cancer Epidemiology, Biomarkers and Prevention (US) 9(1): 65-71, 2000.
Guillemette C, Millikan R, Newman B, Housman D. Genetic Polymorphisms in uridine diphosphoglucuronosyltransferase 1A1 and association with breast cancer among African-Americans. Cancer Research 60(4): 9506, 2000.
Millikan RC. NAT1*10 and NAT1*11 polymorphisms and breast cancer risk. Cancer Epidemiology, Biomarkers, and
Prevention 9(2): 217-9, 2000.
Duell E, Millikan R, Savitz D, Newman B, Smith J, Schell M, Sandler D. A population-based case control study of
farming and breast cancer in North Carolina. Epidemiology 11(5): 523-531, 2000.
Moorman P, Kuwabara H, Millikan R, Newman B. Menopausal hormones and breast cancer in a biracial population.
American Journal of Public Health 90(6): 966-971.
Hall IJ, Newman B, Millikan R, Moorman P. Body size and breast cancer risk in black women and white women.
American Journal of Epidemiology 151(8): 754-764, 2000.
Duell E, Millikan R, Pittman G, Winkel S, Lunn R, Tse C-K, Eaton A, Mohrenweiser H, Newman B, Bell D. XRCC1
polymorphisms and breast cancer risk. Cancer Epidemiology, Biomarkers and Prevention 10: 567-573, 2000.
Millikan R, Pittman G, Tse C-K, Savitz D, Newman B, Bell D. Glutathione S-transferases M1, T1, and P1 and breast
cancer. Cancer Epidemiology, Biomarkers and Prevention 9(6): 567- 573, 2000.
Dunmore C, Plummer P, Regan G, Mattingly D, Jackson S, Millikan R. Re: Race and differences in breast cancer
survival in a managed care population. Journal of National Cancer Institute 92: 1690-91, 2000.
References
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
Duell E, Millikan R, Savitz D, Schell M, Newman B, Tse C-K, Sandler D. Reliability of reported farming activities and
pesticide use in a case-control study of breast cancer in North Carolina. Annals of Epidemiology 11: 178-85, 2001.
Moorman P, Jones B, Millikan R, Hall I, Newman B. Race, Anthropometric Factors and Stage at Diagnosis of Breast
Cancer. American Journal of Epidemiology 153: 284-91, 2001.
Tseng M, Yeatts K, Millikan R, Newman B. Area-level characteristics and smoking in women. American Journal of
Public Health 91. 1847-50 (2001).
Millikan R, DeVoto E, Duell E, Tse C-K, Savitz D, Beach J, Edmiston S, Jackson S, Newman B. DDEs, PCBs, and
breast cancer: a case-control study of African-American and white women. Cancer Epidemiology, Biomarkers and
Prevention 9: 567-73, 2001.
Furberg H, Millikan R, Dressler L, Newman B, Geradts J. Tumor characteristics in African American and white women.
Breast Cancer Research and Treatment 68: 33-43 2001.
Moorman P, Ricciuti M, Millikan R, Newman B. Vitamin and mineral supplements and breast cancer risk. Results from
the Carolina Breast Cancer Study. Public Health and Nutrition 4: 821, 2001.
Van Wijngaarden E, Nylander-French L, Millikan R, Savitz D, Loomis D. Population-based case-control study of
occupational exposure to electromagnetic fields and female breast cancer. Annals of Epidemiology 11: 297-303. 2001.
Moorman P, Millikan R, Newman B. Oral contraceptives and breast cancer among African-American women and white
women. Journal of the National Medical Association. 9: 329-34 (2001).
Conway K, Edmiston S, Cui L, Drouin S, Pang J, He M, Tse C-K, Geradts J, Dressler L, Liu E, Millikan R, Newman B.
Prevalence and spectrum of p53 mutations associated with smoking in breast cancer. Cancer Research 62: 1987-95, 2002
Cooper G, Savitz D, Millikan R, Tse C-K. Organochlorine exposure and age at natural menopause. Epidemiology 13:
729-33, 2002.
Furberg H, Millikan RC, Geradts J, Gammon MD, Dressler LG, Ambrosone CB, Newman B. Environmental Factors in
Relation to Breast Cancer Characterized by p53 Protein Expression. Cancer Epidemiology, Biomarkers and Prevention
11: 829-35, 2002.
Moorman P, Grubber J, Millikan RC, Newman B. Anti-depressant medications and their association with invasive breast
cancer and carcinoma in situ of the breast. Epidemiology 14: 307-14, 2003.
References
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
Millikan R, Eaton A, Worley K, Biscocho L, Hodgson E, Huang W-Y, Geradts J, Iacocca M, Cowan D, Conway K, Dressler
L. HER2 codon 655 polymorphism and risk of breast cancer in African Americans and whites. Breast Cancer Research and
Treatment 79: 355-64, 2003.
Furberg H, Millikan RC, Geradts J, Gammon MD, Dressler LG, Ambrosone CB, Newman B. Reproductive factors in
relation to breast cancer characterized by p53 protein expression (US). Cancer Causes and Control. 14: 609-18, 2003.
Moorman P, Grubber J, Millikan R, Newman B. Association between non-steroidal anti-inflammatory drugs (NSAIDs) and
invasive breast cancer and carcinoma in situ of the breast. Cancer Causes and Control 14: 915-922, 2003.
Millikan R, Player J, de Cotret AR, Moorman P, Pittman G, Vannappagari V, Tse C-K, Keku T. Manganese Superoxide
Dismutase (MnSOD) Ala-9Val polymorphism and risk of breast cancer in a population-based case-control study of African
Americans and whites. Breast Cancer Research 6: R264-274, 2004.
Li Y, Millikan R, Bell D, Cui L, Tse C-K, Newman B, Conway K. Cigarette smoking, cytochrome P4501A1 (CYP1A1)
polymorphisms, and breast cancer among African Americans and white women. Breast Cancer Research 6: 460-473, 2004.
Moorman P. Associations of aspirin use and hormone receptor status with breast cancer risk. Journal of the American
Medical Association. 292: 1426, 2004.
Li Y, Moorman P, Millikan R, Newman B. Comparative analysis of breast cancer risk factors among African-American
women and white women. American Journal of Epidemiology 161: 40-51, 2005.
Millikan R, Hummer A, Wolff M, Begg C. HER2 codon 655 polymorphism and breast cancer: Results from kin-cohort and
case-control analyses. Breast Cancer Research and Treatment. 89: 309-12, 2005.
Conway K, Parrish E, Edmiston S, Tolbert D, Tse J, Geradts J, Livasy C, Singh H, Newman B, Millikan R. The estrogen
receptor alpha A908G (K303R) mutation occurs at a low frequency in invasive breast tumors: results from a population
based study. Breast Cancer Research 7: R871-880, 2005.
Canter J, Kallianpur A, Parl F, Millikan R. Mitochondrial DNA G10398A polymorphism and invasive breast cancer in
African-American women. Cancer Research 65: 8028-33, 2005.
Lark A, Livasy C, Millikan R, Tse C-K, Moore D, Cowan D, Dressler L, Little D, Craven R, Cancer W. High FAK
expression in invasive breast carcinomas is associated with aggressive phenotype. Modern Pathology 18: 1289-94, 2005.
Millikan R, Player J, deCotret A, Tse C-K, Keku T. Polymorphisms in DNA repair genes, medical exposure to ionizing
radiation and breast cancer risk. Cancer Epidemiology, Biomarkers and Prevention 14: 2326-34, 2005.
References
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
Lin D, Zeng D, Millikan R. Maximum likelihood estimation of haplotype effects and haplotype-environment interactions in
association studies. Genetic Epidemiology, 29: 299-312, 2005.
Canter J, Kallianpur A, Parl F, Millikan R. Mitochondrial DNA G10398A Polymorphism and Invasive Breast Cancer in
African-American Women. Cancer Research 66: 1880-1881, 2006.
Carey L, Perou C, Livasy C, Dressler L, Cowan D, Conway K, Karaca G, Troester M, Tse C-K, Edmiston S, Deming S,
Geradts J, Cheang M, Nielson T, Moorman P, Earp H, Millikan R. Race, Breast Cancer Subtypes and Survival in the
Carolina Breast Cancer Study. Journal of the American Medical Association 295: 2492-2502, 2006.
Mechanic L, Millikan R, Player J, Rene de Cotret A, Winkel S, Worley K, Heard K, Tse C-K, Keku T. Polymorphisms in
Nucleotide Excision Repair Genes, Smoking and Breast Cancer in African Americans and Whites: A Population-Based
Case-Control Study. Carcinogenesis 27: 1377-85, 2006.
Pachkowski B, Winkel S, Kubota Y, Swenberg J, Millikan R, Nakamura J. XRCC1 genotype and breast cancer: Functional
studies and epidemiologic data demonstrate interactions between XRCC1 codon 280 His and smoking. Cancer Research
66: 2876-77, 2006.
Millikan R, Heard K, Winkel S, Hill E, Heard K, Massa B, Mayes L, Williams P, Holston R, Conway K, Edmiston S, De
Cotret AR. No association between the MDM2-309 T/G promoter polymorphism and breast cancer in African Americans or
whites. Cancer Epidemiology, Biomarkers and Prevention 15: 175-77, 2006.
Moorman P, Sesay J, Nwosu V, Kane J, de Cotret A, Worley K, Millikan R. COXR Polymorphism (Val511Ala), NSAID Use
and Breast Cancer in African-American Women. Cancer Epidemiology, Biomarkers and Prevention 14: 3013-14, 2005.
Livasy C, Perou C, Karaca G, Cowan D, Maria D, Jackson S, Tse C-K, Millikan RC. Identification of a basal-like subtype
of breast ductal carcinoma in situ. Human Pathology. 38:197-204, 2007.
Conway K, Parrish E, Edmiston S, Tolbert D, Tse C-K, Moorman P, Newman B, Millikan R. Risk Factors for Breast
Cancer Characterized by the Estrogen Receptor Alpha A908G (K303R) Mutation. Breast Cancer Research 9: R36, 2007.
Millikan R, Newman B, Tse C-K, Moorman P, Conway K, Smith L, Labbok M, Geradts J, Bensen, Jackson S, Nyante S,
Livasy C, Carey L, Earp H, Perou C. Epidemiology of basal-like breast cancer. Breast Cancer Research and Treatment 190:
123-139, 2008.
Acknowledgements
Thanks to Bob Millikan and current CBCS study staff:
Mary Beth Bell, Judy Bryan, Dorothy Martin, Sara
Williams, Georgette Regan, Roxan Brock and Jessica Tse.
Thanks to all past CBCS authors and researchers.
Happy Birthday Georgette!