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Past, Present and Future By Leila Family and Katie O ’ Brien October 31, 2008.

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1 Past, Present and Future By Leila Family and Katie O ’ Brien October 31, 2008

2 Study Purpose: Phase I Dr. Beth Newman, Dr. Robert Millikan and other UNC investigators saw need for a population-based, case- control study of breast cancer Environmental, genetic, and lifestyle risk factors Traditionally underserved populations –Younger women (under age 50) –Black women –Rural populations

3 Breast Cancer Incidence by Race, Age <50 Age > 50

4 Breast Cancer Mortality by Race, Age <50 Age > 50

5 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)

6 Eligibility Criteria: Phase I Controls Division of Motor Vehicle Records Women under age 65 Medicare Records Women age 65 to 74 Women living in same geographic region without breast cancer, N = 790 (332 AA, 458 non AA)

7 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

8 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 Possible Risk Factors Sociobehavioral and Environmental

9 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 MenarcheOR, 95% CI 14 or older (1.0, 1.7) (0.9, 1.6) (1.0, 1.9) 10 or younger1.4 (0.9, 2.1) No association with time to regular cycling No difference by race

10 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 OR= 0.2 (0.1, 0.6) Use of oral contraceptives (A-A women)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)

11 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

12 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)

13 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 OR=1.5 (0.9, 2.5) Exposed to ionizing radiation between age OR=1.6 (0.4, 7.8) No effect of ETS age <18 or alcoholic beverage consumption age 10-15

14 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 ( g/ week), OR= 1.3 ( ) No association between for heavy drinking, lifetime drinking, binge drinking and alcohol type did not matter Association with ER+ status?

15 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

16 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 ( 30 servings per week) OR= 1.51 (1.05, 2.17) No association with vitamin use in either race Vitamin useOR, Black womenOR, White women Any multivitamin1.04 (0.74, 1.56)0.91 (0.67, 1.25) Vitamin C0.92 (0.51, 1.67)0.85 (0.59, 1.24) Vitamin E1.12 (0.60, 2.10)0.85 (0.57, 1.28) Vitamin A2.65 (0.83, 8.40)1.49 (0.68, 3.25)  - carotene 0.93 (0.23, 3.68)1.62 (0.78, 3.38)

17 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 OR = 0.6 (0.4, 0.9) Risk increased if mixed or applied pesticidesOR= 1.8 (1.1, 2.8) No clear association with DDE Highest vs. lowest PCB levels, AA onlyOR=1.7 (1.0, 3.0) Total PCBs for obese vs. non-obese, AA only OR=4.9 (1.6, 14.8)

18 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 OR W = 0.8 (0.5, 1.2) OR AA = 0.7 (0.4, 1.2) Ever-OC use did not increase risk OR W = 1.3 (0.8, 2.1) OR AA = 1.4 (0.8, 2.4)

19 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

20 Study Purpose: Phase II Enrolled 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

21 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)

22 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 BCOR= 1.0 (0.7, 1.2) Decreased risk of CISOR= 0.6 (0.4, 0.8) NSAIDs Decreased risk of invasive BCOR= 0.5 (0.3, 0.7) Slightly decreased risk for CISOR= 0.7 (0.4, 1.1)

23 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

24 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 OR=1.5 (1.1, 2.0) High WHROR= 1.4 (1.0, 1.9) Ever Breast-fedOR= 0.7 (0.5, 1.0) OC useOR= 1.4 (1.0, 2.0) ER-PR- breast cancer (28%): OC useOR= 1.4 (1.0, 2.0) First degree relative with breast/ovarian cancer OR= 1.8 (1.2, 2.7) ER+PR- breast cancer (11%): Ever Breast-fedOR= 0.4 (0.2, 0.8) Ever abortion of miscarriageOR= 0.5 (0.3, 0.9)

25 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

26 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-FedOR= 0.6 (0.4, 0.8) Family History of Breast CancerOR= 2.2 (1.3, 3.5) High Waist-Hip RatioOR= 1.4 (1.0, 1.9) Former SmokerOR= 1.8 (1.2, 2.7) Risk factors for young, White women: Early Menarche (< age 11) OR= 1.7 (1.1, 2.6) Family History of Breast CancerOR= 1.7 (1.1, 2.5) High BMIOR= 0.7 (0.5, 0.9) High Waist-Hip RatioOR= 1.4 (1.0, 2.0) Current SmokerOR= 0.7 (0.5, 1.0)

27 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) NulliparityOR= 2.0 (1.1, 3.6) High Waist-Hip RatioOR= 1.5 (1.0, 3.0) Had HRTOR= 0.6 (0.4, 0.8) Risk factors for older, White women: Late menopause (> 50 years) OR= 2.2 (1.3, 3.8) Family History of Breast CancerOR= 1.5 (1.0, 2.2) Former SmokerOR= 1.4 (1.0, 1.9)

28 Breast Cancer Subtypes

29 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) SubtypePercent 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%

30 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)

31 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

32 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)

33 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-feedingOR= 0.7 (0.4, 0.9) Lactation suppressant useOR= 1.5 (1.1, 2.0) High Waist-Hip RatioOR= 2.3 (1.4, 3.6)

34 Integrating population-based epidemiology and molecular biology Newman B, Moorman PG, Millikan RC, et al 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 FactorBreast Cancer i.e. smoking

35 Integrating population-based epidemiology and molecular biology Newman B, Moorman PG, Millikan RC, et al 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

36 Associations with genetic mutations and expression -BRCA1 mutation (inherited) -p53 mutation (somatic) -Estrogen receptor alpha A908G mutation (somatic) -Focal adhesion kinase expression

37 Frequency of BRCA1 mutation in CBCS I Newman B, Mu H, Butler LM, et al 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

38 p53 mutations and smoking in breast cancer Conway K, Edmiston SN, Cui L, et al Found 108 mutations in 456 invasive tumors - 71% point mutations -29% deletions or insertions P53 mutationPrevalenceOR, 95% CI Smoking status Never23.6%1.00 Former16.2%0.6 (0.4,1.2) Current36.5%2.1 (1.2, 3.8) Cigarette smoking modifies the prevalence and spectrum of p53 mutations

39 Reproductive factors in relation to breast cancer characterized by p53 protein expression Furberg H, Millikan RC, Geradts J, et al /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: ) among younger women only A first degree family history of breast cancer was associated with p53+ for younger women (OR=1.5 95% CI: ) and (OR=1.4 95% CI: ) for older women

40 The estrogen receptor alpha A908G (K303R) mutation and breast cancer risk Conway K, Parrish E, Edminston, et al 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: ) – mixed lobular/ductal tumors (OR=2.10, 95% CI: 0.86, 5.12)

41 Risk factors for breast cancer characterized by the estrogen receptor alpha A908G (K303R) mutation Conway K, Parrish E, Edmiston SN, et al 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

42 High focal adhesion kinase expression in invasive breast carcinomas is associated with an aggressive phenotype Lark AL, Livasy CA, Dressler L, et al 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

43 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)

44 Glutathione S-Transferases M1, T1, and P1 and Breast Cancer Millikan RC, Pittman G, Tse C-K, et al 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: ) –Positive association for GSTT1 null (OR=1.9; 95% CI: )

45 HER2 codon 655 polymorphism and breast cancer Millikan RC, Eaton A, Worley K, et al Family history, age at diagnoses Ile/IleIle/ValVal/ValIle/Val + Val/Val Yes, <45ref2.0 (0.9, 4.5)ND2.3 (1.0, 5.3) Yes, >45ref1.0 (0.6, 1.7)0.9 (0.3, 2.4)1.0 (0.6, 1.6) No, <45 ref1.1 (0.8, 1.5)1.3 (0.7, 2.6)1.1 (0.6, 1.5) No, >45 ref0.9 (0.7, 1.1)1.0 (0.6, 1.5)0.9 (0.7, 1.1) 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.

46 HER2 codon 655 polymorphism and breast cancer Millikan RC, Hummer AJ, Wolff MS, et al 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

47 Manganese superoxide dismutase Ala-9Val polymorphism and risk of breast cancer Millikan RC, Player J, de Cotret AR, et al 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 ( ) Radiation to the chest2.3 ( ) Occupational exposure to ionizing radiation1.6 ( ) Long term NSAID use0.4 ( )

48 Polymorphism in Uridine Diphospho- Glucuronosyltransferase 1A1 and breast cancer in African-Americans Guillemente C, Millikan RC, Newman B, et al 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: in premenopausal women) -Associated with ER- tumors (OR=2.1; 95% CI: )

49 DNA repair gene XRCC1 polymorphism and breast cancer Duell E, Millikan RC, Pittman, et al 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: ) Whites: (OR=1.00; 95% CI: ) –ORs for duration of smoking were elevated –ORs for occupational exposure to ionizing radiation were stronger for both African American and white women

50 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 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: ) –OR for smoking and breast cancer were stronger for codon 280 His vs. codon 194 Arg/Arg or 399 Arg/Arg.

51 Polymorphisms in DNA repair genes, medical exposure to ionizing radiation, and breast cancer risk. Millikan RC, Player JS, deCotret AR, et al 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

52 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 p=0.06 Duration p=0.09 Time since cessation p=0.02 Age at initiation p=0.04 Former smoking p=0.03

53 Cigarette smoking, cytochrome P4501A1 polymorphisms, and breast cancer Li Y, Millikan R, Bell DA, et al 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 ) –in African American women with CYP1A1 M3 variant genotypes (OR=1.3 95% CI: 0.8, 2.2)

54 Polychlorinated biphenyls, P450 CYP1A1 polymorphisms and breast cancer risk Li Y, Millikan RC, Bell DA, et al Joint effect for PCBs and CYP1A1 genotype WhiteAfrican-American M1 ICR=0.4 (-0.2, 0.9)ICR=0.0 (-0.9, 0.9) M2ICR=0.8 (0.1, 1.6) M3ICR=0.8 (-0.3, 1.9) 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

55 Mitochondrial DNA G10398A polymorphism and invasive breast cancer Canter JA, Kallianpur AR, Parl FF, et al 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: (7 cases, 3 controls) CBCS: OR=1.60; 95% CI: (654 cases, 605 controls)

56 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

57 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 Cigarette smoking, N-acetyltransferases 1 and 2 and breast cancer risk, Millikan RC, Pittman GS, Newman B, et al 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 Catecho-O-methyltransfersase and breast cancer risk, Millikan RC, Pittman GS, Tse C-K J, et al Risk of breast cancer and HER2/neu oncogene amplification, Huang W-Y, Newman B, Millikan RC, et al. 2000

58 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.

59 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

60 Senator Jeanne Hopkins Lucas ( )

61 Advocacy in CBCS

62 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

63 Phase III Study Map

64 References 1.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, 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, Rockhill B, Newman B, Weinberg C. Uses and abuses of population attributable fraction. American Journal of Public Health 88: 15-19, 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: , 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: , Rockhill B, Moorman PG, Newman B. Age at menarche, time to regular cycling, and risk of breast cancer. Cancer Causes and Control: , Millikan RC, Pittman GS, Tse CKJ, Duell E, Newman B, Savitz D, Moorman PG, Boissy RJ, Bell DA. Catechol-O- methyltransferase (COMT) and breast cancer risk. Carcinogenesis 19: , 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, Furberg H, Newman B, Moorman P, Millikan R. Lactation and breast cancer risk. International Journal of Epidemiology 28: , 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: , 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): , Schildkraut J, Demark-Wahnefried DeVoto E, Hughes C, Laseter J, Newman B. Environmental contaminants and body fat distribution. Cancer Epidemiology, Biomarkers and Prevention 8: , 1999.

65 References 13.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) , 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): , 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): , 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, Guillemette C, Millikan R, Newman B, Housman D. Genetic Polymorphisms in uridine diphospho- glucuronosyltransferase 1A1 and association with breast cancer among African-Americans. Cancer Research 60(4): , Millikan RC. NAT1*10 and NAT1*11 polymorphisms and breast cancer risk. Cancer Epidemiology, Biomarkers, and Prevention 9(2): 217-9, 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): , Moorman P, Kuwabara H, Millikan R, Newman B. Menopausal hormones and breast cancer in a biracial population. American Journal of Public Health 90(6): 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): , 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: , 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): , 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: , 2000.

66 References 25.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: , 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: , Tseng M, Yeatts K, Millikan R, Newman B. Area-level characteristics and smoking in women. American Journal of Public Health (2001). 28.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: , Furberg H, Millikan R, Dressler L, Newman B, Geradts J. Tumor characteristics in African American and white women. Breast Cancer Research and Treatment 68: 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, 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: 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: (2001). 33.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: , Cooper G, Savitz D, Millikan R, Tse C-K. Organochlorine exposure and age at natural menopause. Epidemiology 13: , 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: , 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: , 2003.

67 References 37.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: , 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: , 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: , 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: R , 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: , Moorman P. Associations of aspirin use and hormone receptor status with breast cancer risk. Journal of the American Medical Association. 292: 1426, 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, 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: , 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: R , Canter J, Kallianpur A, Parl F, Millikan R. Mitochondrial DNA G10398A polymorphism and invasive breast cancer in African-American women. Cancer Research 65: , 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: , 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: , 2005.

68 References 49.Lin D, Zeng D, Millikan R. Maximum likelihood estimation of haplotype effects and haplotype-environment interactions in association studies. Genetic Epidemiology, 29: , Canter J, Kallianpur A, Parl F, Millikan R. Mitochondrial DNA G10398A Polymorphism and Invasive Breast Cancer in African-American Women. Cancer Research 66: , 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: , 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: , 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: , 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: , 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: , 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: , 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, 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: , 2008.

69 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!


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