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

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, case-control study of breast cancer Environmental, genetic, and lifestyle risk factors

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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, 1973-1993 Age <50 Age >50

  4. Breast Cancer Mortality by Race, 1969-1993 Age <50 Age >50

  5. Between ages 20 and 74 Living in 24 county study area Eligibility Criteria: Phase I Cases 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. Possible Risk FactorsSociobehavioral 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

  9. Adolescent Reproductive EventsAge at menarche, time to regular cycling, and breast cancerRockhill, Moorman, and Newman (1998) • Modest association with early menarche • No association with time to regular cycling • No difference by race

  10. Adolescent Reproductive EventsAdolescent 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-FeedingLactation 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 ActivityPhysical 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 RadiationThe 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

  14. Adult Lifestyle factors: Alcohol ConsumptionAlcohol consumption and breast cancer among black and white women in North Carolina Kinney, Millikan, Lin, Moorman, Newman (2000) • Slight association for moderate drinkers (91-181.9 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?

  15. Adult Lifestyle factors: ObesityBody 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: NutritionVitamin 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

  17. PesticidesA 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 pesticides OR= 1.8 (1.1, 2.8) • No clear association with DDE • Highest vs. lowest PCB levels, AA only OR=1.7 (1.0, 3.0) • Total PCBs for obese vs. non-obese, AA only OR=4.9 (1.6, 14.8)

  18. Hormone UseMenopausal Hormones and Breast Cancer in a Biracial PopulationMoorman, 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)

  19. Electromagnetic FieldsPopulation-Based Case-Control Study of Occupational Exposure to Electromagnetic Fields and Breast CancerWijngaarden, 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 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

  21. Phase II Participants First diagnosis of invasive breast cancer between 1993 and 2001 N = 1808 (788 AA, 1020 non AA) Between ages 20 and 74 Living in 24 county study area First diagnosis of in-situbreast carcinoma between 1996 and 2001 N = 503 (70 AA, 388 non AA)

  22. NSAIDs and antidepressantsAntidepressant Medications and Their Association with Invasive Breast Cancer and Carcinoma in situ of the BreastMoorman, Grubber, Millkan, and Newman (2003)Association Between Non-Steroidal and Anti-inflammatory drugs (NSAIDs) and Invasive Breast Cancer and Carcinoma in situ of the BreastMoorman, Grubber, Millikan and Newman (2003) Anti-depressants • No effect on invasive BC OR= 1.0 (0.7, 1.2) • Decreased risk of CIS OR= 0.6 (0.4, 0.8) NSAIDs • Decreased risk of invasive BC OR= 0.5 (0.3, 0.7) • Slightly decreased risk for CIS OR= 0.7 (0.4, 1.1)

  23. Known Risk FactorsSociobehavioral 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 WHR OR= 1.4 (1.0, 1.9) Ever Breast-fed OR= 0.7 (0.5, 1.0) OC use OR= 1.4 (1.0, 2.0) ER-PR- breast cancer (28%): OC use OR= 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-fed OR= 0.4 (0.2, 0.8) Ever abortion of miscarriage OR= 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-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) OR= 1.7 (1.1, 2.6) Family History of Breast Cancer OR= 1.7 (1.1, 2.5) High BMI OR= 0.7 (0.5, 0.9) High Waist-Hip Ratio OR= 1.4 (1.0, 2.0) Current Smoker OR= 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) 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) OR= 2.2 (1.3, 3.8) Family History of Breast Cancer OR= 1.5 (1.0, 2.2) Former Smoker OR= 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)

  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. 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

  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-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)

  34. Integrating population-based epidemiology and molecular biologyNewman 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 Breast Cancer i.e. smoking

  35. Integrating population-based epidemiology and molecular biologyNewman 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

  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 INewman 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

  38. 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 • Cigarette smoking modifies the prevalence and spectrum of p53 mutations

  39. Reproductive factors in relation to breast cancer characterized by p53 protein expressionFurberg 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

  40. The estrogen receptor alpha A908G (K303R) mutation and breast cancer riskConway 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)

  41. Risk factors for breast cancer characterized by the estrogen receptor alpha A908G (K303R) mutationConway 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

  42. 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

  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 CancerMillikan 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)

  45. HER2 codon 655 polymorphism and breast cancerMillikan 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.

  46. HER2 codon 655 polymorphism and breast cancerMillikan 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

  47. 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)

  48. Polymorphism in Uridine Diphospho-Glucuronosyltransferase 1A1 and breast cancer in African-AmericansGuillemente 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)

  49. DNA repair gene XRCC1 polymorphism and breast cancerDuell 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

  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. 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.

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