The Breast Cancer Family Registry: Description of Resource and some Applications

Transcription

1 The Breast Cancer Family Registry: Description of Resource and some Applications Mary Beth Terry, PhD Associate Professor Department of Epidemiology Mailman School of Public Health

2 Overview of Talk Description of the Breast CFR Applications of resource Traditional case-control analyses Environmental Modifiers of Carrier Status Gene-environment Interaction Pathology/Risk factors Other ongoing research projects How to use the resource July 5, 2007 Page 2

3 Breast & Ovarian Family Registries A Unique Resource for Gene-Environment Studies *Cancer Control Ontario N. California Cancer Center* *Huntsman U of Utah * Metro NY *Fox Chase Univ of Melbourne NCI Initiated in 1995 Refunded in 2006 July 5, 2007 Page 3

4 Metropolitan NY Registry Columbia Mt Sinai MSKCC NYU Beth Israel Gouverneur Stony Brook NYH Queens July 5, 2007 Page 4

5 John et al. Breast Cancer Res 2004 July 5, 2007 Page 5

6 John et al. Breast Cancer Res 2004 July 5, 2007 Page 6

7 John et al. Breast Cancer Res 2004 July 5, 2007 Page 7

8 Traditional Case-control designs OC use (Milne et al) Ovarian Cyst (Knight et al) July 5, 2007 Page 8

9 Milne et al. Cancer Epidemiol Biomarkers Prev 2005 July 5, 2007 Page 9

10 Knight et al. Int J Cancer 2006 July 5, 2007 Page 10

11 Knight et al. Int J Cancer 2006 July 5, 2007 Page 11

12 Genetic Analyses Examples ATM CHECK2 - CYP1B1 July 5, 2007 Page 12

13 Bernstein et al. Hum Mutat 2006 July 5, 2007 Page 13

14 Bernstein et al. Cancer Epidemiol Biomarkers Prev 2006 July 5, 2007 Page 14

15 Ahsan et al. Breast Cancer Res Treat 2004 July 5, 2007 Page 15

16 Environmental Modifiers OCs (Haile) Alcohol (McGuire) July 5, 2007 Page 16

17 Haile et al. Cancer Epidemiol Biomarkers Prev 2006 July 5, 2007 Page 17

18 Haile et al. Cancer Epidemiol Biomarkers Prev 2006 July 5, 2007 Page 18

19 Risk of Invasive Breast Cancer among White Non- Hispanic BRCA1 and BRCA2 Mutation Carriers According to Alcohol Consumption for Women < 50 McGuire et al. Cancer Epidemiol Biomarkers Prev 2006 July 5, 2007 Page 19

20 Additional examples G X E: Alcohol Pathology July 5, 2007 Page 20

21 Alcohol and Cancer < Breast Cancer Colorectal Cancer Laryngeal Cancer Stomach Cancer Lung Cancer Pharyngeal Cancer Esophageal Cancer Liver Cancer Food, Nutrition and the Prevention of Cancer: a global perspective. American Institute for Cancer Research, World Cancer Research Fund, 1997 July 5, 2007 Page 21

22 Research Questions to Resolve Is the overall modest association driven by confounding? Support against from dose-response biological mechanisms Do genetic differences in alcohol metabolism modify the association Fast metabolizers in risk from alcohol consumption Do women at high-risk of breast cancer also face a greater increase in risk from moderate alcohol consumption? July 5, 2007 Page 22

23 The New Yorker, September 11, 2006 July 5, 2007 Page 23

24 Alcohol Consumption (g/day) and Relative Risk of Breast Cancer Ellison et al. AJE 2001 July 5, 2007 Page 24

25 Alcohol dehydrogenase Alcohol dehydrogenase oxidizes ~80% of ethanol to acetaldehyde, a carcinogen Acetaldehyde induces - sister chromatid exchange - mutations, and - chromosomal aberrations Activity in liver but also expressed in other tissues including breast Several polymorphisms in ADH gene - ADH3 (also known as ADH1C) - ADH2 (also known as ADH1B) July 5, 2007 Page 25

26 GXE Multivariate ORs 95% CI ADH ADH ADH fast intermediate slow Lifetime alcohol consumption Never < 15 g/d 0.8( ) 1.3( ) 0.8( ) ( ) 1.5( ) 1.3( ) > ( ) 0.8( ) 0.9( ) Terry MB et al. Carcinogenesis 2006 July 5, 2007 Page 26

27 The association between alcohol, ADH1C, ADH1B and Breast Cancer Risk, Breast CFR Variable Ageadjusted OR Alcohol non-drinker 1 ADH1C Genotype ADH1B Genotype 95% CI <7 drinks per week drinks per week AA 1 GA GG AA 1 GA GG Terry MB et al. Breast Cancer Research and Treatment, forthcoming July 5, 2007 Page 27

28 ADH1C Genotype and Alcohol Intake and Breast Cancer Risk, Breast CFR Age-adjusted* OR (95% CI) Multivariateadjusted** (N=788) OR (95% CI) Premenopausal Sister Sets (N=523) OR** (95% CI) Postmenopausal Sister Sets (N=265) OR** (95% CI) Fast, non-drinker Intermediate, non-drinker 1.10 ( ) 1.10 ( ) 0.99 ( ) 0.69 ( ) Slow, non-drinker 1.11 ( ) 1.18( ) 0.62 ( ) 1.75 ( ) Fast, < 7 drinks/week 0.84( ) 0.84( ) 0.75 ( ) 1.32 ( ) Intermediate, < 7 drinks/week 0.98( ) 1.03 ( ) 0.74( ) 1.18 ( ) Slow, < 7 drinks/week 1.12 ( ) 1.17 ( ) 1.09 ( ) 1.61 ( ) Fast, > 7 drinks/week 0.93( ) 0.91( ) 0.97 ( ) 1.84 ( ) Intermediate, > 7 drinks/week 0.88 ( ) 0.87( ) 0.61 ( ) 1.32 ( ) Slow, > 7 drinks/week 0.61( ) 0.64( ) 0.36( ) 1.25( ) *Adjusted for reference age. **Adjusted for age, body mass index, age at menarche, and parity. Terry MB et al. Breast Cancer Research and Treatment, forthcoming July 5, 2007 Page 28

29 Table 4. Alcohol consumption, ADH1B genotype and breast cancer risk Age-adjusted* OR (95% CI) Multivariate-adjusted** OR (95% CI) ADH1B*1/1 and ADH1B*1/2, 1.0 (Ref) non-drinker 1.0 (Ref) ADH1B*2/2, non-drinker ADH1B*1/1 and ADH1B*1/2, 1.09 < 7 drinks/day ADH1B*2/2, < 7 drinks/day ADH1B*1/1 and ADH1B*1/2, > 7 drinks/day ADH1B*1/1, > 7 drinks/day * Odds ra tio (OR) and 95% con fidence interval (CI) adjusted for reference age. **Adjusted for reference age and body mass index. Terry MB et al. Breast Cancer Research and Treatment, forthcoming July 5, 2007 Page 29

30 Breast Cancer: A Heterogeneous Disease Other Mucinous Medullary Tubular Lobular ER-PR- ER- Breast Cancer ER-PR+ Ductal ER+PR+ ER+ ER+PR- July 5, 2007 Page 30

31 Competing Hypotheses Risk factor 1 Risk factor 2 Risk factor 3 Phenotype 1 Phenotype 2 Phenotype 3 Phenotype-Specific Breast Cancer Risk factor 4 Phenotype 4 Risk factor 1 Risk factor 2 Risk factor 3 Generalized Increased Risk Phenotype-Independent Phenotype 1 Phenotype 2 Phenotype 3 Risk factor 4 Phenotype 4 July 5, 2007 Page 31

32 Histologic Results (definition 2) Ductal vs. control Lobular vs. control Medullary vs. control Tubular vs. control Mucinous vs. control OR (95%CI) OR (95%CI) OR (95%CI) OR (95%CI) OR (95%CI) Race White Nonwhite 0.85 ( ) 0.33 ( ) 1.40 ( ) 0.48 ( ) 1.33 ( ) Education Up to high school Vocational/technical school or some college 0.92 ( ) 1.03 ( ) 0.50 ( ) 1.92 ( ) 1.20 ( ) Some university degree 0.85 ( ) 0.96 ( ) 0.56 ( ) 2.70 ( ) 1.34 ( ) OC use Nonusers Use< 1 yr 0.91 ( ) 0.72 ( ) 0.25 ( ) 0.52 ( ) 0.96 ( ) Use 1yr 0.90 ( ) 0.84 ( ) 0.94 ( ) 0.91 ( ) 0.62 ( ) HRT use Nonusers Users 0.93 ( ) 0.84 ( ) 1.87 ( ) 1.24 ( ) 1.86 ( ) Age at menarche < ( ) 1.30 ( ) 0.55 ( ) 1.16 ( ) 0.71 ( ) ( ) 1.05 ( ) 0.77 ( ) 0.90 ( ) 0.46 ( ) Parity Parous Nulliparous 1.25 ( ) 1.06 ( ) 0.88 ( ) 0.55 ( ) 1.65 ( ) Age at first birth 1.00 ( ) 1.02 ( ) 0.97 ( ) 0.99 ( ) 0.96 ( ) Cigarette smoking Nonsmokers Former smokers 0.98 ( ) 1.19 ( ) 0.28 ( ) 3.01 ( ) 0.76 ( ) Current smokers 1.12 ( ) 1.16 ( ) 0.60 ( ) 1.84 ( ) 0.37 ( ) Alcohol drinking Nondrinkers < 7 drinks/wk 1.07 ( ) 0.83 ( ) 0.70 ( ) 0.50 ( ) 1.05 ( ) 7 drinks/wk 1.05 ( ) 0.88 ( ) 0.44 ( ) 0.25 ( ) 0.76 ( ) BMI <25 kg/m kg/m ( ) 1.23 ( ) 1.29 ( ) 1.81 ( ) 1.43 ( ) * Adjusted for age, site and all the variables in the table July 5, 2007 Page 32

33 ER/PR Results ER+PR+ vs. control ER+PR- vs. control ER-PR+ vs. control ER-PR- vs. control OR (95%CI) OR (95%CI) OR (95%CI) OR (95%CI) Race White Nonwhite 1.41 ( ) 1.72 ( ) 0.91( ) 1.81 ( ) Education Up to high school Vocational/technical school or some college 0.90 ( ) 0.96 ( ) 0.92 ( ) 0.80 ( ) Some university degree 0.93 ( ) 0.82 ( ) 1.33 ( ) 0.60 ( ) OC use Nonusers Use< 1 yr 0.96 ( ) 0.86 ( ) 0.54 ( ) 0.82 ( ) Use 1yr 0.90 ( ) 0.74 ( ) 0.85 ( ) 1.18 ( ) HRT use Nonusers Users 0.99 ( ) 1.08 ( ) 0.43 ( ) 0.84 ( ) Age at menarche < ( ) 1.22 ( ) 0.84 ( ) 0.97 ( ) ( ) 0.97 ( ) 0.95 ( ) 0.95 ( ) Parity Parous Nulliparous 1.29 ( ) 1.35 ( ) 1.14 ( ) 1.07 ( ) Age at first birth 1.01 ( ) 1.02 ( ) 0.96 ( ) 0.99 ( ) Cigarette smoking Nonsmokers Former smokers 0.92 ( ) 0.96 ( ) 0.81 ( ) 0.88 ( ) Current smokers 1.04 ( ) 1.13 ( ) 1.06 ( ) 1.01 ( ) Alcohol drinking Nondrinkers < 7 drinks/wk 0.99 ( ) 1.16 ( ) 1.25 ( ) 1.01 ( ) 7 drinks/wk 0.99 ( ) 1.09 ( ) 1.08 ( ) 0.75 ( ) BMI <25 kg/m kg/m ( ) 0.88 ( ) 0.88 ( ) 1.14 ( ) * Adjusted for age, site and all the variables in the table July 5, 2007 Page 33

34 Ongoing Research Estimating the Contribution of TP53 Mutations to Breast Cancer Genetics and Breast Cancer in Blacks Extending BRCAPRO to Handle Errors in Family History IGF Pathway and Breast Cancer Risk in African-Americans Admixture and Breast Cancer Susceptibility among Latinas Early Life Factors and Breast Cancer Risk Epigenetic Risk along the Lifecourse Association between the TGFBR1*6A allele and breast cancer Identification of Novel Breast Cancer Susceptibility Genes in Ashkenazi Jewish Families Without BRCA1 or BRCA2 Mutations July 5, 2007 Page 34

35 Ongoing Research Prognosis in BRCA1 Associated Breast Cancer Genetic Studies of Mammographic Density Role of the ATM Gene in Familial Breast Cancer Genomewide Association in Early-onset Breast Cancer - A Multi-site Genetic Epidemiologic Study to Identify Novel Alleles for Breast Cancer Based on High Density SNP Array Breast Cancer Metastasis - a Heritable Trait Comprehensive Evaluation of BRCA1 and BRCA2 Unclassified Variants (UCVs) July 5, 2007 Page 35

36 Using the resource Develop concept proposal One page abstract Description of what the aims are, what type of data is needed Circulated to the steering committee Steering committee assigns to scientific liason Develop full 7 page proposal Data only - Steering committee Data + Biospecimens - circulated to advisory committee All forms and timelines on web July 5, 2007 Page 36

37 Acknowledgements National Cancer Institute New York Investigators: Ruby Senie, PhD, co-pi Regina Santella, PhD co-pi Wendy Chung, MD, coinvestigator Hanina Hibshoosh, MD, coinvestigator Habib Ahsan, MD, coinvestigator July 5, 2007 Page 37