Host Factors that Increase Breast Cancer Risk 30 th Annual Miami Breast Cancer Conference March 7-10, 2013 Debu Tripathy, MD Professor of Medicine University of Southern California Norris Comprehensive Cancer Center
Interactions Between Host Risk Factors Genetic Predisposition Energy Balance Diet, Exercise Estrogen Exposure Radiation? Toxins
Caveats About BC Risk and Relative Risk Amir A, et al. JNCI 2011
Risk Factors for Breast Cancer Factor Cutpoint RR BRCA mutation No Yes 3.0-7.0 Breast density* 0% >75% 1.8-6.0 ADH on prior biopsy No Yes 3.7 Bone density 1 st ¼ 4 th ¼ 2.7-3.5 Age at 1 st delivery <20 >30 1.9-3.5 Mother/sister w/ BC No Yes 2.6 Age at menopause <45 >55 2.0 Prior benign biopsy No Yes 1.7 Postmenopausal BMI >30.7 <22.9 1.7
Risk Factors for Breast Cancer Factor Cutpoint RR Age at menarche >14 <12 1.4 Alcohol (drinks/d) 0 2-5 1.4 HRT Never C 1.2-1.4 OCP use Never P or C 1.1-1.2 Breast feeding >16m none 0.7 Parity >5 0 0.7 Exercise Yes No 0.7 Oophorect < age 35 Yes No 0.6
Breast Cancer Susceptibility Loci and Genes Foulkes WD NEJM 2008
Familial/Hereditary Breast Cancer Sporadic Likely interactions between genes and environment Familial 15-20% Hereditary 5-10% Number of recognized genes/syndromes BRCA1/BRCA2 (MAJORITY) Li Fraumeni (p53) Cowden (PTEN) Peutz-Jeghers (LKB1/STK11) Ataxia Telangiectasia (ATM) Lobular BC and diffuse hereditary gastric syndrome (CDH1/E-cadherin)
NCCN Criteria for Genetic Testing In patient with BC Age 45 Age 50 with 2 primaries or relative w/ BC age < 50 or w/ ovarian cancer (OC) History of OC Any age with 2 relative with BC or OC High risk ethnic background Male relative with BC OC Male BC OC Any individual Immediate relative with known deleterious mutation BC = Breast Cancer OB = Ovarian Cancer NCCN Guidelines 2010
Mammographic Density and BC Risk Harvard s Women Health Study N=1042 Post Meno BC Cases/1794 Controls R e l a t i v e R i s k 4 3 2 1 1.00 1.38 2.39 3.39 0 < 10% 10-24% 25-49& > 50% Breast Density Category Yaghiyan L, et al. JNCI 2011
Breast Density Quantitation and Cancer Risk Data from 3 case/control studies (N=5040) V ar i a ti o n Control Percent Density Case % Density (AUC 0.62) Variation (AUC 0.75) Heine JJ, et al. JNCI 2012
WHI Trial Update: Postmenopausal Estrogen Replacement Chlebowski R, et al. JNCI 2012
WHI Trial Update: Postmenopausal Estrogen Replacement Chlebowski R, et al. JNCI 2012
Age of Menarche and Menopause Meta-analysis of 117 Studies and 118,964 Women Collaborative Group on Hormonal Factors in Breast Cancer Lancet Oncol 2012
Parity and Breast Cancer Risk Meta-analysis of 8 Studies (RR per birth = 0.89, 95% CI = 0.84 0.94) For ER+/PR+ breast cancer Ma H, et al. Breast Cancer Res 2006
Relationship of Metabolism/Obesity, Estrogen and Inflammation in Breast Cancer inflammatory markers Interactions of Estrogen and Insulin/IGF Mechanisms + Adipose Tissue + + estrogens insulin IGFBP-1 + + SHBG + adipocytokines (e.g. leptin, TNF ) + + IGF-I (free) + + * PI3K, ras-raf-map Kinase signalling pathways * + Proliferation Anchorage Independent Growth Reduced Apoptosis * +
Overview of BMI and BC Risk in Women HR 1.12 per 5 kg/m 2 increase in post-meno HR 0.92 in pre-meno Renehan AG, et al. Lancet 2008
Breast Cancer Risk and Diabetes: Overview Analysis Boyle P, et al. Br J Cancer 2012
IGF-1 and Breast Cancer Risk Pooled Analysis Endogenous Hormone and Breast Cancer Collaborative Group Lancet Oncol 2010
Moderate Alcohol Use and BC Risk Million Women Study 1.3 M women enrolled BC screening clinics in UK 1996-2001 7.2 y follow-up Allen N, et al. JNCI 2009
Risk Calculators for Average/Moderate Risk (lack of strong family history) Breast Cancer Risk Assessment Tool of the NCI (Modified Gail Model) Inputs age, age at menarche, number of biopsies, presence of atypia, age at first live birth, and mother/sisters with breast cancer, uses SEER database Validated through the NSABP B-1 (Tamoxifen Prevention Trial) Available at http://cancer.gov/bcrisktool May underpredict patients with atypia, African American race and strong family history CARE Model (Gail modified for African American women) Uses the Women s Contraceptive and Reproductive Experiences database Gives higher estimates, has been validated with WHI AA patients WHI Model Incorporates WHI data and simplified intake data (age, biopsies, FH) Possibly performs better for ER+ cancers than Gail Model
Risk Calculators for Familial Risk BRCAPRO Estimates probability of BRCA mutation using Bayesian model developed at Duke that uses familial databases Incorporates family history (affected/unaffected), not non-familial risk factors Frank/Myriad II Empiric model from 10,000 cases tested by Myriad NCI Model Empiric model for those of Ashkenazi Jewish background Claus Model Uses CASH database from 1980-2, mostly familial factors BOADICEA Model Segregation analysis model, BRCA and polygenic/multiplicative effects Tyrer-Cuzick (IBIS) Model Based on IBIS database, integrates family history and estrogen exposure Multiple readouts from BRCAPRO and other models available at: CancerGene http://www4.utsouthwestern.edu/breasthealth/cagene/
Pre Test BRCA Prediction Models Relative to Spanish (HCSC) Model LUMC HUCH U Penn Frank/Myriad II Genetic Counselor Assessment De la Hoya M, et al. J Med Genet, 2003
Estimation of Breast Cancer Risk Reduction by Modifying Risk Factors (Diet, Activity, Alcohol use) Petracci E, et al, JNCI 2011
WHI: Randomized Dietary Study N = 29,294 N = 19,541 48,835 postmeno women in U.S. 20% fat 5 fruit and vegetables/d 6 grains/d 8.1 y follow-up Prentice RL, et al, JAMA 2006
Key Take Home Points Of the several risk factors for breast cancer, the most dramatic is a strong family history - genetic predisposition dictates screening/prevention measures Body mass and metabolism effects suggest that exercise and diet (AHA or ACS recommendations) is a prudent approach for everyone Breast density is a strong risk factor, but quantitation and interventions for risk-adjusted screening and prevention are needed A risk assessment and tailored plan for surveillance is nevertheless an important part of a general medical and breast-specific intake assessment