1. Julie R. Gralow, M.D. Director, Breast Medical Oncology, Seattle Cancer Care Alliance Professor, Medical Oncology, University of Washington School of Medicine Member, Clinical Division, Fred Hutchinson Cancer Research Center Breast Cancer Prevention and Risk Reduction

2. Primary PreventionPrimary Prevention –Lifestyle –Chemoprevention –Prophylactic surgery Secondary PreventionSecondary Prevention –Screening and early detection Breast Cancer Prevention and Risk Reduction

3. Breast Cancer Risk Reduction: Lifestyle ExerciseDietWeightAlcohol

4. Lifestyle Recommendations for Breast Cancer Risk Reduction Regular exerciseRegular exercise Low fat, high fiber dietLow fat, high fiber diet Good intake of fruits and vegetablesGood intake of fruits and vegetables Low alcoholLow alcohol Maintain a good body weightMaintain a good body weight

5. Report of the President’s Cancer Panel 2006-2007 Healthy Lifestyles www.deainfo.nih.nci.gov/advisory/pcp Tobacco and second hand tobacco smoke exposure account for 1/3 of cancer deaths in the U.S.Tobacco and second hand tobacco smoke exposure account for 1/3 of cancer deaths in the U.S. Unhealthy diet, weight, physical activity may account for another 1/3Unhealthy diet, weight, physical activity may account for another 1/3 Clear evidence that healthy lifestyle behaviors can reduce chance of developing cancerClear evidence that healthy lifestyle behaviors can reduce chance of developing cancer

6. Exercise and Breast Cancer Risk Regular physical activity is associated with decreased breast cancer riskRegular physical activity is associated with decreased breast cancer risk Many studies have found that women who exercise at higher intensity levels for > 3 hours/week reduce their risk of breast cancer by 20-40%Many studies have found that women who exercise at higher intensity levels for > 3 hours/week reduce their risk of breast cancer by 20-40%

7. Women’s Health Initiative (WHI) Cohort: Physical Activity and Breast Cancer Risk McTiernan A et al, JAMA 2003 Patients: 74,171 women ages 50-79Patients: 74,171 women ages 50-79 Study: incidence of breast cancer correlated to physical activityStudy: incidence of breast cancer correlated to physical activity Results:Results: –1,780 cases of breast cancer over 4.7 yrs –Regular physical activity at age 18, 35, and 50 had 14% reduction in breast cancer risk –1.25-2.5 hrs/week brisk walking had 18% decreased risk –Greatest reduction seen for women with >10 hrs/week brisk walking

8. Obesity may account for 25-30% of several major cancersObesity may account for 25-30% of several major cancers Weight gain during adulthood is a consistent and strong predictor of breast cancer riskWeight gain during adulthood is a consistent and strong predictor of breast cancer risk Overweight women are 1.3 – 2.1 times more likely to die from breast cancer compared to women with normal weightOverweight women are 1.3 – 2.1 times more likely to die from breast cancer compared to women with normal weight Obesity and Cancer

9. Primary PreventionPrimary Prevention –Lifestyle –Chemoprevention –Prophylactic surgery Secondary PreventionSecondary Prevention –Screening and early detection Breast Cancer Prevention and Risk Reduction

10. Chemoprevention The use of natural or synthetic chemical agents to reverse, suppress, or prevent cancer The use of natural or synthetic chemical agents to reverse, suppress, or prevent cancer

11. Breast Cancer Chemoprevention Agents FDA approved for breast cancer chemoprevention:FDA approved for breast cancer chemoprevention: –Tamoxifen (Nolvadex) –Raloxifene (Evista) Both drugs are synthetic, non-steroidal, Selective Estrogen Receptor Modulators (SERMs)Both drugs are synthetic, non-steroidal, Selective Estrogen Receptor Modulators (SERMs) –Mixed anti-estrogenic and weak estrogenic effects depending on the tissue

12. NSABP P-01 Tamoxifen Breast Cancer Prevention Trial Fisher B et al, JNCI 90:1371-1378, 1998 13,400 women at high risk for breast cancer13,400 women at high risk for breast cancer Randomized to placebo vs. tamoxifen for 5 yearsRandomized to placebo vs. tamoxifen for 5 years Study stopped at mean 3.5 years of follow-up)Study stopped at mean 3.5 years of follow-up)

13. 5-Year Non-Breast Cancer Events on Tamoxifen (10,000 Women) Gail M et al, JNCI 1999 Age Group (Caucasian) Event 35-39 40-49 50-59 60-69 70-79 Hip fracture -1 -1 -22 -52 -151 Endometrial CA +2 +16 +120 +206 +223 CVA +2 +13 +32 +91 +196 PE +7 +15 +49 +85 +177 DVT +13 +15 +16 +28 +44 Colle’s/Spine Fx -13 -13 -42 -71 -115 Cataracts +35 +35 +101 +269 +384 Quality of life (hot flashes, vaginal discharge) must be factored in as well

14. NSABP P-02 STAR Chemoprevention Trial (Study of Tamoxifen and Raloxifene) Wickerham DL et al, ASCO 2006, abstract 5 19,747 postmenopausal women at risk for breast cancer (5-year risk 1.7%)19,747 postmenopausal women at risk for breast cancer (5-year risk 1.7%) Randomized to tamoxifen vs. raloxifene for 5 yearsRandomized to tamoxifen vs. raloxifene for 5 years 47 month median follow-up47 month median follow-up Concern about implications of difference in DCISConcern about implications of difference in DCIS

15. Tamoxifen and Raloxifene for Breast Cancer Chemoprevention Weighing the Risks and Benefits Both provide women at increased risk with an option to reduce their chance of developing breast cancerBoth provide women at increased risk with an option to reduce their chance of developing breast cancer Influences on mortality and long-term risks and benefits have not been defined in the prevention settingInfluences on mortality and long-term risks and benefits have not been defined in the prevention setting Balance of benefits and risks varies by age, breast cancer risk (and hysterectomy status for tamoxifen)Balance of benefits and risks varies by age, breast cancer risk (and hysterectomy status for tamoxifen)

16. Breast Cancer Chemoprevention: Ongoing Studies PostmenopausalPostmenopausal –Aromatase inhibitors »IBIS 2 (Anastrozole vs. Placebo) »EXCEL (Exemestane vs Placebo) PremenopausalPremenopausal –Ovarian suppression –Vitamin D

17. Primary PreventionPrimary Prevention –Lifestyle –Chemoprevention –Prophylactic surgery Secondary PreventionSecondary Prevention –Screening and early detection Breast Cancer Prevention and Risk Reduction

18. Breast Cancer Risk Reduction: Prophylactic Surgery Prophylactic mastectomy and oophorectomy should be considered only for women at substantial risk

19. Considerations for Women with Inherited Susceptibility to Breast and Ovarian Cancer Prophylactic MastectomyProphylactic Mastectomy –Reduces breast cancer risk by 90% –Rare breast cancers still occur –Disfiguring –An option for women at very high risk

20. L ong-term Satisfaction and Psychological and Social Function Following Bilateral Prophylactic Mastectomy Reduced level of concern about developing breast cancer (74%)Reduced level of concern about developing breast cancer (74%) Some patients reported negative impact on:Some patients reported negative impact on: –Emotional stability (9%) –Level of stress (14%) –Self-esteem (18%) –Sexual relationships (23%) –Feelings of femininity (25%) –Body image (36%) Frost MH et al. JAMA 2000;284:319-24.

21. Considerations for Women with Inherited Susceptibility to Breast and Ovarian Cancer Prophylactic OophorectomyProphylactic Oophorectomy –Reduces ovarian cancer risk by 90-95% –Peritoneal carcinomatosis may still occur –Induces surgical menopause –Reduces breast cancer risk by up to 50% –Recommended for BRCA1/2 mutation carriers after childbearing

22. Primary PreventionPrimary Prevention –Lifestyle –Chemoprevention –Prophylactic surgery Secondary PreventionSecondary Prevention –Screening and early detection Breast Cancer Prevention and Risk Reduction

23. Breast Cancer Risk Reduction Breast Cancer Screening (Secondary Prevention)

24. Early Detection of Breast Cancer: The Controversy Around Breast Imaging Mammogram Ultrasound Magnetic Resonance Imaging (MRI)Magnetic Resonance Imaging (MRI)

25. American Cancer Society Recommendations for Breast Cancer Screening 2010 Mammography: Annually beginning at age 40 and continuing as long as the woman is in good healthMammography: Annually beginning at age 40 and continuing as long as the woman is in good health Health Professional’s Exam: About every 3 years between 20-39, then annuallyHealth Professional’s Exam: About every 3 years between 20-39, then annually Self-Exam: An option for women beginning at about age 20Self-Exam: An option for women beginning at about age 20 MRI: Women at high risk (> 20% lifetime) should get a mammogram and MRI yearly. Women at moderately increased risk (15-20%) should talk with their health care providers about MRI screening.MRI: Women at high risk (> 20% lifetime) should get a mammogram and MRI yearly. Women at moderately increased risk (15-20%) should talk with their health care providers about MRI screening.

26. Screening Recommendations for Women with Inherited Susceptibility for Breast Cancer Breast Cancer SurveillanceBreast Cancer Surveillance –Monthly breast self-exams (begin by age 18) –Clinical breast exam every 6 months –Annual mammography (beginning age 25) –Consider annual MRI Ovarian Cancer SurveillanceOvarian Cancer Surveillance –Annually or semi-annually beginning at 25-35: –Pelvic examination –Transvaginal ultrasound –Serum CA-125

27. Early Detection Imaging in High Risk Individuals SensitivitySpecificity Mammogram33-40%93-99.8% Breast MRI77-91%81-97% Breast MRI is better at detecting cancer than mammogram in high risk women, but has a higher rate of “false positives” e.g. biopsy of benign lesions Kriege M et al. NEJM 2004;351:427-37 Kuhl CK et al. JCO 2005;8469-76. Warner E et al. JAMA 2004;292:1317-25 Leach MO et al. Lancet 2005;365:1769-78

28. Breast Cancer Prevention Strategies in Low- and Middle- Income Countries Public awareness and educationPublic awareness and education Health Professional education and trainingHealth Professional education and training Individualized approaches based on patient riskIndividualized approaches based on patient risk

29. Breast Health Global Initiative (BHGI) Early Detection Strategies in Low- and Middle-Income Countries Yip C et al, Cancer Suppl 113, 2008 Basic levelBasic level –Clinic visits for breast problems (history and exam) –Train health care providers in clinical breast exam (CBE) Limited levelLimited level –Targeted educational outreach encouraging women to seek attention for breast problems »Link to general health/women’s health programs –Screening clinical breast exams for higher risk –Diagnostic imaging (mammogram and ultrasound) for breast problems –?Screening mammogram for select targeted group

30. Breast Health Global Initiative (BHGI) Early Detection Strategies in Low- and Middle-Income Countries Yip C et al, Cancer Suppl 113, 2008 Enhanced levelEnhanced level –Regional awareness programs on breast health –Screening »Mammography where resources sufficient »Every 2 years ages 50-69? »Every 12-18 months ages 40-49 –Image-guided biopsy Maximal levelMaximal level –National awareness campaigns –Annual screening mammography in women > 40 –Consider other imaging technology in women at high risk - Breast MRI

31. American Cancer Society: Major Risk Factors for Breast Cancer Over Which Women Have Some Control Exercise: Women can lower their risk of breast cancer by exercising vigorously for 45-60 minutes on 5 or more days per week. Postmenopausal women can lower their risk with any level of physical activity performed on a regular basis.Exercise: Women can lower their risk of breast cancer by exercising vigorously for 45-60 minutes on 5 or more days per week. Postmenopausal women can lower their risk with any level of physical activity performed on a regular basis. Weight: Obesity increases a woman’s risk of postmenopsaul (but not premenopausal) breast cancer, as does weight gain during adulthoodWeight: Obesity increases a woman’s risk of postmenopsaul (but not premenopausal) breast cancer, as does weight gain during adulthood Alcohol use: Women who drink just 2 alcoholic beverages a day face a 21% increase in their risk for breast cancerAlcohol use: Women who drink just 2 alcoholic beverages a day face a 21% increase in their risk for breast cancer