1. Breast Cancer Prevention Art or Science? Kristi McIntyre M.D. Texas Oncology 2005

2. Patient 59 year old healthy Caucasian postmenopausal female with recent abnormal screening mammogram. She is asymptomatic. No family history of breast cancer Uses deodorant No significant health issues ; normal bone density Has chronic sinusitis and takes antimicrobials frequently Biopsy of breast shows atypical ductal hyperplasia Gail risk 3.5.%

3. You Choose: Start Raloxifene Start Tamoxifen Wait several months and reassess Clinical trial No therapy but observation and surveillance

5. Breast Cancer Risk Factors

6. Breast Cancer Incidence

10. How much of Breast cancer is Hereditary? Hereditary Sporadic 5-7% 15-20% Familial clusters

11. Family history and breast cancer risk Most hereditary breast cancers arise from mutations in BRCA1 and BRCA2 Autosomal dominant, tumor suppressor gene Age breast cancer <50 Bilaterality Male breast cancer ovarian cancer Multiple other cancers Ashkenazi Jews

13. Reproductive Factors and Breast Cancer Menarche Menopause Menarche <15 OR 1.2 Menopause >50 OR 1.5 Null parity OR 2.0 Breastfeeding 4.3% decrease risk/yr First live birth<20 OR 0.5 First live birth >30 OR 1.5 Postmenopausal Estradiol levels

14. WHI Trial of Estrogen plus Progestin E+P placebo p-value Invasive Breast cancers 199 150 0.003 Abnormal Mammograms 716 395 0.0001 SEER high stage 25% 16% 0.041 More breast cancers diagnosed at more advanced stage and increased abnormal mammograms Chlebowski JAMA 2003;289. 3243

15. Benign Breast Disease Nonproliferative 1 Proliferative,no atypia 2X Atypical Hyperplasia 4X In Situ 10-20X Histology RR

16. ASCO 2005 Cuzick L

17. Lifestyle factors and breast cancer risk Body mass index: postmenopausal women >30% excess BMI increased risk Dietary fat intake: increased risk NSAID use: decreases risk Physical activity: 1.25 to 2.5/hrs week brisk walking had 18 % decrease risk Alcohol use: increased (dose dependent)

19. Chemoprevention of breast cancer Can we find an ideal agent? Who should take it?

20. Mechanism of Disease: Estrogen Carcinogenesis; Yager et al NEJM Jan 2006

22. Smith, I. E. et al. N Engl J Med 2003;348:2431-2442 Mechanism of action of Tamoxifen

24. NSABP B-24 TRIAL

25. NSABP P-1

26. *50% reduction

29. BCPT results: bone and endometrial cancer events Bone fractures Endometrial cancers 5.4 13 111 137 placebo Tamoxifen

30. Multiple Outcomes Raloxifene Evaluations Study

31. Multiple Outcomes Raloxifene Evaluation TRIAL Breast cancer risk reduction :76% Raloxifene Placebo

33. STAR trial objectives Evaluate the effect of Tamoxifen vs. Raloxifene in reducing the incidence of: Invasive breast cancer Noninvasive breast cancer Endometrial cancer Vascular events Bone fractures

35. Smith, I. E. et al. N Engl J Med 2003;348:2431-2442 Aromatase Inhibitors

36. Smith, I. E. et al. N Engl J Med 2003;348:2431-2442 Classification of Aromatase Inhibitors

37. Aromatase Inhibitor adjuvant trials and contralateral breast cancer incidence

38. Aromatase Inhibitors : Adverse effects compared to Tamoxifen

39. Aromatase Inhibitor Prevention Trials IBIS -II MAP - 3 Arimidex Placebo Exemestane placebo 6,000 postmenopausal women 5000 postmenopausal women

40. 2 Tamoxifen Raloxifene ? Aromatase Inhibitor NSABP P-4 Future Breast cancer Prevention trial Spring 06

41. Conclusions Chemoprevention will have a tremendous impact on breast cancer incidence Refining criteria of “high risk patient” and measurable surrogate markers LOOK FOR RESULTS STAR trial Encourage clinical trial participation P-4