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

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.%

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

Breast Cancer Risk Factors

Breast Cancer Incidence

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

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

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

WHI Trial of Estrogen plus Progestin E+P placebo p-value Invasive Breast cancers Abnormal Mammograms SEER high stage 25% 16% More breast cancers diagnosed at more advanced stage and increased abnormal mammograms Chlebowski JAMA 2003;

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

ASCO 2005 Cuzick L

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)

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

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

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

NSABP B-24 TRIAL

NSABP P-1

*50% reduction

BCPT results: bone and endometrial cancer events Bone fractures Endometrial cancers placebo Tamoxifen

Multiple Outcomes Raloxifene Evaluations Study

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

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

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

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

Aromatase Inhibitor adjuvant trials and contralateral breast cancer incidence

Aromatase Inhibitors : Adverse effects compared to Tamoxifen

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

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

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