ACP: Breast Cancer Update

1. ACP: Breast Cancer Update Elaine A. Muchmore, M.D. UC San Diego 10/20/07

2. Breast Cancer • Breast cancer affects more than 150,000 women each year, with a lifetime incidence of greater than 10%. • Although there have been advances in genetic risks, these (BRCA1, BRCA2) mutations account for less than 5% of cases. • Mortality has decreased, related to earlier stage at diagnosis, but is still >40,000/year in the U.S.

3. Discussion points today: • Screening strategies, and when to start • Role of MRI in screening • Role of aromatase inhibitors

4. Screening strategies: when to start • Multiple trials have demonstrated reduction in mortality by 30% in women ages 50-69 screened by mammography • NIH consensus panel reviewed 8 trials that included women 40-49: no difference in mortality within 7 years of screening • Trend toward decreased mortality if followed >10 years (16-17%): question whether benefit is from screening before or after age 50

5. What are the real issues? • Breast cancer is the leading cause of death for women aged 40-49 in US • A 40 yo has a 2% chance of DCIS or invasive breast cancer before age 50 • Mortality rate in black women is 50% higher in 40-49 group than whites • False negative mammograms in 40-49 group in 25%, compared to 10% in 50-69 group • False positive mammograms more common in 40-49 group: 30% of women will have abnormal mammogram between 40-50 • Subset analysis reveals that false negative and positive rates not significantly different in 40-49 vs 50-59 groups.

6. Consensus panel recommendation: • “Data currently available do not warrant a universal recommendation for all women in their forties.” • Sequelae: • Costs for screening have not been covered by HMOs and third-party payers • Psychological burden (whether or not screening performed) • Concern that black women may not be included and engaged in the controversies about medical care

7. Should you recommend screening for women at age 40? • Yes for high risk, as defined by • Positive test for BRCA 1/2 mutation in pt. OR 1st OR 2nd degree relative • 2 cases in family of breast and/or ovarian cancer • >20% likelihood of carrying mutation when tested by BRCAPRO • Ashkenazi jewish descent with personal h/o breast cancer or 2 family members with same • Yes for breasts difficult to examine (fibrocystic changes, dense)

8. Discussion points today: • Screening strategies, and when to start • Role of MRI in screening • Role of aromatase inhibitors

9. Modality Exam (self or physician) Mammogram Ultrasound MRI Sensitivity* Poor 38% 25% 85% *Exams all performed same time in pts with BRCA1/2 mutations (JAMA(2004) 292:1317) Breast cancer screening strategies

10. No free lunch: costs of screening • 236 high-risk women examined with exam, US, mammogram, MRI (JAMA 292:1317, 2004). Strategy: biopsy if 1 of 4 screening studies positive. Av age: 47 • Results: • 22 breast cancers in 3 years • 14% biopsies benign • 2 cancers detected by mammogram alone, 2 by US alone, 9/12 not detected by exam+mammogram detected by MRI • Conclusion: all screening strategies required in high risk patients for maximum sensitivity

11. Costs of screening • In another study of high-risk women (Radiology 244:381, 2007), 171 women screened with MRI+US+mammogram. Av. Age=45 • Results: • 60 positives • 31 MRI+ only, yielding 4 CA • 6 MRI+, mammogram +, yielding 1 CA • 1 MRI+, mammogram+, US+, yielding 1 CA • Positives on MRI+US, only on US, mammogram+US yielded no cancers

12. MRI: good and bad • Good • Definitely most sensitive screening modality • Year 1 screens 85% sensitive for MRI, compared with 25% US, 38% mammogram • (Specificity excellent with all modalities) • Low rate of false negatives • Bad • Relatively high rate of false positives • Year 1 true positives 11, 15 false positives • Need for frequent repeat studies • To increase yield need both US and mammogram JAMA 292:1317 (2004)

13. What should you recommend to your patients? • Difficult to ignore the large number of positives in multiple studies of high-risk pts, so, once identified, ere on side of complete screening for this group • Data insufficient to recommend to broader group

14. Discussion points today: • Screening strategies, and when to start • Role of MRI in screening • Role of aromatase inhibitors

15. Performance of AIs is excellent • ATAC Trial (Anastrozole). Adjuvant trial, median F/U 68 mos. Hazard ratio for DFS with AI: 0.87 • BIG 1-98 (Letrozole). Adjuvant trial, median F/U 26 mos. Hazard ratio for DFS with AI: 0.81 • IES (Exemestane). Sequential trial, median F/U 31 mos. Hazard ratio for DFS with AI: 0.68 • MA.17 (Letrozole) Extended adjuvant trial, median F/U 30 mos. Hazard ratio for DFS with AI 0.58

16. Side-effects • Gynecologic sx • Hot flashes • Sexual dysfunction • Cognitive dysfunction • Non-ischemic cardiac events • Osteopenia/arthralgias

17. Osteopenia/arthralgias: interventions • Osteopenia • Weight-bearing exercise • Calcium/vitamin D • Bisphosphonates • (insufficient trials to determine efficacy) • Arthralgias • Resistance-exercise, weight loss • May need to switch to tamoxifen

18. Side-effects less common with AIs than Tamoxifen • Endometrial CA • Stroke • Thromboembolic disease

19. Unanswered questions • Results of all cross-over arms of trials (with TAM and AIs) • Duration of therapy • Discrimination of mechanisms of resistance, and which pts require • Increased estrogen blockade • Blockade of alternate signal pathways • Inhibition of angiogenesis