Adam M. Brufsky, MD, PhD

1. Improving Bone Health in Patients With EarlyBreast Cancer: 12-Month Bone MineralDensity Results – The Z-Fast Trial Adam M. Brufsky, MD, PhD Co-Director, Comprehensive Breast Cancer CenterMagee-Women’s HospitalUniversity of Pittsburgh Medical CenterPittsburgh, Pennsylvania

2. Background • Further reduction or elimination of estrogen activity by AIs in PMW with BCa may result in bone loss and bone-related complications1,2 • Anastrozole has been associated with greater incidence of fractures vs tamoxifen in PMW with primary BCa (5.9% vs 3.7%;P<0.0001)3 • Exemestane, following 2–3 yrs of tamoxifen therapy, has been associated with greater incidence of osteoporosis vs tamoxifen in PMW with primary BCa (7.4% vs 5.7%)4 • Letrozole has been associated with greater risk of bone fractures vs tamoxifen in PMW with primary BCa (5.8% vs 4.1%,P=0.0006).5 • An effective therapy that will prevent bone loss associated with AIs in PMW with BCa is needed

3. Background (cont’d) • In clinical trials, zoledronic acid (ZA) increased bone mineral density (BMD) vs placebo or no ZA.6,7 • In PMW with low BMD, ZA (4-mg single dose) increased lumbar spine (LS) BMD by 4.3%–5.1% and femoral neck BMD by 3.1%–3.5% compared with placebo at 12 mo (P<0.001 for both).6 • In premenopausal women with BCa receiving anastrozole or tamoxifen with goserelin, LS BMD at 36 mo was higher in patients receiving ZA (4 mg q 6 mo) compared with patients not receiving ZA (P<0.0001).7 ZA = zoledronic acid

4. Study Design and Objectives

5. Z/ZO-FAST Trial DesignZometa Femara Adjuvant Synergy Trial R A N DO M I Z E D • Eligibility:ER+/PgR+ BCaPMW withT score ≥ -2 • Stratification: • Adjuvant chemo(yes or no) • T score (> -1 or between -1 and -2 ) UPFRONT Zoledronic acid 4 mg q 6 mo + Letrozole 2.5 mg/d* DELAYED† Zoledronic acid 4 mg q 6 mo + Letrozole 2.5 mg/d* 0 1 yr 3 yr 5 yr Final analysis Accrual complete: ZO-FAST: N = 1066; ZFAST: N = 602 *Plus daily calcium (1,000–1,200 mg) and vitamin D (400–800 IU). †Initiation determined by a postbaseline T score < -2, any clinical fracture, or an asymptomatic fracture at 36 mo.

6. Study Objectives Primary objective • % change in LS BMD at 12 mo Secondary objectives • % change in LS BMD at 2 yr, 3 yr, 5 yr • % change in total hip (TH) BMD at 12 mo, 2 yr, 3 yr, 5 yr • Changes in biochemical markers of bone turnover at 12 mo, 2 yr, 3 yr, 5 yr • N-telopeptide (NTX) • Bone-specific alkaline phosphatase (BSAP) • Incidence of fractures at 3 yr • Time to disease progression • Rate of decrease in LS and TH BMD

7. Eligibility Criteria • PMW with stage I–IIIa ER+ and/or PgR+ BCa • Baseline LS and TH T score ≥ -2 • ECOG PS between 0 to 2 • Serum creatinine level < 3 mg/dL • Adjuvant CT, if administered, must have been completed before randomization • No evidence of existing fracture in LS or TH • Prior oral bisphosphonate therapy allowed but must have been discontinued at least 3 weeks before baseline evaluation

8. Methods

9. Study Assessments • BMD • DXA used to measure BMD of LS (L1–L4) and TH at baseline, 6, 12, 24, 36, and 48 mo and at final visit • DXA machines cross-calibrated and films analyzed by central reader • Biochemical Markers (NTX and BSAP) • Evaluated in subset of ~150 patients • At baseline, every 3 mo for year 1, then every 6 mo up to 48 mo and final visit. • Analyzed by central laboratory • Fractures • X-ray at baseline to exclude patients with existing fractures • Additional x-rays and/or bone scans at discretion of investigator to confirm clinical fracture throughout study and at 36 mo • Adverse Events (AEs)/Disease Progression • Evaluated every 6 mo • AEs graded using NCI Common Toxicity Criteria, version 2.0 DXA = Dual-energy x-ray absorptiometry

10. Statistical Analysis • ITT population—all randomized pts who received  1 dose of letrozole or ZA and had  1 postbaseline assessment • Safety population—all randomized pts who received  1 dose of letrozole or ZA • Sample size and power considerations • 250 pts per arm—90% power to detect 3% change in BMD and a common SD of 9% with a significance level of .05 and a 25% dropout rate • Enrollment closed December 2003 with 602 patients accrued at 93 sites in the US and Canada.

11. Results

12. Demographics *One patient each in the upfront and delayed groups were randomized in error.

13. Demographics (cont’d) *One patient each in the upfront and delayed groups were randomized in error.

14. ZA Initiation in Delayed Group *Because T score decreased to < -2 and/or clinical fracture.

15. Mean (SD) Percentage Change in BMD (g/cm2) P<0.0001 P<0.0001 Month 6 Month 12 Month 6 Month 12 Lumbar Spine Total Hip

16. Mean (-SD) T Scores P<0.0004 P<0.0001 Baseline Month 6 Month 12 Baseline Month 6 Month 12 Lumbar Spine Total Hip

17. Shift in LS T-Score Distribution at 12 Months in Patients With Normal Baseline BMD At 12 months

18. Shift in LS T-Score Distribution at 12 Months in Patients With Osteopenic Baseline BMD At 12 months

19. Mean (SD) Percentage Change in Bone Markers From Baseline *P<0.0001. BCE=bone collagen equivalent.

20. Mean (SD) Percentage Change in Mean NTX From Baseline P<0.0001 Month 3 Month 9 Month 12 Month 6

21. Mean (SD) Percentage Change in Serum BSAP From Baseline P<0.0001 Month 3 Month 9 Month 12 Month 6

22. Adverse Events Occurring in >5% of Patients

23. Additional Safety Results • Renal disorders • No grade 3-4 renal disorders reported • 1 patient with a grade-1 increase in serum creatinine level in the upfront group • Jaw disorders • No osteonecrosis of the jaw reported • 3 patients reported grade 1-2 jaw pain in the upfront group • Cardiac disorders • Grade 3-4 cardiac disorders reported in < 2.5% of patients • None were related to study drugs • Serious adverse events (SAEs) reported • 16.7% of patients (upfront group), 18.7% of patients (delayed group) • Treatment discontinued due to SAEs • 1.3% of patients (upfront group), 1% of patients (delayed group)

24. Conclusions • Based on 12-mo data, upfront ZA (4 mg IV q 6 mo) prevents CTIBL in PMW with early-stage BCa receiving adjuvant letrozole • Primary endpoint of LS BMD was statistically significant in favor of the upfront ZA group • TH BMD was also statistically significant in favor of the upfront ZA group • 4% and 8% of patients in the delayed group experienced a decrease in BMD at 6 and 12 months, respectively, and required initiation of ZA • Bone markers were significantly decreased in patients receiving upfront ZA vs delayed ZA • Additional follow-up is needed to fully define the long-term benefit of ZA combined with AIs in PMW with early-stage BCa

25. References • Pfeilschifter J, et al. J Clin Oncol. 2000;18:1570-1593. • Heshmati HM, et al. J Bone Miner Res. 2002;17:172-178. • Baum M, et al. Lancet. 2002;359:2131-2139. • Coombes RC, et al. N Engl J Med. 2004;350:1081-1092. • BIG 1-98 Collaborative Group. Breast. 2005;14:Suppl 1:S3. Abstract. • Reid IR, et al. N Engl J Med. 2002;346:653-661. • Gnant M, et al. Presented at: SABCS; December 8-11, 2004; San Antonio, Tex. Abstract 6.

27. Questions and Answers