These slides were released by the speaker for internal use by Novartis

Risk/benefit analysis: tamoxifen vs aromatase inhibitors Edith A Perez (Mayo Clinic, Jacksonville, FL; Mayo Foundation, Rochester, MN, USA)

Adverse event profiles Tamoxifen Hot flushes Genitourinary symptoms Endometrial cancer Thromboembolism Favorable effects on lipids? Reduction in baseline CVD? Protective effect on bone AIs Hot flushes Arthralgia/arthritis Myalgia Bone loss/fractures vs tamoxifen Increase in CVD & hypercholesterolemia? Fewer gynecological symptoms Fewer endometrial cancers Fewer thromboembolic and DVT events (including grade 3–5)

Hot flushes reported in adjuvant AI trials Significant reduction vs tamoxifen with upfront AI (anastrozole, letrozole) No significant reduction vs tamoxifen with sequential tamoxifen-AI therapy (exemestane, anastrozole) Significant increase vs placebo with extended adjuvant letrozole ATAC Trialists’ Group Lancet 2005;365:60–2; Thürlimann et al. N Engl J Med 2005;353:2747–57; Coombes et al. N Engl J Med 2004;350:1081–92; Jakesz et al. Lancet 2005;366:455–62; Goss et al. J Natl Cancer Inst 2005;97:1262–71

Gynecological symptoms/endometrial cancer reported in adjuvant AI trials Compared with tamoxifen Significant reduction in vaginal bleeding, vaginal discharge, endometrial biopsies Non-significant reduction in endometrial cancer Compared with placebo Significant reduction in vaginal bleeding ATAC Trialists’ Group Lancet 2005;365:60–2; Thürlimann et al. N Engl J Med 2005;353:2747–57; Coombes et al. N Engl J Med 2004;350:1081–92; Jakesz et al. Lancet 2005;366:455–62; Goss et al. J Natl Cancer Inst 2005;97:1262–71

Thromboembolic (TE) events reported in adjuvant AI trials Compared with tamoxifen Significant reduction in TE events including venous TE, deep venous TE and SAEs Compared with placebo No difference in incidences of TE events or stroke/transient ischemic attack ATAC Trialists’ Group Lancet 2005;365:60–2; Thürlimann et al. N Engl J Med 2005;353:2747–57; Coombes et al. N Engl J Med 2004;350:1081–92; Jakesz et al. Lancet 2005;366:455–62; Goss et al. J Natl Cancer Inst 2005;97:1262–71

Arthralgia reported in adjuvant AI trials In upfront and switching trials All AIs associated with significant increase in arthralgia vs tamoxifen AIs 5.4–36% vs tamoxifen 3.6 –29% In extended adjuvant setting Significant increase in arthralgia vs placebo ATAC Trialists’ Group Lancet 2005;365:60–2; Thürlimann et al. N Engl J Med 2005;353:2747–57; Coombes et al. N Engl J Med 2004;350:1081–92; Jakesz et al. Lancet 2005;366:455–62; Goss et al. J Natl Cancer Inst 2005;97:1262–71

CV disease reported in adjuvant AI trials Within the limitations of trial methodology and cross-trial comparisons, data suggest Non-significant increase in CV events: AI vs tamoxifen ATAC BIG 1-98 IES ABCSG-8/ARNO No difference in CV events: AI vs placebo MA.17 core analysis post-unblinding analysis ATAC Trialists’ Group Lancet 2005;365:60–2; Thürlimann et al. N Engl J Med 2005;353:2747–57; Coombes et al. N Engl J Med 2004;350:1081–92; Jakesz et al. Lancet 2005;366:455–62; Goss et al. J Natl Cancer Inst 2005;97:1262–71 Letrozole is not licensed in all European countries for use in the early adjuvant setting

Cardioprotective effect of tamoxifen EBCTCG experience at 15 years 1 Subset of ~15,000 women treated with 5 years of tamoxifen vs control 189 vs 169 vascular deaths (tamoxifen vs control, NS) 32 trials comparing tamoxifen with control group: metastatic, adjuvant, and prevention settings 2 > 52,000 patients Relative risk ratio for fatal MIs, tamoxifen vs control: 0.62 (95% CI: 0.41–0.93) 1. EBCTCG Lancet 2005;365:1687–717; 2. Braithwaite et al. J Gen Intern Med 2003;18:937–47

Hypercholesterolemia reported in adjuvant AI trials Data from adjuvant AI trials suggest Non-significant increase in hypercholesterolemia: AI vs tamoxifen ATAC: 9% vs 3.5% (p = NR) BIG 1-98:All grades: 43.5% vs 19.1% (p = NR) Grade 1: 35.1% vs 17.3% (p = NR) ITA: 9.3% vs 4.0% (p = 0.04) IES: NR ABCSG-8/ARNO: NR No difference in hypercholesterolemia: AI vs placebo (fasting) MA.17: 16% vs 16% (p = 0.79) Arimidex PI Sept 2005; Thürlimann et al. N Engl J Med 2005;353:2747–57; Coombes et al. N Engl J Med 2004;350:1081–92; Jakesz et al. Lancet 2005;366:455–62; Goss et al. J Natl Cancer Inst 2005;97:1262–71 NR: not reported Letrozole is not licensed in all European countries for use in the early adjuvant setting

In BIG 1-98 cholesterol data were collected every 6 months Simpler data collection in the ATAC trial – non-specific request to report AE Differences in data capture

BIG 1-98 targeted AE: cholesterol All grades: 43% vs 19% Measurements: 90% non-fasting, variable time of day ≥ grade 1 hypercholesterolemia: any cholesterol measurement above ULN at 6-month visit No central laboratory measurements Grading of hypercholesterolemia 01234Unit WNL > ULN–300 > ULN–7.75 > 300–400 > 7.75–10.34 > 400–500 > 10.34–12.92 > 500 > mg/dL mmol/L

*To convert mmol/L to mg/dL, multiply by 39 Letrozole Tamoxifen Total cholesterol (mmol/L*) Months Let 3209 Tam Effect of letrozole vs tamoxifen on total serum cholesterol † Cholesterol values remained stable in the letrozole arm and decreased in the tamoxifen arm by ~12% Perez E. Personal communication

Lipid lowering effect of tamoxifen? Yes Tamoxifen studies 10 trials, 6 vs placebo; 657 patients Decrease in cholesterol seen in all studies Median decrease: 12.5% (range 3–17) Decrease due to LDL cholesterol Herrington & Klein Womens Health Issues 2001;11:95  102

Effect of AI on lipid levels vs placebo ATENA 1 and MA.17 lipid substudy 2 Increase in serum cholesterol observed 6 months after tamoxifen discontinuation No relevant difference between two treatment groups for any lipid parameters LEAP study 3 (early results) Anastrozole (n = 29), exemestane (n = 32) and letrozole (n = 29) have similar, non-detrimental effects on serum lipids in postmenopausal women Conclusion AIs lack the lipid-lowering effects of tamoxifen 1. Markopoulos et al. Anticancer Drugs 2005;16:879–83; 2. Wasan et al. Ann Oncol 2005;16:707–15 3. McCloskey et al. Breast Cancer Res Treat 2005;94:(abstract 2052)

Osteoporosis/fractures reported in adjuvant AI trials Compared with tamoxifen Upfront trials: significant increase in osteoporosis and/or fractures Switching trials: significant increase in osteoporosis Significant increase or trend for increase in fractures Compared with placebo Significant increase in new patient-reported osteoporosis No significant increase in fracture rate ATAC Trialists’ Group Lancet 2005;365:60–2; Thürlimann et al. N Engl J Med 2005;353:2747–57; Coombes et al. N Engl J Med 2004;350:1081–92; Jakesz et al. Lancet 2005;366:455–62; Boccardo et al. J Clin Oncol 2005;23:5138–47; Goss et al. J Natl Cancer Inst 2005;97:1262–71; Mincey & Perez ASCO Edu Book 2005;27–34

Management of AEs Bone loss, osteoporosis and fractures Tamoxifen protects against bone loss in postmenopausal women HRT – contraindicated in patients with BC Routine monitoring, calcium/vitamin D supplements Bisphosphonates prevent bone loss Efficacy differs between agents Early generation oral bisphosphonates often poorly tolerated CTIBL more rapid than ‘natural’ postmenopausal bone loss – may need more potent IV agents CTIBL, cancer treatment-induced bone loss HRT, hormone replacement therapy

Z-FAST, ZO-FAST and E-ZO-FAST Accrual completed: ZO-FAST, n = 1066; Z-FAST, n = 602; E-ZO-FAST: n = 500 * Initiation of zoledronic acid determined by post-baseline BMD Upfront zoledronic acid 4 mg q 6 months + Letrozole (2.5 mg/day) x 5 years Delayed* zoledronic acid 4 mg q 6 months + Letrozole (2.5 mg/day) x 5 years RANDOMIZERANDOMIZE Mean  in BMD (total hip) Letrozole + upfront ZOL +1.40% Letrozole + delayed ZOL -2.10% Overall difference 3.50% p value < BMD at 12 months 1 1. Brufsky et al. J Clin Oncol 2005;23:12s(abstract 533)

Upfront zoledronic acid 4 mg q 6 months Delayed* zoledronic acid 4 mg q 6 months NCCTG N03CC Inclusion criteria Postmenopausal Prior tamoxifen T-score ≥ -2.0 SD (n = 550) *Initiation of zoledronic acid determined by post-baseline BMD T-score < -2.0 SD 10/05: enrollment complete; PI: BA Mincey Letrozole x 5 years Calcium, vitamin D (all patients) RANDOMIZERANDOMIZE Upfront or delayed bisphosphonate for women receiving letrozole after tamoxifen

ASCO bone health guidelines BMD screening in breast cancer All women aged > 65 years All women aged 60–64 years with risk factors Postmenopausal women of any age receiving AIs Premenopausal women with medical/surgical premature menopause Repeat BMD annually after initial exam Treatment T-Score > -1.5: lifestyle, reassurance T-Score -1.5 to -2.5: calcium, vitamin D T-Score <-2.5: bisphosphonates Hillner et al. J Clin Oncol 2003;21:4042–57

Effect of AIs on QoL Censoring at recurrence may underestimate QoL advantage of AIs No significant adverse effects of AIs on QoL reported in adjuvant trials to date AI vs tamoxifen: anastrozole (ATAC), exemestane (IES) AI vs placebo: letrozole (MA.17) Fallowfield et al. J Clin Oncol 2004;22:4261–71; Fallowfield et al. J Clin Oncol 2006;24:910–17; Whelan et al. J Clin Oncol 2005;23:6931–40

Adverse event profiles Conclusions Tamoxifen associated with thromboembolic and gynecological events AIs generally well tolerated but associated with some bone loss and arthralgia Tamoxifen protects against postmenopausal bone loss Routine monitoring, calcium/vitamin D supplements can minimize fracture risk in most patients Bisphosphonates can prevent AI-associated bone loss Further investigation of effects on cardiovascular system and lipid metabolism Beneficial effects of tamoxifen No increase in cardiovascular disease or hypercholesterolemia, letrozole vs placebo (MA.17) AEs associated with AIs generally more preventable or manageable than AEs associated with tamoxifen