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

2. Improving risk reduction: the successors to tamoxifen Beat Thürlimann (Kantonsspital, St Gallen, Switzerland)

3. Adjuvant tamoxifen Tamoxifen for 5 years has remained the standard adjuvant endocrine therapy for many years However –relapses still occur, even with tamoxifen –Up to 40% of patients on adjuvant tamoxifen develop breast cancer recurrences 1 –Peak risk of relapse occurs in first 2–3 years after surgery 2 –Need to introduce new drugs to overcome de novo and acquired resistance to tamoxifen 1 Early Breast Cancer Trialists’ Collaborative Group. Lancet 2005;365:1687–717 2 Saphner et al. J Clin Oncol 1996;14:2738–46

4. Significant risk of recurrence remains even with tamoxifen therapy Adapted with permission. Early Breast Cancer Trialists’ Collaborative Group Meeting, 2000 Early Breast Cancer Trialists’ Collaborative Group. Lancet 2005;365:1687–717 Years RecurrencesBreast cancer deaths 85.2 73.7 0 20 40 60 80 100 051015 Tamoxifen Control 15%17% 0 20 40 60 80 100 051015 87.8 Tamoxifen Control 9%18% 91.4 % of patients 54.9 68.2 73.0 64.0

5. Different mode of action from tamoxifen Proven equivalent or superior efficacy to tamoxifen in –First-line treatment of advanced disease –Letrozole, anastrozole and exemestane superior or equivalent to tamoxifen –Neoadjuvant setting –Letrozole * superior to tamoxifen –Anastrozole * at least equivalent to tamoxifen AIs: rationale for use Buzdar et al. J Clin Oncol 2001;19:3357–66; Buzdar et al. J Clin Oncol 1996;14:2000–11; Kaufmann et al. J Clin Oncol 2000;18: 1399–411; Mouridsen et al. J Clin Oncol 2003;21:2101–9; Paridaens et al. Ann Oncol 2003;14:1391–8; Smith et al. J Clin Oncol 2005;23:5108–16; Eiermann et al. Ann Oncol 2001;12:1527–32; Semiglazov et al. J Clin Oncol 2005;23:11s(abstract 530) *Not licensed in all European countries for use in the neoadjuvant setting

6. Postoperative adjuvant treatment Third-generation AIs have shown superior efficacy to tamoxifen in the adjuvant setting in postmenopausal women with HR+ early breast cancer 5 years of tamoxifen is no longer considered the standard of care for most patients Should AIs be used upfront, following surgery or in a sequential strategy with tamoxifen? Use of letrozole following standard 5 years’ tamoxifen (extended adjuvant therapy) will be discussed tomorrow (Dr Gradishar) Winer et al. J Clin Oncol 2005;23:619–29; Goldhirsch et al. Ann Oncol 2005;19:3817–27; Rieber & Theriault J Natl Compr Canc Netw 2005;3:309–14

7. Trials using AIs upfront TAMOXIFEN ANASTROZOLE LETROZOLE EXEMESTANE ATAC* BIG 1-98* 5 years 5 years † 5 years 2 years 3 years 5 years Randomization TEAM ‡ *Registration trials; † Combination arm discontinued at first analysis; ‡ amended TEAM protocol 5 years 2–3 years

8. Switching and sequential therapy trials TAMOXIFEN ANASTROZOLE LETROZOLE EXEMESTANE BIG 1-98 ABCSG-8 IES 5 years 3 years 2 years 2–3 years 2 years 3 years 5 years Randomization ITA 2–3 years Sequential trials include all events from start of adjuvant therapy Switching trials only include events from point of switch (after 2–3 years’ tamoxifen) 3 years 2 years ARNO TEAM 5 years 2–3 years

9. Combination † Upfront substitution trials † Combination arm discontinued at first analysis: inferior efficacy to anastrozole; *Primary core analysis of upfront therapy included all 4 arms: events in sequential arms only included up to point of switching therapy +30 days ATAC 123450 Time from randomization (years) Randomization Anastrozole Tamoxifen BIG 1-98* Letrozole Tamoxifen Letrozole Tamoxifen Letrozole

11. At risk A261825402448235522682014830 T259825162398230421891932 774 Follow-up (years) 0 5 10 15 20 25 0123456 Absolute difference: 1.6%2.6%2.5%3.3% Proportion with recurrence (%) Anastrozole (A) Tamoxifen (T) HR 0.83 0.87 HR+ 95% CI (0.73–0.94) (0.78–0.97) p value 0.005 0.01 ITT A 424 575 T 497 651 ATAC Trialists’ Group. Lancet 2005;365:60  2 ATAC: cumulative incidence of recurrence: HR+ population

12. Adapted from Howell et al. Breast Cancer Res Treat 2004;88(abstract 1) 0.4 0.6 0.8 1.0 1.2 1.5 2.0 Hazard ratio (ANA:TAM) Favors ANAFavors TAM DFS (w/o second malignancy) Time to recurrence Time to distant recurrence OS ATAC: key endpoints (HR+ population) (0.73–0.94) 0.74 0.84 0.97 (0.70–1.00)0.06 (0.64–0.87)0.0002 0.010.83 (0.85–1.12)0.7 HR(95% CI)p value

13. Overall survival (HR+ population) Anastrozole not superior to tamoxifen A261825662505243723772117867 T259825492502243023332080855 At risk: Follow-up (years) 0123456 Anastrozole (A) Tamoxifen (T) 0 5 10 15 20 25 Rate of mortality (%) ATAC Trialists’ Group. Lancet 2005;365:60  2 HR 0.97 A vs T 95% CI (0.83–1.14) p value 0.7

15. BIG 1-98: trial design Primary core analysis Compares letrozole with tamoxifen Letrozole: arms B and D Tamoxifen: arms A and C Excludes events and follow-up beyond switch for C & D Years n = 1548 Tamoxifen Letrozole Tamoxifen RANDOMIZERANDOMIZE 025 A B C D n = 2459 n = 2463 n = 1540 n = 8010

16. BIG 1-98: trial design Primary core analysis Compares letrozole with tamoxifen Letrozole: arms B and D Tamoxifen: arms A and C Excludes events and follow-up beyond switch for C & D Tamoxifen Letrozole RANDOMIZERANDOMIZE 025 Years A B C D Tamoxifen n = 2459 n = 2463 n = 1548 n = 1540 n = 8010

17. BIG 1-98: disease-free survival No. at risk 3892 3896 2964 2926 1261 1238 892 866 4003 4007 567 544 0.0030.81 (0.70–0.93)8010 p valueHR (95% CI)n 0 20 40 60 012345 Alive and disease-free (%) Years from randomization TAM 80 100 97.7 97.6 Yearly DFS (%) 95.1 93.4 90.5 89.0 86.8 84.6 84.0 81.4 LET Absolute benefit at 5 years: 2.6% Adapted from Thürlimann et al. N Engl J Med 2005;353:2747–57 Letrozole is not licensed in all European countries for use in the early adjuvant setting

18. Treatment failures in BIG 1-98 Letrozole Tamoxifen p First failure sites (DFS events)8.8%10.7%0.003 Local0.5%0.9%0.034 Contralateral breast (invasive)0.4%0.7%0.092 Regional*0.3% 0.842 Distant4.4%5.8%0.005 Second (non-breast) malignancy1.7%2.0%0.288 Death without cancer event1.4%0.9%0.077 Deaths4.1%4.8%0.155 Systemic failures**8.1%9.6%0.017 *Regional includes axilla or internal mammary **SDFS ignores local and contralateral events Adapted from Thürlimann et al. N Engl J Med 2005;353:2747–57 Letrozole is not licensed in all European countries for use in the early adjuvant setting

19. BIG 1-98: key endpoints *Systemic DFS DFS OS SDFS* Time to recurrence DFS (w/o 2nd malignancy) Favors LETFavors TAM 0.81 0.86 0.83 0.79 0.73 1.00.50.751.332.0 Hazard ratio (LET:TAM) Time to distant metastases 0.72 Adapted from Thürlimann et al. N Engl J Med 2005;353:2747–57 Letrozole is not licensed in all European countries for use in the early adjuvant setting

20. BIG 1-98: DFS subgroup analysis * Based on local assessment Hazard ratio (LET:TAM) Favors LETFavors TAM 1.00.50.751.332.0 CT given (n = 2024) CT not given (n = 5986) 0.70 0.85 N+ (n = 3311) N– (n = 4174) 0.71 0.99 ER+ / PgR+ (n = 5055)* ER+ / PgR– (n = 1631)* 0.84 0.83 Adapted from Thürlimann et al. N Engl J Med 2005;353:2747–57 Letrozole is not licensed in all European countries for use in the early adjuvant setting

21. Indirect trial comparison ATAC & BIG 1-98 ATAC HR+ 68 mo 1,3 33 mo 2 –– 0.97 * – 0.93*– 0.830.78 0.84 * – 0.740.73 Favors Tam Hazard ratio (Let:Tam) DFS OS Distant DFS Time to recurrence DFS (w/o 2nd malignancy) 0.81 0.86* 0.73 0.79 0.73 Time to distant metastasis 0.72 Favors Let 1.00.50.751.332.0 *Not significant 1 Howell et al. Lancet 2005;365:60–2; 2 Baum et al. Lancet 2002;359:2131–9; 3 Arimidex ® PI, 2005 Update of Thürlimann et al. N Engl J Med 2005;353:2747–57 Letrozole is not licensed in all European countries for use in the early adjuvant setting

22. AI efficacy in upfront use Upfront AIs achieve a DFS benefit over tamoxifen –Includes reduced risk of contralateral breast cancer Risk of distant metastases reduced with letrozole No OS benefit with current follow-up –68-month follow-up ATAC –Longer follow-up of BIG 1-98 awaited Letrozole superior to tamoxifen –In whole trial population –In patients with higher-risk disease Guidelines: upfront AI should be considered in all eligible patients

23. Switching and sequential therapy trials TAMOXIFEN ANASTROZOLE LETROZOLE EXEMESTANE BIG 1-98* ABCSG-8 IES 5 years 3 years 2 years 2–3 years 2 years 3 years 5 years Randomization ITA 2–3 years Sequential trials include all events from start of adjuvant therapy Switching trials only include events from point of switch (after 2–3 years’ tamoxifen) 3 years 2 years ARNO TEAM ‡ 5 years 2–3 years

24. Switching and sequential therapy trials TAMOXIFEN ANASTROZOLE LETROZOLE EXEMESTANE BIG 1-98 ABCSG-8 IES 5 years 3 years 2 years 2–3 years 2 years 3 years 5 years Surgery ITA 2–3 years Sequential trials include all events from start of adjuvant therapy Switching trials only include events from point of switch (after 2–3 years’ tamoxifen) 3 years 2 years ARNO TEAM 5 years 2–3 years Randomization Analysis

25. IES: risk reduction Follow-up (mo)Relativep 30.632% (18–44%)0.00005 37.427% (14–38%)0.0001 DFS At (years)Absolute 34.7% Coombes et al. N Engl J Med 2004;350:1081–92, Breast Cancer Res Treat 2004;88:S7(abstract 3) At 30.6 months Significant improvements in DFS, distant DFS and CLBC Trend towards reduction in mortality At 30.6 months: 12% (-16–33%) p = 0.37 At 37.4 months: 17% (-2–33%) p = 0.08 IES results generated in different patient population than upfront trials

26. ABCSG-8/ARNO: risk reduction Follow-up (mo)Relativep 2840% (19–56%)0.0009 At (mo)Absolute 283.1% Jakesz et al. Lancet 2005;366:455–62 At 28 months Significantly better distant RFS: 39% (13–58%) p = 0.0067 No significant reduction in mortality: 24% (-12–48%) p = 0.167 (small number of events: 59 vs 45) Analysis started at time of switching therapy Patient populations different in these two trials Event-free survival Anastrozole not licensed in this indication

27. ABCSG-8 trial Event-free survival (n = 2926) EFS (%) Time since surgery (mo) Therapy switch TA Events7750 HR0.63 p value0.010 After switch events Jakesz et al. Breast Cancer Res Treat 2005;94:(abstract 13) Time since surgery (mo) 94.4% 92.9% Therapy sequence 0.068p value 0.76HR 79101Events T→AT All events EFS (%) Anastrozole not licensed in this indication

28. ABCSG-8: risk reduction EventsRelative RRp 127 1 37%0.01 180 2 24%0.07 Event-free survival Absolute RR NR 1.5% 1 With analysis started at therapy switch –Switching to anastrozole reduces events by 37% (p = 0.01) 2 With analysis started immediately after surgery –Switching to anastrozole reduces events by 24% (p = 0.07) –More difficult to show a difference when early events are included RR risk reduction Jakesz et al. Breast Cancer Res Treat 2005;94:(abstract 13) Anastrozole not licensed in this indication

29. Efficacy in switching/sequential AI trials Switching to an AI after 2–3 years of tamoxifen superior to continuing on tamoxifen –Significant improvements in DFS and distant DFS –Significant reductions in contralateral breast cancer BUT –Patient population after 2–3 years tamoxifen ≠ after surgery and has lower risk of recurrence –ABCSG-8 From point of randomization, trend towards superior DFS From point of therapy switch, significantly superior DFS Treatment decisions after surgery –Currently no convincing data to support planned therapy switch from tamoxifen at 2–3 years

30. OS in switching/sequential AI trials To date, no improvement in survival demonstrated with switching/sequential therapies in individual trials Combined analysis of ITA, ARNO and ABCSG-8 presented at SABCS 1 –Type of meta-analysis –A marginal but statistically significant improvement in OS was demonstrated –Criticized for methodological reasons –Showed 1.2% improvement in OS (p < 0.0377) 1 Jonat et al. Breast Cancer Res Treat 2005;94(abstract 18)

31. Combined analysis Overall survival (ITT population) Hazard ratio 4006 0.71 0.038 448 0.50 0.094 2579 0.930.726 979 0.48 0.026 Patients HR p value ARNO 95 ABCSG-8 ITA Meta-analysis 0.20.4 0.60.81.0 1.2 1.4 1.6 Jonat et al. Breast Cancer Res Treat 2005;94(abstract 18) Favors AI Favors Tam

32. OS in switching/sequential AI trials Combined analysis shows significant improvement in OS – HR 0.71, p = 0.038 1 BUT –Different patient characteristics –Favorable populations selected –Statistical methodology has been questioned Results should be interpreted with caution Until substantiated, remains unproven Jonat et al. Breast Cancer Res Treat 2005;94(abstract 18)

33. Risk of recurrence at 5 years 38% experience recurrence with no adjuvant treatment (EBCTCG) 50% risk reduction with tamoxifen Further 20–30% risk reduction with AIs EBCTCG Lancet 2005;365:1687

34. Conclusions: AI adjuvant therapy 1 Winer et al. J Clin Oncol 2005;23:619–29; 2 Goldhirsch et al. Ann Oncol 2005;19:3817–27; 3 Rieber & Theriault J Natl Compr Canc Netw 2005;3:309–14 AIs demonstrate superior efficacy to tamoxifen in upfront and switching/sequential strategies Recent guidelines recommend inclusion of an AI in early adjuvant therapy 1,2,3 The balance between efficacy and safety/tolerability is different for patients at high risk of relapse and patients at low risk of relapse Analyses of studies comparing sequential therapy with continuous AI awaited –BIG 1-98 –Amended TEAM

35. Sequential therapy trials Randomization 123450 Time from surgery (years) Exemestane (5 years) Tamoxifen (2–3 years) Exemestane (2–3 years) Tamoxifen (3 years) Letrozole (2 years) Letrozole (3 years) Tamoxifen (2 years) Letrozole (5 years) Tamoxifen (5 years) BIG 1-98 TEAM* (amended) * TEAM initially compared 5 years of tamoxifen with 5 years of exemestane Protocol amended to effect switch from tamoxifen to exemestane at 2–3 years