2. Edith A. Perez, MD Director, Cancer Clinical Study Unit Mayo Clinic Jacksonville, Florida Welcome and Introductions

3. John F. Forbes, MB, BS, MS, FRACS Professor of Surgical Oncology University of Newcastle Director, Department of Surgical Oncology Newcastle Mater Misericordiae Hospital Newcastle, Australia The Early Use of Adjuvant Aromatase Inhibitors for Early Breast Cancer: New Contributions from the BIG 1-98 Letrozole Trial

4. 44 Outline Trial Design Statistical Analyses Population Efficacy Endpoints Subgroups Safety Conclusions Perspective

5. 55 Argentina123New Zealand157 Australia667Peru51 Belgium634Poland277 Brazil17Portugal64 Canada20Russia240 Chile22Slovenia15 Czech Rep.109South Africa187 Denmark1396Spain70 France1016Sweden64 Germany113Switzerland611 Hungary334Turkey54 Iceland6United Kingdom401 Italy1285Uruguay1 Netherlands94TOTAL8028 BIG 1-98 Worldwide Collaborative 8028 patients enrolled March 1998-May 2003

6. 66 BIG 1-98 Design Tamoxifen Letrozole Tamoxifen RANDOMIZERANDOMIZE 025 YEARS A B C D Compares Letrozole versus Tamoxifen Letrozole: Arms B and D Tamoxifen: Arms A and C Excludes events and FU beyond switch for C & D Tamoxifen

7. 77 BIG 1-98  New since St. Gallen (January 2005) - Medical review of all cerebrovascular, cardiac, unclear AEs (538 cases) and all deaths without prior cancer event (93 cases) - Overall survival outcome by subgroups - Identification of myalgia and arthralgia AEs  Still to come - Central review of ER, PgR, Her-2 - Update of safety and efficacy - Results of sequential treatment comparisons

8. 88 Primary Core Analysis 8028 Randomized 8010 Primary Core Analysis 4007 T4003 L versus 18 withdrew consent (no treatment / FU) 133 (1.66%) ineligible cases included in primary core analysis Median Follow-Up=25.8 months

9. 99 Patient/Tumor Characteristics LetrozoleTamoxifen Median age61 Tumor size > 2 cm36.5%37.7% Node positive41.5%41.2% Chemotherapy given25.3% ER+ / PgR+63.5%62.7% ER+ / PgR-20.2%20.5% ER+ / PgR unk14.5%14.3% Receptor positivity was a study requirement: 99.8% of patients had receptor positive tumors

10. 10 Primary End Point: DFS Time from randomization to first of: Invasive recurrence in - Ipsilateral breast - Chest wall - Regional site (internal mammary/axilla) - Distant site (including ipsi supraclavicular) Contralateral breast (invasive) Second (non breast) malignancy Death without prior cancer event

11. 11 Secondary End Points  Overall survival (OS)  Systemic disease-free survival (SDFS)*  Distant disease-free survival (DDFS)**  Safety * Excluding locoregional and contralateral events ** Excluding locoregional and 2 nd non-breast cancer

12. 12 T 0 20 40 60 80 100 012345 Percent Alive and Disease-Free Years from Randomization Disease-Free Survival L 97.7 97.6 Yearly DFS % 95.1 93.4 90.5 89.0 86.8 84.6 84.0 81.4 No. at Risk 3892 3896 2964 2926 1261 1238 892 866 4003 4007 567 544 NHR (95% CI)p 80100.81 (.70-.93)0.003 Events 779

13. 13 Years from Randomization 0 23451 0 10 5 15 20 Proportion Failure (%) L T Cumulative Incidence Breast Cancer Event 13.6% 10.2% 8.1% 6.2% 5-year diff (L-T) = -3.4% (S.E. 1.2) Cum incidence P=0.0002

14. 14 Treatment Failures 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

15. 15 Deaths LetrozoleTamoxifen Patients40034007 Deaths 166192 Deaths following cancer event111154 Deaths w/o prior cancer event5538 - Cerebro-vascular accident71 - Venous thromboembolic22 - Cardiac136 - Sudden death (cause unk)10 - Other2319

16. 16 Protocol Endpoints DFS OS SDFS Favors LFavors T 0.81 0.86 0.83 1.00.50.751.332.0 Hazard Ratio (L:T)

17. 17 Other Endpoints DFS OS SDFS Time to recurrence DFS (w/o 2 nd malignancy) Favors LFavors T 0.81 0.86 0.83 0.79 0.73 1.00.50.751.332.0 Hazard Ratio (L:T) Time to distant recurrence 0.72

18. 18 Sub group Analyses Subgroup analyses should concentrate on: differences from the average overall treatment effect (via tests of heterogeneity or interaction) It is inappropriate to assess the effects of treatment on a single subgroup by examination of the 95% CI for that subgroup. Cuzick J 1982; Lancet 2005 365:1308

19. 19 Sub group Analyses Two types of error can occur 1. Attribution of an effect to a subgroup when there is no overall effect and no evidence for heterogeneity (more common) 2. To claim a lack of effect in a subgroup when the overall effect is significant Cuzick J 1982; Lancet 2005 365: 1308

20. 20 Sub group Analyses Confidence intervals in subgroups are always wider than those for the main effect because of smaller numbers. If the interval for a subgroup crosses the no effect point, this is widely misinterpreted as a lack of effect in the subgroup even when the overall effect is significant. The correct approach is to determine whether the effect size for different subgroups varies significantly from the main effect by a test for heterogeneity. Cuzick J 1982; Lancet 2005 365: 1308

21. 21 Subgroups - DFS Favors LFavors T 1.00.50.751.332.0 Hazard Ratio (L:T) CT given (n=2024) CT not given (n=5986) 0.70 0.85 N-positive (n=3311) N-negative (n=4174) 0.71 0.99 ER+ / PgR+ (n=5055)* ER+ / PgR- (n=1631)* 0.84 0.83 * Based on local assessment

22. 22 Subgroup - OS 0.76 0.90 Favors LFavors T 1.00.50.751.332.0 Hazard Ratio (L:T) CT given (n=2024) CT not given (n=5986) 0.82 0.88 N-positive (n=3311) N-negative (n=4174) 1.00 0.79 ER+ / PgR+ (n=5055)* ER+ / PgR- (n=1631)* * Based on local assessment

23. 23 Summary of Efficacy Letrozole significantly decreased overall risk of recurrence (19% P=0.003) Letrozole significantly reduced the risk of distant metastases (27% P=0.0012) Letrozole was associated with a non significant decreased risk of death (14% P=0.16) The results are consistent with a similar effect in all subgroups examined

24. 24 Adverse Events, Any Grade Letrozole Tamoxifen *Grade 1: 35.1% L, 17.3% T; Grade 2+: 8.5% L, 1.9% T Serial cholesterol levels are being reviewed.

25. 25 Cardiovascular Events, Grade 3-5 LetrozoleTamoxifen Patients39753988P CVA/TIA gr 3-51.0% 1.0 Thromboembolic gr 3-50.8%2.1%< 0.0001 Cardiac gr 3-52.1%1.1%0.0003 Ischemic heart disease gr 3-51.1%0.6%0.013 Cardiac failure gr 3-50.5%0.1%0.006

26. 26 Summary: Cardiovascular Events Compared with tamoxifen - AIs reduce the risk of thromboembolic adverse events - Adjuvant treatment with AIs has been associated with some increase in the risk of CV events Current information is conflicting and insufficient to fully determine the longer-term effect of AIs on CV health It is not possible at present to assign different cardiovascular risk profiles to the individual AIs Further analyses of ongoing AI trials is required

27. 27 Bone Fractures LetrozoleTamoxifen Patients39753988 Bone fractures244164 Patients w/ bone fracture225 (5.7%)159 (4.0%) Bone fracture rate (fracture/100 patient-years) 2.21.5 Risk ratio, p-value (L:T)1.42 p=0.0006

28. 28 Endometrial Events LetrozoleTamoxifen Patients*30893157 Endometrial biopsies (pts)72 (2.3%)288 (9.1%) Invasive endometrial cancer 6 (0.2%) 15 (0.5%) Invasive endometrial cancer Risk ratio, p-value (L:T)0.40, p=0.087 *Excludes 1717 patients with hysterectomy at baseline

29. 29 Perspective Interpretation Predictions

30. 30 RECURRENCE MORTALITY in trials of ~5 years of tamoxifen versus Not, ER+/unknown: 15-year outcome (life-table curve: 10386 women, all ages, 80% ER+, 30% N+) Lancet May 14 2005 HR Abs RRn HR Abs RRn 0.57 10.4 0.64 13.7 0.74 11.8 0.70 3.6 0.70 7.9 0.74 9.2 EBCTCG 2000 (2005) Recurrence EBCTCG 2000 (2005) Mortality 11.7 HR 0.44 14.8

31. 31 Smoothed hazard rates for recurrence ? Start Early or Switch 0.5 1.0 1.5 2.0 2.5 3.0 0123456 Follow-up time (years) Anastrozole Tamoxifen 0 Letrozole: Prevention of early distant relapses Should translate into mortality reduction ? Acquired Tamoxifen resistance developing at ~ 2-3 years Annual HR HR+ %

32. 32 0 0.5 1 1.5 2 2.5 3 123456 Years since randomization Annual rates % Anastrozole Tamoxifen 0 Fracture rates over time Fracture rates per 1000 women years: Anastrozole 22.6; Tamoxifen 15.6; P1 control 18.4; WHI control 19.1

33. 33 Cross trial Comparisons Cross trial (indirect) comparisons may be unreliable: - Different end-point definitions - Different populations - Different treatments - Non randomised comparisons They should be interpreted with caution both for efficacy and side effects comparisons But they may lead to new hypotheses

34. 34 Endpoint: Comparisons BIG 1-98 and ATAC Favors TAM Hazard ratio (LET:TAM) DFS OS SDFS Time to recurrence DFS (w/o 2nd malignancy) 0.81 0.86 0.83 0.79 0.73 Time to distant metastasis (DDFS) 0.72 Favors LET 1.00.50.751.332.0 ATAC HR+ 68 mo 1 33 mo 2 1. Lancet. Jan 7, 2005. 2. Lancet. June 22, 2002. 0.97 0.84 0.73 0.830.78 - - 0.74 - - - -

35. 35 Subgroups: OS 0.76 0.90 0.82 0.88 1.00 0.79 Favors LFavors T 1.00.50.751.332.0 Hazard Ratio (L:T) CT given (n=2024) CT not given (n=5986) N-positive (n=3311) N-negative (n=4174) ER+ / PgR+ (n=5055)* ER+ / PgR- (n=1631)* * Based on local assessment

36. 36 Retrospective analysis of time to recurrence for ER/PgR subgroups At risk: A451435417400390347124 T42941237535332727696 Follow-up time (years) 25 0 5 10 15 20 0123456 Anastrozole (A) Tamoxifen (T) Patients (%) Patient group HR+ ER+PgR+ ER+PgR- Hazard ratio 0.79 0.84 0.43 ER+/PgR-

37. 37 ATAC: Ischemic CV Disease and Deaths ATAC (68 month F/U) ANA* (n=2618) TAM * (n=2598) Overall Deaths296301NS Breast Cancer Deaths Cardiac Deaths 152172NS Ischemic Cardiovascular Disease 127 (4.1%)104 (3.4%)NS *Data from HR+ patients Distler W, St. Gallen 2005, poster P128; Howell A, St Gallen 2005, poster P127

38. 38 IES: MI and Deaths IES (37.4 month F/U) EXE (n=2352) TAM (n=2372) All MI’s20 (0.9%)8 (0.4%)NS MI’s on Treatment14 (0.7%)6 (0.3%)NS Deaths, All152187NS Deaths, Vascular157 Deaths, Cardiac1312 Coombes RC et al, SABCS 2004, Abstract 3 (Oral Presentation)

39. 39 Protective Effect of Tamoxifen on cholesterol? 1) http://www.nhlbi.nih.gov/about/framingham/index.html; 2) McDonald CC et al.: BMJ 1995;311:977– 80; 3) Rutqvist LE et al.:J Natl Cancer Inst 1993;85:1398–406, 4) Bradbury BD et al, Cancer March 2005, 5) Reis SE et al.; J Natl Cancer Inst 2001, Vol 93, No 1, Jan 3:16-21http://www.nhlbi.nih.gov/about/framingham/index.html  Cardiovascular risk substantially and progressively increases in women age >65 (Framingham study) 1  The cardio protective effect of tamoxifen has been studied in several trials – The data are conflicting, some studies showed a cardio protective effect 2-4, others did not 5.

40. 40 RECURRENCE MORTALITY in trials of ~5 years of tamoxifen versus Not, ER+/unknown: 15-year outcome (life-table curve: 10386 women, all ages, 80% ER+, 30% N+) Lancet May 14 2005 HR Abs RRn HR Abs RRn 0.57 10.4 0.64 13.7 0.74 11.8 0.70 3.6 0.70 7.9 0.74 9.2 EBCTCG 2000 (2005) Recurrence EBCTCG 2000 (2005) Mortality 11.7 HR 0.44 14.8

42. Questions and Answers

43. 43 Lipid Data BIG 1-98 revealed an increase in hypercholesterolemia measured in the letrozole arm vs tamoxifen - The majority (>80%) were categorized as grade 1 hypercholesterolemia, < 300 ųg/mL - Measurements reflect non-fasting lipid levels, - single pathologic measurements sufficed to qualify as an event Further review to be completed

44. 44

45. 45 Conclusions  Letrozole significantly prolongs DFS compared with tamoxifen for postmenopausal women with endocrine- responsive breast cancer (especially reducing relapse in distant sites).  Compared with tamoxifen in postmenopausal women, more skeletal and grade 3-5 cardiac events and less venous thromboembolic and endometrial events occurred with letrozole.

46. 46 Conclusions  Letrozole can now be considered part of standard adjuvant therapy for postmenopausal women with endocrine-responsive breast cancer.  Longer follow-up of this study will provide assessment of the role of sequential endocrine agents compared with endocrine monotherapy.

47. 47 The Use of Adjuvant Aromatase Inhibitors In Post Menopausal Early Breast Cancer New Contributions from BIG 1 98 Coordinated by the International Breast Cancer Study Group International Study Chair: Dr Beat Thürlimann Professor John F Forbes IBCSG / ANZ BCTG Newcastle Mater Hospital University of Newcastle