1. ‘Arimidex’, Tamoxifen, Alone or in Combination (ATAC) trial: Completed Treatment Analysis

2. Introduction

3. Which problems does ATAC address? Is tamoxifen still the best adjuvant therapy for early breast cancer (EBC)? Is anastrozole superior to tamoxifen in the adjuvant setting? Can we improve upon the tolerability problems associated with adjuvant tamoxifen? How do we reduce recurrences in the first few years of treatment?

4. If tamoxifen is not the best adjuvant treatment: Should anastrozole be considered the preferred initial endocrine therapy? When should anastrozole be given? Is there robust and mature data to support the use of anastrozole in this setting?

5. Trial design & patient recruitment

6.      9366 Postmenopausal women with invasive breast cancer mean age 64 years; 84% hormone receptor positive 61% node negative; 64% with tumour  2 cm in diameter Surgery  radiotherapy  chemotherapy Randomisation 1:1:1 for 5 years Anastrozole n=3125 Tamoxifen n=3116 Combination n=3125  Regular follow-up  Primary trial endpoints: Disease-free survival Safety / tolerability Secondary trial endpoints: Incidence of contralateral breast cancer Time to distant recurrence Overall survival Time to breast cancer death Discontinued following initial analysis as no efficacy or tolerability benefit compared with tamoxifen arm ATAC trial design

7. ATAC completed treatment analysis Follow-up: –Data cut-off 31st March 2004, based on at least 704 deaths in the two monotherapy arms combined –68 months’ median follow-up – beyond completion of treatment –59 months’ median treatment duration –Only 8% of patients remain on treatment – the great majority of these nearing completion Results: –Anastrozole demonstrates superior efficacy to tamoxifen –Anastrozole demonstrates superior tolerability to tamoxifen –The results of this analysis are mature and the overall risk:benefit profile of anastrozole can be considered final

8. Efficacy analysis

9. Smoothed hazard rates for recurrence ( HR*-positive population ) 0123456 Follow-up time (years) Annual hazard rates (%) Anastrozole Tamoxifen 0.5 1.0 1.5 2.0 2.53.0 0 *HR=hormone receptor

10. A261825402448235522682014830 T259825162398230421891932774 Disease-free survival (HR*-positive population) 0123456 p-value 0.005 HR 0.83 A vs T 95% CI (0.73–0.94) At risk: Follow-up time (years) Anastrozole (A) Tamoxifen (T) 0 5 10 15 20 25 Patients (%) Absolute difference: 1.6%2.6%2.5%3.3% *HR=hormone receptor

11. A261825402448235522682014830 T259825162398230421891932774 Recurrence (HR*-positive population) 0123456 Anastrozole (A) Tamoxifen (T) p-value 0.0002 HR 0.74 A vs T 95% CI (0.64–0.87) Follow-up time (years) At risk: 0 5 10 15 20 25 Patients (%) Absolute difference: 1.7%2.4%2.8%3.7% *HR=hormone receptor

12. Analysis of time to recurrence for subgroups of the HR*-positive population 0.800.600.401.001.251.501.75 Nodal status+ve -ve unknown** Tumour size  2 cm 2–5 cm >5 cm* Previous chemotherapy Yes No All patients *HR=hormone receptor Anastrozole betterTamoxifen better **Confidence limit extends beyond plot Hazard ratio (A:T) and 95% CI

13. A261825492463238523082051845 T259825332437235922552005816 Time to distant recurrence (HR*-positive population) 0123456 p-value 0.06 HR 0.84 A vs T 95% CI (0.70–1.00) Anastrozole (A) Tamoxifen (T) Follow-up time (years) At risk: 0 5 10 15 20 25 Patients (%) *HR=hormone receptor

14. A261825662505243723772117867 T259825492502243023332080855 Overall survival (HR*-positive population) 0123456 p-value 0.7 HR 0.97 A vs T 95% CI (0.83–1.14) Anastrozole (A) Tamoxifen (T) Follow-up time (years) At risk: 0 5 10 15 20 25 Patients (%) *HR=hormone receptor

15. Incidence of new (contralateral) breast primaries in HR*- population *p=0.001 for invasive cancers. *HR=hormone receptor 21 Invasive* 53 Tamoxifen (TAM) (n=3116) Anastrozole (AN) (n=3125) 26 5 DCIS HR95% CIp-value AN vs TAM 0.470.29–0.750.001 48 Invasive* Number of cases 5 DCIS

16. Recurrence rate/year (%) Year Saphner et al JCO 1996; 14: 2738-2746 Most recurrences occur within the first 5 years of primary therapy Need to give most effective treatment first to reduce risk of recurrence

17. A261825402448235522682014830 T259825162398230421891932774 Disease-free survival (HR*-positive population) 0123456 p-value 0.005 HR 0.83 A vs T 95% CI (0.73–0.94) At risk: Follow-up time (years) Anastrozole (A) Tamoxifen (T) 0 5 10 15 20 25 Patients (%) Absolute difference: 1.6%2.6%2.5%3.3% *HR=hormone receptor

18. Anastrozole demonstrates superior efficacy to tamoxifen Anastrozole is more effective than tamoxifen in reducing the risk of recurrence, distant recurrence and contralateral breast cancer The absolute difference between anastrozole and tamoxifen continues to increase over time, and extends beyond completion of treatment As expected, overall survival is similar for both treatments, with a trend in favour of anastrozole for breast cancer death There are no significant subgroup interactions

19. Added benefit versus tamoxifen Hormone receptor-positive population Reduction in risk of recurrence Reduction in risk of breast cancer mortality Reduction in risk of contralateral breast cancer EBCTCG Benefit for tamoxifen vs placebo 50% 28% 47%* ATAC Additional benefit of anastrozole vs tamoxifen 26% 13% 52% *hormone receptor-positive and -negative patients EBCTCG = Early Breast Cancer Trialists’ Collaborative Group

20. Added benefit versus tamoxifen 38% risk of recurrence with no adjuvant treatment 50% reduction in risk with tamoxifen Further 26% risk reduction with anastrozole

21. When to treat? Recurrence rates I early breast cancer are highest in the first 5 years after surgery, with a peak at 2 years, regardless of baseline prognostic factors Tamoxifen is associated with higher rates of recurrence, AEs and withdrawals than anastrozole Substantial benefit with anastrozole in the first 3 years justifies offering the most effective therapy at the earliest opportunity

22. Tolerability analysis

23. Overview of adverse events* All adverse events Adverse events leading to withdrawal Drug-related adverse events leading to withdrawal All serious adverse events Serious adverse events leading to withdrawal Serious adverse events leading to death Drug-related serious adverse events leading to death p-value 0.2 0.0002 0.0005 0.03 0.04 0.6 0.5 Tamoxifen (%) (n=3094) 94.6 14.3 8.9 36.0 5.9 3.6 0.3 Anastrozole (%) (n=3092) 93.9 11.1 6.5 33.3 4.7 3.3 0.2 *Adverse events on treatment or within 14 days of discontinuation

24. T 40.9 10.2 13.2 0.8 2.8 4.5 2.4 29.4 7.7 A 35.7 5.4 3.5 0.2 2.0 2.8 1.6 35.6 11.0 Completion analysis p-value <0.0001 0.01 0.03 0.0004 0.02 <0.0001 Hot flushes Vaginal bleeding Vaginal discharge Endometrial cancer* Ischaemic cerebrovascular event Venous thromboembolic events Deep venous thromboembolic events Joint symptoms Total fractures *Excludes patients with prior hysterectomy and includes on- and off-therapy AEs Pre-defined adverse events

25. 0.20.40.60.81.02.01.5 Fractures Hot flushes Joint symptoms Venous thromboembolic events Ischaemic cerebrovascular events Endometrial cancer Vaginal bleeding Vaginal discharge Relative risk (anastrozole / tamoxifen) In favour of anastrozoleIn favour of tamoxifen

26. Tolerability summary Compared with tamoxifen, anastrozole is associated with significantly fewer: –SAEs, treatment-related AEs and withdrawals due to SAEs or AEs –potentially life threatening AEs such as endometrial cancer, thromboembolic, and cerebrovasular events No new safety concerns have emerged with long-term follow-up Only anastrozole has a tolerability profile of this robustness and maturity, as it covers the full 5 year treatment period Anastrozole now has a known, predictable and manageable safety profile

27. Summary

28. ATAC summary ATAC Completed Treatment Analysis extends and strengthens the evidence that 5 years of anastrozole is significantly more effective and better tolerated than 5 years of tamoxifen Overall risk:benefit profile remains clearly in favour of anastrozole The absolute benefits for anastrozole over and above those of tamoxifen continue to increase with time and extend beyond the completion of therapy

29. ATAC in context Anastrozole is a more effective and better-tolerated adjuvant treatment than tamoxifen These findings provide a basis for establishing anastrozole as the standard of care for the initial 5 years’ adjuvant treatment of postmenopausal women with hormone receptor-sensitive early breast cancer Howell, SABCS 2004

30. Back-up slides

31. Definition of endpoints (1) Disease-free survival (DFS) –loco-regional recurrence (inc. ipsilateral new breast cancer) or new contralateral breast cancer –distant recurrence or death (for any reason) Distant disease-free survival (DDFS) –distant recurrence –death (for any reason) Time to recurrence (TTR) –loco-regional recurrence (inc. ipsilateral new breast cancer) or new contralateral breast cancer –distant recurrence or death due to breast cancer

32. Definition of endpoints (2) Overall survival (OS) –death (for any reason) Time to distant recurrence (TTDR) –distant recurrence or any death following a loco- regional recurrence (inc. ipsilateral new breast cancer) –breast cancer death Time to breast cancer death (TTBCD) –any death following a loco-regional (inc. ipsilateral new breast cancer) or distant recurrence –breast cancer death

33. ATAC: patient characteristics Tamoxifen (n=3116) Anastrozole (n=3125) Mean age (years) Mean weight (kg) Receptor status (%) positive negative unknown Primary treatment (%) mastectomy axillary surgery radiotherapy chemotherapy prior tamoxifen 64.1 70.8 83.7 8.3 8.0 47.8 95.5 63.3 22.3 1.6 64.1 71.1 83.4 8.7 7.9 47.3 95.7 62.5 20.8 1.6

34. ATAC: baseline disease characteristics Primary tumour size (%) T1 (  2 cm) T2 (  2 cm to  5 cm) T3 (  5 cm) Nodal status (%) node-positive Grading (%) well differentiated moderately differentiated poorly / undifferentiated not assessed / recorded 63.9 32.6 2.7 34.9 20.8 46.8 23.7 8.5 62.9 34.2 2.2 33.6 20.5 47.8 23.3 8.3 Tamoxifen (n=3116) Anastrozole (n=3125)

35. ATAC trial analysis history First analysis – June 2002 Median follow-up : 33 months 1 Updated analysis – November 2003 Median follow-up : 47 months 2 Completion analysis – November 2004 Median follow-up : 68 months Women years’ follow up: 49,941 Total events: 1867 1.The ATAC Trialists’ Group. Lancet 2002; 359: 2131–2139 2.The ATAC Trialists’ Group. Cancer 2003; 98: 1802 – 1810

36. Smoothed hazard rates for recurrence (ITT* population) 0.5 1.0 1.5 2.0 2.5 3.0 0123456 Follow-up time (years) Annual hazard rates (%) Anastrozole Tamoxifen 0 *ITT=intent-to-treat

37. At risk: A312530042874275726452350984 T311629922835270925752273933 Follow-up time (years) Includes non breast cancer deaths *ITT=intent-to-treat Disease-free survival (ITT* population) 0 5 10 15 20 25 0123456 p-value 0.013 HR 0.87 A vs T 95% CI (0.78–0.97) Anastrozole (A) Tamoxifen (T) Patients (%) Absolute difference: 1.5%2.0%2.4%2.9%

38. A312530042874275726452350984 T311629922835270925752273933 0123456 p-value 0.0005 HR 0.79 A vs T 95% CI (0.70–0.90) Follow-up time (years) At risk: Recurrence (ITT* population) Anastrozole (A) Tamoxifen (T) 0 5 10 15 20 25 Patients (%) Absolute difference: 1.6%2.1%2.8%3.4% *ITT=intent-to-treat

39. **Confidence limit extends beyond plot Analysis of time to recurrence for subgroups of the ITT* population Hazard ratio (A:T) and 95% CI Nodal status+ve -ve unknown All patients Tumour size≤ 2 cm >2 cm unknown** Receptor status+ve -ve unknown Previous chemotherapy yes no 0.401.501.750.801.001.25 0.60 Anastrozole betterTamoxifen better *ITT=intent-to-treat

40. A3125302228992802270324061009 T311630202890278326562364985 At risk: p-value 0.043 HR 0.86 A vs T 95% CI (0.74–0.99) Follow-up time (years) Time to distant recurrence (ITT* population) 0123456 Anastrozole (A) Tamoxifen (T) 0 5 10 15 20 25 Patients (%) *ITT=intent-to-treat

41. A3125 3051 29562865278424791037 T3116 3048 29722872274724611037 p-value 0.7 HR 0.97 A vs T 95% CI (0.85–1.12) 0123456 At risk: Follow-up time (years) Overall survival (ITT* population) Anastrozole (A) Tamoxifen (T) 0 5 10 15 20 25 Patients (%) Includes non breast cancer deaths *ITT=intent-to-treat

42. A3125305129562865278424791037 T3116304829722872274724611037 0123456 p-value 0.2 HR 0.88 A vs T 95% CI (0.74–1.05) At risk: Follow-up time (years) Time to breast cancer death (ITT* population) Anastrozole (A) Tamoxifen (T) 0 5 10 15 20 25 Patients (%) *ITT=intent-to-treat

43. Incidence of new (contralateral) breast primaries in ITT* population 27 Invasive* 58 Tamoxifen (TAM) (n=3116) Anastrozole (AN) (n=3125) 35 6 DCIS HR95% CIp-value AN vs TAM 0.580.38–0.880.01 52 Invasive* Number of cases 8 DCIS *p=0.004 for invasive cancers. *ITT=intent-to-treat

44. Summary of efficacy endpoints In the overall ITT population, compared with tamoxifen, anastrozole provides significantly reduced risk of : –all events: 13% (p=0.013) –recurrence: 21% (p=0.0005) –distant recurrence: 14% (p=0.043) –contralateral recurrence: 42% (p=0.01)