1. Trial Comparison: ‘Arimidex’, Tamoxifen, Alone or in Combination (ATAC) and Breast International Group (BIG) 1-98

2. Trial design and patient recruitment

3. 9366 patients recruited from 381 centres in 21 countries ATAC trial: 2222 30 160 201 Belgium 192 Czech Republic 84 France 366 Germany 121 Hungary 243 Ireland 41 Italy 654 Netherlands 195 Poland 107 Portugal 74 Slovakia 33 Spain 417 Sweden 291 Turkey 53 UK 3228 14 640

5. Combination n=3125 Discontinued following initial analysis as no efficacy or tolerability benefit compared with tamoxifen arm Regular follow-up 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 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 ATAC trial design

6. ATAC Completed Treatment Analysis Data cut-off 31 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 ATAC Trialists’ Group. Lancet 2005; 365: 60-62

7. 8028 postmenopausal women with ER+ disease Median age 61 years 52% node negative 63% tumour  2 cm in diameter Tamoxifen BIG 1-98 trial design RANDOMISERANDOMISE Letrozole Tamoxifen LetrozoleTamoxifen Letrozole 025 A B C D Arm A vs B: March 1998 – March 2000; (n=1835) A vs B vs C vs D; September 1999 – May 2003; (n = 6193) BIG = Breast International Group ER+ = estrogen receptor-positive Time (years) 134 Adapted from Thürlimann B. St Gallen presentation 2005

8. Total number of DFS events (monotherapy arms)1226 <11–<22–<33–<44–<5>5>5 Duration of follow-up (years) Patients (%) ATAC: 73% of patients have been followed-up for 5 years or more Updated analysis (median follow-up 47 months) Treatment completion analysis (median follow-up 68 months) DFS = disease-free survival

9. BIG 1-98: only 15% of patients have been followed-up for 5 years 11 22 33 44 55 Follow-up (years) Patients (%) Thürlimann B. St Gallen presentation 2005

10. Demographics

11. Patient characteristics BIG 1-98 (n=8010) ATAC (n=6291) Age (years) Primary treatment (%) mastectomy radiotherapy chemotherapy Mean 64.1 47.6 62.9 21.6 Median 61.0 43.0 71.6 25.3 ATAC Trialists’ Group. Lancet 2002; 359: 2131-39 Adapted from Thürlimann B. St Gallen presentation 2005

12. Baseline disease characteristics Tumour size  2 cm (%) Nodal status (%) node-positive node-negative unknown HR status (%) ER+/PgR+ ER+/PgR- ER+/PgR unknown ER-/PgR+ 63.4 34.2 60.7 5.0 61.5 14.1 5.5 2.2 62.9 41.3 52.2 6.5 63.1 20.4 14.4 1.8 BIG 1-98 (n=8010) ATAC (n=6291) ATAC Trialists’ Group. Lancet 2002; 359: 2131-39 Adapted from Thürlimann B. St Gallen presentation 2005

13. Efficacy analyses

14. Definition of disease-free survival differs ATAC –loco-regional recurrence or new contralateral breast cancer (invasive or DCIS) –distant recurrence or death (for any reason) BIG 1-98 –breast cancer recurrence (local, regional and distant) or invasive contralateral breast cancer –non-breast cancer deaths (deaths without recurrence) –non-breast cancer second primaries Time to recurrence is similar for both trials DCIS = ductal carcinoma in situ ATAC Trialists’ Group. Lancet 2002; 359: 2131-39 Thürlimann B et al. The Breast 2005;14; S3. Abstract S4

15. Definition of time to distant recurrence appears to differ ATAC - time to distant recurrence (TTDR) –distant recurrence or any death following a loco-regional recurrence (including ipsilateral new breast cancer) or breast cancer death –~45% of first events were distant events –~18% of first events were locoregional BIG 1-98 - time to distant metastasis (TTM) –breast cancer recurrence (excluding local or regional recurrences, and contralateral breast cancer) –censoring for non-breast cancer deaths –~65% of first events* were distant events –~12% of first events* were local or regional ATAC Trialists’ Group. Lancet 2005; 365: 60-62 Thürlimann B et al. The Breast 2005;14; S3. Abstract S4 *excluding second primary events

16. A261825402448235522682014830 T259825162398230421891932774 ATAC: 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 Absolute difference: 1.6%2.6%2.5%3.3% Patients (%) CI, confidence interval Howell A. SABCS presentation 2004

17. 4003389229641261892567 4007389629261238866544 L T At risk: Follow-up time (years) N=8010 Letrozole Tamoxifen p value 0.003 HR 0.81 L vs T 95% CI (0.70, 0.93) 012345 0 20 15 10 5 25 BIG 1-98: disease-free survival 97.795.190.586.884.0Yearly 97.693.489.084.681.4DFS % L T Adapted from Thürlimann B. St Gallen presentation 2005

18. ATAC: recurrence (HR-positive population) A261825402448235522682014830 T259825162398230421891932774 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 Absolute difference: 1.7%2.4%2.8%3.7% Patients (%) ATAC Trialists’ Group. Lancet 2005;365:60-62

19. BIG 1-98: breast cancer relapse (Time to recurrence) Cumulative incidence 012345 Proportion failure (%) 20 15 10 5 0 5-year difference (L-T) = -3.4  1.2% p=0.0002 (based on CI) 6.2% 10.2% 8.1% 13.6% Letrozole (L) Tamoxifen (T) Years from randomisation Thürlimann B. St Gallen presentation 2005

20. A261825502464238623092051845 T259825332438236122512005816 ATAC: 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 (%) Howell A. SABCS presentation 2004

21. A261825662505243723772117867 T259825492502243023332080855 ATAC: 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 (%) Howell A. SABCS presentation 2004

22. Hazard ratio (A:T) and 95% CI Disease-free survival Time to recurrence Time to distant recurrence Overall survival Time to breast cancer death Contralateral breast cancer 0.2 0.4 0.6 0.8 1.0 1.2 1.5 2.0 ATAC: efficacy summary (HR-positive population) Anastrozole (A) betterTamoxifen (T) better 0.83 0.74 0.84 0.97 0.87 0.47 Hazard ratio ATAC Trialists’ Group. Lancet 2005;365:60-62

23. ATAC: efficacy analysis (ITT and HR +ve) HR (A:T) and 95% CI Disease-free survival Time to recurrence Time to distant recurrence Overall survival Time to breast cancer death Contralateral breast cancer 0.2 0.4 0.6 0.8 1.0 1.2 1.5 2.0 ITT population HR +ve population Anastrozole (A) betterTamoxifen (T) better ATAC Trialists’ Group. Lancet 2005;365:60-62 0.87 0.79 0.86 0.97 0.88 0.58 ITTHR+ 0.83 0.74 0.84 0.97 0.87 0.47

24. Time to distant recurrence Time to recurrence BIG 1-98: efficacy summary Disease-free survival Systemic disease-free survival Disease-free survival (without 2nd primary) Hazard ratio (L:T) and 95% CI 0.2 0.4 0.6 0.8 1.0 1.2 1.5 2.0 Letrozole (L) betterTamoxifen (T) better Overall survival 0.81 0.72 0.73 0.86 0.83 0.79 Hazard ratio Adapted from Thürlimann B. St Gallen presentation 2005 0.83 0.74 0.84 0.97 BIG 1-98ATAC

25. BIG 1-98: sites of first failure Failures (DFS events) local contralateral breast regional* distant second (non-breast) malignancy death without recurrence Deaths Systemic failures** 8.8 0.5 0.4 0.3 4.4 1.7 1.4 4.1 8.1 10.7 0.9 0.7 0.3 5.8 2.0 0.9 4.8 9.6 0.004 0.047 0.125 0.845 0.006 0.324 0.077 0.176 0.020 Letrozole (%)Tamoxifen (%)p value *Regional includes axilla or internal mammary **SDFS ignores local and contralateral events Thürlimann B. St Gallen presentation 2005

26. ATAC vs BIG 1-98 efficacy summary Anastrozole is more effective than tamoxifen in reducing the risk of recurrence, distant recurrence and contralateral breast cancer –absolute difference between anastrozole and tamoxifen continues to increase over time, and extends beyond completion of treatment Letrozole demonstrates DFS benefits and early benefits in distant recurrence –BIG 1-98 has a comparatively higher number of patients per arm, resulting in a higher number of events per unit time –patient population in BIG 1-98 has a slightly worse prognosis –Absolute differences at 5 years for BIG 1-98 data are projected out to 5 years and are calculated from immature data hence liable to change

27. Sub-group analysis

28. ATAC: time-to-recurrence by subgroup Intent-to-treat population Hazard ratio (A:T) and 95% CI Nodal status+ve -ve All patients Tumour size≤ 2 cm >2 cm Receptor status+ve -ve Previous chemotherapy yes no 0.401.501.750.600.801.001.25 Anastrozole (A) betterTamoxifen (T) better Howell A. SABCS presentation 2004

29. Intent-to-treat population Hazard ratio (L:T) and 95% CI Nodal status+ve -ve All patients Previous chemotherapy yes no 0.401.501.750.600.801.001.25 Letrozole (L) betterTamoxifen (T) better Previous radiotherapy yes no BIG 1-98: disease-free survival by subgroup Adapted from Thürlimann B. St Gallen presentation 2005

30. ATAC vs BIG 1-98 subgroup summary (1) Anastrozole demonstrated advantages over tamoxifen for all subgroups examined –no heterogeneity of subgroups –no significant interaction with any baseline prognostic factor, including prior chemotherapy or nodal status –more effective than tamoxifen in overall HR+ve group  even greater improvement in ER+PgR- subgroup Subgroup analyses must be interpreted with caution –should not be used as a basis for making clinical decisions

31. ATAC vs BIG 1-98 subgroup summary (2) Letrozole demonstrated benefits over tamoxifen –node positive patients  no apparent benefit in node negative patients –prior chemotherapy patients  slightly worse prognosis, more patients received prior chemotherapy (25% vs 20%) No apparent difference between ER+/PgR+ and ER+/PgR- subgroups for letrozole and tamoxifen –tamoxifen does not appear to be performing in line with expectations  previous studies demonstrate that ER+/PgR- patients on tamoxifen have a higher rate of recurrence than ER+/PgR+ Subgroup analyses must be interpreted with caution –should not be used as a basis for making clinical decisions

32. Tolerability analysis

33. BIG 1-98: safety analysis Included all patients that had received at least 1 treatment dose Protocol-specified only ‘targeted’ adverse event data was collected every 6 months Number of patients experiencing at least 1 serious adverse event: –587 vs 643 (letrozole vs tamoxifen)

34. ATAC: 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 Howell A. SABCS presentation 2004

35. 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 0.02 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*** *Adverse events on treatment or within 14 days of discontinuation; **Excludes patients with prior hysterectomy and includes on- and off-therapy AEs; ***Fractures occurring at anytime prior to recurrence (includes patients no longer receiving treatment) ATAC: pre-defined adverse events* ATAC Trialists’ Group. Lancet 2005;365:60-62

36. T 38.1 6.6 16.2 9.5 2.4 2.6 1.1 8.3 4.1 19.2 L 33.6 3.3 14 8.8 1.0 2.7 1.2 8.7 5.8 43.6 Primary core analysis (%) Hot flushes Vaginal bleeding Night sweats Nausea Thromboembolic events Vomiting CVA/TIA Other cardiovascular Bone fracture Hypercholesterolemia BIG 1-98: targeted adverse events Adapted from Thürlimann B. St Gallen presentation 2005 No arthralgia/joint symptoms or osteoporosis data are available from BIG 1-98 Endometrial cancer shows no significant difference between L and T

37. ATAC vs BIG 1-98 : bone fractures Patients with bone fracture340 vs 237 (11.0% vs 7.7%) 1.49, p<0.0001 ATAC (A vs T) BIG 1-98 (L vs T ) Patients 228 vs 162 (5.8% vs 4.1%) 1.44, p=0.0006 Odds ratio, p value 2.2 vs 1.5 (per 100 patient years) 2.3 vs 1.6 (per 100 patient years) Bone fracture rate Adapted from ATAC Trialists’ Group. Lancet 2005;365:60-62 ; Thürlimann B. St Gallen presentation 2005

38. ATAC: fracture risk is predictable and manageable Years Arimidex Tamoxifen 0 3092 3094 1 2923 2932 2 2724 2741 3 2553 2579 4 2393 2401 5 2070 2100 6 845 846 Number at risk 0 0.5 1 1.5 2 2.5 3 123456 Years since randomisation *Calculated using Kaplan-Meier estimates Annual rates, %* Anastrozole 1 mg od Tamoxifen 20 mg od 0 Howell A. SABCS presentation 2004

39. ATAC vs BIG 1-98 : endometrial cancer Patients with endometrial cancer 5 vs 17 (0.2% vs 0.8%) 0.29, p=0.02 ATAC (A vs T) BIG 1-98 (L vs T ) Patients 6 vs 15 (0.2% vs 0.4%) 0.40, p=0.078 Odds ratio, p value Adapted from ATAC Trialists’ Group. Lancet 2005;365:60-62 ; Thürlimann B. St Gallen presentation 2005

40. BIG 1-98: Grade 3-5 cardiovascular events CVA/TIA Thromboembolic Other cardiovascular 46 (1.2%) 30 (0.8%) 143 (3.6%) Letrozole (n=3965) Tamoxifen (n=3984) Patients 42 (1.1%) 79 (2.0%) 101 (2.5%) Thürlimann B. St Gallen presentation 2005 There is a significantly higher number of other cardiovascular events on letrozole compared with tamoxifen (p=0.006)

41. BIG 1-98: death without recurrence Cumulative incidence 12345 20 15 10 5 0 Years from randomisation 5-year difference (L-T) = 1.3  0.6% p=0.08 (based on CI) 1.4% 1.8% 0.8% 3.1% Proportion failure (%) 0 Letrozole (L) Tamoxifen (T) Thürlimann B. St Gallen presentation 2005

42. BIG 1-98: deaths without recurrence (non-breast cancer deaths) Total CVA thromboembolic cardiac other Overall p value based on cumulative incidence 55 7 3 26 19 Letrozole (n=4003) Tamoxifen (n=4007) 38 1 2 13 22 0.08 Patients Adapted from Thürlimann B. St Gallen presentation 2005 In ATAC, the numbers of cardiovascular deaths are comparable between anastrozole and tamoxifen (49 vs. 46, respectively)

43. ATAC: deaths Median follow-up 68 months All deaths non-breast cancer deaths cerebrovascular cardiac 411 176 14 49 Anastrozole (n=3125) Tamoxifen (n=3116) 420 155 21 46 Patients A detailed review found that the non-breast cancer deaths in the anastrozole arm were due to a variety of apparently unrelated causes, with no link to anastrozole ATAC Trialists’ Group. Lancet 2005 ;365:60-62 ATAC Trialists’ Group. Lancet 2005 In Press

44. Comparison of safety between ATAC and BIG 1-98 L NS    ?   ? A  NS   Endometrial cancer Risk of stroke Venous thromboembolic events Cardiovascular deaths Joint symptoms Fractures Hot flushes Vaginal bleeding Vaginal discharge Hysterectomy Compared with tamoxifen ? – not reported

45. ATAC: tolerability and safety summary vs tamoxifen 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 cerebrovascular events No new safety concerns have emerged with long-term follow- up. There is no issue with cardiovascular safety Anastrozole now has a known, predictable and manageable safety profile The ATAC Trialists’ Group. Lancet 2005; 365: 60-62; Howell A. Breast Cancer Res Treat 2004; 88 (Suppl 1): S7, abs 1 AEs = adverse events; SAEs = serious AEs Only anastrozole has a tolerability profile of this robustness and maturity, as it covers more than 5-years’ follow-up

46. BIG 1-98: tolerability and safety summary vs tamoxifen Serious safety concerns about letrozole have emerged in this first analysis –increased incidence of stroke and cardiovascular events –increase in number of cerebrovascular and cardiovascular deaths No significant reduction in the incidence of endometrial cancer was observed The long-term safety profile of letrozole is unknown at this stage –cardiovascular effects of letrozole require further evaluation BIG 1-98 has raised serious safety concerns for letrozole at this early stage

47. Summary

48. Conclusions (1) The 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 The efficacy benefit continues to increase with time and extends beyond the completion of therapy These data support using anastrozole as initial adjuvant therapy The higher rates of recurrence, adverse events, and withdrawals from treatment with tamoxifen and the substantial benefit of anastrozole over the first 3 years justify the approach of offering the most effective therapy at the earliest opportunity

49. Conclusions (2) BIG 1-98 provides further evidence that tamoxifen should no longer be the standard of care for EBC No overall efficacy benefits have emerged for letrozole in BIG 1-98 that have not already been demonstrated for anastrozole in the ATAC trial There appear to be marked differences emerging in the safety of the aromatase inhibitors in the adjuvant setting –women treated with letrozole have a greater risk of stroke and cardiac events The ATAC completed treatment analysis demonstrates that the overall benefit:risk profile remains clearly and consistently in favour of anastrozole Only anastrozole has established efficacy and safety with >5 years’ long-term follow-up data

50. Back-up slides

51. ATAC: patient characteristics Tamoxifen (n=3116) Anastrozole (n=3125) Mean age (years) Receptor status (%) positive negative unknown Primary treatment (%) mastectomy radiotherapy chemotherapy 64.1 83.7 8.3 8.0 47.8 63.3 22.3 64.1 83.4 8.7 7.9 47.3 62.5 20.8 ATAC Trialists’ Group. Lancet 2002; 359: 2131-39

52. BIG 1-98: patient characteristics Tamoxifen (n=4007) Letrozole (n=4003) Median age (years) Primary treatment (%) chemotherapy Surgery/RT group (%) BC with RT BC without RT mastectomy with RT mastectomy without RT 61.0 25.3 53.3 2.8 18.3 25.4 61.0 25.3 54.0 3.3 17.6 24.8 BC = breast conservation; RT = radiotherapy Adapted from Thürlimann B. St Gallen presentation 2005

53. ATAC: baseline disease characteristics Primary tumour size (%) T1 (  2 cm) Nodal status (%) node-positive node-negative node-unknown HR status (%) ER+/PgR+ ER+/PgR- ER+/PgR unknown ER-/PgR+ 63.9 34.9 60.0 5.0 61.8 14.4 5.3 2.0 62.9 33.6 61.5 4.9 61.1 13.8 5.8 2.4 Tamoxifen (n=3116) Anastrozole (n=3125) HR = hormone receptor; ER = oestrogen receptor; PgR = progesterone receptor ATAC Trialists’ Group. Lancet 2002; 359: 2131-39

54. BIG 1-98: baseline disease characteristics Tumour size  2 cm (%) Nodal status (%) node-positive node-negative unknown HR status (%) ER+/PgR+ ER+/PgR- ER+/PgR unknown ER-/PgR+ 63.5 41.5 52.0 6.5 63.5 20.2 14.5 1.5 62.3 41.2 52.3 6.5 62.7 20.5 14.3 2.1 Tamoxifen (n=4007) Letrozole (n=4003) Adapted from Thürlimann B. St Gallen presentation 2005

55. ATAC vs BIG 1-98 demographics Patients in the ATAC trial had an improved prognosis compared with patients in BIG 1-98 –fewer patients in ATAC had node positive disease –fewer patients in ATAC had received prior radiotherapy –fewer patients in ATAC had received prior chemotherapy

56. Definition of further ATAC endpoints Time to recurrence (TTR) –loco-regional recurrence (including ipsilateral new breast cancer) or new contralateral breast cancer –distant recurrence or death due to breast cancer Overall survival (OS) –death (for any reason) Time to breast cancer death (TTBCD) –any death following a loco-regional (including ipsilateral new breast cancer) or distant recurrence –breast cancer death

57. Definition of further BIG 1-98 endpoints Time to recurrence (TTR) –breast cancer recurrence or new contralateral breast cancer (excluding non-breast cancer second primaries*) –censoring for non-breast cancer deaths Overall survival (OS) –death (for any reason) DFS without second primary events –as DFS (excluding non-breast second primaries*) Systemic disease-free survival (SDFS) † –regional or distant recurrence (not including local and contralateral) –non-breast second primaries –non-breast cancer death Thürlimann B et al. The Breast 2005;14; S3. Abstract S4 *allows comparison with ATAC † no ATAC equivalent

58. ATAC: efficacy analysis (ITT and HR +ve) HR (A:T) and 95% CI Disease-free survival Time to recurrence Time to distant recurrence Overall survival Time to breast cancer death Contralateral breast cancer 0.2 0.4 0.6 0.8 1.0 1.2 1.5 2.0 ITT population HR +ve population Anastrozole (A) betterTamoxifen (T) better ATAC Trialists’ Group. Lancet 2005;365:60-62 0.87 0.79 0.86 0.97 0.88 0.58 ITTHR+ 0.83 0.74 0.84 0.97 0.87 0.47

59. ATAC: recurrence in ER+/PgR- patients At risk: A451435417400390347124 T42941237535332727696 Follow-up time (years) 0 5 10 15 20 25 0123456 Anastrozole (A) Tamoxifen (T) Patients (%)

60. ATAC: recurrence in ER+/PgR+ patients Follow-up time (years) 0 5 10 15 20 25 0123456 Anastrozole (A) Tamoxifen (T) Patients (%) At risk: A193018801820175516901505641 T190418491779171616391459597

61. ATAC: retrospective analysis of HR subgroups Anastrozole was more effective than tamoxifen in the overall HR+ group The improvement with anastrozole in the ER+PgR+ subgroup was comparable to that for the HR+ group There was even greater improvement with anastrozole in the ER+PgR- subgroup The relative benefit for anastrozole over tamoxifen appears to be larger in patients with ER+PgR- tumours than in those with ER+PgR+ tumours, but prospective studies are needed to confirm this Patient group HR+ ER+/PgR+ ER+/PgR- Hazard ratio 0.79 0.84 0.43

62. BIG 1-98: DFS in ER/PgR* subgroups Hazard Ratio (A:T) and 95% CI ER+ PgR+ (n=5055) ER+ PgR- (n=1631) ER+ PgR unknown (n=1154) 0.5 0.75 1.0 1.33 2.0 Letrozole betterTamoxifen (T) better *Based on local assessment Thürlimann B. St Gallen presentation 2005

63. Introduction to ‘best first’ The risk of recurrence is highest in the first five years after surgery, with a peak at 2 years Patients deserve to receive the best treatment first in order to reduce the risk of breast cancer recurrence

64. When to treat? Recurrence rates in 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

65. 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

66. Annual risk of recurrence: ECOG data Hazard of recurrence by yearly interval (%) Time (years) Total Positive nodes (0) Positive nodes (>4) Postmenopausal Premenopausal ER +ve ER -ve Tumour size (>3 cm) Tumour size (<1 cm) ECOG = Eastern Cooperative Oncology Group Saphner T et al. J Clin Oncol 1996;14:2738-2746

67. Timing of recurrence in the first 10 years post-diagnosis Adapted from EBCTCG meta–analysis EBCTCG, Lancet 1998; 351; 1451-1467 80 62%61% Node +ve Node -ve 38% 0-5 years5-10 years 39% 60 40 20 0 Proportion of recurrence (%)

68. ATAC: 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 2.5 3.0 0

69. Patients deserve the best treatment first Recurrence rates in early breast cancer are highest in the first 5 years after surgery, with a peak at 2 years, for all patients (irrespective of risk) Anastrozole demonstrated substantial benefits over tamoxifen throughout the entire 5-year follow-up period in the ATAC trial, regardless of baseline prognostic factors –the peak of recurrences at years’ 1-3 is suppressed by anastrozole All patients deserve the best treatment available at the earliest opportunity in order to reduce the risk of recurrence