1. A randomized three-arm multi-centre comparison of: 1 year Herceptin®1 year Herceptin® 2 years Herceptin®2 years Herceptin® or no Herceptin®or no Herceptin® in women with HER-2 positive primary breast cancer who have completed adjuvant chemotherapy Martine J. Piccart-Gebhart, MD, PhD on behalf of: The Breast International Group (BIG), NON-BIG participating groups, Independent sites, F. Hoffmann – La Roche Ltd. FIRST RESULTS OF THE HERA TRIAL ASCO, Scientific Session, May 16, 2005

2. EU 71.5% EASTERN EUROPE:  11% JAPAN  12% ASIA PACIFIC CENTRAL & SOUTH AMERICA 5.5% ACCRUAL: 5090 WOMEN 478 centers from 39 countries (2002-2005) CANADA NORDIC COUNTRIES SOUTH AFRICA AUSTRALIA – NEW ZEALAND AUSTRALIA – NEW ZEALAND

3. HERA TRIAL DESIGN Women with HER2 POSITIVE invasive breast cancer IHC3+ or FISH+ centrally confirmed Surgery + (neo)adjuvant chemotherapy (CT)  radiotherapy StratificationStratification Nodal status, adjuvant CT regimen, hormone receptor status and endocrine therapy, age, region RandomizationRandomization Trastuzumab 8 mg/kg  6 mg/kg 3 weekly x 2 years Trastuzumab 8 mg/kg  6 mg/kg 3 weekly x 1 year Observation

4. KEY INCLUSION CRITERIA Centrally confirmed HER-2 overexpression or amplificationCentrally confirmed HER-2 overexpression or amplification Node-positive or (sentinel) node-negative with  T1cNode-positive or (sentinel) node-negative with  T1c Completed  4 cycles of approved (neo)adjuvant chemotherapy regimenCompleted  4 cycles of approved (neo)adjuvant chemotherapy regimen Baseline LVEF  55% (Echo or MUGA)Baseline LVEF  55% (Echo or MUGA) Known hormone receptor statusKnown hormone receptor status

5. Primary endpoint: DFS Secondary endpoints: RFS, DDFS, OS, 2 years vs 1 year trastuzumab EFFICACY ENDPOINTS AND ANALYSIS PLAN Target accrual: 4482 HR = 0.77 (power 80% 2 sided  = 0.025) for each pairwise test (1y vs nil or 2y vs nil) Target accrual: 4482 HR = 0.77 (power 80% 2 sided  = 0.025) for each pairwise test (1y vs nil or 2y vs nil) One interim efficacy analysis (n = 475 events) One primary core analysis (n = 951 events) SAFETY TolerabilityTolerability Incidence of cardiac dysfunction.Incidence of cardiac dysfunction. Three interim analysis of cardiac endpoints after n = 300n = 600n = 900 pts Stopping rule:  4% absolute increase in primary cardiac events

6. HERA FLOW CHART 5090 Women enrolled 5081 with available data 1 year median follow-up 2y trastuzumab N=1694 Efficacy Analysis N=3387 N= 1677 1y trastuzumab N=1736Observation Safety Analysis N=3413 N=3 N=20 N=26 ObservationN=1693 1y trastuzumab N=1694

7. PATIENT/TUMOR CHARACTERISTICS Age (%) < 35 y 35- 49 y 50 - 59 y  60 y missing Observation (n = 1693)1 year trastuzumab (n = 1694) Adjuvant chemotherapy (%) Anthracyclines + taxanes No anthracyclines, no taxane Anthracyclines missing 7.37.6 31.8 44.343.7 16.2 0.2 32.7 0.2 16.2 6.26.1 26.0 25.5 0.10.2 68.3 67.9

8. Menopausal status at randomization (%) Observation (N=1693) 1 year trastuzumab (N=1694) 50.0 37.9 16.115.4 37.2 47.1 Postmenopausal Uncertain Prem PATIENT/TUMOR CHARACTERISTICS

9. Observation (N=1693) 1 year trastuzumab (N=1694) 28.5 32.1 11.1 28.3 28.9 32.9 10.2 27.9 Node neg. 1-3 + nodes  4 + nodes 0.20.1 missing Nodal Status (%) Hormone Receptor (%) 49.9 50.0 49.0 HR negative HR positive Any (neoadjuvant) 50.9 49.0 PATIENT/TUMOR CHARACTERISTICS

10. ADJUVANT ENDOCRINE THERAPY Observation 1 year trastuzumab TAM 64% AI TAM  AI 9% 11% LHRH ± TAM 16% TAM 66% 8% 8% 17% AI TAM  AI LHRH ± TAM

11. OVERVIEW OF ADVERSE EVENTS 7.91324.375 Patients with at least one grade 3 or 4 AE 8.5 143 (c) Treatment withdrawals 6 (b) 3 (a) Fatal AE 7.01174.781 Patients with at least one SAE %N%N 1 year trastuzumab (N=1677) (N=1677)Observation(N=1736) a) Cardiac failure, suicide, unknown b) Cerebral hemorrhage, cerebrovascular accident, sudden death, appendicitis, two unknown c) Reason: safety in 6%, refusal in 2.5%

12. SAFETY ANALYSIS POPULATION Cardiotoxicity 0.5% (95% CI: 0.25-1.02) 0 % (95% CI: 0.00-0.21) Same LVEF criteria and symptomatic CHF NYHA class III/IV, confirmed by cardiologist Cardiac death 7.1 % 2.2 % Decrease by  10 EF points and LVEF < 50% 1 year trastuzumab N=1677ObservationN=1736 0.1% 0%

13. DISEASE-FREE SURVIVAL % alive and disease free

14. 3%n=6 n=32% n=65% DISEASE-FREE SURVIVAL Type of First Event Observation n= 220 events 1 year trastuzumab n= 127 events n=154 n= 85 67% 23% n=50 3%n=7 1%n=3 n=65% Distant event Loco regional event Contralateral breast Ca Death as first event Second non breast malignancy 70% n=27 21%

15. DFS BENEFIT IN SUBGROUPS HR: 1 year trastuzumab vs observation 012 All Any, neo-adjuvant chemotherapy Nodalstatus 0 pos, no neo-adjuvant chemotherapy 3387 358 1100 872 203 2307 n 0.54 0.53 0.52 0.77 0.64 0.43 Hazard ratio 1-3 pos, no neo-adjuvant chemotherapy  4 pos, no neo-adjuvant chemotherapy No anthracycline or taxane Adjuvant chemotherapy regimen Anthracycline, no taxane Anthracycline + taxane Negative Receptor status/endocrine therapy Pos + no endocrine therapy Pos + endocrine therapy <35 yrs Age group 35-49 yrs 50-59 yrs  60 yrs Europe, Nordic, Canada, SA, Aus, NZ Region Asia Pacific, Japan Eastern Europe Central + South America 972 953 0.51 0.53 16740.51 467 1234 0.49 0.68 2510.47 1490 1091 0.52 0.53 5490.70 24300.58 405 364 0.42 0.31 1880.90 Favors trastuzumab Favors observation 012 All Any, neo-adjuvant chemotherapy Nodalstatus 0 pos, no neo-adjuvant chemotherapy 3387 358 1100 872 203 2307 n 0.54 0.53 0.52 0.77 0.64 0.43 Hazard ratio 1-3 pos, no neo-adjuvant chemotherapy  4 pos, no neo-adjuvant chemotherapy No anthracycline or taxane Adjuvant chemotherapy regimen Anthracycline, no taxane Anthracycline + taxane Negative Receptor status/endocrine therapy Pos + no endocrine therapy Pos + endocrine therapy <35 yrs Age group 35-49 yrs 50-59 yrs  60 yrs Europe, Nordic, Canada, SA, Aus, NZ Region Asia Pacific, Japan Eastern Europe Central + South America 972 953 0.51 0.53 16740.51 467 1234 0.49 0.68 2510.47 1490 1091 0.52 0.53 5490.70 24300.58 405 364 0.42 0.31 1880.90 Favors trastuzumab Favors observation

16. SECONDARY EFFICACY ENDPOINTS Intent-to-treat Analysis RFSDDFSOS 0.50 0.51 0.76 95% CI p value (logrank) 2y outcome (%) 0.40-0.63 < 0.0001 78.6 vs 87.2 0.40-0.66 < 0.0001 81.8 vs 89.7 0.47-1.23<0.26 95.0 vs 96.0 Observation 1 year trastuzumab No of events 209113179983729

17. CONCLUSIONS At one year median follow-up: Trastuzumab given every 3 weeks for one year following adjuvant chemotherapy significantly prolongs DFS and RFS for women with HER-2 positive early breast cancer Trastuzumab given every 3 weeks for one year following adjuvant chemotherapy significantly prolongs DFS and RFS for women with HER-2 positive early breast cancer Trastuzumab significantly reduces the risk of distant metastases Trastuzumab significantly reduces the risk of distant metastases Trastuzumab’s clinical benefits are independent of patients’ baseline characteristics (nodal status, hormone receptor status,...) and of type of adjuvant chemotherapy received Trastuzumab’s clinical benefits are independent of patients’ baseline characteristics (nodal status, hormone receptor status,...) and of type of adjuvant chemotherapy received

18. Trastuzumab therapy is associated with a low incidence of severe symptomatic congestive heart failure; longer follow-up is needed to better quantify this risk Trastuzumab therapy is associated with a low incidence of severe symptomatic congestive heart failure; longer follow-up is needed to better quantify this risk All patients continue to be followed for long-term safety: patients in the observation arm will be offered trastuzumab (guidelines in preparation) All patients continue to be followed for long-term safety: patients in the observation arm will be offered trastuzumab (guidelines in preparation) Results regarding optimal trastuzumab duration (1 versus 2 years) should be available by 2008 Results regarding optimal trastuzumab duration (1 versus 2 years) should be available by 2008 CONCLUSIONS

19. HERA Study Design Elements Randomized following ctx DFS was primary endpoint Most patients did not receive taxane In contrast to the Joint analysis, HERA included a large percentage of node negative pts(About 1/3). Very short median follow-up

20. Adjuvant Trastuzumab Summary and Conclusions Does adjuvant trastuzumab improve DFS? YES! Should we give trastuzumab with or following CTX? What is the appropraite duration of trastuzumab? What is the price of trastuzumab?

21. Should we give Trastuzumab before or after CTX? Preclinical data suggest that trastuzumab may amplify ctx’s pro-apoptotic effects. Synergistic activity in preclinical models for some ctx Cardiotoxicity concerns when trastuzumab is given in proximity to anthracyclines.

22. What is the appropriate duration of Trastuzumab? Unknown (HERA 1 vs. 2 yr pending) Current data supports one year of therapy Current data supports initiation of therapy for up to 6 months following completion of chemotherapy or radiation therapy Could we get by with less trastuzumab? ( ie. only with chemo?)

23. What is the price of Trastuzumab? Cardiac Toxicity(CHF) can be consequence of using trastuzumab Rate = 3.3-4.3% AC-TH vs. 0-0.5% AC-T (B31/ N9831) Rate = 0.5-2.2% post ctx (HERA/N9831) Degree of reversibility uncertain and requires further follow- up Long term effects unknown While benefit far outweighs the risks, the price is real and should be discussed with patients

24. BCIRG 006 Adjuvant Breast Cancer Node Positive and High Risk Node Negative HER2 + FISH 4 x AC 60/600 mg/m 2 4 x Docetaxel 100 mg/m 2 6 x Docetaxel and Platinum salts 75 mg/m 2 75 mg/m 2 or AUC 6 1 Year Trastuzumab N=3150 480 centres 1 Year Trastuzumab AC  T AC  TH TCH

25. BCIRG 006 LVEF Decline by NYHA Class AC-TAC-THTCH >10 < LLN9347 >15%< LLN6254 Grade 3-4 CHF1181 Implication: Trastuzumab by itself is not cardiotoxic; it becomes so when it keeps company with doxorubicin.

26. Intergroup Guidelines for N9831 For women receiving trastuzumab, continue until 1 year is completed. For women randomized to 1 yr TH, continue as planned For women on Arm A: AC-T and are at most 6 months from completion of paclitaxel, begin weekly trastuzumab and continue until you have completed 1 yr of trastuzumab with cardiac testing.

27. Intergroup Guidelines for N9831 For women on Arm A: AC-T and have not started paclitaxel, begin weekly trastuzumab with paclitaxel and continue until 1 yr of trastuzumab is completed, with cardiac testing. For women on Arm B: AC-T-H, and you have not begun trastuzumab, begin trastuzumab with paclitaxel and continue for 1 yr. with cardiac testing. If ctx completed > 6 mo. and have not received trastuzumab, discuss risks and benefits.