1. Herceptin ® in the adjuvant setting

5. HERA TRIAL: study design *Observation group to receive the same follow-up as the Herceptin ® treatment groups Herceptin ® q3w x 1 year Herceptin ® q3w x 2 years Observation* Stratification Randomisation Primary management (surgery, [neo]adjuvant chemotherapy ± adjuvant radiotherapy)

10. HERA TRIAL: planned duration Interim safety analyses Enrolment complete Main efficacy analysis Enrolment starts Interim efficacy analysis 10-year follow-up complete Enrolment Follow-up 2003 2004 2005 2006 2007 2002 2016 2008

14. NSABP trial B-31: study design *Tamoxifen for ER+ or PgR+; tamoxifen optional for ER– and PgR– patients  50 years old Operable breast cancer HER2-positive tumour Pathologically positive axillary nodes Randomisation AC x 4* Paclitaxel x 4 AC x 4* Paclitaxel x 4 + Herceptin ®

19. NSABP trial B31: patient accrual 1,200 1,000 800 600 400 200 0 0 4 8 12 16 20 24 Months Number of patients Actual Projected

20. NSABP trial B31: overall toxicity 50 40 30 20 10 0 Percentage of patients 2 3 4 5 Grade of overall toxicity P (n=251) P + H (n=245)

21. NSABP trial B31: toxicity (paclitaxel versus paclitaxel plus Herceptin ® ) Neutropenic infection Febrile neutropenia 0 1 2 Percentage of patients Grade 3 Grade 4 P P + H P

22. NSABP trial B31: toxicity (paclitaxel versus paclitaxel plus Herceptin ® ) Sensory neuropathy Arthralgia Myalgia Fatigue 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 P P + H Grade 2 Grade 3 Percentage of patients P P + H P P + H P P + H

23. Intergroup trial N9831: study design Operable breast cancer HER2-positive tumour Node positive Randomisation AC q3w x 4 Paclitaxel x 12 + Herceptin ® x 12 Herceptin ® x 40 AC q3w x 4 Paclitaxel x 12 AC q3w x 4 Paclitaxel x 12 + Herceptin ® x 52

29. BCIRG trial 006: study design AC x 4 Docetaxel + cisplatin or carboplatin x 6 + Herceptin ® weekly  3-weekly Herceptin ® for 1 year from date of first administration Docetaxel x 4 Operable node-positive, HER2-positive (FISH) breast cancer AC x 4 Docetaxel x 4 + Herceptin ® weekly  3-weekly Herceptin ® for 1 year from date of first administration Randomisation

33. Comparison of the four large Herceptin ® adjuvant trials OS = overall survival DFS = disease-free survival

34. Other Herceptin ® adjuvant trials: ECOG trial E2198 234 anthracycline-naive patients IHC 2+/3+ Paclitaxel + Herceptin ® AC  observation Paclitaxel + Herceptin ® Sledge G, et al. Breast Cancer Res Treat 2001;69:209 (Abstract 4) AC  Herceptin ®

37. ECOG trial E2198: cardiotoxicity Sledge G, et al. Breast Cancer Res Treat 2001;69:209 (Abstract 4)

38. Other Herceptin ® adjuvant trials: PACS 04 Second randomisation n=2,600 (HER2 positive/negative) First randomisation FEC100 x 6 Epirubicin + docetaxel x 6 1-year Herceptin ® monotherapy Observation n=520 (HER2 positive)