1. Moving forward: Herceptin ® in the adjuvant setting – Trials in which Herceptin ® is combined with chemotherapy Elizabeth Tan-Chiu Medical Oversight NSABP Operations Office Pittsburgh, Pennsylvania, USA

2. NSABP B-31 *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 ®

7. MUGA schedule Arm I AC Paclitaxel 18 months 6 months 9 months 3 months 0 months 0 months 18 months 6 months 9 months 3 months Arm II AC Paclitaxel + Herceptin ®

8. Post-AC left ventricular ejection fraction (LVEF) in asymptomatic patients *LLN = lower limit of normal

9. Herceptin ® management in asymptomatic patients *Repeat MUGA after 4 weeks

12. B-31 accrual 1,200 1,000 800 600 400 200 0 0 4 8 12 16 20 24 Months Number of patients Projected Actual

13. Patient characteristics Age (years) Race No. of positive nodes  39 40–49 50–59  60 White Black Other 1–3 4–9 10+ 100 80 60 40 20 0 Percentage of patients AC = anthracycline/cyclophosphamide; P = paclitaxel; H = Herceptin ® AC   P AC  P + H

14. Pathological tumour size (cm)  1.0 1.1–2.0 2.1–3.0 3.1–4.0 4.1–5.0  5.1 AC   P (mean 2.9cm) AC  P + H (mean 2.8cm) 100 80 60 40 20 0 Percentage of patients

15. Patient characteristics Operation and radiotherapy Tamoxifen treatment AC  P AC   P + H Mastectomy + no radiotherapy Mastectomy + left and/or right radiotherapy Lumpectomy + left radiotherapy Lumpectomy + left and right radiotherapy No tamoxifen Received tamoxifen 100 80 60 40 20 0 Percentage of patients

16. Overall toxicity 50 40 30 20 10 0 Percentage of patients 2 3 4 5 Grade of overall toxicity AC (n=615)

17. Overall toxicity (cont’d) 50 40 30 20 10 0 Percentage of patients 2 3 4 5 Grade of overall toxicity P (n=251) P + H (n=245)

18. Toxicity in patients receiving paclitaxel (n=251) versus paclitaxel plus Herceptin ® (n=245) Neutropenic infection Febrile neutropenia 0 1 2 Percentage of patients Grade 3 Grade 4 P P + H P

19. Toxicity in patients receiving paclitaxel (n=251) versus paclitaxel plus Herceptin ® (n=245) 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

22. HER2 retesting at control reference laboratory (Lab Corp): initial test done at large volume * laboratories *More than 100 assays/month

23. HER2 retesting at control reference laboratory (Lab Corp): initial test done at smaller volume * laboratories *Less than 100 assays/month

24. Central FISH (PathVysion TM ): correlation between reference laboratory (Lab Corp) and NSABP pathology laboratory retesting 77/81 = 95% correlation

26. Herceptin ® adjuvant therapy: summary of ongoing trials *H q3w at 6mg/kg NSABP B-31 Paclitaxel q3w x 4 Paclitaxel q3w x 4 + H AC x 4 HERA Trial H q3w* x 12 months H q3w* x 24 months Observation Any CT and/or RT Intergroup N9831 Paclitaxel qw x 12 Paclitaxel qw x 12 Paclitaxel qw x 12 + H AC x 4 BCIRG 006 Docetaxel q3w x 4 AC x 4 AC x 4 Docetaxel q3w x 4 + H Carboplatin + docetaxel q3w x 6 + H H