Update on the 2006 San Antonio Breast Cancer Symposium

1. Update on the 2006 San Antonio Breast Cancer Symposium Helen K. Chew, MD, FACP UC Davis Cancer Center

2. Objectives • To review the 4 most clinically relevant abstracts: • Adjuvant trastuzumab (abstract #52) • Trastuzumab combined with aromatase inhibitors in the advanced setting (abstract #3) • Taxanes in the adjuvant setting (abstract #53) • Endocrine therapy in metastatic disease (abstract #49)

5. High-risk node negative • T > 2 cm or • ER and PgR negative or • Histological grade 2-3 or • Age < 35 y/o

27. How does this affect clinical practice? • Platinum doublet appears as effective as anthracycline-containing regimen in the adjuvant setting • Toxicities of regimens distinct and acceptable • Role of Topo II amplification unclear in this patient population

28. Trastuzumab prolongs progression-free survival in hormone-dependent and HER2‑positive metastatic breast cancer John R. Mackey MDCross Cancer Institute, Edmonton, Canada On behalf of the TAnDEM investigators

29. Growth factor Estrogen SOS RAS RAF P P P P P P P P P P P P Basal transcription machinery P ER P CBP MEK MAPK p160 PI3-K Akt ER ER ERE ER target gene transcription Cross-talk between signal transduction and endocrine pathways IGFR Trastuzumab HER2 Plasma membrane Anastrozole Cell survival p90RSK Cell growth Cytoplasm Nucleus Adapted from Johnston 2005

30. TAnDEM study design Anastrozole 1 mg daily + trastuzumab 4 mg/kg loading dose  2 mg/kg qw until disease progression • Crossover to receive trastuzumab was actively offered to all patients who progressed on anastrozole alone HER2-positive, hormone receptor-positive MBC (n=208a) R Anastrozole 1 mg daily until disease progression aOne patient did not receive study drug and was excluded from analysesMBC, metastatic breast cancer

31. Primary efficacy PFS Secondary efficacy Clinical benefit rate Overall response rate TTP Duration of response OS 2-year survival Safety AEs and SAEs Cardiac function End points PFS, progression-free survival; TTP, time to progression; OS, overall survival; AE, adverse event; SAE, serious adverse event

32. Key inclusion criteria • Postmenopausal women with MBC • HER2 positive (IHC 3+ and / or FISH+, centrally confirmed) • ER and / or PgR positive (local testing) • Tamoxifen allowed for adjuvant and 1st treatment of MBC • No chemotherapy for metastatic disease • ECOG performance status 0-1 • Baseline LVEF >50% without serious cardiac conditions IHC, immunohistochemistry; FISH, fluorescence in situ hybridisation; ER, estrogen receptor; PgR, progesterone receptor; ECOG, Eastern Cooperative Oncology Group; LVEF, left ventricular ejection fraction

33. Baseline patient demographics Age, years Time from initial diagnosis, months Duration of metastatic disease, months No. metastatic sites/patient No. lesions/patient Sites of metastases, % patients lung liver bone soft tissue other Previous therapy, % patients hormonal chemotherapy anthracycline LVEF, % A+H (n=103) 56 (31-85) 25.6 (0.6-419) 1.6 (0.3-67) 2 (1-5) 4 (1-14) 4232624570 6053 45 62 (50-82) A (n=104) 54 (27-77) 27.3 (0.6-154) 1.2 (0.3-19) 2 (1-5) 4 (1-13) 4628514263 6660 51 63 (51-89) All data are median (range) unless otherwise noted; A, anastrozole; H, trastuzumab

34. Events Median PFS 95% CI p value 4.8 months 2.4 months 87 99 3.7, 7.0 2.0, 4.6 0.0016 Progression-free survival Probability 1.0 0.8 0.6 0.4 0.2 0.0 0 5 10 15 20 25 30 35 40 45 50 55 60 Months 2.4 months No. at risk A+H 103 48 31 17 14 13 11 9 4 1 1 0 0 A 104 36 22 9 5 4 2 1 0 0 0 0 0 CI, confidence intervalPFS = time from randomisation to date of progressive disease or death

35. A+H (n=103) A (n=104) Clinical benefit rate in all patients Patients(%) 60 p=0.026 50 42.7 40 27.9 30 20 10 0 Clinical benefit

36. Events Median OS 95% CI p value 28.5 months 23.9 months 58 64 22.8, 42.4 18.2, 37.4 0.325 Overall survival Probability 1.0 0.8 0.6 0.4 0.2 0.0 0 5 10 15 20 25 30 35 40 45 50 55 60 Months No. at risk A+H 103 91 83 76 63 49 36 24 12 4 3 0 0 A 104 96 87 73 58 42 34 22 5 2 1 1 0 73 / 104 patients (70%) received H later during the course of disease

37. Most common AEs (>10%) Patients, % AE A+H (n=103) A (n=104) Fatigue Vomiting Diarrhoea Pyrexia Nasopharyngitis Nausea Arthralgia Back pain Chills Cough Headache Dyspnoea Constipation Bone pain 21 21 20 17 17 17 15 15 15 14 14 13 12 11 10 5 8 7 2 5 10 7 – 6 6 9 5 6

38. Safety profile Patients, % Cardiac disorders asymptomatic CHF (NYHA class I) symptomatic CHF (NYHA class II) myocardial infarction, ischaemia dysrythmia>1 AE >1 SAE Death due to AE Grade 3/4 AEs A+H(n=103) A(n=104) 13 4a 1 2 787 23 0 25 2 0 0 1 165 6 2b 15 a1 patient had a myocardial infarction and subsequent CHF class Ib1 event occurred after crossover to A+H CHF, congestive heart failure; NYHA, New York Heart Association

39. Conclusions • Trastuzumab added to anastrozole significantly improves PFS for women with HER2 and HR co-positive MBC • >15% of patients receiving A + H did not progress for at least 2 years; thus chemotherapy can be delayed • Despite 70% of patients receiving H after progression on A alone OS seems to be improved • Treatment with A + H was manageable, with no new or unexpected AEs

40. How does this affect clinical practice? • In patients with HER-2/neu positive and hormone receptor positive advanced breast cancer, the combination of trastuzumab and anastrazole is well tolerated • Small study (n=207), underpowered? • Does not address whether sequential therapy may be optimal in this uncommon patient population

41. A Randomized Trial of CEF vs. Dose Dense EC followed by Paclitaxel vs. AC followed by Paclitaxel in Women with Node Positive or High Risk Node Negative Breast CancerNCIC CTG MA21 Results of an Interim Analysis

42. Background • Milan Cancer Institute: 15 yr DFS 42% (CMF) vs. 28% (no Rx) • NSABP B - 15: 3yr DFS 62% (4 cycles AC) vs. 68% (AC delayed CMF) vs. 63% (6 cycles CMF) • NCIC CTG MA5: 5yr DFS 63% (CEF) vs. 53% (CMF) • EORTC, NCIC CTG, SAKK: PFS 34m (CEF) vs. 34m (12 weeks dose dense EC) in LABC • CALGB 9344: 3 yr DFS 77% (AC/T) vs. 73% (AC)

43. Patient Population: Inclusion • ≤ 60 years • Histologically confirmed operable breast cancer • Axillary node +ve, high risk node –ve (tumor ≥ 1cm, grade III or ER –ve, or LVI) • Able to start protocol Rx within 12 weeks of surgery

44. AC → T EC →T NCIC CTG MA 21 E C F Stratification: No. of nodes +ve (0,1-3, 4-10, >10); Surgery (partial vs. mastectomy), ER (+ vs. -)

45. Regimens • CEF:6 cycles of C 75 mg/m2 po days 1-14, E 60mg/m2 and 5FU 500mg/m2 both iv Days 1 & 8 plus antibiotics (cotrimoxazole or cipro) • Dose dense EC: 6 cycles every 2 weeks of E 120mg/m2 and C 830mg/m2 both iv, plus filgrastim and epoetin alfa followed by 4 cycles of T 175 mg/m2 every 3 weeks • AC/T: 4 cycles of A 60mg/m2 and C 600mg/m2 both iv every 3 weeks followed by T 175 mg/m2 every 3 weeks

46. Other Therapy • ER +ve or PR +ve: tamoxifen, and after 2004 aromatase inhibitors in postmenopausal women • Radiation: post-lumpectomy breast radiation and post-mastectomy as per local institutional policy • Trastuzumab: allowed after June 2005 if completed chemotherapy within previous 6 months

47. OUTCOMES • Primary: Relapse-free survival (recurrence or death) • Secondary: Overall survival Toxicity Quality of life

48. Statistics • Sample size 2100 • One planned interim analysis when 1/2 expected recurrences (227) • Stratified log rank test for RFS • The interim analysis (O’Brien-Fleming type boundaries) would use global test of significance for 3-way comparison. If p<0.005, would then proceed to pair-wise comparisons

49. Baseline Characteristics

50. Baseline Characteristics