1. Clinical Dilemma: Which Adjuvant Chemotherapy is Just Right? Dr. Maureen Trudeau Head, Division of Medical Oncology/Hematology Toronto Sunnybrook Regional Cancer Centre Associate Professor, University of Toronto June 15, 2007

2. Systemic Therapy - Chemotherapy Overall survival improvement in clinical trials both for standard and newer treatments Choice – for patients, for physicians (anthracycline +/- taxanes) Better decision making aids –www.adjuvantonline.comwww.adjuvantonline.com Molecular profiles – Oncotype Dx, MammoPrint Improved supportive care

3. Decision Making in Adjuvant Therapy Tumour characteristics T, N, Grade, ER, PgR, HER2, LVI Patient Characteristics Age, Comorbidities Prior Therapy Performance Status Patient Preference Work/Family/Self Clinical Trials, Guidelines Recent Reports Molecular Profile

4. Select Breast Cancer Treatments Based on Tumor Phenotype Tumor phenotype defines treatment options Hormone receptor Positive Hormonal therapy Negative Chemotherapy Positive HER2-targeted therapy HER2 Negative Positive HER2-targeted therapy Negative

6. Breast Cancer is not ONE Disease HER-2 Basal-like Luminal A Luminal B“Normal” Sorlie T et al, PNAS 2001

8. All Breast Cancer ER+ 65-75% HER2+ 15-20% Basaloid 15%

9. Molecular Classifications of Breast Tumors Luminal AER + high Prolif - P53 mutations 16% Luminal BER + low +71% Basal -likeER - +75%, also BRCA1 ERBB2 +ER-/+ -/+86% Normal-likeER - - Sorlie 2007

17. Oncotype DX A multigene assay to predict recurrence of Tamoxifen-treated, node-negative breast cancer (Paik NEJM 204) 21 genes - proliferation (5), invasion (2), HER 2 (2), Estrogen (4), 3 others and 5 reference genes with a Recurrence Score (RS) algorithm For node negative, tam treated (JCO 2007): –Luminal A = low risk oncotype DX –Luminal B = mod/high risk

24. Adapted by Dr. Maureen E. Trudeau, MD

25. Anthracycline-based Regimens Superior To CMF/AC RegimenTrials GroupDFS / OS (1)CEF(NCIC-CTG) (2)dd (EC)  CEF (NCIC/EORTC/SAKK) -- -- (3)FEC100 > FEC50(FASG) FEC50  CMF(ICCG) -- -- (4)CAF(SWOG) (5)E  CMF(NEAT/SCTBG) (6)AV CF(MISSET) (7)TC(Jones) --

26. Taxane Regimens Superior To AC-type Regimens RegimenTrials GroupDFS / OS (1)AC  P(CALGB) (2)AC  P(NSABP) -- (3)P  FAC(MDACC) -- -- (4)DAC(BCIRG) (5)FEC  D(PACS 01) (6)A(C)  D  CMF(BIG 2-98) -- Regimens superior to AC  P (1)dd AC  P (CALGB) or dd A  P  C (2)CEF or dd (EC)  P - -

27. Adjuvant Chemotherapy Options – A Growing List 2007 Options CEF(CMF) FEC 100(FEC 50) AC  Taxol (AC) TAC(FAC) FEC 100  Docetaxel (FEC 100) Dose-dense AC  Taxol (AC  Taxol) Dose-dense (EC)  Taxol (AC  Taxol) CEF (AC  Taxol) 1998 Options CMF(1970’s) (F) AC (1980’s)

28. TAXANES AS ADJUVANT THERAPY SECOND GENERATION OF CLINICAL TRIALS N  5000 Best taxane ECOG 1199 (intergroup trial) AC x 4 P x 4 P weekly x 12 D x 4 D weekly x 12 2800 pts AC x 4

29. Are There Factors that May Predict Response or Suggest which Therapy to Use?

30. TAXANES AS ADJUVANT THERAPY SECOND GENERATION OF CLINICAL TRIALS N  8700 Taxane ± Herceptin® HERA: any chemo  Herceptin: 0 vs 1 vs 2 yr AC  D vs AC  D + H 1 yr vs DCH x 6  H 1 yr AC  P vs AC  P + H 1 yr AC  P weekly x 12 vs AC  P weekly x 12  H 1 yr vs AC  P weekly x 12 + H 1 yr

31. Trastuzumab DFS Piccart-Gebhart et al 2005; Romond et al 2005; Slamon et al 2005; Joensuu et al 2005 012 HERA1 year Combined analysis2 years Median follow-up Favors Trastuzumab Favors no Trastuzumab HR BCIRG 006 DCarboH 2 years BCIRG 006 AC DH FinHER VH / DH CEF 3 years

32. Adjusted for pos nodes, T size, menopausal status Courtesy: Berry et al SABCS 2004

33. PACS 01 DFS by Age, ITT Kaplan-Meier Estimate Log-rank P-Value = 0.690 HR (Cox model) = 0.98 [0.77-1.25] 0.00 0.25 0.50 0.75 1.00 Survival Time (years) 012345678 6FEC100 3FEC100-3D Age < 50 yrs Log-rank P-Value = 0.001 HR (Cox model) = 0.67 [0.51-0.88] Kaplan-Meier Estimate 0.00 0.25 0.50 0.75 1.00 Survival Time (years) 012345678 6FEC100 3FEC100-3D Age  50 yrs Multivariate Interaction Test HR: 0.66 [0.46-0.95] P-value = 0.026

34. HR = 0.76 P = 0.046 0612182430364248546066 100 90 80 70 60 50 FAC TAC Negative 0612182430364248546066 90 80 70 60 50 FAC TAC HR = 0.60 P = 0.0088 Positive Time to First Event 100 TAC vs FAC DFS by HER2 Status Time to First Event % Alive and Disease-Free (Centrally reviewed, FISH centrally reviewed) Ratio of HRs 0.85 p= 0.4122 NEJM 2005

35. Topoisomerase II Topoisomerase II  is essential for DNA replication and recombination Anthracyclines target topoisomerase II  Increased sensitivity to HER2 due to co- amplification of TOP2A?

36. A pooled analysis on the interaction between HER-2 expression and responsiveness of breast cancer to adjuvant chemotherapy Alessandra Gennari, Maria Pia Sormani, Matteo Puntoni and Paolo Bruzzi National Cancer Research Institute - Genoa and University of Genoa - Italy SABCS 2006

37. Characteristics of studies - I StudyComparison HER2 status determined (%) NSABP B11PF vs PAF 638/682 (94%) NSABP B15CMF vs AC 2.034/2.295 (89%) GUN 3CMF vs CMF/EV 123/220 (56%) BrusselsCMF vs HEC/EC 354/777 (46%) MilanCMF vs CMF→ A 506/552 (92%) DBCCG - 89 - DCMF vs FEC 805/980 (82%) NCIC MA5CMF vs CEF 628/710 (88%) SABCS 2006 Total (available/randomised) 5.088/6.216 (82%)

38. Disease Free Survival Test for interaction  2 = 13.7 p < 0.001 non anthra better 0.34 - 0.80 0.71 - 1.17 0.52 0.91 NCIC MA-5 0.61 - 0.83 0.90 - 1.11 0.53 - 1.06 0.60 - 1.05 0.46 - 1.49 0.91 - 1.64 0.65 - 1.08 0.86 - 1.20 0.44 - 0.82 0.75 - 1.23 0.71 1.00 Overall 0.75 0.79 DBCCG-89-D 0.83 1.22 Milan 0.34 - 1.27 0.93 - 1.97 0.65 1.35 Brussels NSABP B15 0.60 0.96 NSABP B11 0.84 1.02 heterogeneity  2 5 = 5.3, p = 0.38 heterogeneity  2 5 = 7.6, p = 0.18 Study HR95% CIanthra better 0.6 1 25 0.4 p < 0.0001 p = 1.0 0.9 HER2 positive HER2 negative SABCS 2006 0.82 - 0.980.90Total p = 0.01

39. Efficacy summary Risk of relapse 29% HR 0.71 (0.61-0.83) (p < 0,0001) Risk of death 27% HR 0.73 (0.62-0.85) (p < 0,0001) HER2 positive Risk of relapse anthra ≈ non anthra HR 1.00 (0.90-1.11) (p = 1,0) Risk of death anthra ≈ non anthra HR 1.03 (0.92-1.16) (p < 0,86) HER2 negative SABCS 2006

40. Hierarchy of Chemotherapy Regimens Appropriate high risk population Older, no GCSF Younger, + GCSF Younger, +/- GCSF Younger, + GCSF Younger, # of cycles 6 cycles 10 cycles 6 cycles (12 visits) (12 visits) 8 cycles 6 cycles High risk FEC  D dd(EC)  P CEF dd(AC)  P TAC is better than Moderate risk FEC 100 CEF (MA 5) AC  P AC  D is better than Low Risk FEC 50 CMFACDCAD No Therapy P = paclitaxel D = docetaxel CAFFAC

41. The choice of chemotherapy Depends on the following: Tumour characteristics and risk of relapse Patient comorbidities Patient age Social determinants Drug availability / costs Physician or patient preference

42. Cost of common regimens Regimen N+ Study Total Treatment Costs USD (drug acquisition + incidental + administration) DACBCIRG001$8,226 AC ->P CALGB9344 $4,340 AC->PCALGB9741 $11,741 CE 120 FMA-5 $4,852 FE 100 CFASG-5 $3,557 FE 100 C->DPACS-01 ~ $6,200

43. Convenience of common regimens Regimen N+ Study VisitsChair time (h) TAC BCIRG001 614 AC ->T CALGB9344 821.6 AC->T CALGB9741 821.6 CE 120 F MA-5 12 5.4 FE 100 C FASG-5 6 9 FE 100 C->D PACS-01 6 8

44. Adapted by Dr. Maureen E. Trudeau, MD Where are we going?

45. Cases

46. A 68-year old woman presents with an infiltrating duct carcinoma 1.2 cm in size ER 80% PR 60% HER 2 - Sentinel node negative

47. A 68-year old woman presents with an invasive ductal carcinoma

48. A 59-year old postmenopausal woman with invasive ductal carcinoma 1.9 cm in size ER 30% PR 0% HER 2+ (3+ by IHC) Grade 3 Sentinel node negative

49. A 59-year old postmenopausal women with invasive ductal carcinoma

50. A 49-year old premenopausal woman with invasive lobular carcinoma 2.5 cm in size ER 70% PR 30% HER 2- Grade 2 2/10 positive lymph nodes

51. A 49-year old premenopausal woman with invasive lobular carcinoma

52. A 39-year old premenopausal woman with invasive ductal carcinoma 2.8 cm in size ER 0% PR 0% HER 2 - Grade 3 5 nodes positive

54. A 44-year old premenopausal woman with invasive ductal carcinoma 2.0 cm in size ER 100% PR 100% HER 2 - Grade 2 1/17 nodes positive 2 other smaller lesions, grade 1