1. Advances in Adjuvant Systemic Therapy of Breast Cancer Anne F. Schott, MD University of Michigan

2. Who to Treat With What? Current struggles in the real world…

5. Adjuvant! 8.0 10-Year Prognosis

6. NCCN Guidelines 2008

7. Worldwide Overview: Chemotherapy vs no chemotherapy, by age &ER, ratio of recurrence rates in years 0-4 Sir Richard Peto, SABCS, 2007 0.81 (0.05) 0.78 ( 0.08) 60-69 0.75 (0.05) 0.65 (0.07) 50-59 0.51 (0.06) 0.57 (0.07) <50 ER+ ER-poor Age

8. Common Adjuvant Regimens 20% 20% TC*4 -> AC*4 Dose Dense (CA*4 -> Txl*4 q2wk) -> AC*4 -> Txl*4 q3wk -> AC*4 FEC*3 ->D*3 -> CE(100)F*6 -> CE(50)F*6 TAC*6 -> FAC*6 -> CMF*6 CAF*6, CEF*6 -> CMF*6 Third Generation -> Second Generation -> First Generation

9. Worldwide Overview: Taxane vs no chemo: Age <50 Sir Richard Peto, SABCS, 2007 0.86 (0.05) 0.84 ( 0.04) Taxane vs Anthr. 0.46 (0.08) 2p>0.00001 Taxan vs no chem 0.38 (0.07) Multiplying 3 RR 2p<0.00001 0.81 (0.05) 0.84 (0.05) Anthr. Vs CMF 0.68 (0.05) 0.56 (0.05) CMF vs no chem BREAST CANCER MORTALITY rate ratio RECURRENCE rate ratio years 0-4 only

11. 2 nd Versus 3 rd Generation Regimen: Differences in Relapse at 10 years (Adjuvant! 8.0) 2 nd Generation Regimen 3rd Generation Regimen

12. ER Neg ER Pos HER2 NEG HER2 POS HER2 is Predictive of Paclitaxel Benefit By Estrogen Receptor Disease Free Survival n = 1322 paclitaxel No paclitaxel paclitaxel No paclitaxel paclitaxel No paclitaxel paclitaxel No paclitaxel Years Hayes D.F., et al. N Engl J Med. 357:1496-506, 2007 n=390 (29%) n=144 (11%) n=703 (53%) n=79 (6%)

13. Common Adjuvant Regimens 20% 20% TC*4 -> AC*4 Dose Dense (CA*4 -> Txl*4 q2wk) -> AC*4 -> Txl*4 q3wk -> AC*4 FEC*3 ->D*3 -> CE(100)F*6 -> CE(50)F*6 TAC*6 -> FAC*6 -> CMF*6 CAF*6, CEF*6 -> CMF*6 Third Generation -> Second Generation -> First Generation

14. US Oncology: TC vs AC RANDOMIZE Doxorubicin 60 mg/m2 IV Day 1 Cyclophosphamide 600 mg/m2 IV Day 1 Every 21 days x 4 cycles Docetaxel 75 mg/m2 IV Day 1 Cyclophosphamide 600 mg/m2 IV Day 1 Every 21 days x 4 cycles

17. 2 nd Generation Adjuvant Chemo Trials CALGB 40101 ddAC versus ddTaxol TC*4 -> AC*4 Dose Dense (CA*4 -> Txl*4 q2wk) -> AC*4 -> Txl*4 q3wk -> AC*4 FEC*3 ->D*3 -> CE(100)F*6 -> CE(50)F*6 TAC*6 -> FAC*6 -> CMF*6 CAF*6, CEF*6 -> CMF*6 Third Generation -> Second Generation -> First Generation

18. 3rd Generation Adjuvant Chemo Trials Anthracycline regimen and trastuzumab FEC-docetaxel AC-weekly Taxol Dose dense AC-Taxol Control Arm Adds/substitutes new agent lapatinib Her-2 positive ALTTO Substitutes new agent ixabepilone Triple Negative PACS08 Adds new agent bevacizumab Her-2 negative E5103 Optimal scheduling metronomic AC-Taxol High Risk S0221 Concept Experimental Therapy Patient Population Trial Name

19. Can Bisphosphonates Prevent Bone Metastasis?

20. Effects of Bisphosphonates on Antitumor Activity in Preclinical Models Tumor-induced osteolysis Tumor cell proliferation and viability Metastatic behavior of tumor cells Activity of cytostatic drugs Angiogenesis Tumor burden in vivo

22. Adjuvant Clodronate vs Placebo: Survival Powles TJ et al, Br Cancer Res, 2006

25. First DFS Events (ITT Population) ASCO 2008 meeting, Gnant 60 months HR=0.64 P=.011

27. First DFS Events (ITT Population) ASCO 2008 meeting, Gnant 60 months HR=1.096 P=.593

29. Petrek et al JCO 2006 Bleeding after Chemotherapy by Patient Age

30. Bleeding after Chemotherapy by Type of Regimen Petrek et al JCO 2006

32. Schema HR+ patients with postmenopausal E2, amenorrhea > 8 weeks Start AI therapy Monitor E2 levels at 2, 4, 6, 8, 10, 12 wks Measure other hormone levels less often E2<10 E2 10-20 E2>20 Continue AI therapy, monitoring (18 mo) Off study Recheck E2 levels in 1 week E2<10 E2>10

34. Neoadjuvant Chemotherapy: Issues and Controversies

36. NSABP B-18 Stratification • Age • Clinical Tumor Size • Clinical Nodal Status + TAM if > 50 y AC x 4 + TAM if > 50 yrs. AC x 4 Operable Breast Cancer Operation Operation

37. B-18 Lumpectomy Rate P < 0.01 Preop Chemo Postop Chemo 60% 68% 80% 60% 40% 20% 0

40. Which tumors > 1, <5 cm definitely get chemotherapy (pre or post)? ++ ++ Node positive ++ ?? Node negative ER/PR both negative ER or PR positive

41. Which tumors > 1, <5 cm definitely get endocrine therapy (pre or post)? - ++ Node positive - ++ Node negative ER/PR both negative ER or PR positive

43. Patient Example: OncotypeDX Results

44. Probability of pathologic complete response (pCR) as a function of Recurrence Score Gianni, L. et al. J Clin Oncol; 23:7265-7277 2005 Gianni, L. et al. J Clin Oncol; 23:7265-7277 2005 doxorubicin (60 mg/m2) and paclitaxel (200 mg/m2) every 3 weeks x 3, followed by weekly paclitaxel (80 mg/m2) x 12.

45. Recurrence Score Predicts CR to Neoadjuvant Docetaxel (Chang, BCRT 2008)

47. Using the Neoadjuvant Model To Develop New Systemic Therapies

48. Common Adjuvant Regimens 20% 20% TC*4 -> AC*4 Dose Dense (CA*4 -> Txl*4 q2wk) -> AC*4 -> Txl*4 q3wk -> AC*4 FEC*3 ->D*3 -> CE(100)F*6 -> CE(50)F*6 TAC*6 -> FAC*6 -> CMF*6 CAF*6, CEF*6 -> CMF*6 Third Generation -> Second Generation -> First Generation

49. pCR as Surrogate Marker for DFS Bear, et al. JCO. May 1, 2006

50. pCR in The Neoadjuvant Model Would Have Predicted Trastuzumab Efficacy Journal of Clinical Oncology , Vol 23, No 16 (June 1), 2005: pp. 3676-3685

51. National Neoadjuvant Chemo Trials Nab-paclitaxel then AC Anthracycline then taxane-trastuzumab Docetaxel then AC FEC-75 then paclitaxel-trastuzumab Control Arm Adds new agent, support schedule “equivalence” Add sunitinib or not, AC first or second Locally advanced, Her-2 negative S0800 Adds and/or substitutes new agent Add carbo or not, add or substitute lapatinib Her-2 positive CALGB 40601 Adds new agents, data mines for predictive factors Add gemcitabine or capecitabine, add bevacizumab or not Palpable and operable cancer NSABP B40 Optimal scheduling, toxicity Paclitaxel-trastuzumab then FEC-75-trastuzumab Her-2 positive ACOSOG-Z1041 Concept Experimental Therapy Patient Population Trial Name

52. Diffusion MRI: Functional Diffusion Mapping Red – increase ADC Green – stable ADC Blue – decrease ADC

53. Schema Pre-Treatment Evaluation Baseline MRI Repeat Baseline MRI Chemotherapy A Post-Chemo A MRI Chemotherapy B Surgery Chemotherapy A Post-Chemo A MRI Chemotherapy B Post-Chemo B MRI Part One Part Two Pre-Chemo B MRI 10 patients 14 patients

54. Diffusion MRI, Interim Results cSD -2.40 -1.62 7 cSD -0.33 -0.23 5 cPR 1.40 1.04 4 cPR 1.75 1.14 2 cPR 1.61 1.02 1 after Part A only ±.05 null thresh ±.025 null thresh Case # Response % vol inc > 2.5%

55. Diffusion MRI Interim Results cPR, pPR cPR, pPR cPR, pPR cPR, pCR cCR, pCR after Parts A & B cSD -2.40 -1.62 7 cSD -0.33 -0.23 5 cPR 1.40 1.04 4 cPR 1.75 1.14 3 cPR 1.61 1.02 1 after Part A only ±.05 null thresh ±.025 null thresh Case # Response % vol inc > 2.5%