1. Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer This program is supported by an educational grant from Friday, December 14, 2007 San Antonio, Texas

2. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Disclaimer The materials published on the Clinical Care Options Web site reflect the views of the authors, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.  Users are encouraged to include these slides in their own presentations, but we ask that content and attribution not be changed. Users are asked to honor this intent.  These slides may not be published or posted online or used for any other commercial purpose without written permission from Clinical Care Options.  We are grateful to the speakers in the Session who gave us permission to use a select group of their slides from the symposium to make this slideset possible: Kathy S. Albain, MD; Kathy D. Miller, MD; Hope S. Rugo, MD; and Linda T. Vahdat, MD. About These Slides

3. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Faculty PROGRAM CHAIR Kathy D. Miller, MD Associate Professor Indiana University School of Medicine Indianapolis, Indiana Kathy S. Albain, MD Professor of Medicine Loyola University Chicago Stritch School of Medicine Director, Breast Clinical Research Program Director, Thoracic Oncology Program Cardinal Bernardin Cancer Center Loyola University Medical Center Maywood, Illinois Hope S. Rugo, MD Clinical Professor of Medicine UCSF Comprehensive Cancer Center University of California, San Francisco San Francisco, California Linda T. Vahdat, MD Associate Professor of Clinical Medicine New York Presbyterian Hospital Weill Cornell Medical College New York, New York

4. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Setting the Agenda: Poll Results A CCO readership survey was conducted which included cases in the adjuvant, neoadjuvant, and metastatic settings. Readers were asked to rank the cases in importance of educational need. The same poll was conducted at the live event and both sets of results were compared at the live event. See next slide for graphical comparison.

5. Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer

6. Hope S. Rugo, MD Clinical Professor of Medicine UCSF Comprehensive Cancer Center University of San Francisco San Francisco, California

7. Case Presentation: Early Breast Cancer 1.0 cm, ER+, HER2+ Tumor With Negative Nodes Ranked 1st in readership survey for educational need

8. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Case History  60-year-old lawyer –Routine yearly mammogram reveals a spiculated density –Confirmed by diagnostic mammogram and ultrasound –Core biopsy positive for ductal carcinoma in situ mixed with invasive cancer  Lumpectomy and sentinel lymph node biopsy performed –1.0 cm high grade, ER+ (60%, moderate), PR+ (50%, moderate), HER2 3+ by HERCEP test –FISH testing confirms HER2+ with amplification to centromere 17 ratio of 8.5

9. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Case History (cont’d)  A 21-gene recurrence score assay (Oncotype Dx) score is obtained –Recurrence score is 36, for a 10-year risk of distant recurrence of 25%

10. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer  Standard of care? –Local therapy with radiation followed by systemic hormone therapy for 5 years –Is the correct approach? Is this the standard?  Additional options –Hormone therapy and trastuzumab –Chemotherapy and trastuzumab –AC/T plus trastuzumab, TCH –Docetaxel and cyclophosphamide with trastuzumab –Weekly paclitaxel with trastuzumab Treatment Considerations

11. Recurrence Risk in Node- Negative HER2-Positive Patients

12. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer  4150 patients with tumors in breast cancer tumor bank, all with > 10-year follow-up  2088 used as part of training set for IHC testing, etc  HER2 results: –Neg: 45.7% –1+: 37.5% –2+: 4.5% –3+: 12.3% 399 tumors tested for HER2 by FISH: 17% amplified Norris, et al. SABCS 2006. Abstract 2031. Prognosis of T1 HER2+ Tumors

13. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer HER2-/ER+HER2-/ER-HER2+/ER+HER2+/ER- All = 20881192 (64%)421 (23%)96 (5.2%) 10-yr BCSS79%68%61%52% 10-yr RFS69%64%51%45% T1N0 = 6474451402043 10-yr BCSS91%89%85%70% 10-yr RFS78%77%75%61% Norris, et al. SABCS 2006. Abstract 2031. Prognosis of Small HER2+ Tumors

14. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Black D, et al. SABCS 2006. Abstract 2037. T1a-b (n = 74)T1c (n = 60)T2 (n = 30) Distant metastasis6 (8.0%)3 (5.0%)4 (13.0%) Locoregional events4 (5.4%)3 (5.0%)2 (6.7%) Contralateral events4 (5.4%)3 (5.0%)1 (3.3%) Any events14 (19.0%)9 (15.0%)7 (23.0%) 5-year DFS90.5%89.5%79.5%  N = 164 patients; retrospective analysis in patients with ≤ 5 cm breast tumors; median follow-up: 62 months  Grade 3 tumors: 48%; lymphovascular invasion: 24%; ER positive: 76%  In tumors < 1 cm, chemotherapy: 34%, hormonal therapy: 54% Recurrence Risk in T1a-b, Node- Negative, HER2+ Breast Cancer

15. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Black D, et al. SABCS 2006. Abstract 2037. DFS in Patients With Node-Negative, HER2+ Tumors DFS 2 Yr3 Yr5 Yr ≤ 1.099%97%90% 1.1-2.097%93%89% 2.1-5.097%90%79%

16. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer RS by Tumor Size% of Cases (n = 55) % of Controls (n = 150) 10-Yr Absolute Risk* RS: Low (< 18) ≤ 1.0 cm13281.3% 1.1-2.0 cm50473.0% ≥ 2.1 cm38244.5% RS: Intermediate (18-30) ≤ 1.0 cm27437.6% 1.1- 2.0 cm453112.9% ≥2.1 cm272612.0% RS: High (≥ 31) ≤ 1.0 cm62510.1% 1.1- 2.0 cm354510.2% ≥ 2.1 cm593026.1% *Based on methods by Langholz B, et al. Biometrics. 1997;53:767-774. Risk of Breast Cancer Death at 10 Years: ER+, TAM+ Patients

17. Adjuvant Data With Trastuzumab in the Node-Negative Subset

18. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer AC (doxorubicin/cyclophosphamide 60/600 mg/m 2 Q3W × 4) T (paclitaxel 80 mg/m 2 /wk × 12) T (paclitaxel 175 mg/m 2 q3w × 4 or 80 mg/m 2 /wk × 12) H (trastuzumab 4 mg/kg loading dose + 2 mg/kg/wk × 51) Control Group (n = 1979): AC  T N9831 Group A B-31 Group 1 Trastuzumab Group (n = 1989): AC  T + H N9831 Group C B-31 Group 2 AC T H T T H T Joint Analysis of HER2+ Adjuvant Trials: 2 Arms of N9831 + B-31 Romond EH, et al. N Engl J Med. 2005;353:1673-1684.

19. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer AC  T + H, % (n = 1989) AC  T, % (n = 1979) Age, yrs < 40 40-49 50-59 ≥ 60-69 16.0 34.1 32.4 17.5 16.8 33.2 33.9 16.1 Tumor size, cm ≤ 2.0 2.1-5.0 ≥ 5.0 NS 38.1 51.7 9.4 0.8 40.3 51.1 7.4 1.2 Nodal involvement None 1-3 4-9 ≥ 10 6.7 53.3 26.9 13.1 7.4 52.4 26.9 13.3 Tumor grade 1-2 3 NS 28.4 69.8 1.8 30.1 68.0 1.9 ER+ and/or PR+54.254.8 Romond EH, et al. N Engl J Med. 2005;353:1673-1684. N9831/B-31 Patient and Tumor Characteristics

20. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer 4 x AC 60/600 mg/m 2 4 x Docetaxel 100 mg/m 2 6 x Docetaxel and Carboplatin 75 mg/m 2 AUC 6 1 Year Trastuzumab N = 3222 1 Year Trastuzumab AC  T AC  TH TCH HER2+ (Central FISH) N+ or high risk N- 4 x AC 60/600 mg/m 2 4 x Docetaxel 100 mg/m 2 Stratified by nodes and hormonal receptor status Slamon D. SABCS 2006. Abstract 52. BCIRG 006

21. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Randomized (n = 3222), % AC  T (n = 1073) AC  TH (n = 1074) TCH (n = 1075) Number of + nodes 029 1-338 39 4-10222423 > 1011910 Tumor size (cm)  2 2 413840 > 2 and  5 535554 > 5 6 7 6 ER and/or PR+54 Slamon D. SABCS 2006. Abstract 52. BCIRG: Tumor Characteristics

22. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Women with locally determined HER2+ invasive early breast cancer Centrally confirmed IHC 3+ or FISH+ and LVEF ≥ 55 Observation 1 year trastuzumab 8 mg/kg  6 mg/kg 3 weekly schedule 2 years trastuzumab 8 mg/kg  6 mg/kg 3 weekly schedule Surgery + (neo)adjuvant CT ± RT Randomization X Gelber R, et al. SABCS 2005. Abstract 11. Piccart MJ, et at. N Engl J Med. 2005;353: 1659-1672. HERA Trial Design

23. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer No. of Patients (%) Observation (n = 1693)1-Yr Trastuzumab (n = 1694) Menopausal status* Premenopausal261 (15.4)272 (16.1) Uncertain629 (37.2)642 (37.9) Postmenopausal797 (47.1)779 (46.0) Hormone receptor status Negative844 (49.9)830 (49.0) Positive849 (50.1)861 (50.8) Nodal status Not assessed (neoadjuvant CT)172 (10.2)186 (11.1) Negative557 (32.9)543 (32.1) 1-3490 (28.9)482 (28.5) ≥ 4473 (27.9)480 (28.3) Patient Characteristics *Status at randomization Note: the few (≤ 0.2%) cases with missing values are not shown. Gelber R, et al. SABCS 2005. Abstract 11. Piccart MJ, et at. N Engl J Med. 2005;353: 1659-1672.

24. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Exploratory Disease-Free Survival Subgroup Analysis: 1-Year Trastuzumab vs Observation 0.00.51.01.5 HR Europe, Canada, SA, Australia, NZ (2430)98 vs 1590.58 (0.45-0.75) Asia Pacific, Japan (405)12 vs 260.42 (0.21-0.84) Eastern Europe (364)10 vs 270.31 (0.15-0.65) Region of the world < 35 yrs (251)12 vs 230.47 (0.23-0.94) 35-49 yrs (1490)55 vs 950.52 (0.37-0.72) 50-59 yrs (1091)39 vs 730.53 (0.36-0.79) ≥ 60 yrs (549)21 vs 290.70 (0.40-1.23) Premenopausal (533)25 vs 430.56 (0.34-0.92) Uncertain (1271)45 vs 770.51 (0.36-0.74) Postmenopausal (1576)57 vs 980.56 (0.41-0.78) Not assessed (neoadjuvant CT) (358)25 vs 390.53 (0.32-0.88) Negative (1100)20 vs 400.51 (0.30-0.87) 1-3 positive nodes (972)26 vs 480.51 (0.32-0.82) Nodal status Menopausal status at randomisation Age at randomisation No. of Events T vs Obs HR (95% CI)Subgroup (No. of Patients) ≥ 4 positive nodes (953)56 vs 930.53 (0.38-0.73) Central, South America (188)7 vs 80.90 (0.33-2.48) All patients (3387)127 vs 2200.54 (0.43-0.67) Gelber R, et al. SABCS 2005. Abstract 11. Piccart MJ, et at. N Engl J Med. 2005;353: 1659-1672.

25. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Exploratory Disease-Free Survival Subgroup Analysis: 1 Year Trastuzumab vs Observation (cont’d) ER-/PgR- (1615)73 vs 1330.52 (0.39-0.69) ER-/PgR+ (173)0.67 (0.24-1.84)7 vs 8 ER+/PgR- (456)15 vs 290.63 (0.34-1.17) Pathological tumour size ER+/PgR+ (985)28 vs 380.61 (0.38-1.00) 3: poorly differentiated (2027)93 vs 1360.62 (0.48-0.81) 2: moderately differentiated (1100)26 vs 700.36 (0.23-0.57) Mastectomy (1959)86 vs 1410.59 (0.45-0.77) Yes (2583)108 vs 1820.53 (0.42-0.68) No (799)19 vs 380.51 (0.30-0.89) Anthracyclines, no taxanes (2307)67 vs 1480.43 (0.32-0.57) All patients (3387)127 vs 2200.54 (0.43-0.67) Anthracyclines + taxanes (873)51 vs 590.77 (0.53-1.13) Type of (neo)adjuvant CT Previous radiotherapy Surgery for primary tumour No anthracyclines (206)0.63 (0.27-1.47)9 vs 13 Breast-conserving procedure (1424)41 vs 790.46 (0.32-0.67) Histologic grade > 5 cm (172)8 vs 150.85 (0.36-2.03) Hormone receptor status > 2-5 cm (1479)57 vs 1010.47 (0.34-0.65) 0-2 cm (1347)37 vs 640.59 (0.39-0.88) Any (neoadjuvant CT) (358)25 vs 390.53 (0.32-0.88) No. of Events T vs Obs Subgroup (No. of Patients)HR (95% CI) 0.00.51.01.5 HR Gelber R, et al. SABCS 2005. Abstract 11. Piccart MJ, et at. N Engl J Med. 2005;353: 1659-1672.

26. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer  Clearly HER2 positivity confers risk even to small, ER+ tumors –Strong ER positivity is not common in HER2+ tumors  Must weigh risk vs benefit of chemotherapy  I would offer this patient either –Paclitaxel and trastuzumab x 1 year –Docetaxel, cyclophosphamide, and trastuzumab x 1 year –5 years of hormone therapy What Is the Best Treatment?

27. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer HER2+, ER+, or ER-; node negative; ≤ 3 cm; PS 0-1; adequate organ fx (N = 400) Enroll T P T P T P T P T P T P T P T P T P T P T P T P 12 Weeks of Paclitaxel/Trastuzumab TTTTTTTTTTTTT Followed by 13 Every 3 Week Doses of Trastuzumab DFCI-Led Single-Arm Multicenter Trial in “Low-Risk” Patients With HER2+ Disease

28. Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Linda T. Vahdat, MD Associate Professor of Clinical Medicine New York Presbyterian Hospital Weill Cornell Medical Center New York, New York

29. Case Presentation: Patient With HER2+ MBC After PD on Trastuzumab + CT Ranked 2nd in readership survey for educational need

30. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Patient Presentation  53-year-old woman with a previous history of an IBC diagnosis (2002)  Left breast biopsy: poorly differentiated invasive ductal cancer with dermal lymphatic invasion ER/PR positive; HER2/neu: 3+ by Dako –Neoadjuvant doxorubicin/cyclophosphamide + tipifarnib (NCI 5598) followed by paclitaxel every 2 weeks –Left MRM: residual tumor 4.5 cm; N = 23/38 with tumor emboli –Chest wall RT + low dose capecitabine (radiosensitizing) –Started anastrozole in September 2005

31. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Patient Presentation  August 2007 –Large mass superior to mastectomy scar and nodules on chest wall –Biopsy positive for ER/PR positive BC –HER2/neu 3+ –Options?

32. What Are the Best Treatment Options Available to This Patient?

33. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Standard treatmentsClinical trials 1. Chemotherapy 2. Hormonal therapy 3. Radiation therapy 4. Biologic therapy 1. Phase I trials 2. Phase II trials 3. Phase III trials Treatment Options for Stage 4 BC

34. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Treatment for Advanced Breast Cancer  No standard approach  Many options  QOL important endpoint  Site specific palliation frequently used (ie, VAT, bisphosphonates)  Many good clinical trials available

35. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Management of Advanced Breast Cancer: Efficacy vs Toxicity

36. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Chemotherapy Hormonal therapy Biologics Options for Advanced BC Tamoxifen, SAIs, fulvestrant (2ME) Trastuzumab, bevacizumab, lapatinib, sunitinib,* tipifarnib* Oral capecitabine, vincas, taxanes, camptothecins, liposomal preparations, nanoparticle preparations, ixabepilone *Not currently approved for use in the treatment of breast cancer.

37. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Efficacy vs Toxicity  Symptomatic from disease  Short disease-free interval Efficacy Toxicity

38. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer The Recommended Treatment Options for This Patient  Chemotherapy + biologic (trastuzumab)  Randomized data –Docetaxel –Paclitaxel and doxorubicin/cyclophosphamide  Phase II data multiple agents –Vinorelbine –Capecitabine –Gemcitabine –Combinations

39. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Patient Outcome  Treated with docetaxel and trastuzumab  Initial partial regression of chest wall nodules and adenopathy lasting 4 months  Options to consider after failure of first line: trastuzumab + chemotherapy

40. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Treatment Options  HER2/neu-directed therapy –Continue trastuzumab –Stop trastuzumab –Change to lapatinib  Chemotherapy –Change or continue if switching from HER2/neu-directed therapy?

41. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer French Hermine Cohort Study  Research question –In the first-line setting of MBC, evaluate outcome (TTP, OS) of those who discontinued trastuzumab at progression vs those who continued Extra JM, et al. SABCS 2006. Abstract 2064.

42. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer French Hermine Cohort Study (cont’d)  Retrospective and prospective observational study  102 oncologists in practice  Patients started with trastuzumab from January- December 2002  Data collection from March 2003 - March 2005 Extra JM, et al. SABCS 2006. Abstract 2064.

43. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer French Hermine Cohort Study (cont’d) Extra JM, et al. SABCS 2006. Abstract 2064. Trastuzumab continued in 107 pts ( 60%) Eligible patients: 623 Evaluable patients: 221 Progressed during evaluation period: 184 Data unavailable: 7 Trastuzumab continued in 107 patients ( 60%) Trastuzumab discontinued in 70 patients ( 40%) Median TTP: 10.2 mos Median OS: not reached Median TTP: 7.1 Median OS: 16.8 mos OS P <.001

44. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer What Are the Best Treatment Options?  Favor continuing HER2/neu-directed therapy –Continue trastuzumab –Stop trastuzumab and begin lapatinib

45. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Downstream signaling Survival ProliferationMotilityInvasion Extracellular Intracellular EGFR erbB2 Lapatinib: Dual Kinase Inhibitor

46. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Phase I/II Data of Lapatinib Pts=patients; RR=response rate; SD=stable disease AuthorLine of Therapy No. of Patients Dose, mgRR, % SD, % Grade 3/4 Tox > 10% Gomez1st20100037420 Gomez1st20150037270 BlackwellNo limit81Varied920NA StornioloNo limit40 1000 + trastuzumab 3033 Diarrhea/ fatigue

47. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer HER2+ locally advanced breast cancer or MBC with previous exposure to an anthracycline, a taxane, and trastuzumab* (N = 324) Lapatinib 1250 mg orally QD continuously + Capecitabine 2000 mg/m 2 /day orally on Days 1-14 every 3 weeks (n =163) Capecitabine 2500 mg/m 2 /day orally on Days 1-14 every 3 weeks (n = 161) Patients on treatment until progression or unacceptable toxicity, then followed for survival *Trastuzumab must have been administered for metastatic disease. Geyer CE, et al. N Engl J Med. 2006;355;2733-2743. Phase III Study: Capecitabine ± Lapatinib

48. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Geyer CE, et al. N Engl J Med. 2006;355;2733-2743. Lapatinib + Capecitabine (n = 160) Capecitabine (n = 161) Anthracyclines, n (%)156 (98)156 (97) Taxanes, n (%)157 (98)159 (99) Trastuzumab  98% “resistant” 155 (97) 7(4) 156 (97) 10 (6)  Prior adjuvant/neoadjuvant use Median duration, wks (range)42.3 (3-296)44.1 (5-329) Phase III Study: Capecitabine ± Lapatinib—Previous Therapy

49. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Time (Weeks) 90 Cumulative Progression Free (%) 100 90 80 70 60 50 40 30 20 10 0 0 203040506070 80.00013 P value (log rank, 1 sided) 0.57 (0.43, 0.77) Hazard ratio (95% CI) 4.3 6.2 Median TTP, mo Capecitabine Lapatinib + Capecitabine 102 (51%) 82 (41%) Progressed or died 201 198 No. of patients Geyer, et al. ASCO 2007. Abstract 1035. Time to Progression - ITT Population Analysis Based on 4/3/06 Data Lock

50. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Patient Outcome to Date  Patient is doing well with good tumor shrinkage on capecitabine and lapatinib

51. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer How Best Should We Use Lapatinib?

52. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Rationale: Use of Lapatinib  Probably best in HER2/neu-positive breast cancer  Activity demonstrated in brain metastases  Future: identify target more specifically –Is there activity in truncated HER2/neu?

53. Data Supporting Use in Only HER2/neu-Positive Breast Cancer

54. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Paclitaxel ± Lapatinib as First-Line Treatment  Key inclusion –Incurable stage III/IV –No previous treatment for M+ –HER2 negative (0, 1+, 2+ FISH-, or FISH-) or untested  Primary aim: 40% proportional increase in TTP (90% power) → required sample size: 580 patients  Patient accrual by world region: North America 17%, South America 17%, Far East 6%, Middle East 7%, Eastern Europe 38%, Western Europe 9%, Africa 6%  Accrual dates: January 2004 - July 2005  Trial funded and conducted by GlaxoSmithKline Paclitaxel 175 mg/m 2 every 3 weeks + Lapatinib 1500 mg orally QD Paclitaxel 175 mg/m 2 every 3 weeks + Placebo orally QD DiLeo A, et al. ASCO 2007. Abstract 1011.  Stratification –Disease site –Disease stage

55. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Results: Paclitaxel ± Lapatinib Paclitaxel + Lapatinib (n = 291) Paclitaxel + Placebo (n = 288) OR P Value Response (CR + PR), %35.125.3 1.7.008 Clinical benefit rate (CR + PR + SD ≥ 6 mos), % 40.531.9 1.5.025 Median duration of response, mos6.56.2NS DiLeo A, et al. ASCO 2007. Abstract 1011.

56. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer 36 (21-53) 60 (45-73) Paclitaxel ± Lapatinib: Response Rate and Duration by HER2 Status DiLeo A, et al. ASCO 2007. Abstract 1011. Odds ratio: 2.9 (1.1, 7.9) P =.027 ORR (%) Paclitaxel + lapatinib (n = 52) Paclitaxel (n = 39) Median Duration of Response (Mos) Paclitaxel + lapatinib7.4 (n = 31) Paclitaxel5.5 (n = 14) HER2 Positive

57. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Paclitaxel ± Lapatinib: Response Rate & Duration by HER2 Status DiLeo A, et al. ASCO 2007. Abstract 1011. Odds ratio:1.5 (0.9-2.3); P =.118 ORR (%) Paclitaxel + lapatinib (n = 199) Paclitaxel (n = 202) Median Duration of Response (Mos) 24 (18-30) 31 (24-38) Paclitaxel + lapatinib 6.2 (n = 61) Paclitaxel8.5 (n = 48) HER2 Negative Odds ratio: 2.9 (1.1-7.9); P =.027 ORR (%) Median Duration of Response (Mos) 36 (21-53) 60 (45-73) Paclitaxel + lapatinib7.4 (n = 31) Paclitaxel5.5 (n = 14) HER2 Positive Paclitaxel + lapatinib (n = 52) Paclitaxel (n = 39)

58. Lapatinib: May Be Useful in MBC With Brain Metastases

59. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Phase II Study of Lapatinib in MBC With Brain Metastases  Eligibility criteria –Radiographically documented progressive CNS disease –Previous cranial radiotherapy (WBRT and/or SRS) –Target brain lesion (≥ 10 mm diameter) –Previous trastuzumab –ECOG PS 0-2; normal EF  Treatment: lapatinib 750 mg BID Lin N, et al. ASCO 2007. Abstract 1012.

60. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Volumetric Change From Baseline (%) Subject 20% 50% CRNone PR15 (6%) Stable ≥ 8 wks102 (42%) ≥ 50% ↓ volume20% Grade 3 diarrhea12% Volumetric reduction Lin N, et al. ASCO 2007. Abstract 1012. 020406080100120140160180200 -100 0 50 100 150 200 250 300 350 400 450 Volumetric reductionVolumetric increase Lapatinib Response Rate in MBC With Brain Metastases (N = 241)

61. All HER2/neu Might Not Be Created Equal...

62. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Activation mediates multiple processes Extracellular domain Trastuzumab binding site Intracellular domain Lapatinib binding site HER2 receptors Multiple Approaches to Targeting the HER Pathways

63. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Truncated HER2 continues to mediate multiple processes Truncation of HER2 Multiple Approaches to Targeting the HER Pathways (cont’d)

64. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer 20 Effect of Lapatinib on Breast Cancer Cells In Vitro Effective in truncated and full-length HER2/neu-expressing tumors ControlHER2p95HER2 MCF-7 Inhibition (%) A 70 60 50 40 30 Inhibition (%) ControlHER2p95HER2 50 40 30 20 15 25 35 45 T47D G0-G1 Increase (%) B MCF-7 ControlHER2p95HER2 T47D ControlHER2p95HER2 10 6 4 0 2 8 12 14 16 # # ٭ ٭ † ‡ † 10 4 0 2 8 6 12 14 16 18 20 Scaltriti M, et al. J Natl Cancer Inst. 2007;99:628-638. Reprinted with permissions from Oxford University Press.

65. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Antitumor Activity of Lapatinib in HER2 and p95HER2 Tumor Xenografts ▲ ▲ ■ Scaltriti M, et al. J Natl Cancer Inst. 2007;99:628-638. Reprinted with permissions from Oxford University Press. 600 500 400 300 200 100 700 20 2326 29 32 35 38 Tumor Volume (mm³) ■ ▲ ■ ■ ■ ▲ ▲ ▲ ■ ■ ■ ■ ■ ■ ■ Days Postinjection Control Trastuzumab Lapatinib HER2 ٭ # p95HER2 600 500 400 300 200 100 Tumor Volume (mm³) 20 2326 29 32 35 38 Days Postinjection ▲ ▲ ▲ ▲ ▲▲ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ † ■ ▲ ■ Control Trastuzumab Lapatinib ■ ■ ■ ■ ▲  Both drugs effective in HER2/neu-positive breast cancer  Lapatinib more effective in p95 HER2 tumor breast cancer

66. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Truncated p95HER2/neu vs Intact and Response to Trastuzumab  Retrospective study of 46 patients treated with trastuzumab –RR full-length HER2/neu: 51% –RR p95HER2/neu: 11% Scaltriti M, et al. J Natl Cancer Inst. 2007;99:628-638.

67. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Back to the Drawing Board...

68. Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Kathy S. Albain, MD Professor of Medicine Loyola University Chicago Stritch School of Medicine Director, Breast Clinical Research Program Director, Thoracic Oncology Program Cardinal Bernardin Cancer Center

69. Case Presentation: Adjuvant Therapy Case Study 2 cm, 3+ nodes, HER2+ Ranked 6th in readership survey for educational need

70. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer  43 yo premenopausal patient with no medical problems, LVEF 64%  Lumpectomy and sentinel node: 2 cm tumor, 1 positive SN; axillary dissection 2/11 additional positive nodes  ER and PgR positive at intermediate levels, HER2 status 2+ by IHC, with FISH+  From her internet research, she elects treatment with chemotherapy plus trastuzumab  She asks if there is an optimal regimen, wanting the “most aggressive therapy possible”. Adjuvant 2 cm, 3+ Nodes HER2+ Clinical Scenario #1

71. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Adjuvant CT + Trastuzumab for 1-2 Yrs: 4 Large Adjuvant Trials, All N+ NSABP-B31 (NA) (n=1960) NCCTG N9831 (NA) (n=3046) HERA (global ex-US) (n=5090) BCIRG 006 (global) (n=3222) >13,000 patients AC Paclitaxel Docetaxel Standard CT Carbo+docetaxel Trastuzumab

72. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer 1 Perez ASCO 2006; 2 Smith Lancet 2007 3 Slamon SABCS 2006. Abstract 52; 4 Joensuu NEJM 2006. Combined US (3968) 1 HERA (3501) 2 BCIRG ACT (2147) 3 BCIRG TCH (2148) HR 0.48 0.64 0.61 0.67 12.8% 6.3% 6% 5% Absolute gain (4yrs) Median FU yrs 3 3 3 2 210 *3yrs FinHER (232) 4 0.4211.7%* 3 Adjuvant Trastuzumab Trials: DFS

73. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Perez, ASCO 2006; Smith, Lancet 2007; Slamon, SABCS 2006. Abstract 52; Joensuu, NEJM 2006 0.65 0.66 0.59 0.66 0.41 3.2% 2.7% 6% 5% 6.6%* 3 3 3 2 3 Combined US (3968) HERA (3501) BCIRG ACT (2147) BCIRG TCH (2148) FinHER (232) Adjuvant Trastuzumab Trials: OS HR Median FU yrs Difference 4yrs 210 *3yrs

74. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer  Patient instead is 67 years old, has controlled hypertension, LVEF reported “normal” at 51%  Same tumor biology, except ER and PgR 100% positive (Allred score 8 and 8)  TCH recommended, but patient, still concerned about cardiotoxicity, wants to know if endocrine therapy alone plus trastuzumab is an option Adjuvant 2 cm, 3+ Nodes HER2+ Clinical Scenario #2

75. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Time from start of Trastuzumab (H) AC  T+H (n=875) % AC  T* (n=767) % 3 months1.40 6 months1.80.2 1 year2.50.2 2 years2.50.2 3 years2.50.2 Number of events22 CHF 1 CHF 1 cardiac death Perez, et al. ASCO 2007. Abstract 512. N9831 Cumulative Cardiac Events: No Additional Effects Beyond Year 1

76. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Rastogi, et al. ASCO 2007. LBA513. Arm 1: AC→PTX n=898, 6 CHFs, 1 cardiac death 0.9% 3.8% Arm 2: AC→PTX + trastuzumab n=947, 35 CHF, no cardiac deaths Years Post Day 1 Cycle 5 012345 0 1 2 3 4 5 % NSABP B31: Cumulative Incidence of Cardiac Events at 5 years

77. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer [7.4 + (0.03xAge) - (0.1xLVEF) + (0.68 if on BP meds)] x100 4.82 Risk Factors Identified in B31: older age, on HTN meds, low-normal post-AC LVEF Rastogi et al. ASCO 2007. LBA513. Cardiac Risk Score: A Prediction Model for Cumulative Cardiac Events

78. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Studies Analyzing Cardiotoxicity from Previous Adjuvant Anthracycline Use Study% Patients (n)Reference N98315% (104 pts)Perez, et al ASCO 2007 NSABP B-317.5% (149 pts)Rastogi, et al. ASCO 2007 BCIRG ACT2% (23 pts)Slamon, et al. SABCS 2006 HERANA

79. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer AC-T n = 1012 /1014 AC-TH n = 1040 /1042 TCH n = 1029 /1030 Patients 91 / 102 180 / 189 82 / 89 % 9 / 10 17.3 / 18 8 / 8.6 first interim analysis second interim analysis P =.002 P <.0001 P <.0001 P =.5 Slamon, D et al. SABCS 2006. Abstract 52. BCIRG 006: Patients with >10% Relative LVEF Decline

80. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer  Back to the same 43 year old patient of Scenario #1  Biology the same, HER2 by IHC is 2+, but FISH now reported to be “negative”, with ratio = 1.8 (HER2/CEP 17)  Should you consider giving trastuzumab-based therapy to this patient? Adjuvant 2 cm, 3+ Nodes HER2+ Clinical Scenario #3

81. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer  Common clinical scenarios: –FISH neg and IHC 1+/2+ = 40% of cases –FISH ratio 1-2 = 25%-40% of cases –Polysomy 17 = 8%-27% of cases  Does give one pause… –Retest negatives? –Consider trastuzumab if the FISH –ratio = 1-2, or if polysomy 17? This Situation is Quite Common

82. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Interaction P =.60 for FISH Interaction P =.26 for IHC Note: RR adjusted for ER and nodal status Paik, et al. ASCO 2007. Abstract 511. RR of ACTH/ACT for DFS (NSABP B-31) 0.000.250.500.751.001.251.50 FISH- & IHC <3 (174) IHC <3 (299) IHC 3+ (1488) FISH- (207) FISH+ (1588) RR Categories (N) NSABP B31: Results by Central Laboratory Determination of IHC/FISH

83. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer HER2/CEP17 = 13/10 =1.3 But one cell has amplification (ratio=5/2=2.5) Slide courtesy of S. Paik, 2007. 1.01.52.0 0 10 20 30 40 50 Final HER2/CEP17ratio N of cells with HER2 amplification Tumors With HER2/CEP17 ratio 1-2 May Have Focal Amplified Cells

84. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer  What about other chemotherapy + trastuzumab combinations? Lots of rationale, but no adjuvant data  Could lapatinib be prescribed instead in any of the previous scenarios? Not yet… adjuvant clinical trials are just underway Adjuvant 2 cm, 3+ Nodes HER2+ The Future

85. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Are anthracyclines and taxanes necessary?  In metastatic breast cancer… TCarboH = TH  In the adjuvant setting… AC-TH = TCarboH  Therefore, does AC-TH = TH? Quite a Quandary!

86. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Test for interaction  2 = 13.2 p < 0.001 Gennari et al. SABCS 2006. Abstract 41. HER 2 negative Non-anthra better 0.34 - 0.80 0.71 - 1.18 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 HER 2 specific 0.75 0.79 DBCG 89D 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 0.61250.40.9 0.82 - 0.980.90Overall p = 0.01 HER 2 positive Pooled Analysis DFS

87. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer “ALL OVER THE MAP” AC-TH TCH Docetaxel/cyclophos + trastuzumab* FAC/FEC then trastuzumab Endocrine Rx +/- trastuzumab* Vinorelbine/trastuzumab* AC/EC then trastuzumab Trastuzumab alone* Chemo then “short course” trastuzumab* Vin/trastuz. then FEC Adjuvant Regimens Prescribed for HER2+ Disease *not based on phase III data

88. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer HER2+ BC Tumors  1 cm after completion of anthracycline based therapy with LVEF  50% RANDOMIZERANDOMIZE (paclitaxel) trastuzumab (trast for 1 yr) (paclitaxel) lapatinib (lap for 1 yr) (paclitaxel) trastuzumab+ lapatinib (trast + lap for 1 yr) (paclitaxel) trastuzumab (12 weeks), 6-week wash out, lapatinib (34 weeks) N = 8,000 Treatment Schema 1: No taxane: all neoadjuvant/adjuvant chemo before targeted therapy. Treatment Schema 2: Taxane included: targeted therapy after neoadjuvant/adjuvant anthracycline-based chemo, and concurrent with weekly paclitaxel. BIG 2.06/N063D Adjuvant HER2+

89. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Adjuvant Node+, HER2+ Unresolved Clinical Questions  Concurrent vs sequential trastuzumab  Which chemotherapy regimen?  Anthracycline or not?  Duration of trastuzumab?  Endocrine therapy plus trastuzumab only?  Trastuzumab alone?

90. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer *Awaiting concurrent vs sequential from N9831 and 1 vs 2 yrs from HERA  Patient in Scenario #1 asks “Is there is an optimal regimen?” –Select one of published trastuzumab-based combinations; concurrent chemotherapy plus trastuzumab favored, because PD during chemotherapy alone may not be salvaged (miss chance for cure) –Trastuzumab duration? Use as published!*  Scenario #2 cardiac risk factors and high-ER, nonanthra options? –DCH probably favored (taxane/H tempting by extrapolation, or, “TC” + H, but no prospective adjuvant data for any of these) –Premature to give endocrine + trastuzumab, even though high-level receptors; studies to date indicate similar trastuzumab benefit by ER status Adjuvant 2 cm, 3+ Nodes HER2+ Clinical Scenarios #1-3

91. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer  Patient in Scenario #3 is hoping for trastuzumab despite “negative FISH” with the ratio = 1.8 I would strongly consider doing so, given the provocative NSABP data taken together with this patient’s young age and high risk of recurrence Adjuvant 2 cm, 3+ Nodes HER2+ Clinical Scenarios #1-3

92. Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Kathy D. Miller, MD Associate Professor Indiana University School of Medicine Indianapolis, Indiana

93. Case Presentation: Early Breast Cancer 1.5 cm ER- HER2- With 1 Positive Node Ranked 4th in readership survey for educational need

94. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Patient Presentation  42-year-old school teacher presented with a 1.5-cm palpable mass in her left breast; fine needle aspiration biopsy confirmed malignancy  Patient underwent lumpectomy and sentinel node biopsy  Pathology reviewed –1.5-cm grade 3 tumor, margins > 5 mm –Positive for lymphovascular invasion –ER-, PR-, HER2- by FISH (ratio: 1 to 4) –1 sentinel node involved with 4-mm focus –12 additional axillary nodes resected; all negative

95. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Adjuvant Therapy Decisions: State of the Art  Step 1: estimate absolute risk of recurrence if untreated based on stage and pathology  Step 2: estimate relative risk reduction from adjuvant interventions based on widely accepted data  Step 3: translate the relative risk reduction into absolute benefits based on patient/tumor characteristics  Step 4: decide if adjuvant treatment is “worth it” –Consider absolute benefit, likely adverse effects, comorbid conditions, patient preference

96. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer

97. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer What Is the Optimal Third-Generation Regimen? Reasonable = superior DFS and/or OS compared with FAC or every 3 weeks AC → paclitaxel  ddAC → paclitaxel as in C9741  AC → weekly paclitaxel as in E1199  AC → every 3 weeks docetaxel as in E1199  TAC x 6 as in BCIRG  CEF as in MA.21  ddEC x 6 → paclitaxel as in MA.21

98. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Stratification Factors:  ER/PR expression  No. positive nodes  T size ( 5 cm)  Mastectomy vs BCS E1199 Study Design ACTaxane RT Hormonal Therapy P3 P1 D3 D1 A: 60 mg/m 2 C: 600 mg/m 2 Every 3 weeks Maximum total dose Dose/ cycle 175 Paclitaxel 80 700 Paclitaxel 960 100 Docetaxel 35 400 Docetaxel 420 mg/m 2 Sparano JA, et al. ASCO 2007. Abstract 516.

99. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer 5-Year DFS E1199: Disease-Free Survival Months From Randomization 020406080 0.5 0.6 0.7 0.8 0.9 1.0 DFS Probability Sparano JA, et al. ASCO 2007. Abstract 516. P3: 76.9% P1: 81.5% D3: 81.2% D1: 77.6%

100. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer E1199: Grade 3-4 Toxicity for ≥ 5% of Patients Adverse Event P3P1D3D1 Neutropenia4%2%47%3% GCP fever< 0.5%1%16%1% Infection3% 13%4% Stomatitis< 0.5%0%5%2% Fatigue2%3%9%11% Neuropathy5%8%4%6% Myalgia7%2%6%1% Arthralgia6%2%6%1% Tearing< 0.5%0%< 0.5%5%

101. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Burnell MJ, et al. ASCO 2007. Abstract 550. C: 75 mg/m 2 orally Days 1-14 E: 60 mg/m 2 IV Days 1 and 8 F: 500 mg/m 2 IV Days 1 and 8 EC: 120 mg/m 2 + 830 mg/m 2 q2wks x 6 T: 175 mg/m 2 q3wks x 4 AC: 60 mg/m 2 + 600 mg/m 2 q2wks x 4 T: 175 mg/m 2 q3wks x 4 MA.21 Study Design

102. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer MA.21: Efficacy and Safety Efficacy and Safety Parameters CEF* (n = 701) EC → T † (n = 701) AC → T (n = 702) 3-yr RFS, %90.189.585 GCP fever, %22.316.44.8 Clots, %3.52.90.4 G3 neuropathy, %0.35.95.5 G3/4 cardiotoxicity, no. of patients 1452 AML/ALL, no. of patients440 *Prophylactic antibiotics. † Prophylactic G-CSF and erythropoietin.

103. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Comparison of Regimens RegimenDuration, Wks Growth Factors Nonheme Tox ?? ddAC → T16+ G/± E? need G with T AC → Wkly T24No↓ $ AC → D24± G↑ TAC18+ G↑ CEF24No↑ AML ddEC → T24+ G/+ E↑ AML

104. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer My Choice(s) RegimenDuration, Wks Growth Factors Nonheme Tox ?? ddAC → T16+ G/± E? need G with T AC → Wkly T24No↓ $ AC → D24± G↑ TAC18+ G↑ CEF24No↑ AML ddEC → T24+ G/+ E↑ AML

105. Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Kathy S. Albain, MD Professor of Medicine Loyola University Chicago Stritch School of Medicine Director, Breast Clinical Research Program Director, Thoracic Oncology Program Cardinal Bernardin Cancer Center

106. Case Presentation: Preoperative Therapy Case Study 4 cm and HER2+ Ranked 3rd in readership survey for educational need

107. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer  59 yo, fit, excellent cardiac function  4 cm movable tumor, no skin or inflammatory changes, small breast size  Core biopsy analyzed: infiltrating ductal carcinoma, grade III, ER strongly positive, HER2 3+/FISH+  Patient wants to conserve her breast if at all possible Preoperative, 4 cm, ER+, HER2+ Clinical Scenario

108. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer  IS THERE AN OPTIMAL POINT TO ADD TRASTUZUMAB?  AND, DO THE CHEMOTHERAPY DRUGS MATTER? Surgery Extended therapy: anti-ER anti-HER2 RT Combination Chemotherapy A Typical Neoadjuvant Treatment Program: What if HER2+?

109. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer What if the same clinical scenario, EXCEPT classic inflammatory skin changes? Is there an optimal regimen?  Is there a “standard” trastuzumab-based regimen that can be recommended in the preoperative (neoadjuvant) setting?  Can endocrine therapy substitute for chemotherapy in this patient? Preoperative, 4 cm, ER+, HER2+ Systemic Therapy Decision-Making

110. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer 0102030405060708090100 Christofanilli et al 2006, n=30 Bines et al 2003, n=32 Burstein et al 2003, n=40 Kelly et al 2006, n=37 Harris et al 2003, n=40 Hurley et al 2002, n=48 Griggs et al 2005, n=18 Limentani et al 2007, n=31 Gianni et al 2007, n=115 Lybaert et al 2006, n=89 Coudert et al 2005, n=33 Buzdar et al 2007, n=64 Pernas et al 2006, n=16 pCR (%) T + L (IBC only) D + H T + H (including IBC) AC → T + H (including IBC) V + H (including IBC) D + cisplatin + H (including IBC) D + H D + V + H (including IBC) X + D + H ATH → TH → CMF + H (including IBC) D + H TH → FEC + H Study NOAH, IBC only ATH → TH → CMF + H (IBC cohort)Baselga et al 2007, n=31 Lapatinib NOAH, all patients Preoperative Therapy: pCR Rates in HER2-Positive Disease

111. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer  N = 31 –Stage II n = 12 –Stage III n = 18 –Stage IV n = 1  Docetaxel 60 mg/m 2 and vinorelbine 45 mg/m 2 q 2 weeks + trastuzumab q wk X 12 wks total rx  pCR rates –Breast only 14/31 = 45% –Breast and nodes 12/31 = 39% Average tumor size = 6.6 cm 68% T3 90% palpable nodes Limentani SA, et al. J Clin Oncol. 2007;25:1232-1238. No correlation of ER status and response to treatment Docetaxel + Vinorelbine +Trastuzumab Phase II Preoperative Stage IIB-IIIB

112. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Phase II Preoperative HER2+ Docetaxel + Carboplatin + Trastuzumab  6 cycles TCH, n = 70  T2/T3 (100%), N1/N2 (53%)  Clinical response 95%  Breast conservation 64% Median f/up = 25 months  5 local recurrences  8 distant recurrences Path CR in breast and nodes 39% Coudert BP, et al. J Clin Oncol.2007;25:2678-2684.

113. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer %pCR 65% n=23 26% n=19 50 MD Anderson Buzdar A, et al. Clin Ca Res. 2007;13:228-233; Gianni L, et al. ASCO Breast 2007. Abstract 144. Chemo + T Chemo P =.02 P x4 FECx4 38% n=114 20% n=114 Chemo + T Chemo P =.003 NOAH 288 pts LABC (40% Inflammatory) AP x3 Px4 CMFx4 Preoperative Chemo + Trastuzumab Two Randomized Trials pCR Rates

114. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Stage II only HER2+ Planned Sample N = 168 Buzdar A, et al. J Clin Oncol. 2005;23:3676-3685. Paclitaxel q3 x 4 FEC X 4 Paclitaxel q3 x 4 FEC X 4 TRASTUZUMAB q wk x 24 SURGERYSURGERY MD Anderson Randomized HER2+ Preoperative Trial

115. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer 65.2% N=23 25% N=19 P =.016 22 additional patients treated on single arm extension trial With P FEC and concurrent trastuzumab: Path CR 54% [32-76%] 0 10 20 30 40 50 60 70 P + FEC P + FEC + H 65% [43-84] 26% [9-51] N=23N=19 Buzdar A, et al. Clin Cancer Res. 2007;13:228-233. pCRs in Randomized MD Anderson Trial

116. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Buzdar A, et al. J Clin Oncol. 2005;23:3676-3685; Budzar A, et al. Clin Cancer Res 2007;13:228-233.  Epirubicin dose was limited at 300 mg/m 2  No cases of CHF were observed during or immediately following treatment  Two cases of clinical cardiac dysfunction with trastuzumab-containing regimen reported after longer follow-up  Acknowledged only 45 pts; phase III trial planned to validate MD Anderson Randomized Preoperative HER2+: Cardiac Safety

117. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer a Hormone receptor-positive patients receive adjuvant tamoxifen HER2-positive LABC (IHC 3+ and / or FISH+) n=113 H + AT q3w x 3 H + T q3w x 4 H q3w x 4 + CMF q4w x 3 Surgery followed by radiotherapy a H continued q3w to Week 52 T q3w x 4 CMF q4w x 3 Surgery followed by radiotherapy a n=115 AT q3w x 3 T q3w x 4 CMF q4w x 3 Surgery followed by radiotherapy a n=99 HER2-negative LABC (IHC 0/1+) NOAH: Phase III Preoperative Trial in Locally Advanced Breast Cancer

118. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer 43% 23% 17% 38% 20% 16% 0 10 20 30 40 50 With HWithout HHER2 negative With HWithout HHER2 negative Patients,% HER2 positive pCRtpCR P =.29 P =.002 P =.003 P =.43 (pCR = pCR in breast; tpCR = total pCR in breast and nodes) Gianni L, et al. ASCO Breast Symposium 2007. Abstract 144. NOAH First Planned Interim Analysis: Response Data (ITT)

119. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Gianni L, et al. ASCO Breast Symposium 2007. Abstract 144. NOAH Cardiac Safety Data at First Planned Interim Analysis, % LVEF worst value HER2-positive cohort HER2-negative (n=97) With H (n=114)Without H (n=113) No change758487 Absolute decrease ≥10% <20% 211512 Absolute decrease ≥20% 211 CHF responsive to treatment 200

120. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer +H-H Patients (%) HER2 negative +H HER2 negative -H P =.004 P =.002 HER2 positive tpCRpCR 4 (29%) 6 (19%) 17 (55%) 4 (29%) 4 (13%) 15 (48%) P =.49 P =.20 eradication of invasive cancer in the breast eradication of invasive cancer in the breast plus axillary nodes *Confidence intervals not provided Baselga J, et al. Proc ECCO 2007. Abstract 2030. 0 10 20 30 40 50 60 NOAH IBC Subset: Significant Improvement of pCR* by Trastuzumab

121. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer  NOAH is the largest randomized preoperative trial to date, addressing only locally advanced disease  Study is ongoing, requires more follow-up for survival outcomes and for mature cardiac safety data  At this first interim analysis, cardiac safety data reassuring (low cumulative dose of administered anthracycline)  pCR and tpCR rates encouraging overall and in IBC cohort, compared with non-trastuzumab arm Perspectives on the NOAH Trial

122. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Cristofanilli M, et al. SABCS 2006. Abstract 1.  30 patients in HER2+ cohort  Lapatinib X 14 days, then continue lapatinib + weekly paclitaxel X 12  3 cCR, 20 cPR  3/18 pathologic responses (17%) MD Anderson Phase III Preoperative Lapatinib Study IBC

123. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer  Data are limited, but some trials (especially NOAH) suggest pCR rates may be higher in HER2+ than in HER2- disease  In Italian study, high RS group (containing the HER2+ subset) had greater pCR rate  IF (a big if) higher pCR predicts improved OS, then perhaps preoperative trastuzumab-based will be optimal  For now, however, either pre- or postoperative adjuvant can be used Might the Preoperative Approach Be Favored in HER2+ Disease?

124. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer HER2 + Operable BC Paclitaxel/trastuzumab x 12 FEC/trastuzumab x 4 FEC x 4 (no trastuzumab) Paclitaxel/trastuzumab x 12 SURGERYSURGERY Endpoint: Pathologic CR Subsequent therapy: XRT, trastuzumab, endocrine rx Arms differ in 1) duration of preoperative trastuzumab AND 2) whether trastuzumab is concurrent with anthracycline ACOSOG Phase III Trial

125. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Breast imaging Blood MUGA Tumor biopsy* SURGERYSURGERY Paclitaxel x 16 wks Breast imaging Blood MUGA Dose-dense AC Trastuzumab x 1 year Endocrine Rx and RT as indicated Trastuzumab Trastuzumab + Lapatinib Lapatinib HER2 + Stage II/III Paclitaxel x 16 wks Primary objective: To determine if pCR paclitaxel + trastuzumab + lapatinib is at least 20% greater than paclitaxel + trastuzumab or paclitaxel + lapatinib CALGB-40601: Paclitaxel + Trastuzumab, Lapatinib, or Both

126. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Other Lapatinib-Based Preoperative Phase III Trials  Neo-ALTTO Nearly identical to CALGB study (has 6 week lead-in of biologic prior to chemo)  NSABP Like the CALGB trial, except the AC is also given preoperatively

127. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Clinical Perspectives HER2+ Preoperative Therapy  Wide range pCR rates in trials to date (12%-65%), most of which were small and not randomized  Two randomized trials showed benefit to addition of trastuzumab  Variables: stage (early, locally advanced +/- IBC, or mixed); definition of pCR; concurrent anthracycline or not; duration of trastuzumab; regimen  No clear correlation of response by ER/PgR status

128. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer  Reassuring cardiac safety so far, but short follow-up and small sample sizes  While concurrent anthra + trastuzumab yields highest pCR, duration of trastuzumab also longest in those arms  Unclear whether pCR is surrogate endpoint for improved OS  Downstaging and/or unresectable disease are indications for preoperative choice in HER2+ disease (ie, no data exist re: superior outcomes for pre- vs postoperative systemic therapy in HER2+) Clinical Perspectives HER2+ Preoperative Therapy

129. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer  Is there an optimal trastuzumab-based regimen that can be recommended in the preoperative (neoadjuvant) setting? No! Pick one of proven standard regimens from adjuvant setting and give full amount before surgery (ie, only PD should prompt switch of therapy preop)  Can endocrine therapy substitute for chemotherapy in this patient? Only if patient refuses chemotherapy – no prospective randomized data in adjuvant or neoadjuvant setting yet (pCR rates lower)  Should therapy be modified if IBC? As of now, only intriguing data for anthracyclines and high pCRs in locally advanced disease Preoperative, 4 cm, ER+, HER2+ Systemic Therapy Decision-Making

130. Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Hope S. Rugo, MD Clinical Professor of Medicine UCSF Comprehensive Cancer Center University of San Francisco San Francisco, California

131. Case Presentation: Early Breast Cancer 4.0 cm, ER+, HER2- Preoperative Ranked 5th in readership survey for educational need

132. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer  60-year-old healthy woman presents with a large, central breast mass –Palpable 4-cm mass –Clinical negative axilla –Visible on mammogram and ultrasound –Desires breast conservation  Core biopsy reveals –Grade 1, ER/PR strongly positive, HER2/neu negative infiltrating ductal cancer  What would you do? Case History

133. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer What Do We Know?  Neoadjuvant therapy improves chances of breast conservation –Similar disease-free and overall survival  The greatest benefit from chemotherapy is for ER- and HER2+ disease  What is the best neoadjuvant therapy for a postmenopausal woman with a grade 1, strongly ER/PR+ tumor?

134. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Adjusted for positive nodes, T size, menopausal status Average Hazard Reduction (95% CI) ER8541 Low  High 9344  Tax 9741 Q3  Q2 Overall Low  Q2 DFS Neg 36% (15% to 52%) 25% (11% to 36%) 23% (0% to 42%) 63% (43% to 76%) Pos 14% (-18% to 37%) 12% (-4% to 25%) 10% (-19% to 33%) 52% (-7% to 56%) OS Neg 29% (3% to 48%) 25% (11% to 37%) 22% (-5% to 43%) 59% (34% to 74%) Pos 8% (-27% to 36%) 10% (-10% to 26%) 1% (-44% to 32%) 18% (-41% to 52%) Wood WC, et al. N Engl J Med. 1994;330:1253-1259. Average Hazard Reduction

135. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Ellis MJ, et al. J Clin Oncol. 2001;19:3808-3816. *Stratified Mantel-Haenszel chi-squared test. P024: Efficacy of Letrozole LetrozoleTamoxifenP Value* Confirmed (ER+/PgR+)124 (100%)126 (100%) Overall tumor response (CR + PR) Clinical74 (60%)52 (41%).004 Ultrasound48 (39%)37 (29%).119 Mammography47 (37%)25 (20%).002 Breast-conserving surgery60 (48%)45 (36%).036 Clinical disease progression10 (8%)15 (12%).303

136. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Smith I, et al. J Clin Oncol. 2005;23:5108-5116. IMPACT: Efficacy of Anastrozole AnastrozoleTamoxifenP Value* 113 (100%)108 (100%) Overall tumor response (CR + PR) Clinical38 (37%)39 (36%).87 Ultrasound25 (24%)22 (20%).53 Mammography?? Breast-conserving surgery20/46 (44%)11/36 (31%)NS Clinical disease progression?? *Stratified Mantel-Haenszel chi-squared test.

137. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Cataliotti L. Cancer. 2006;106:2095-2103. PROACT: Efficacy of Anastrozole AnastrozoleTamoxifenP Value 103 (100%)108 (100%) Overall tumor response (CR + PR) Clinical49.739.7NS Ultrasound36.226.5NS Mammography?? Surgical improvement rate43.030.8.04 Clinical disease progression??

138. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Semiglazov V, et al. ASCO 2005. Abstract 530. Efficacy of Exemestane ExemestaneTamoxifenP Value 76 (100%)75 (100%) Overall tumor response (CR + PR) Clinical76.340NS Ultrasound60.537.3NS Mammography6437.3 Breast-conserving surgery36.820<.05 Clinical disease progression??

139. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Decisions, Decisions...  Neoadjuvant hormone therapy –Improves breast conservation –Is well tolerated –Can be used as a marker for hormone responsiveness; may reduce unnecessary chemotherapy –Low pathologic CR rates for ER+ disease treated with chemotherapy plus hormone therapy –4% to 6% overall

140. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer How to Best Treat This Patient?  I would discuss options carefully –First choice –Neoadjuvant hormone therapy with an aromatase inhibitor x 4 months –If poor response at time of surgery, can consider adjuvant chemotherapy –Careful monitoring is important

141. Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Kathy D. Miller, MD Associate Professor Indiana University School of Medicine Indianapolis, Indiana

142. Case Presentation: Metastatic Breast Cancer With ER- HER2- on Recurrence After Adjuvant FEC Ranked 7th in readership survey for educational need

143. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer  After appropriate surgical recovery, the patient in case 4 received adjuvant FEC x 6 cycles followed by whole breast radiation  At 4-month follow-up after RT, she had no complaints –Mammogram negative –CA27.29 normal Patient Presentation

144. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Patient Presentation (cont’d)  She comes to the office 5 months later (10-11 months after completion of adjuvant chemotherapy) complaining of a persistent cough for the last month associated with right rib pain  She denies SOB, nausea, or weight loss  She admits to mild fatigue

145. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Evaluation  A chest x-ray reveals multiple pulmonary nodules (the largest measuring 0.6 cm) with right hilar adenopathy (the largest measuring 2.3 cm) –Biopsy confirms breast cancer similar to her initial tumor  Bone scan reveals increased uptake in the right ribs, left proximal humerus, LS spine, and right ischium; no cortical destruction on plain x-ray  A CT scan reveals 2 indeterminate liver lesions, measuring 5 mm and 8 mm  A CBC, liver function tests, and a head CT are all normal

146. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Goals of Therapy in Breast Cancer Goals of Therapy  Relieve pain and discomfort  Improve or maintain quality of life  Extend survival  Generate hypotheses for early-stage trials Vulcan oncology: help patients “live long and prosper” Trial Outcome  Response rate  Response duration  TTP  Overall survival  Quality of life

147. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer E2100 Study Design Stratify  DFI ≤ 24 vs > 24 months  < 3 vs ≥ 3 metastatic sites  Adjuvant chemotherapy: yes vs no  ER+ vs ER- vs ER unknown 28-Day Cycle  Paclitaxel 90 mg/m 2 Days 1, 8, and 15  Bevacizumab 10 mg/kg Days 1 and 15 (N = 715) Paclitaxel + Bevacizumab (n = 365) Paclitaxel (n = 350) Miller K, et al. SABCS 2005. N Engl J Med. In press.

148. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Median Progression-Free Survival/TTP ET Pacilio 2006 9 months 0246 8 10 Gem + Vin Mu-oz 2006 Flu + Epi Zielinski 2005 GT Albain 2004 TX O’Shaughnessy 2002 AT Jassem 2001 Vinorelbine Mu-oz 2006 Paclitaxel Seidman 2004 Doxorubicin Chan 1999 Docetaxel Chan 1999

149. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Median OS 24 months Months Bars represent superior arms in study 0510152530 TX O’Shaughnessy 2002 GT Melemed 2007 E1193 Sledge 2003 C9840 Seidman 2004 Tax 311 Jones 2005 20

150. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Treatment  Paclitaxel 90 mg/m 2 weekly for 3 of 4 weeks plus bevacizumab 10 mg/kg every 2 weeks  Zolendronate 4 mg/kg every 4 weeks for skeletal protection

151. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Clinical Course  When patient returns to start cycle 2, she reports that her cough has completely resolved and her rib pain has improved  Repeat imaging after 2 cycles –Significant decrease in pulmonary nodules –Largest is now 6.0 mm and right hilar node is now 1.3 cm –Liver lesions no longer visible

152. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Clinical Course (cont’d)  After 6 cycles of combined therapy, she reports increasing fatigue and grade 2 peripheral neuropathy; no cough or rib pain present  Imaging confirms continued response –Pulmonary nodules no longer visible –Right hilar node is 1.3 cm, unchanged from previous scan following cycle 2 –Sclerotic lesion in right rib c/w healing –Bone scan: stable to slightly decreased uptake in previously identified areas; no new areas seen

153. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Clinical Course (cont’d)  Paclitaxel was discontinued  Patient continued bevacizumab monotherapy (same dose and schedule)  After 6 weeks of treatment, fatigue had improved, neuropathy decreased to grade 1  BP was 156/92 mm Hg (previous BPs all 120-130/ 60-84 mm Hg)  After 2 weeks, BP was 168/96 mm Hg, patient asymptomatic  Bevacizumab held; patient started on hydrochlorothiazide/ triamterene once daily

154. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Clinical Course (cont’d)  2 weeks later, repeat BP 134/86 mm Hg –Bevacizumab resumed  Patient continued bevacizumab for additional 6 months without progression or further hypertension  On routine follow-up, dipstick urinalysis 1+ proteinuria –24-hour urine protein = 668 mg –Bevacizumab continued  2 months later, dipstick urinalysis 2+ proteinuria –24-hour urine protein = 2.1 grams –Bevacizumab held

155. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Clinical Course (cont’d)  24-hour urine protein repeated monthly –After 2 months off bevacizumab: 256 mg  Bevacizumab resumed –Continued therapy without toxicity for an additional 6 months until PD

156. Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Linda T. Vahdat, MD Associate Professor of Clinical Medicine New York Presbyterian Hospital Weill Cornell Medical Center New York, New York

157. Case Presentation: Patient With HER2-Positive MBC on Recurrence 3 Years After dd AC → T Ranked 8th in readership survey for educational need

158. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Patient Presentation  46-year-old woman with stage IIIA breast cancer diagnosed in 2001 –Left lumpectomy and axillary node dissection: T = 2.3 cm; N = 5/15; M =0 –ER/PR negative –Her2/neu: 3+ –AC followed by T dd –Left breast/chest wall RT  In 2005 –Cough developed; worse when supine –Chest x-ray: left pleural effusion –CT CAP: mediastinal/hilar adenopathy; subcentimeter pulmonary nodules with some interlobar septal thickening

159. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Patient Presentation (cont’d)  Bone scan: negative  Thoracentesis: adenocarcinoma chest wall previous breast primary  ER/PR negative  HER2/neu: 3+

160. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer What Are the Best Treatment Options?  Symptomatic  Biologic + chemotherapy

161. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Phase III Trials: Trastuzumab Added to Chemotherapy in First-Line MBC ChemotherapyNo. of Patients RR, %TTP, mos CC + TC Docetaxel [1] 18634616.111.7 Paclitaxel [2] 18817413.06.9 Paclitaxel [3] 12456759.112.3 AC [2] 281 42 566.17.8 1. Marty M, et al. J Clin Oncol. 2005;23:4265-4274. 2. Slamon DJ, et al. N Engl J Med. 2001; 344:783-792. 3. Gasparini G, et al. Breast Cancer Res Treat. 2007;101:355-365.

162. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Phase II Trials: Trastuzumab Added to Chemotherapy in MBC ChemotherapyLine of Therapy No. of Patients RR, %TTP Vinorelbine [1] 1st54685.6 Vinorelbine [2] 1st69639.9 Vinorelbine [3] 1st407818 Capecitabine [4] 1st4363Not reached Gemcitabine [5] 3rd*64385.8 1. Burstein HJ, et al. J Clin Oncol. 2003;21:2889-2895. 2. Jahanzeb M, et al. The Oncologist. 2002;7:410-417. 3. Burstein HJ, et al. J Clin Oncol. 2001;19:2722-2730. 4. Xu L, et al. SABCS 2006. Abstract 2065. 5. O’Shaughnessy JA, et al. Clin Breast Cancer. 2004;5:142-147. *Including adjuvant.

163. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Jackisch C. Oncologist 2006;11(suppl 1):34-41. Copyright ©2006 AlphaMed Press. At least 50% of the patients benefit Objective Response Rate (%) First-line therapy Second-line or subsequent-line therapy Jahanzeb et al, 30 mg/m² Burstein et al, 25 mg/m² Bernado et al, 25 mg/m² Chan et al, 30 mg/m² De Wit et al, 25 mg/m² Burstein et al, 25 mg/m² Papaldo et al, 25 mg/m² Bayo et al, 25 mg/m² Glogowska et al, 35 mg/m² Vinorelbine Schedule 0 20 40 60 80 100 Response Rates in Phase II Trials of Trastuzumab + Vinorelbine

164. Does One Combination Stand Out?

165. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer The TRAVIOTA Trial: Trastuzumab and Vinorelbine or Taxane Trial  Measurable metastatic disease  First-line therapy; no previous chemotherapy or H  Randomized to –Vinorelbine 25 mg/m 2 /week –Taxane: paclitaxel 80 mg/m 2 /week or docetaxel 35 mg/m 2 /week  Primary endpoint: response Burstein HJ, et al. ASCO 2006. Abstract 650.

166. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer The TRAVIOTA Trial Trastuzumab + Vinorelbine Trastuzumab + Taxane P Value No. of patients4140 RR-strict,* %5140.37 RR, %6658.50 TTP, mos8.56.0.09 Burstein HJ, et al. ASCO 2006. Abstract 650. *Strict criteria: CT scans repeated to confirm response 4 weeks later.

167. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer How Much Chemotherapy Is Enough?

168. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Trastuzumab-Based Triple Combination Regimens 1. Robert N, et al. ASCO 2004. Abstract. 2. Pegram MD, et al. J Natl Cancer Inst. 2004. 3. Miller KD. Breast Cancer Res Treat. 2002;75(suppl 1):S45-S50. 4. Perez EA, et al. Clin Breast Cancer. 2005;6:425-432. 5. Yardley. Breast Cancer Res Treat. 2002. Abstract 439. 6. Venturini M, et al. Breast Cancer Res Treat. 2006;95:45-53. 7. Yardley D. ASCO 2004. Abstract 643. 0 20 40 60 80 100 CBDCA/Pac [1] CBDCA/Pac [2] Gem/Pac [3] CBDCA/pac3W [4] CBDCA/Pac [5] Epi/doc [6] Vin/doc [7] CDDP/Pac [2] CBDCA/pacW [4]

169. clinicaloptions.com/oncology Practical Answers to Key Clinical Challenges: Optimizing Patient Outcomes in Breast Cancer Patient Outcome  Patient was treated with CBDCA/weekly paclitaxel and trastuzumab  Patient achieved excellent response with resolution of symptoms by Week 4

170. Capsule Summaries of all the key data, plus Expert Analysis panel discussions exploring the clinical implications Expert Highlights: download mp3 files and listen to our experts review the highlights of this conference Expert Recap (slides and audio) plus downloadable PowerPoint slides clinicaloptions.com/SanAntonio2007 Go Online for More CCO Coverage of This Conference!