1. Overcoming Resistance to HER2-Targeted Therapy in Patients With Advanced Breast Cancer

2. Metastatic HER2+ Breast Cancer: Resistance

3. Overall Program Goals

5. Trastuzumab and Chemotherapy: Combination Index Scores for In Vitro Activity Against HER2+ BC Cell Lines

6. Trastuzumab: Activity in Combination With Multiple Chemotherapeutic Agents

8. BCIRG 007: Docetaxel + Trastuzumab vs Docetaxel + Carboplatin + Trastuzumab

9. BCIRG 007: Efficacy

10. HER2-Targeted Therapy Plus Endocrine Therapy

11. Trastuzumab Monotherapy Trials: Summary of Efficacy

12. Initial Treatment of HER2+ mBC

13. Initial Treatment of HER2+ mBC (cont)

14. Initial Treatment of HER2+ mBC

15. Is HER2 Still a Relevant Target After Progression With Trastuzumab?

16. Oncogene Addiction: Trastuzumab Beyond Progression in HER2+ mBC

17. Capecitabine vs Capecitabine + Trastuzumab: Time to Progression*

18. Capecitabine vs Capecitabine + Lapatinib

19. Combination of HER2-Directed Agents (Dual Blockade)

20. Total Blockade of HER2 May Provide Greater Antitumor Activity and Overcome Resistance

21. Lapatinib +/− Trastuzumab After Progression With Trastuzumab: PFS

22. Trastuzumab + Lapatinib in HER2+ mBC

23. NeoALTTO: Benefit of Combining HER2 Agents

24. First-Line Treatment of HER2+ mBC (Prior Trastuzumab Exposure)

25. Capecitabine vs Capecitabine + Lapatinib

26. Capecitabine vs Capecitabine + Lapatinib (cont)

27. Is Lapatinib Active After Progression?

28. HER2 Remains a Valid Target After Progression With Trastuzumab

29. Defining Trastuzumab Resistance

30. HER2 Signaling Pathway—Mechanisms of Trastuzumab Resistance

31. Mechanisms of Trastuzumab Resistance

32. HER2 Status After Preoperative Trastuzumab-Based Therapy

33. p95: A Truncated Form of the HER2 Protein

34. p95 Expression: Associated With Decreased Response Rates to Trastuzumab-Based Therapy

35. GeparQuattro Study Schema

37. Mechanisms of Trastuzumab Resistance (cont)

39. HER2:HER3 Dimers: A Trastuzumab Escape Mechanism?

40. Mechanisms of Trastuzumab Resistance (cont)

41. HER2+ Breast Cancer: Frequent Alterations in PI3K Pathway Signaling Components

44. Interaction Between PTEN Protein Status and Treatment Arm: Disease-Free Survival

45. HER2 Resistance: Critical Questions

46. First…the Bad News

47. Mechanisms of Trastuzumab Resistance (cont)

48. High Risk of Brain Metastases in Patients With HER2+ mBC

49. Median Survival (mo) After CNS Diagnosis by Subtype

52. LANDSCAPE: Phase 2 Lapatinb + Capecitabine as Upfront Therapy

53. Brain Metastases in HER2+ mBC

54. Summary