1. Targeted Therapy: A Giant Step Forward
Ian Krop, MD-PhD
Dana-Farber Cancer Institute
Brigham and Women’s Hospital
Harvard Medical School
May 2009
C and J asked me to talk about an exciting topics in breast cancer, the new drugs that being developed to help conquer this disease.
When we saySubtypes
HER2
Herceptin
Lapatinib, HKI272
Pertuzumab
HSP90
TDM1 TN
Cisplatinum
PARP inhibitors
EGFR inhibitors ER AI
IGF1R
Bone

2. “Targeted” therapy
Drug which inhibits a protein or molecule that is only expressed in cancer or which only the cancer is dependent
Offer the promise of reduced side effects compared to less targeted drugs

3. Breast cancer is family of different cancers
Triple Negative
HER2+
Estrogen receptor +
GENES
There are two basic ways to analyze genomic data, unsupervised and supervised. In both, data is displayed in a heat map, in which expression of individual genes is displayed with red corresponding to high relative expression of a given gene and green low expression. In unsupervised analysis as was used in the perou study we ask the computer to group together samples based on similar patterns of gene expression, such as shown here with the now familiar basal, her2 and luminal subsets
TUMORS 3

4. Percentage of women WITHOUT recurrence
Kaplan Meier plots allow comparison of clinical outcome over time
100-
Percentage of women WITHOUT recurrence
Time

5. Breast cancer is family of different cancers
Triple Negative
HER2+
Estrogen receptor +
Percentage of women WITHOUT recurrence
GENES
There are two basic ways to analyze genomic data, unsupervised and supervised. In both, data is displayed in a heat map, in which expression of individual genes is displayed with red corresponding to high relative expression of a given gene and green low expression. In unsupervised analysis as was used in the perou study we ask the computer to group together samples based on similar patterns of gene expression, such as shown here with the now familiar basal, her2 and luminal subsets
TUMORS 5

6. Breast Cancer in the U.S. 20% = 36,000 cases HER 2 + Disease
All Breast Cancer
180,000 + cases
20% =
36,000 cases
HER 2 +
Disease

7. Amplification of the HER2 gene observed in a subset of breast cancers
FISH -
FISH +

8. HER2 amplification impacts prognosis
% without recurrence
Time (months)

9. HER2 is a cell surface signaling protein

10. HER2 is a cell surface signaling protein
<10,000 HER2 proteins on normal breast cell

11. HER2 gene amplification results in marked overexpression of HER2 proteins
2,000,000 HER2 proteins on cancer cell

12. Herceptin (trastuzumab) is a recombinant antibody that specifically binds to the HER2 protein
HER2 binding domain

13. By attaching to HER2, Herceptin prevents HER2 proteins from binding to each other, leading to inhibition of signaling

14. Herceptin given with chemotherapy improves outcome for patients with HER2+ advanced breast cancer
Slamon, et al. NEJM 2001 (data originally presented 1998)

15. U.S. Adjuvant Herceptin Trials (May, 2005)
Chemo+herceptin
85%
ACT %
Chemo alone
67%
Romond, Perez et al, NEJM 2005
Years From Randomization
B31/N9831

16. Herceptin given with chemotherapy improves outcome for patients with HER2+ advanced breast cancer
Slamon, et al. NEJM 2001 (data originally presented 1998)

17. Overcoming Herceptin resistance
From Hanahan and Weinberg, 2000 17

18. HER2 is a kinase, a protein that adds phosphate to other proteins

19. Lapatinib is an oral inhibitor of the HER2 kinase

20. Clinical trial of lapatinib for women with HER2+ metastatic breast cancer that had progressed on Herceptin
Lapatinib +
Capecitabine
Capecitabine alone R A N D O M I Z E

21. Lapatinib improves outcome in patients with metastatic HER2+ breast cancer
Geyer CE et al. N Engl J Med 2006;355:

22. HER2 Kinase inhibitors Additional inhibitors in development
Results of first study confirm role for HER2 targeted therapy after progression on Herceptin
Is it better than Herceptin?
Can it add to benefit of Herceptin
Are there particular types of tumors that are better treated with one or the other
Lapatinib being tested in adjuvant setting
Additional inhibitors in development
HKI272
BIBW227

23. Clinical trial of Herceptin and xeloda for women with HER2+ metastatic breast cancer that had progressed on Herceptin
Herceptin +
Capecitabine
Capecitabine alone R A N D O M I Z E

24. Trastuzumab Treatment Beyond Progression in Locally Advanced or MBC
Von Minckwitz, G et al, SABCS 2007 and ASCO 2008

25. Courtesy of Kenneth Bloom.
The HER Family
HER2 can dimerize with itself or other HER family members
Courtesy of Kenneth Bloom.
Intracellular

26. Herceptin and pertuzumab bind to distinct epitopes on HER2 extracellular domain
Hubbard 2005

27. HSP90 is a chaperone for proteins like HER2

28. Trastuzumab-DM1, a novel antibody drug conjugate
Herceptin
DM1
Her2
by selectively delivering drugs to overexpressed antigens on tumor cells than could be achieved by administration of either antibody or chemotherapy as free agents
Delivers high concentrations of drug to tumor
Spares normal tissue from toxicity 28

29. Trastuzumab-DM1, a novel antibody drug conjugate
Herceptin
DM1
Her2
by selectively delivering drugs to overexpressed antigens on tumor cells than could be achieved by administration of either antibody or chemotherapy as free agents
Delivers high concentrations of drug to tumor
Spares normal tissue from toxicity 29

30. Trastuzumab-DM1, a novel antibody drug conjugate
Herceptin
DM1
Her2
by selectively delivering drugs to overexpressed antigens on tumor cells than could be achieved by administration of either antibody or chemotherapy as free agents
Delivers high concentrations of drug to tumor
Spares normal tissue from toxicity 30

31. HER2  A Good ADC Target
Tumor expression >>> Normal-tissue expression
Absolute Expression levels very high
Internalized without down regulation
“A novel exploitation of HER2 biology”
The green fluorophore Alexa-488 was conjugated to trastuzumab
BT474 cells incubated with 488trastuzumab +/- were incubated 1 micromolar GA for 3h and then imaged by fluorescence microscopy
Austin et al. (2004) Mol Biol Cell 15,

32. Trastuzumab-DM1, a novel antibody drug conjugate
Results of early studies of TDM1 encouraging
Response rate ≈40% in patients whose tumors had progressed on Herceptin
Side effects minimal (validates strategy of antibody–drug conjugate)
Larger trials are underway

33. PI3-kinase may be an important target in breast cancer

34. Targeting HER2+ Tumors Antibody conjugates Moderate receptor
Inhibit
Dimerization
Moderate
receptor
expression
Inhibit
Kinase
activity
Inhibit
downstream
effects
Interactions between Trastuzumab and Tumor Cells. HER2 serves as a coreceptor with related members of the HER family of tyrosine kinase-associated growth factors. Acquired amplification of the HER2/neu gene on chromosome 17 in HER2-positive breast cancer leads to marked overexpression of HER2 on the cell surface, which alters normal signaling function. Trastuzumab is a humanized monoclonal antibody that binds to HER2 and inhibits tumor-cell growth through a variety of intracellular, and possibly extracellular, mechanisms.
Burstein, H. J.
N Engl J Med 2005;353:

35. Breast cancer is family of different cancers
Triple Negative
HER2+
Estrogen receptor +
Percentage of women WITHOUT recurrence
GENES
There are two basic ways to analyze genomic data, unsupervised and supervised. In both, data is displayed in a heat map, in which expression of individual genes is displayed with red corresponding to high relative expression of a given gene and green low expression. In unsupervised analysis as was used in the perou study we ask the computer to group together samples based on similar patterns of gene expression, such as shown here with the now familiar basal, her2 and luminal subsets
TUMORS 35

36. The link between BRCA1 associated breast cancer and basal like cancers
Inherited mutations in the BRCA1 gene account for a small percentage of breast cancers
80% of BRCA1 associated breast cancers are basal like (triple negative)

37. The link between BRCA1 associated breast cancer and basal like cancers
BRCA1 associated breast cancers have a fundamental defect in DNA repair
Evolving data suggest that spontaneous TN breast cancers share this defect

38. Basal-like Tumors Show DNA Damage Sensitivity

39. © 2001 Macmillan Magazines Ltd
NATURE REVIEWS | GENETICS VOLUME 2 | JUNE 2001 | 447
© 2001 Macmillan Magazines Ltd
NATURE REVIEWS | GENETICS VOLUME 2 | JUNE 2001 | 447

40. Platinum Damages DNA

41. 04-183 Preoperative Cis-Platinum in Triple Negative Breast Cancer
SURGERY
Women with newly diagnosed ER-/PR- /HER2- breast cancer
Standard Treatment
CisPlatinum x 4 doses
Research Biopsy, Blood
Tissue for Research

42. Redundant Mechanisms of DNA RepairX
Homologous Recombination
Base excision repair

43. Base excision repair requires PARP
Huber et al.
DNA Repair 3 (2004)
1103–1108

44. Redundant Mechanisms of DNA RepairX
Homologous Recombination
Base excision repair

45. Hereditary ovarian cancer summary
AZD2281 – PARP inhibitor
Hereditary ovarian cancer summary
Total number of patients
No. of evaluable patients
Platinum resistant
Ongoing response
GCIG CA125 and/or
RECIST radiological response 13 11
7/11
5/11
6/11

46. Women with newly diagnosed ER-/PR-/HER2- breast cancer
Next Step
SURGERY
Women with newly diagnosed ER-/PR-/HER2- breast cancer
CisPlatinum/PARP INHIBITOR x 4 doses
Standard Treatment
Research Biopsy, Blood
Tissue for Research

47. Cancers are dependent on new blood vessel growth (angiogenesis)

48. Blocking VEGF with Avastin leads to loss of tumor vasculature and tumor regression

49. Blocking VEGF may also lead to “normalization” of blood vessels

50. ECOG 2100: Trial Design Patients enrolled Dec. 2001- March 2004
Doubling of RR (14% vs 28%)
Nearly 5 month improvement in median PFS (6.1 vs 11 months)
Preliminary improvement in overall survival
Patients enrolled Dec March 2004
First interim analysis with data cut-off Feb with 355 events
Miller KD ASCO 2005

51. Progression Free Survival
*Benefit the same in ER+ and ER- patients
Miller KD ASCO 2005

52. Cancer stem cell model of therapeutic resistance

53. Novel strategies for estrogen receptor expressing cancers
Hormonal therapy + therapies targeting growth factor receptors
Avastin and other anti-angiogenic drugs seem to work well in ER+ breast cancer
Currently, major advance is observation that for many women, prolonged adjuvant therapy (>5yr) can offer additional benefit

54. How long does it take?

55. Conclusion
The number of new drugs in development is increasing quickly
Targeted therapy’s promise of improved effectiveness and decreased side effects is being fulfilled
If a good target is identified, the drugs will come
Participation in clinical trials in needed to accelerate the pace of drug development