Crown_subbed.qxp 26/11/08 02:46 Page 38
Breast Cancer
Novel Strategies Targeting EGFR/HER-2 Signaling HER-2-dependent tumor cells and may enhance response to EGFR and HER-2
inhibitors. The mammalian target of rapamycin (mTOR) is a key downstream
ADAM Protease Inhibition signaling intermediate in the Akt pathway. The inhibition of mTOR potentiates
Signaling through EGFR is controlled by the release of ligands such as EGF, response to gefitinib and cetuximab in EGFR positive cell lines
86
and blocks
TGF-alpha, amphiregulin, HB-EGF, and epigen. While these ligands do not bind multiple stages in HER-2-induced tumor progression in a transgenic mouse
directly to HER-2, they influence HER-2 signaling via heterodimerization with model of HER-2-positive breast cancer.
87
Initial results from phase I studies show
EGFR and HER-3. The release of EGFR/HER ligands is mediated by a disintegrin that the mTOR inhibitor everolimus (RAD001) is well tolerated in combination
and metalloproteases (ADAM) proteases.
76
Recent findings suggest that with trastuzumab and chemotherapy, and shows promising activity in heavily
increased production of the ligands confers resistance to both trastuzumab and pre-treated patients with HER-2-overexpressing metastatic breast cancer.
88,89
EGFR inhibitors.
77,78
ADAM17 is also responsible for cleavage of the extracellular Combinations of everolimus with erlotinib, trastuzumab, lapatinib, and
domain of HER-2,
79
which is associated with resistance to trastuzumab.
80
chemotherapy are currently under investigation in clinical trials.
Inhibition of specific ADAMs could therefore improve response to HER-2 and
EGFR targeted therapies. A dual ADAM10/ADAM17 inhibitor, INCB7839 Conclusions
(Incyte), is currently in phase I/II trials in HER-2-positive breast cancer.
81
The role of HER-2 antagonists in the treatment of HER-2-positive breast
cancer is now well established. Trastuzumab, and more recently lapatinib,
Hsp90 Inhibition have had a significant impact on improving outcome for HER-2-positive
Hsp90 is a molecular chaperone that regulates the stability and maturation breast cancer patients. In addition to the studies examining combinations
of HER-2
82
and is expressed at higher levels in breast tumors than in non- of trastuzumab and lapatinib, another exciting area in the development of
cancerous breast tissue.
83
The inhibition of Hsp90 has been shown to therapies for HER-2-positive breast cancer will be the addition of
downregulate HER-2 and improve responses to trastuzumab in vitro.
84
A phase antiangiogenic therapies such as bevacizumab to HER-2 inhibitors.
I study of tanespimycin (17-AAG) plus trastuzumab has been completed.
85
The Another key area in the development of treatment strategies for HER-2
combination was well tolerated and showed antitumor activity in patients with breast cancer will be understanding mechanisms of resistance and
trastuzumab-refractory HER-2-positive breast cancers. Hsp90 inhibitors may developing strategies to overcome resistance. The future of EGFR
also have therapeutic benefits in HER-2-negative breast cancers, as Hsp90 inhibitors in breast cancer is less certain and requires better definition of
inhibition targets a number of key signaling pathways including Akt. the patient populations that are likely to benefit from EGFR inhibition.
EGFR inhibition may play an important role in overcoming resistance to
Targeting Downstream Signaling Pathways endocrine therapies and may provide the first targeted therapy option for
The PI3 kinase/Akt pathway is activated by EGFR and HER-2 signaling, and is a the treatment of triple negative breast cancer. Dual targeting of EGFR and
key survival and antiapoptotic signal transduction pathway. Targeting HER-2 may also provide added benefit for a subset of HER-2-positive
components of the Akt pathway may inhibit the growth of EGFR or patients whose tumors also express EGFR. ■
1. Kim, H Muller WJ, Exp Cell Res, 1999;253:78–87. 32. Joensuu H, et al., N Engl J Med, 2006;354:809–20. 61. Ciardiello F, et al., Br J Cancer, 2006;94:1604–9.
2. Hynes NE, Lane HA, Nat Rev Cancer, 2005;5:341–54. 33. Viani GA, et al., BMC Cancer, 2007;7:153. 62. Tubiana-Hulin M, et al., Breast Cancer Res Treat, 2007;106:S69.
3. Normanno N, et al., Breast Cancer Res Treat, 1994;29:11–27. 34. Spielmann M, et al., Breast Cancer Res Tr, 2007;106:S19. 63. Polychronis A, et al., Lancet Oncol, 2005;6:383–91.
4. Peles E, et al., Embo J, 1993;12:961–71. 35. Verma S, Curr Oncol, 2008;15:66–7. 64. Graham DL, et al., J Clin Oncol, 2005;23(Suppl. 16): abstract
5. Garrett TP, et al., Mol Cell, 2003;11:495–505. 36. Pegram MD, et al., J Natl Cancer Inst, 2004;96:739–49. 644.
6. Toi M, et al., Breast Cancer Res Treat, 1994;29:51–8. 37. Press MF, et al., Breast Cancer Res Tr, 2005;94(Suppl. 1): 65. Kaur H, et al., J Clin Oncol, 2006;(Suppl. 18): abstract 10623.
7. Slamon DJ, et al., Science, 1987;235:177–82. S54, abstract 1045. 66. Modi S, et al., Clin Breast Cancer, 2006;7:270–77.
8. Tandon AK, et al., J Clin Oncol, 1989;7:1120–28. 38. Slamon DJ, et al., Breast Cancer Res Tr, 2007;106:S5. 67. Carey LA, et al., J Clin ONcol, 2008;26: abstract 1009.
9. Paik S, et al., J Clin Oncol, 1990;8:103–12. 39. Jackisch C, Oncologist, 2006;(Suppl. 1):34–41. 68. O’Donovan N, et al., Breast Cancer Res Tr, 2006;100(Suppl. 1):
10. Sainsbury JR, et al., Lancet, 1987;1:1398–1402. 40. Mackey J, et al., Breast Cancer Res Tr, 2006;100:S5. S105.
11. Perou CM, et al., Nature, 2000;406:747–52. 41. Amar S, et al., Breast Cancer Res Tr, 2008;109:1–7. 69. Xia W, et al., Oncogene, 2005;24:6213–21.
12. Bhargava R, et al., Mod Pathol, 2005;18:1027–33. 42. Repka T, et al., Clin Cancer Res, 2003;9:2440–46. 70. Gschwantler-Kaulich D, et al., Oncol Rep, 2005;14:305–11.
13. Park K, et al., Eur J Surg Oncol, 2007;33:956–60. 43. Parihar R, et al., Clin Cancer Res, 2004;10:5027–37. 71. Ye D, Mendelsohn, J Fan, Oncogene, 1999;18:731-738.
14. DiGiovanna MP, et al., J Clin Oncol, 2005;23:1152–60. 44. Franklin MC, et al., Cancer Cell, 2004;5:317–28. 72. Normanno N, et al., Ann Oncol, 2002;13:65–72.
15. Nicholson RI, et al., Ann N Y Acad Sci, 2002;963:104–15. 45. Nahta R, et al., Cancer Res, 2004;64:2343–6. 73. Arteaga CL, et al., Breast Cancer Res Tr, 2004;88(Suppl. 1):
16. Nicholson RI, et al., Clin Cancer Res, 2004;10:346–54S. 46. Cortes J, et al., J Clin Oncol, 2005;23(16S): abstract 3068. S15–16.
17. Nahta R, Esteva FJ, Cancer Lett, 2006;232:123–38. 47. Fumoleau P, et al., Breast Cancer Res Tr, 2007;106:S19. 74. Normanno N, et al., Ann Oncol, 2005;16:1709.
18. Nahta R, Esteva FJ, Oncogene, 2007;26:3637–43. 48. Moy B, Goss PE, Oncologist, 2006;11:1047–57. 75. O’Shaughnessy J, et al., J Clin Oncol, 2008;26: abstract 1015.
19. Wolff AC, et al., J Clin Oncol, 2007;25:118–45. 49. Burris HA 3rd, et al., J Clin Oncol, 2005;23:5305–13. 76. Duffy MJ, et al., Thromb Haemost, 2003;89:622–31.
20. Baselga J, et al., J Clin Oncol, 1996;14:737–44. 50. Burstein H, et al., Ann Oncol, 2004;15(Suppl. 3):27. 77. Ritter CA, et al., Clin Cancer Res, 2007;13:4909–19.
21. Vogel CL, et al., J Clin Oncol, 2002;20:719–26. 51. Blackwell KL, et al., J Clin Oncol, 2005;23 Suppl. 16): 78. Valabrega G, et al., Oncogene, 2005;24:3002–10.
22. Cobleigh MA, et al., J Clin Oncol, 1999;17:2639–48. abstract 3004. 79. Liu X, et al., Breast Cancer Res Tr, 2005;94:S265–6.
23. Slamon DJ, et al., N Engl J Med, 2001;344:783–92. 52. Geyer CE, et al., N Engl J Med, 2006;355:2733–43. 80. Scaltriti M, et al., J Natl Cancer Inst, 2007;99:628–38.
24. Tokunaga E, et al., Int J Clin Oncol, 2006;11:199–208. 53. Cameron D, et al., J Clin Oncol, 2000;18:2349–51. 81. Infante J, et al., Breast Cancer Res Tr, 2007;106:S269.
25. O’Brien ME, et al., Ann Oncol, 2004;15:440–49. 55. Spector NL, et al., Proc Natl Acad Sci USA, 2007;104: 82. Xu W, et al., Cell Stress Chaperones, 2002;7:91–6.
26. Chia S, et al., J Clin Oncol, 2006;24:2773–8. 10607–12. 83. Yano M, et al., Jpn J Cancer Res, 1996;87:908–15.
27. Wolff AC, et al., Breast Cancer Res Tr, 2004;88:S125. 56. Crown JP, et al., Breast Cancer Res Treat, 2008;112:317–25. 84. Zsebik B, et al., Immunol Lett, 2006;104:146–55.
28. Verma S, et al., Cancer Treat Rev, 2008. 57. Johnston S, et al., J Clin Oncol, 2008;26:1066–72 85. Modi S, et al., J Clin Oncol, 2007;25:5410–17.
29. Piccart-Gebhart MJ, et al., N Engl J Med, 2005;353:1659–72. 58. von Minckwitz G, et al., Breast Cancer Res Treat, 2005;89: 86. Bianco R, et al., Br J Cancer, 2008;98:923–30.
30. Romond EH, et al., N Engl J Med, 2005;353:1673–84. 165–72. 87. Mosley JD, et al., Mol Cancer Ther, 2007;6:2188–97.
31. Slamon, D, et al., San Antonio Breast Cancer Symposium, 2006; 59. Baselga J, et al., J Clin Oncol, 2005;23:5323–33. 88. André F, et al., J Clin Oncol, 2008;26: abstract 1003.
abstract 52. 60. Fountzilas G, et al., Breast Cancer Res Tr, 2005;92:1–9. 89. Jerusalem GH, et al., J Clin Oncol, 2008;26: abstract 1057.
38 US ONCOLOGY