Development of New Targeted Therapies for Breast Cancer

  • Danielle M. Doyle
  • Kathy D. Miller
Part of the Cancer Treatment and Research book series (CTAR, volume 141)

Oncologists typically thought of systemic therapies for breast cancer as belonging to one of two categories: either cytotoxic chemotherapy or hormonal therapy. Though this simple approach served well for decades, the recent development of trastuzumab showed its inadequacies. Trastuzumab, neither broadly cytotoxic nor a classic hormonal manipulation, didn’t fit. Thus, a third category, biologic therapy, or alternatively, targeted therapy, emerged. Targeted therapy is a type of medication which blocks the growth of cancer cells by interfering with specific targeted molecules needed for carcinogenesis and tumor growth, rather than by simply interfering with rapidly dividing cells. Though we tend to think of targeting growth signals in cancer as recent developments, perhaps they are not so novel after all. First proposed as adjunctive therapy by Schinzinger in 1889, Beatson introduced ovariectomy into clinical practice in 18961. While hormonal therapy is not traditionally categorized as targeted therapy, the estrogen receptor remains arguably the most important growth factor receptor identified for breast cancer, as adjuvant hormonal therapies have a bigger impact on recurrence and survival than any other treatment.


Breast Cancer Vascular Endothelial Growth Factor Clin Oncol Metastatic Breast Cancer Inflammatory Breast Cancer 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Beatson, G. 1896. On the treatment of inoperable cases of carcinoma of the mamma: suggestions for a new method of treatment, with illustrative cases. Lancet 2:104–7.CrossRefGoogle Scholar
  2. 2.
    Hanahan, D., R. A. Weinberg. 2000. The hallmarks of cancer. Cell 100(1):57–70.PubMedCrossRefGoogle Scholar
  3. 3.
    Ross, J. S., J. A. Fletcher, G. P. Linette, et al. 2003. The Her-2/neu gene and protein in breast cancer 2003: biomarker and target of therapy. Oncologist 8(4):307–25.PubMedCrossRefGoogle Scholar
  4. 4.
    King, C. R., M. H. Kraus, S. A. Aaronson. 1985. Amplification of a novel v-erbB-related gene in a human mammary carcinoma. Science 229(4717):974–6.PubMedCrossRefGoogle Scholar
  5. 5.
    Slamon, D. J., G. M. Clark, S. G. Wong, W. J. Levin, A. Ullrich, W. L. McGuire. 1987. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235(4785):177–82.PubMedCrossRefGoogle Scholar
  6. 6.
    Slamon, D. J., W. Godolphin, L. A. Jones, et al. 1989. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 244(4905):707–12.PubMedCrossRefGoogle Scholar
  7. 7.
    Hudziak, R. M., G. D. Lewis, M. Winget, B. M. Fendly, H. M. Shepard, A. Ullrich. 1989. p185HER2 monoclonal antibody has antiproliferative effects in vitro and sensitizes human breast tumor cells to tumor necrosis factor. Mol Cell Biol 9(3):1165–72.PubMedGoogle Scholar
  8. 8.
    Pietras, R. J., B. M. Fendly, V. R. Chazin, M. D. Pegram, S. B. Howell, D. J. Slamon. 1994. Antibody to HER-2/neu receptor blocks DNA repair after cisplatin in human breast and ovarian cancer cells. Oncogene 9(7):1829–38.PubMedGoogle Scholar
  9. 9.
    Shepard, H. M., G. D. Lewis, J. C. Sarup, et al. 1991. Monoclonal antibody therapy of human cancer: taking the HER2 protooncogene to the clinic. J Clin Immunol 11(3):117–27.PubMedCrossRefGoogle Scholar
  10. 10.
    Carter, P., L. Presta, C. M. Gorman, et al. 1992. Humanization of an anti-p185HER2 antibody for human cancer therapy. Proc Natl Acad Sci U S A 89(10):4285–9.PubMedCrossRefGoogle Scholar
  11. 11.
    Pietras, R. J., M. D. Pegram, R. S. Finn, D. A. Maneval, D. J. Slamon. 1998. Remission of human breast cancer xenografts on therapy with humanized monoclonal antibody to HER-2 receptor and DNA-reactive drugs. Oncogene 17(17):2235–49.PubMedCrossRefGoogle Scholar
  12. 12.
    Slamon, D. J., B. Leyland-Jones, S. Shak, et al. 2001. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344(11):783–92.PubMedCrossRefGoogle Scholar
  13. 13.
    Romond, E. H., E. A. Perez, J. Bryant, et al. 2005. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 353(16):1673–84.PubMedCrossRefGoogle Scholar
  14. 14.
    Piccart-Gebhart, M. J., M. Procter, B. Leyland-Jones, et al. 2005. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 353(16):1659–72.PubMedCrossRefGoogle Scholar
  15. 15.
    Smith, I., M. Procter, R. D. Gelber, et al. 2007. 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial. Lancet 369(9555):29–36.PubMedCrossRefGoogle Scholar
  16. 16.
    Joensuum H., P. L. Kellokumpu-Lehtinen, P. Bono, et al. 2006. Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med 354(8):809–20.CrossRefGoogle Scholar
  17. 17.
    Slamon, D., W. Eiermann, N. Robert. Phase III trial comparing AC-T with AC-TH and with TCH in the adjuvant treatment of HER2 positive early breast cancer: First planned interim efficacy analysis (abstract 1). In: 28th Annual San Antonio Breast Cancer Symposium; 2005; San Antonio, TX; 2005.Google Scholar
  18. 18.
    Storniolo, A., H. Burris, M. Pegram, et al. 2005. A phase I, open-label study of lapatinib (GW572016) plus trastuzumab; a clinically active regimen Journal of Clinical Oncology 23(16S, Part I of II (June 1 Supplement), 2005 ASCO Annual Meeting Proceedings):559.Google Scholar
  19. 19.
    Storniolo, A., H. Burris, M. Pegram. A phase I, open-label study of lapatinib (GW572016) plus trastuzumab; a clinically active regimen. J Clin Oncol, 2005 ASCO Annual Meeting Proceedings 2005;Vol 23, No. 16S:559.Google Scholar
  20. 20.
    Blackwell, K., E. Kaplan, S. Franco. 2004. A phase II, open-label, multicenter study of GW572016 in patients with trastuzumab-refractory metastatic breast cancer. J Clin Oncol 22(14 suppl): 3006.Google Scholar
  21. 21.
    Burstein, H., A. Storniolo, S. Franco. 2004. A phase II, open-label, multicenter study of lapatinib in two cohorts of patients with advanced or metastatic breast cancer who have progressed while receiving trastuzumab-containing regimens Annals of Oncology 15(suppl 3) 1040.Google Scholar
  22. 22.
    Kaplan, E., C. Jones, M. Berger. 2003. A phase II, open-label, multicenter study of GW572016 in patients with trastuzumab refractory metastatic breast cancer. Proc Am Soc Clin Oncol 22: 981.Google Scholar
  23. 23.
    Blackwell, K., H. Burstein, M. Pegram. 2005. Determining relevant biomarkers from tissue and serum that may predict response to single agent lapatinib in trastuzumab-refractory metastatic breast cancer. J Clin Oncol 23(16 suppl) 3004.Google Scholar
  24. 24.
    Spector, N., K. Blackwell, J. Hurley, et al. EGF 103009, a phase II trial of lapatinib monotherapy in patients with relapsed/refractory inflammatory breast cancer (IBC): clinical activity and biologic predictors of response Journal of Clinical Oncology 2006;24(18S (June 20 Supplement), ASCO Ann Meeting Proc):502.Google Scholar
  25. 25.
    Geyer, C. E., J. Forster, D. Lindquist, et al. 2006. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 355(26):2733–43.PubMedCrossRefGoogle Scholar
  26. 26.
    Moy, B., P. E. Goss. 2006. Lapatinib: current status and future directions in breast cancer. Oncologist 11(10):1047–57.PubMedCrossRefGoogle Scholar
  27. 27.
    Folkman, J. 1971. Tumor angiogenesis: therapeutic implications. New England Journal of Medicine 285:1182–86.PubMedCrossRefGoogle Scholar
  28. 28.
    Relf, M., S. LeJeune, P. A. Scott, et al. 1997. Expression of the angiogenic factors vascular endothelial cell growth factor, acidic and basic fibroblast growth factor, tumor growth factor beta-1, platelet-derived endothelial cell growth factor, placenta growth factor, and pleiotrophin in human primary breast cancer and its relation to angiogenesis. Cancer Res 57(5):963–9.PubMedGoogle Scholar
  29. 29.
    Ferrara, N., B. Keyt. 1997. Vascular endothelial growth factor: basic biology and clinical implications. Exs 79:209–32.PubMedGoogle Scholar
  30. 30.
    Cobleigh, M., K. Miller, V. Langmuir. 2001. Phase II dose escalation trial of Avastin (bevacizumab) in women with previously treated metastatic breast cancer. Breat Cancer Res Treat 69:301.Google Scholar
  31. 31.
    Miller, K. D., L. I. Chap, F. A. Holmes, et al. 2005. Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol 23(4):792–9.PubMedCrossRefGoogle Scholar
  32. 32.
    Miller, K. D. 2003. E2100: a phase III trial of paclitaxel versus paclitaxel/bevacizumab for metastatic breast cancer. Clin Breast Cancer 3(6):421–2.PubMedCrossRefGoogle Scholar
  33. 33.
    Miller, K., W. Gradishar, C. Moisa, G. Sledge. Capecitabine plus bevacizumab in first line metastatic breast cancer: an interim safety and efficacy report of the first phase of xeloda plus avastin 1st line metastatic breast cancer trial. 29th annual San Antonio Breast Cancer Symposium 2006:abstract #2068.Google Scholar
  34. 34.
    Miller, K., H. Burstein, A. Elias. Phase II study of SU11248, a multitargeted tyrosine kinase inhibitor in patients with previously treated metastatic breast cancer 28th Annual San Antonio Breast Cancer Symposium 2005:abstract #1066.Google Scholar
  35. 35.
    Campbell, I. G., S. E. Russell, D. Y. Choong, et al. 2004. Mutation of the PIK3CA gene in ovarian and breast cancer. Cancer Res 64(21):7678–81.PubMedCrossRefGoogle Scholar
  36. 36.
    Yu, K., L. Toral-Barza, C. Discafani, et al. 2001. mTOR, a novel target in breast cancer: the effect of CCI-779, an mTOR inhibitor, in preclinical models of breast cancer. Endocr Relat Cancer 8(3):249–58.PubMedCrossRefGoogle Scholar
  37. 37.
    Chow, L., Y. Sun, J. Jassem. 2006. Phase 3 study of temsirolimus with letrozole or letrozole alone in postmenopausal women with locally advanced or metastatic breast cancer. Breast Cancer Research and Treatment 100(Supplement 1):S286.Google Scholar
  38. 38.
    Herbert, B. S., W. E. Wright, J. W. Shay. 2001. Telomerase and breast cancer. Breast Cancer Res 3(3):146–9.PubMedCrossRefGoogle Scholar
  39. 39.
    Mueller, C., U. Riese, H. Kosmehl, R. Dahse, U. Claussen, G. Ernst. 2002. Telomerase activity in microdissected human breast cancer tissues: association with p53, p21 and outcome. Int J Oncol 20(2):385–90.PubMedGoogle Scholar
  40. 40.
    Shpitz, B., S. Zimlichman, R. Zemer, et al. 1999. Telomerase activity in ductal carcinoma in situ of the breast. Breast Cancer Res Treat 58(1):65–9.PubMedCrossRefGoogle Scholar
  41. 41.
    Mokbel, K. M., C. N. Parris, M. Ghilchik, C. N. Amerasinghe, R. F. Newbold. 2000. Telomerase activity and lymphovascular invasion in breast cancer. Eur J Surg Oncol 26(1):30–3.PubMedCrossRefGoogle Scholar
  42. 42.
    Bieche, I., C. Nogues, V. Paradis, et al. 2000. Quantitation of hTERT gene expression in sporadic breast tumors with a real-time reverse transcription-polymerase chain reaction assay. Clin Cancer Res 6(2):452–9.PubMedGoogle Scholar
  43. 43.
    Kyo, S., M. Takakura, T. Kanaya, et al. 1999. Estrogen activates telomerase. Cancer Res 59(23):5917–21.PubMedGoogle Scholar
  44. 44.
    Wang, Z., S. Kyo, M. Takakura, et al. 2000. Progesterone regulates human telomerase reverse transcriptase gene expression via activation of mitogen-activated protein kinase signaling pathway. Cancer Res 60(19):5376–81.PubMedGoogle Scholar
  45. 45.
    Izbicka, E., R. T. Wheelhouse, E. Raymond, et al. 1999. Effects of cationic porphyrins as G-quadruplex interactive agents in human tumor cells. Cancer Res 59(3):639–44.PubMedGoogle Scholar
  46. 46.
    Xu, D., Q. Wang, A. Gruber, et al. 2000. Downregulation of telomerase reverse transcriptase mRNA expression by wild type p53 in human tumor cells. Oncogene 19(45):5123–33.PubMedCrossRefGoogle Scholar
  47. 47.
    Ludwig, A., G. Saretzki, P. S. Holm, et al. 2001. Ribozyme cleavage of telomerase mRNA sensitizes breast epithelial cells to inhibitors of topoisomerase. Cancer Res 61(7):3053–61.PubMedGoogle Scholar
  48. 48.
    Muller, A., G. Saretzki, T. von Zglinicki. 1998. Telomerase inhibition by induced expression of antisense RNA. Adv Exp Med Biol 451:23–6.PubMedGoogle Scholar
  49. 49.
    Kossakowska, A. E., S. A. Huchcroft, S. J. Urbanski, Edwards DR. 1996. Comparative analysis of the expression patterns of metalloproteinases and their inhibitors in breast neoplasia, sporadic colorectal neoplasia, pulmonary carcinomas and malignant non-Hodgkin’s lymphomas in humans. Br J Cancer 73(11):1401–8.PubMedGoogle Scholar
  50. 50.
    Monteagudo, C., M. J. Merino, J. San-Juan, L. A. Liotta, W. G. Stetler-Stevenson. 1990. Immunohistochemical distribution of type IV collagenase in normal, benign, and malignant breast tissue. Am J Pathol 136(3):585–92.PubMedGoogle Scholar
  51. 51.
    Zucker, S., R. M. Lysik, M. H. Zarrabi, U. Moll. 1993. M(r) 92, 000 type IV collagenase is increased in plasma of patients with colon cancer and breast cancer. Cancer Res 53(1):140–6.PubMedGoogle Scholar
  52. 52.
    Sledge, G. W., Jr., M. Qulali, R. Goulet, E. A. Bone, R. Fife. 1995. Effect of matrix metalloproteinase inhibitor batimastat on breast cancer regrowth and metastasis in athymic mice. J Natl Cancer Inst 87(20):1546–50.PubMedCrossRefGoogle Scholar
  53. 53.
    Bramhallm S. R., A. Rosemurgy, P. D. Brown, C. Bowry, J. A. Buckels. 2001. Marimastat as first-line therapy for patients with unresectable pancreatic cancer: a randomized trial. J Clin Oncol 19(15):3447–55.Google Scholar
  54. 54.
    Hidalgo, M., S. G. Eckhardt. 2001. Development of matrix metalloproteinase inhibitors in cancer therapy. J Natl Cancer Inst 93(3):178–93.PubMedCrossRefGoogle Scholar
  55. 55.
    Shepard, F., Giaccone, G. Debruyne. 2001. Randomized double-blind placebo-controlled trial of marimastat in paitents with small cell lung cancer following response to first-line chemotherapy. An NCIC-CTG and EORTC study. Proc Am Soc Clin Oncol 20:4a.Google Scholar
  56. 56.
    Sparano, J., Bernardo, P. Gradisher. 2002. Randomized Phase III trial of marimastat versus placebo in patients with metastatic breast cancer who have responding or stable disease after first-line chemotherapy: an Eastern Cooperative Oncology Group trial (E2196). Proc Am Soc Clin Oncol 21:45a (Abstract # 173).Google Scholar
  57. 57.
    Miller, K. D., W. Gradishar, L. Schuchter, et al. 2002. A randomized phase II pilot trial of adjuvant marimastat in patients with early-stage breast cancer. Ann Oncol 13(8):1220–4.PubMedCrossRefGoogle Scholar
  58. 58.
    Malmstrom, P., P. O. Bendahl, P. Boiesen, N. Brunner, I. Idvall, M. Ferno. 2001. S-phase fraction and urokinase plasminogen activator are better markers for distant recurrences than Nottingham Prognostic Index and histologic grade in a prospective study of premenopausal lymph node-negative breast cancer. J Clin Oncol 19(7):2010–9.PubMedGoogle Scholar
  59. 59.
    Prechtl, A., N. Harbeck, C. Thomssen, et al. 2000. Tumor-biological factors uPA and PAI-1 as stratification criteria of a multicenter adjuvant chemotherapy trial in node-negative breast cancer. Int J Biol Markers 15(1):73–8.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Danielle M. Doyle
    • 1
  • Kathy D. Miller
    • 1
  1. 1.Indiana University School of MedicineIndiana Cancer PavillionIndianapolisUSA

Personalised recommendations