Skip to main content
SpringerLink
Log in

Monoclonal Antibody-Based Targeted Therapy in Breast Cancer

Current Status and Future Directions

  • Review Article
  • Published:
Drugs Aims and scope Submit manuscript

Abstract

The recent development of monoclonal antibodies targeting growth factor receptors in cancer treatment represents a milestone for both researchers and physicians. Advances in the understanding of key molecular pathways for tumour growth and survival have facilitated the development of these targeted therapies, in particular in breast cancer. This review focuses on the three most important recombinant humanised monoclonal antibodies that have shown activity in women with breast cancer: trastuzumab, pertuzumab and bevacizumab. Trastuzumab, an anti-erbB2 (human epidermal growth factor receptor) monoclonal antibody, is currently routinely used in both the metastatic and adjuvant settings for patients with erbB2-positive tumours. Pertuzumab, a monoclonal antibody binding to a different epitope on erbB2 than trastuzumab, is under early clinical evaluation. This drug has been developed for breast cancer patients, whether overexpressing erbB2 or not. Bevacizumab, a monoclonal antibody directed against vascular endothelial growth factor-A, is being evaluated in the metastatic setting for its antiangiogenic properties, and is showing promising results.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Table I
Table II
Table III
Table IV

Similar content being viewed by others

References

  1. Nahta R, Esteva FJ. HER-2-targeted therapy: lessons learned and future directions. Clin Cancer Res 2003; 9: 5078–84

    PubMed  CAS  Google Scholar 

  2. De Laurentiis M, Cancello G, Zinno L, et al. Targeting HER2 as a therapeutic strategy for breast cancer: a paradigmatic shift of drug development in oncology. Ann Oncol 2005; 16 Suppl. 4: iv7–13

    PubMed  Google Scholar 

  3. Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med 1995; 1: 27–31

    PubMed  CAS  Google Scholar 

  4. Gschwind A, Fischer OM, Ullrich A. The discovery of receptor tyrosine kinases: targets for cancer therapy. Nat Rev Cancer 2004; 4: 361–70

    PubMed  CAS  Google Scholar 

  5. Holbro T, Hynes NE. Erb B receptors: directing key signaling networks throughout life. Annu Rev Pharmacol Toxicol 2004; 44: 195–217

    PubMed  CAS  Google Scholar 

  6. Schlessinger J. Common and distinct elements in cellular signaling via EGF and FGF receptors. Science 2004; 306: 1506–7

    PubMed  CAS  Google Scholar 

  7. Petit AM, Rak J, Hung MC, et al. Neutralizing antibodies against epidermal growth factor and ErbB-2/neu receptor tyrosine kinases down-regulate vascular endothelial growth factor production by tumor cells in vitro and in vivo: angiogenic implications for signal transduction therapy of solid tumors. Am J Pathol 1997; 151: 1523–30

    PubMed  CAS  Google Scholar 

  8. Slamon DJ, Clark GM, Wong SG, et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 1987; 235: 177–82

    PubMed  CAS  Google Scholar 

  9. Zhou B, Hung M. Dysregulation of cellular signaling by HER2/neu in breast cancer. Semin Oncol 2003; 30: 38–48

    PubMed  CAS  Google Scholar 

  10. Menard S, Pupa S, Campiglio M, et al. Biologic and therapeutic role of HER2 in cancer. Oncogene 2003; 22: 6570–8

    PubMed  CAS  Google Scholar 

  11. Linderholm BK, Andersson J, Lindh B, et al. Overexpression of c-erbB-2 is related with higher expression of vascular endothelial growth factor (VEGF) and of prognostic value in primary node-positive breast cancer following adjuvant systemic therapy. Eur J Cancer 2004; 40(1): 33–42

    PubMed  CAS  Google Scholar 

  12. Cooley S, Burns LJ, Repka T, et al. Natural killer cell cytotoxicity of breast cancer targets is enhanced by two distinct mechanisms of antibody-dependent cellular cytotoxicity against LFA-3 and HER2/neu. Exp Hematol 1999; 27: 1533–41

    PubMed  CAS  Google Scholar 

  13. Clynes RA, Towers TL, Presta LG, et al. Inhibitory Fc receptors modulate in vivo cytoxicity against tumour targets. Nat Med 2000; 6: 443–6

    PubMed  CAS  Google Scholar 

  14. Carson WE, Parihar R, Lindemann MJ, et al. Interleukin-2 enhances the natural killer cell response to Herceptin-coated Her2/neu-positive breast cancer cells. Eur J Immunol 2001; 31: 3016–25

    PubMed  CAS  Google Scholar 

  15. Kubo M, Morisaki T, Kuroki H, et al. Combination of adoptive immunotherapy with Herceptin for patients with HER2-expressing breast cancer. Anticancer Res 2003; 23: 4443–9

    PubMed  CAS  Google Scholar 

  16. Repka T, Chiorean EG, Gay J, et al. Trastuzumab and interleukin-2 in HER2-positive metastatic breast cancer: a pilot study. Clin Cancer Res 2003; 9: 2440–6

    PubMed  CAS  Google Scholar 

  17. Gennari R, Menard S, Fagnoni F, et al. Pilot study of the mechanism of action of preoperative trastuzumab in patients with primary operable breast tumours overexpressing HER 2. Clin Cancer Res 2004; 10: 5650–5

    PubMed  CAS  Google Scholar 

  18. Arnould L, Gelly M, Penault-Llorca F, et al. Trastuzumab-based treatment of HER2-positive breast cancer: an antibody-dependent cellular cytotoxicity mechanism? Br J Cancer 2006; 94: 259–67

    PubMed  CAS  Google Scholar 

  19. Hancock MC, Langton BC, Chan T, et al. A monoclonal antibody against the c-erbB-2 protein enhances the cytotoxicity of cisdiamminedichloroplatinum against human breast and ovarian tumor cell lines. Cancer Res 1991; 51: 4575–80

    PubMed  CAS  Google Scholar 

  20. Pietras RJ, Fendly BM, Chazin VR, et al. Antibody to HER-2/neu receptor blocks DNA repair after cisplatin in human breast and ovarian cancer cells. Oncogene 1994; 9: 1829–38

    PubMed  CAS  Google Scholar 

  21. Arteaga CL, Winnier AR, Poirier MC, et al. pl85c-erbB-2 signal enhances cisplatin-induced cytotoxicity in human breast carcinoma cells: association between an oncogenic receptor tyrosine kinase and drug-induced DNA repair. Cancer Res 1994; 54: 3758–65

    PubMed  CAS  Google Scholar 

  22. Pietras RJ, Pegram MD, Finn RS, et al. Remission of human breast cancer xenografts on therapy with humanized monoclonal antibody to HER-2 receptor and DNA-reactive drugs. Oncogene 1998; 17: 2235–49

    PubMed  CAS  Google Scholar 

  23. Pegram M, Hsu S, Lewis G, et al. Inhibitory effects of combinations of HER-2/neu antibody and chemotherapeutic agents used for treatment of human breast cancers. Oncogene 1999; 18(13): 2241–51

    PubMed  CAS  Google Scholar 

  24. Pegram MD, Konecny GE, O'Callaghan C, et al. Rational combinations of trastuzumab with chemotherapeutic drugs used in the treatment of breast cancer. J Natl Cancer Inst 2004; 96: 739–49

    PubMed  CAS  Google Scholar 

  25. Nahta R, Esteva FJ. In vitro effects of trastuzumab and vinorelbine in trastuzumab-resistant breast cancer cells. Cancer Chemother Pharmacol 2004; 53: 186–90

    PubMed  CAS  Google Scholar 

  26. Folkman J. What is the evidence that tumors are angiogenesis dependent? J Natl Cancer Inst 1990; 82: 4–6

    PubMed  CAS  Google Scholar 

  27. Rosen LS. Clinical experience with angiogenesis signaling inhibitors: focus on vascular endothelial growth factor (VEGF) blockers. Cancer Control 2002; 9 (2 Suppl.): 36–44

    PubMed  Google Scholar 

  28. Sledge GW. Vascular endothelial growth factor in breast cancer: biologic and therapeutic aspects. Semin Oncol 2002; 29 Suppl. 11: 104–10

    PubMed  CAS  Google Scholar 

  29. Linderholm B, Lindh B, Beckam L, et al. Prognostic correlation of basic fibroblast growth factor and vascular endothelial growth factor in 1307 primary breast cancers. Clin Breast Cancer 2003; 4(5): 340–7

    PubMed  CAS  Google Scholar 

  30. Foekens JA, Peters HA, Grebenchtchikov N, et al. high tumor levels of vascular endothelial growth factor predict poor response to systemic therapy inadvanced breast cancer. Cancer Res 2001; 61: 5407–14

    PubMed  CAS  Google Scholar 

  31. Willett CG, Boucher Y, di Tomaso E, et al. Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat Med 2004; 10: 145–7

    PubMed  CAS  Google Scholar 

  32. Uzzan B, Nicolas P, Cucherat M, et al. Microvessel density as a prognostic factor in women with breast cancer: a systematic review of the literature and meta-analysis. Cancer Res 2004; 64: 2941–55

    PubMed  CAS  Google Scholar 

  33. Li CY, Shan S, Huang Q, et al. Initial stages of tumor cell-induced angiogenesis: evaluation via skin window chambers in rodent models. J Natl Cancer Inst 2000; 92: 143–7

    PubMed  CAS  Google Scholar 

  34. Vogel CL, Cobleigh MA, Tripathy D, et al. Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol 2002; 20: 719–26

    PubMed  CAS  Google Scholar 

  35. Lane HA, Beuvink I, Motoyama AB, et al. ErbB2 potentiates breast tumor proliferation through modulation of p27Kip1-Cdk2 complex formation: receptor overexpression does not determine growth dependency. Mol Cell Biol 2000; 20: 3210–23

    PubMed  CAS  Google Scholar 

  36. Motoyama AB, Hynes NE, Lane HA. The efficacy of ErbB receptor-targeted anticancer therapeutics is influenced by the availability of epidermal growth factor-related peptides. Cancer Res 2002, 58

  37. Agus DB, Akita RW, Fox WD, et al. Targeting ligand-activated ErbB2 signaling inhibits breast and prostate tumor growth. Cancer Cell 2002; 2: 127–37

    PubMed  CAS  Google Scholar 

  38. Cho HS, Mason K, Ramyar KX, et al. Structure of the extracellular region of HER2 alone and in complex with the Herceptin Fab. Nature 2003; 421: 756–60

    PubMed  CAS  Google Scholar 

  39. Franklin MC, Carey KD, Vajdos FF, et al. Insights into ErbB signaling from the structure of the ErbB2-pertuzumab complex. Cancer Cell 2004; 5: 317–28

    PubMed  CAS  Google Scholar 

  40. Jackson JG, St Clair P, Sliwkowski MX, et al. Blockade of epidermal growth factor- or heregulin-dependent ErbB2 activation with the anti-ErbB2 monoclonal antibody 2C4 has divergent downstream signaling and growth effects. Cancer Res 2004; 64: 2601–9

    PubMed  CAS  Google Scholar 

  41. Janmaat ML, Kruyt FA, Rodriguez JA, et al. Response to epidermal growth factor receptor inhibitors in non-small cell lung cancer cells: limited antiproliferative effects and absence of apoptosis associated with persistent activity of extracellular signal-regulated kinase or Akt kinase pathways. Clin Cancer Res 2003; 9: 2316–26

    PubMed  CAS  Google Scholar 

  42. Bianco R, Shin I, Ritter CA, et al. Loss of PTEN/MMAC1/TEP in EGF receptor-expressing tumor cells counteracts the antitumor action of EGFR tyrosine kinase inhibitors. Oncogene 2003; 22: 2812–22

    PubMed  CAS  Google Scholar 

  43. Neshat MS, Mellinghoff IK, Tran C, et al. Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR. Proc Natl Acad Sci U S A 2001; 98: 10314–9

    PubMed  CAS  Google Scholar 

  44. Dibb NJ, Dilworth SM, Mol CD. Switching on kinases: oncogenic activation of BRAF and the PDGFR family. Nat Rev Cancer 2004; 4: 718–27

    PubMed  CAS  Google Scholar 

  45. Mitsiades CS, Mitsiades NS, McMullan CJ, et al. Inhibition of the insulin-like growth factor receptor-1 tyrosine kinase activity as a therapeutic strategy for multiple myeloma, other hematologic malignancies, and solid tumors. Cancer Cell 2004; 5: 221–30

    PubMed  CAS  Google Scholar 

  46. Shaheen RM, Ahmad SA, Liu W, et al. Inhibited growth of colon cancer carcinomatosis by antibodies to vascular endothelial and epidermal growth factor receptors. Br J Cancer 2001; 85: 584–9

    PubMed  CAS  Google Scholar 

  47. Ross JS, Fletcher JA. The HER-2/Neu oncogene, in breast cancer: prognostic factor, predictive factor and target for therapy. Stem Cells 1998; 16: 413–28

    PubMed  CAS  Google Scholar 

  48. De Placido S, Carlomagno C, De Laurentiis M, et al. C-ErbB2 expression predicts tamoxifen efficacy in breast cancer patients. Breast Cancer Res Treat 1998; 52: 55–64

    PubMed  Google Scholar 

  49. De Placido S, De Laurentiis M, Carlomagno C, et al. Twenty-year results of the Naples GUN randomized trial: predictive factors of adjuvant tamoxifen efficacy in early breast cancer. Clin Cancer Res 2003; 9: 1039–46

    PubMed  Google Scholar 

  50. De Laurentiis M, Arpino G, Massarelli E, et al. A meta-analysis on the interaction between HER-2 expression and response to endocrine treatment in advanced breast cancer. Clin Cancer Res 2005; 11(13): 4741–8

    PubMed  Google Scholar 

  51. Kurokawa H, Arteaga CL. ErbB (HER) receptors can abrogate antiestrogen action in human breast cancer by multiple signaling mechanisms. Clin Cancer Res 2003; 9 (1 Pt 2): 511–15S

    Google Scholar 

  52. Izumi Y, Xu L, di Tomaso E, et al. Tumour biology: Herceptin acts as an anti-angiogenic cocktail. Nature 2002; 416: 279–80

    PubMed  CAS  Google Scholar 

  53. Baselga J, Norton L, Albaneil J, et al. Recombinant humanized anti-HER2 antibody (Herceptin) enhances the antitumor activity of paclitaxel and doxorubicin against HER2/Neu overexpressing human breast cancer xenografts. Cancer Res 1998; 58: 2825–31

    PubMed  CAS  Google Scholar 

  54. Pegram MD, Pienkowski T, Northfelt DW, et al. Results of two open-label, multicenter phase II studies of docetaxel, platinum salts, and trastuzumab in HER2-positive advanced breast cancer. J Natl Cancer Inst 2004; 96: 759–69

    PubMed  CAS  Google Scholar 

  55. Lopez AM, Pegram MD, Slamon DJ, et al. A model-based approach for assessing in vivo combination therapy interactions. Proc Natl Acad Sci U S A 1999; 96: 13023–8

    PubMed  CAS  Google Scholar 

  56. Cobleigh MA, Vogel CL, Tripathy D, et al. Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol 1999; 17: 2639–48

    PubMed  CAS  Google Scholar 

  57. Vogel CL, Cobleigh M, Tripathy D, et al. Superior outcomes with Herceptin (trastuzumab) (H) in fluorescence in situ hybridization (FISH)-selected patients [abstract]. Proc Am Soc Clin Oncol 2001; 20: 86

    Google Scholar 

  58. Baselga J, Tripathy D, Mendelsohn J, et al. Phase II study of weekly intravenous trastuzumab (Herceptin) in patients with HER2/neu-overexpressing metastatic breast cancer. Semin Oncol 1999 Aug; 26 (4 Suppl. 12): 78–83

    PubMed  CAS  Google Scholar 

  59. Agus DB, Gordon MS, Taylor C, et al. Phase I clinical study of pertuzumab, a novel erbB dimerization inhibitor, in patients with advanced cancer. J Clin Oncol 2005; 23(11): 2534–43

    PubMed  CAS  Google Scholar 

  60. Cortes J, Baselga J, Kellokumpu-Lehtinen P, et al. Open label, randomized, phase II study of pertuzumab (P) in patients (pts) with metastatic breast cancer (MBC) with low expression of HER2 [abstract no. 3068]. Proc Am Soc Clin Oncol 2005; 23(16S): 208S

    Google Scholar 

  61. Gordon MS, Margolin K, Talpaz M, et al. Phase I safety and pharmacokinetic study of recombinant human anti-vascular endothelial growth factor in patients with advanced cancer. J Clin Oncol 2001; 19: 843–50

    PubMed  CAS  Google Scholar 

  62. Cobleigh MA, Langmuir VK, Sledge GW, et al. A phase I–II dose-escalation trial of bevacizumab in previously treated metastatic breast cancer. Semin Oncol 2003; 30 (5 Suppl. 16): 117–24

    PubMed  CAS  Google Scholar 

  63. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER-2. N Engl J Med 2001; 344: 783–92

    PubMed  CAS  Google Scholar 

  64. Seidman AD, Fornier MN, Esteva FJ, et al. Weekly trastuzumab and paclitaxel therapy for metastatic breast cancer with analysis of efficacy by HER2 immunophenotype and gene amplification. J Clin Oncol 2001; 19: 2587–95

    PubMed  CAS  Google Scholar 

  65. Robert NJ, Leyland-Jones B, Asmar L, et al. Randomized phase III study of trastuzumab, paclitaxel and carboplatin versus trastuzumab and paclitaxel in women with HER-2 overexpressing metastatic breast cancer: an update including survival [abstract]. Proc Am Soc Clin Oncol 2004; 23: 573

    Google Scholar 

  66. Toi M, Sasaki Y, Tokuda Y, et al. Phase I/II study of trastuzumab (Herceptin) on pharmacokinetics and safety in combination with paclitaxel or docetaxel for metastatic breast cancer [abstract 182P]. Ann Oncol 2002; 13 Suppl. 5: 51

    Google Scholar 

  67. Leyland-Jones B, Gelmon K, Ayoub JP, et al. Pharmacokinetics, safety, and efficacy of trastuzumab administered every three weeks in combination with paclitaxel. J Clin Oncol 2003; 21: 3965–71

    PubMed  CAS  Google Scholar 

  68. Fountzilas G, Tsavdaridis D, Kalogera-Fountzila A, et al. Weekly paclitaxel as first-line chemotherapy and trastuzumab in patients with advanced breast cancer. A Hellenic Cooperative Oncology Group phase II study. Ann Oncol 2001; 12: 1545–51

    CAS  Google Scholar 

  69. Krasna L, Janku F, Petruzelka L, et al. Herceptin (H) and taxol (T) in the treatment of women with HER-2/Neu overexpressing metastatic breast cancer (MBC): prospective study [abstract]. Proc Am Soc Clin Oncol 2001; 20: 2006

    Google Scholar 

  70. Janku F, Pribylova O, Zimovjanova M, et al. 4-years results of weekly trastuzumab and paclitaxel in the treatment of women with HER2/neu overexpressing advanced breast cancer: single institution prospective study. Bull Cancer 2004; 91(10): E279–83

    PubMed  Google Scholar 

  71. Gasparini G, Morabito A, De Sio L, et al. Preliminary clinical results of a randomized phase IIb study of weekly paclitaxel (PCT) trastuzumab (T) as first-line therapy of patients (pts) with HER2/neu positive metastatic breast cancer (MBC) [abstract no. 227]. Breast Cancer Res Treat 2003; 82 Suppl. 1: S51

    Google Scholar 

  72. John M, Kriebel-Schmitt R, Stauch M, et al. Weekly paclitaxel plus trastuzumab shows promising efficacy in advanced breast cancer [abstract no. 221]. Breast Cancer Res Treat 2003; 82 Suppl. 1: S49

    Google Scholar 

  73. Yeung K, Gupta R, Haidak D, et al. Weekly (W) Herceptin (H, trastuzumab) and one hour Taxol (T, paclitaxel) infusion (WHT) regimen for human epidermal growth factor receptor-2 (HER2) overexpressed (+) metastatic breast cancer (MBC) [abstract]. Proc Am Soc Clin Oncol 2000; 19: 559

    Google Scholar 

  74. Esteva FJ, Valero V, Booser D, et al. Phase II study of weekly docetaxel and trastuzumab for patients with HER-2-overexpressing metastatic breast cancer. J Clin Oncol 2002; 20: 1800–8

    PubMed  CAS  Google Scholar 

  75. Kuzur M, Albain K, Huntington M, et al. Phase II trial of docetaxel and H/erceptin in metastatic breast cancer patients overexpressing HER-2 [abstract]. Proc Am Soc Clin Oncol 2000; 19: 512

    Google Scholar 

  76. Bauer-Kosinska B, Lemanska I, Glogowska I, et al. Efficacy and toxicity of docetaxel or cisplatin chemotherapy in combination with trastuzumab in the treatment of patients with chemotherapy pre-treated HER-2/neu overexpressed metastatic breast cancer [abstract no. 464]. EurJCancer 2003; 1 Suppl. 5: S141

    Google Scholar 

  77. Montemurro F, Choa G, Faggiuolo R, et al. A phase II study of three-weekly docetaxel and weekly trastuzumab in HER2-overexpressing advanced breast cancer. Oncology 2004; 66(1): 38–45

    PubMed  CAS  Google Scholar 

  78. Raab G, Brugger W, Harbeck N, et al. Multicenter randomized phase II study of docetaxel (Doc) given q3w vs q1w plus trastuzumab (Tra) as first line therapy for HER2 overexpressing adjuvant anthracyclin pretreated metastatic breast cancer (MBC) [abstract no. 443]. Breast Cancer Res Treat 2002; 76 Suppl. 1: S114

    Google Scholar 

  79. Tabei T, Kimura M, Sano M, et al. Multicenter phase II trial of three-weekly docetaxel and weekly trastuzumab in HER-2-overexpressing metastatic breast cancer patients: Japan East cancer center breast cancer consortium (JECBC 01 trial) [abstract no. 258]. Eur J Cancer 2004; 2 Suppl. 3: 131

    Google Scholar 

  80. Meden H, Beneke A, Hesse T, et al. Weekly intravenous recombinant humanized anti-P185HER2 monoclonal antibody (Herceptin) plus docetaxel in patients with metastatic breast cancer: a pilot study. Anticancer Res 2001; 21(2B): 1301–5

    PubMed  CAS  Google Scholar 

  81. Schwartz GH, Steis R, Mathew L, et al. Patients with MBC prospectively selected by FISH derive clinical benefit from first-line treatment with Herceptin plus a taxane [abstract no. 429]. Breast Cancer Res Treat 2002; 76 Suppl. 1: S111

    Google Scholar 

  82. Raff JP, Rajdev L, Malik U, et al. Phase II study of weekly docetaxel alone or in combination with trastuzumab in patients with metastatic breast cancer. Clin Breast Cancer 2004; 4(6): 420–7

    PubMed  CAS  Google Scholar 

  83. Takao S, Kohno N, Miyashita M, et al. Weekly docetaxel and trastuzumab for HER-2-overexpressing metastatic breast cancer: efficacy and correlation with biological markers in a phase II, multicenter study [abstract no. 302]. Eur J Cancer 2004; 2 Suppl. 3: 137

    Google Scholar 

  84. Tedesco KL, Thor AD, Johnson DH, et al. Docetaxel combined with trastuzumab is an active regimen in HER-2 3+ overexpressing and fluorescent in situ hybridization-positive metastatic breast cancer: a multi-institutional phase II trial. J Clin Oncol 2004; 22(6): 1071–7

    PubMed  CAS  Google Scholar 

  85. Uber K, Nicholson B, Thor A, et al. A Phase II trial of weekly docetaxel (D) and Herceptin (H) as first- or second-line treatment in HER2 over-expressing metastatic breast cancer [abstract]. Proc Am Soc Clin Oncol 2001; 20: 1949

    Google Scholar 

  86. Burris HA. Docetaxel (Taxotere) plus trastuzumab (Herceptin) in breast cancer. Semin Oncol 2001; 28 (1 Suppl. 3): 38–44

    PubMed  CAS  Google Scholar 

  87. Extra J, Cognetti F, Maraninchi D, et al. Long-term survival demonstrated with trastuzumab plus docetaxel: 24-month data from a randomised trial (M77001) in HER2-positive metastatic breast cancer [abstract no. 555]. Proc Am Soc Clin Oncol 2005; 23: 17S

    Google Scholar 

  88. Bangemann N, Kuhle A, Ebert A, et al. Capecitabine combined with trastuzumab in the therapy of intensively pretreated HER2 overexpressing metastatic breast cancer. Ann Oncol 2000; 11 Suppl. 4: 143

    Google Scholar 

  89. Yamamoto D, Iwase S, Kitamura K, et al. Multicenter phase II study of trastuzumab (H) and capecitabine (X) as first- or second-line treatment in HER2 over-expressing metastatic breast cancer (Japan Breast Cancer Study Group: JBCSG-003) [abstract no. 802]. Proc Am Soc Clin Oncol 2005; 23: 78S

    Google Scholar 

  90. Burstein HJ, Harris LN, Marcom PK, et al. Trastuzumab and vinorelbine as first-line therapy for HER2-overexpressing metastatic breast cancer: multicenter phase II trial with clinical outcomes, analysis of serum tumor markers as predictive factors, and cardiac surveillance algorithm. J Clin Oncol 2003; 21(15): 2889–95

    PubMed  CAS  Google Scholar 

  91. Bernardo G, Palumbo R, Bernardo A, et al. Weekly trastuzumab (Herceptin) and vinorelbine (Navelbine) in chemonaive patients with HER2-overexpressing metastatic breast cancer: a phase II trial [abstract]. Ann Oncol 2002; 13 (Suppl. 5): 51

    Google Scholar 

  92. Jahanzeb M, Mortimer JE, Yunus F, et al. Phase II trial of weekly vinorelbine and trastuzumab as first-line therapy in patients with HER2(+) metastatic breast cancer. Oncologist 2002; 7(5): 410–7

    PubMed  CAS  Google Scholar 

  93. Papaldo P, Fabi A, Ferretti G, et al. A phase II study on metastatic breast cancer patients treated with weekly vinorelbine with or without trastuzumab according to HER2 expression: changing the natural history of HER2-positive disease. Ann Oncol 2006; 17(4): 630–6

    PubMed  CAS  Google Scholar 

  94. Bayo J, Mayordomo J, Sanchez Rovira P, et al. Trastuzumab and vinorelbine combination in the treatment of Her2 positive metastatic breast cancer [abstract no. 763]. Proc Am Soc Clin Oncol 2004; 23: 67

    Google Scholar 

  95. Untch M, Kahlert S, Petruzelka L, et al. A multinational phase II study of Navelbine (N) and Herceptin (H) as first-line therapy for patients with HER2-positive metastatic breast cancer (HER2+ MBC) [abstract no. 243]. Eur J Cancer 2004: 2 (Suppl. 3): 127

    Google Scholar 

  96. Chan A, Petruzelka L, Untch M, et al. Long term survival of vinorelbine (N) and trastuzumab (H) as first line therapy for HER2-positive metastatic breast cancer patients (HER2+MBC) (pts) [abstract no. 587]. Proc Am Soc Clin Oncol 2005; 23(16S): 25S

    Google Scholar 

  97. Filipovich E, Mayordomo JI, Isla D, et al. Chemotherapy with trastuzumab plus vinorelbine in patients with erb-B2 overexpressed tumor is active in metastatic breast cancer [abstract no. 436]. Breast Cancer Res Treat 2002; 76 Suppl. 1: S112

    Google Scholar 

  98. Guillem Porta V, Martin M, Gil M, et al. Evaluation of vinorelbine (N) and trastuzumab (H) as first-line therapy for patients (pts) with HER2-positive metastatic breast cancer (HER2+ MBC): impact on clinical response and cardiac function [abstract no. 363]. Proc Am Soc Clin Oncol 2004; 23: 36

    Google Scholar 

  99. Glogowska I, Jagiello-Gruszfeld A, Sienkiewicz-Kozlowska R, et al. The combination of trastuzumab and vinorelbine as an atractive regimen in overexpressing metastatic breast cancer patients [abstract no. 3212]. Proc Am Soc Clin Oncol 2005; 23: 244S

    Google Scholar 

  100. Franquesa RM, Centelles M, Villadiego K, et al. A multicenter study of trastuzumab (H) and vinorelbine (N) as first and second line therapy for patients (pts) with HER2-positive metastatic breast cancer (HER2+ MBC) [abstract no. 868]. Proc Am Soc Clin Oncol 2005; 23: 94S

    Google Scholar 

  101. O'Shaughnessy JA, Vukelja S, Marsland T, et al. Phase II study of trastuzumab plus gemcitabine in chemotherapy-pretreated patients with metastatic breast cancer. Clin Breast Cancer 2004; 5(2): 142–7

    PubMed  Google Scholar 

  102. Christodoulou C, Fountzilas G, Razi E, et al. Gemcitabine and trastuzumab combination as salvage treatment in patients with HER 2-positive metastatic breast cancer [abstract no. 166]. Proc Am Soc Clin Oncol 2003; 22: 42

    Google Scholar 

  103. Peacock NW, Bearden J, Schnell F, et al. Phase II trial of gemcitabine plus trastuzumab in minimally pretreated HER2 overexpressing metastatic breast cancer [abstract no. 704]. Proc Am Soc Clin Oncol 2005; 23: 54S

    Google Scholar 

  104. Nabholtz J, Pienkowski T, Nothfelt D, et al. Results of two open label multicentre phase II pilot studies with Herceptin in combination with docetaxel and platinum salts (cis or carboplatin) (TCH) as therapy for advanced breast cancer (ABC) in women with tumors over-expressing the HER2-neu proto-oncogene [abstract 695]. Eur J Cancer 2001; 31: S190

    Google Scholar 

  105. Polyzos A, Mavroudis D, Boukovinas J, et al. A multicenter phase II study of docetaxel, gemcitabine and trastuzumab administration as first-line treatment in patients with advanced breast cancer (ABC) overexpressing HER-2 [abstract no. 728]. Proc Am Soc Clin Oncol 2004; 23: 58

    Google Scholar 

  106. Perez EA, Suman VJ, Rowland KM, et al. Two concurrent phase II trials of paclitaxel/carboplatin/trastuzumab (weekly or every-3-week schedule) as first-line therapy in women with HER2-overexpressing metastatic breast cancer: NCCTG study 983252. Clin Breast Cancer 2005; 6(5): 425–32

    PubMed  CAS  Google Scholar 

  107. Miller KD, Sisk J, Ansari R, et al. Gemcitabine, paclitaxel, and trastuzumab in metastatic breast cancer. Oncology (Huntingt) 2001; 15 (2 Suppl. 3): 38–40

    CAS  Google Scholar 

  108. Fountzilas G, Christodoulou C, Tsavdaridis D, et al. Paclitaxel and gemcitabine, as first-line chemotherapy, combined with trastuzumab in patients with advanced breast cancer: a phase II study conducted by the Hellenic Cooperative Oncology Group (HeCOG). Cancer Invest 2004; 22(5): 655–62

    PubMed  CAS  Google Scholar 

  109. Venturini M, Bighin C, Monfardini S, et al. Multicenter phase II study of trastuzumab in combination with epirubicin and docetaxel as first-line treatment for HER2-overexpressing metastatic breast cancer. Breast Cancer Res Treat 2006; 95(1): 45–53

    PubMed  CAS  Google Scholar 

  110. Theodoulou M, Campos S, Batist G, et al. TLC D-99 (D, Myocet) and Herceptin (H) is safe in advanced breast cancer (ABC): final cardiac safety and efficacy analysis [abstract]. Proc Am Soc Clin Oncol 2002; 21(55a): 216

    Google Scholar 

  111. Cortes J, Climent M, Lluch A, et al. Updated results of a phase II study (M77035) of myocet combined with weekly Herceptin and paclitaxel in patients with HER2-positive locally advanced or metastatic breast cancer (LABC/MBC) [abstract]. Breast Cancer Res Treat 2005; 88 Suppl. 1: 3041

    Google Scholar 

  112. Chia SK, Clemons M, Martin LA, et al. A multi-centre phase II trial of pegylated liposomal doxorubicin and trastuzumab in HER2 overexpressing metastatic breast cancer (MBC) [abstract]. Proc Am Soc Clin Oncol 2004; 23: 630

    Google Scholar 

  113. Wolff AC, Wang M, Sparano JA, et al. Cardiac safety and clinical activity of pegylated liposomal doxorubicin (D) and docetaxel (T) with and without trastuzumab (H) as first line chemotherapy in HER2-positive and HER2-negative metastatic breast cancer (MBC): Eastern Cooperative Oncology Group (ECOG) Trial E3198 [abstract]. Breast Cancer Res Treat 2004; 88 Suppl. 1: 3040

    Google Scholar 

  114. Attard G, Kitzen JJ, de Bono J, et al. A phase Ib study of pertuzumab (P), a recombinant humanized antibody to HER2, and docetaxel (D) in patients (pts) with advanced solid tumors [abstract no. 3166]. Proc Am Soc Clin Oncol 2005; 23 (16S Part I of II): 3166

    Google Scholar 

  115. Burstein HJ, Parker LM, Savoie J, et al. Phase II trial of the anti-VEGF antibody bevacizumab in combination with vinorelbine for refractory advanced breast cancer [abstract no. 446]. Breast Cancer Res Treat 2002; 76 Suppl. 1: S115

    Google Scholar 

  116. Ramaswamy B, Elias AD, Kelbick NT, et al. Phase II trial of bevacizumab in combination with weekly docetaxel in metastatic breast cancer patients. Clin Cancer Res 2006; 12(10): 3124–9

    PubMed  CAS  Google Scholar 

  117. Miller KD, Chap LI, Holmes FA, et al. Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol 2005; 23(4): 792–9

    PubMed  CAS  Google Scholar 

  118. Miller KD, Wang M, Gralow J, et al. A randomized phase III trial of paclitaxel versus paclitaxel plus bevacizumab as firstline therapy for locally recurrent or metastatic breast cancer [abstract no. 3]. Breast Cancer Res Treat 2005; 94 Suppl. 1: S6

    Google Scholar 

  119. Mass RD, Press MF, Anderson S, et al. Evaluation of clinical outcomes according to HER2 detection by fluorescence in situ hybridization in women with metastatic breast cancer treated with trastuzumab. Clin Breast Cancer. 2005; 6(3): 240–6

    PubMed  Google Scholar 

  120. Seidman A, Hudis C, Pierri MK, et al. Cardiac dysfunction in the trastuzumab clinical trials experience. J Clin Oncol 2002; 20: 1215–21

    PubMed  CAS  Google Scholar 

  121. Ozcelik C, Erdmann B, Pilz B, et al. Conditional mutation of the ErbB2 (HER2) receptor in cardiomyocytes leads to dilated cardiomyopathy. Proc Natl Acad Sci U S A 2002; 99: 8880–5

    PubMed  CAS  Google Scholar 

  122. Untch M, Eidtmann H, Du Bois A, et al. Cardiac safety of trastuzumab in combination with epirubicin and cyclophosphamide in women with metastatic breast cancer: results of a phase I trial. Eur J Cancer 2004; 40: 988–97

    PubMed  CAS  Google Scholar 

  123. Schiff R, Massarweh S, Shou J, et al. Breast cancer endocrine resistance: how growth factor signaling and estrogen receptor coregulators modulate response. Clin Cancer Res 2003; 9 (1Pt2): 447–54S

    Google Scholar 

  124. Ellis MJ, Coop A, Singh B, et al. Letrozole is more effective neoadjuvant endocrine therapy than tamoxifen for ErbB-1-and/or ErbB-2-positive, estrogen receptor-positive primary breast cancer: evidence from a phase III randomized trial. J Clin Oncol 2001; 19: 3808–16

    PubMed  CAS  Google Scholar 

  125. Markom PK, Isaacs C, Harris L, et al. A phase II trial of letrozole and trastuzumab for ER and/or PgR and HER2 positive metastatic breast cancer: final results [abstract no. 596]. Proc Am Soc Clin Oncol 2005; 23 (16S Suppl. Part I): 27s

    Google Scholar 

  126. US National Institutes of Health. Trastuzumab and letrozole in treating postmenopausal women with progressive advanced breast cancer [online]. Available from URL: http://clinicaltrials.gov/ct/show/nct00238290 [Accessed 2006 Aug 11]

  127. US National Institutes of Health. A study to evaluate the efficacy and safety of Herceptin (trastuzumab) in combination with an aromatase inhibitor in patients with metastatic breast cancer [online]. Available from URL: http://clinicaltrials.gov/ct/show/nct00022672 [Accessed 2006 Aug 11]

  128. US National Institutes of Health. Trastuzumab and exemestane in treating postmenopausal women with metastatic or locally advanced breast cancer [online]. Available from URL: http://clinicaltrials.gov/ct/show/nct00057993 [Accessed 2006 Aug 11]

  129. Tripathy D, Slamon DJ, Cobleigh M, et al. Safety of treatment of metastatic breast cancer with trastuzumab beyond disease progression. J Clin Oncol 2004; 22: 1063–70

    PubMed  CAS  Google Scholar 

  130. Gelmon KA, Mackey J, Verma S, et al. Use of trastuzumab beyond disease progression: observations from a retrospective review of case histories. Clin Breast Cancer 2004; 5: 52–8

    PubMed  CAS  Google Scholar 

  131. Fountzilas G, Razis E, Tsavdaridis D, et al. Continuation of trastuzumab beyond disease progression is feasible and safe in patients with metastatic breast cancer: a retrospective analysis of 80 cases by the Hellenic Cooperative Oncology Group. Clin Breast Cancer 2003; 4: 120–5

    PubMed  CAS  Google Scholar 

  132. US National Institutes of Health. TBP study with capecitabine plus minus trastuzumab [online]. Available from URL: http://clinicaltrials.gov/ct/show/nct00148876 [Accessed 2006 Aug 11]

  133. Tan-Chiu E, Yothers G, Romond E, et al. Assessment of cardiac dysfunction in a randomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel, with or without trastuzumab as adjuvant therapy in node-positive, human epidermal growth factor receptor 2-overexpressing breast cancer: NSABP B-31. J Clin Oncol 2005; 23(31): 7811–9

    PubMed  CAS  Google Scholar 

  134. Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 2005; 353: 1673–84

    PubMed  CAS  Google Scholar 

  135. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 2005; 353: 1659–72

    PubMed  CAS  Google Scholar 

  136. Slamon D, Eiermann W, Robert N, et al. Phase III randomized trial comparing doxorubicin and cyclophosphamide followed by docetaxel (AC-T) with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab (AC-TH) with docetaxel, carboplatin and trastuzumab (TCH) in HER2 positive early breast cancer patients: BCIRG 006 study [abstract no. 1]. Breast Cancer Res Treat 2005; 94 Suppl. 1: S5

    Google Scholar 

  137. Joensuu H, Kellokumpu-Lehtinen PL, Bono P, et al. Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med 2006; 354(8): 809–20

    PubMed  CAS  Google Scholar 

  138. Burstein HJ, Harris LN, Gelman R, et al. Preoperative therapy with trastuzumab and paclitaxel followed by sequential adjuvant doxorubicin/cyclophosphamide for HER2 overexpressing stage II or III breast cancer: a pilot study. J Clin Oncol 2003; 21(1): 46–53

    PubMed  CAS  Google Scholar 

  139. Bines J, Murad A, Lago S, et al. Multicenter Brazilian study of weekly docetaxel and trastuzumab as primary therapy in stage III, HER-2 overexpressing breast cancer [abstract no. 268]. Proc Am Soc Clin Oncol 2003; 22: 67

    Google Scholar 

  140. Coudert BP, Arnould L, Moreau L, et al. Pre-operative systemic (neo-adjuvant) therapy with trastuzumab and docetaxel for HER2-overexpressing stage II or III breast cancer: results of a multicenter phase II trial. Ann Oncol 2006; 17(3): 409–14

    PubMed  CAS  Google Scholar 

  141. Schiffhauer L, Griggs J, Ahrendt G, et al. Docetaxel and trastuzumab as primary systemic therapy for HER-2/neu-overexpressing breast cancer [abstract no. 969]. Proc Am Soc Clin Oncol 2003; 22: 242

    Google Scholar 

  142. Griggs JJ, Schiffhauer LM, Sahasrabudhe DM, et al. Safety and effectiveness of primary systemic therapy with docetaxel and trastuzumab in HER-2 positive breast cancer [abstract no. 793]. Proc Am Soc Clin Oncol 2005; 23(16S): 76S

    Google Scholar 

  143. Harris L, Burstein H, Gelman R, et al. Preoperative trastuzumab and vinorelbine (HN) is a highly active, well-tolerated regimen for HER2 3+/FISH+ stage II/III breast cancer [abstract no. 86]. Proc Am Soc Clin Oncol 2003; 22: 22

    Google Scholar 

  144. Hurley J, Doliny P, Silva O, et al. Neoadjuvant Herceptin/Taxotere/cisplatin in the treatment of locally advanced and inflammatory breast cancer [abstract no. 196]. Proc Am Soc Clin Oncol 2002; 21 (Part I): 50a

    Google Scholar 

  145. Steger G, Wenzel C, Locker G, et al. Pilot-trial of trastuzumab + weekly epidoxorubicin/docetaxel in the neoadjuvant treatment of primary breast cancer: preliminary results [abstract no. 1966]. Proc Am Soc Clin Oncol 2002; 21 (Part II): 39b

    Google Scholar 

  146. Jahanzeb M, Brufsky A, Erban J, et al. Dose-dense neoadjuvant treatment of women with breast cancer utilizing docetaxel, vinorelbine and trastuzumab with growth factor support [abstract no. 591]. Proc Am Soc Clin Oncol 2005; 23(16S): 26S

    Google Scholar 

  147. Buzdar AU, Ibrahim NK, Francis D, et al. Significantly higher pathologic complete remission rate after neoadjuvant therapy with trastuzumab, paclitaxel and epirubicin chemotherapy: results of a randomized trial in human epidermal growth factor receptor 2-positive operable breast cancer. J Clin Oncol 2005; 23: 3676–85

    PubMed  CAS  Google Scholar 

  148. Kim C, Bryant J, Home Z, et al. Trastuzumab sensitivity of breast cancer with co-amplification of HER2 and cMYC suggests pro-apoptotic function of dysregulated cMYC in vivo [abstract no. 46]. Breast Cancer Res Treat 2005; 94: s6

    Google Scholar 

  149. Bossenmaier B, Hasmann M, Koll H, et al. Presence of HER2/HER3 heterodimers predicts antitumor effect of pertuzumab (Omnitarg™) in different human xenograft models [abstract no. 5342]. Proc Am Assoc Cancer Res 2004; 45: 1232

    Google Scholar 

  150. Allison DE, Malik M, Qureshi F, et al. Pharmacokinetics of HER2-targeted rhuMAb 2C4 (pertuzumab) in patients with advanced solid malignancies: phase Ia results [abstract no. 790]. Proc Am Soc Clin Oncol 2003; 22: 197

    Google Scholar 

  151. US National Institutes of Health. Trastuzumab and pertuzumab in treating patients with unresectable locally advanced or metastatic breast cancer that did not respond to previous trastuzumab [online]. Available from URL: http://clinicaltrials.gov/ct/show/nct00301899 [Accessed 2006 Aug 11]

  152. Kim KJ, Li B, Winer J, et al. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature 1993; 362: 841–4

    PubMed  CAS  Google Scholar 

  153. Netti PA, Hamberg LM, Babich JW, et al. Enhancement of fluid filtration across tumor vessels: implication for delivery of macromolecules. Proc Natl Acad Sci U S A 1999; 96: 3137–42

    PubMed  CAS  Google Scholar 

  154. Borgstrom P, Gold DP, Hillan KJ, et al. Importance of VEGF for breast cancer angiogenesis in vivo: implications from intravital microscopy of combination treatments with an anti-VEGF neutralizing monoclonal antibody and doxorubicin. Anticancer Res 1999; 19: 4203–14

    PubMed  CAS  Google Scholar 

  155. Margolin K, Gordon MS, Holmgren E, et al. Phase Ib trial of intravenous recombinant humanized monoclonal antibody to vascular endothelial growth factor in combination with chemotherapy in patients with advanced cancer: pharmacologic and long-term safety data. J Clin Oncol 2001; 19: 851–6

    PubMed  CAS  Google Scholar 

  156. Traina TA, Rugo H, Caravelli J, et al. Letrozole (L) with bevacizumab (B) is feasible in patients (pts) with hormone receptor-positive metastatic breast cancer (MBC) [abstract 3050]. Proc Am Soc Clin Oncol, J Clin Oncol 2006; 24 (18 Part I): 133s

    Google Scholar 

  157. Nahta R, Hung MC, Esteva FJ. The HER-2-targeting antibodies trastuzumab and pertuzumab synergistically inhibit the survival of breast cancer cells. Cancer Research 2004; 64: 2343–6

    PubMed  CAS  Google Scholar 

  158. Friess T, Scheuer W, Hasmann M. Combination treatment with erlotinib and pertuzumab against human tumor xenografts is superior to monotherapy. Clin Cancer Res 2005; 11(14): 5300–9

    PubMed  CAS  Google Scholar 

  159. US National Institutes of Health. Bevacizumab and trastuzumab (Herceptin®) in treating women with relapsed or metastatic breast cancer [online]. Available from URL: http://clinicaltrials.gov/ct/show/nct00093535 [Accessed 2006 Aug 11]

  160. Konecny GE, Meng YG, Untch M, et al. Association between HER-2/neu and vascular endothelial growth factor expression predicts clinical outcome in primary breast cancer patients. Clin Cancer Res 2004; 10: 1706

    PubMed  CAS  Google Scholar 

Download references

Acknowledgements

The authors wish to thank Ms Carolyn Straehle for editorial assistance. Drs Bernard-Marty, Lebrun and Awada have no conflicts of interest relevant to the contents of this review. Dr Piccart has received honoraria from Roche (in relation to her role as speaker in educational symposia). The authors received no funding for the preparation of this article.

Author information

Authors and Affiliations

  1. Department of Medical Oncology, Jules Bordet Institute, Boulevard de Waterloo, Brussels, 125.1000, Belgium

    Chantal Bernard-Marty, Fabienne Lebrun, Ahmad Awada &  Martine J. Piccart

Authors
  1. Chantal Bernard-Marty
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Fabienne Lebrun
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ahmad Awada
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Martine J. Piccart
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Martine J. Piccart.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bernard-Marty, C., Lebrun, F., Awada, A. et al. Monoclonal Antibody-Based Targeted Therapy in Breast Cancer. Drugs 66, 1577–1591 (2006). https://doi.org/10.2165/00003495-200666120-00004

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00003495-200666120-00004

Keywords

Search

Navigation