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Mechanisms of Disease: angiogenesis and the management of breast cancer

Abstract

Demonstration of the clinically significant activity of bevacizumab in breast cancer has attracted a great deal of interest. Numerous other antiangiogenic treatments are in clinical development and some established therapies including tamoxifen and trastuzumab might function, in part, by suppressing angiogenesis. In this Review, we discuss the potential of various components of the angiogenic pathway as prognostic and predictive factors in breast cancer. In addition, we describe existing clinical trials of antiangiogenic agents and the challenges facing the clinical development and optimum use of these agents for the treatment of breast cancer.

Key Points

  • Angiogenesis and VEGF have important roles in the pathogenesis of breast cancer

  • VEGF is regulated by complex factors including hypoxia, growth factors, hormones and activated oncogenes

  • Angiogenic markers, such as VEGF, can be of prognostic and predictive value in breast cancer

  • Clinical trials of antiangiogenic agents such as bevacizumab and tyrosine kinase inhibitors in breast cancer are ongoing

  • Bevacizumab in combination with paclitaxel can improve progression-free survival in patients with previously untreated metastatic breast cancer

  • Challenges facing the success of antiangiogenic therapy in breast cancer include the identification of biomarkers to guide management, overcoming drug resistance and identifying the correct target population

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Figure 1: Factors influencing tumor angiogenesis
Figure 2: Regulation of VEGF expression

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References

  1. Hanahan D et al. (1996) Transgenic mouse models of tumour angiogenesis: the angiogenic switch, its molecular controls, and prospects for preclinical therapeutic models. Eur J Cancer 32A: 2386–2393

    Article  CAS  PubMed  Google Scholar 

  2. Skobe M et al. (1997) Halting angiogenesis suppresses carcinoma cell invasion. Nat Med 3: 1222–1227

    Article  CAS  PubMed  Google Scholar 

  3. Folkman J (1971) Tumor angiogenesis: therapeutic implications. N Engl J Med 285: 1182–1186

    Article  CAS  PubMed  Google Scholar 

  4. von Tell D et al. (2006) Pericytes and vascular stability. Exp Cell Res 312: 623–629

    Article  CAS  PubMed  Google Scholar 

  5. Hicklin DJ and Ellis LM (2005) Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol 23: 1011–1027

    Article  CAS  PubMed  Google Scholar 

  6. Rafii S et al. (2002) Vascular and haematopoietic stem cells: novel targets for anti-angiogenesis therapy? Nat Rev Cancer 2: 826–835

    Article  CAS  PubMed  Google Scholar 

  7. Bergers G and Benjamin LE (2003) Tumorigenesis and the angiogenic switch. Nat Rev Cancer 3: 401–410

    Article  CAS  PubMed  Google Scholar 

  8. Neufeld G et al. (1999) Vascular endothelial growth factor (VEGF) and its receptors. Faseb J 13: 9–22

    Article  CAS  PubMed  Google Scholar 

  9. Ferrara N et al. (2003) The biology of VEGF and its receptors. Nat Med 9: 669–676

    Article  CAS  PubMed  Google Scholar 

  10. Relf M 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: 963–969

    CAS  PubMed  Google Scholar 

  11. Tischer E et al. (1991) The human gene for vascular endothelial growth factor: multiple protein forms are encoded through alternative exon splicing. J Biol Chem 266: 11947–11954

    CAS  PubMed  Google Scholar 

  12. Mandriota SJ et al. (1995) Vascular endothelial growth factor increases urokinase receptor expression in vascular endothelial cells. J Biol Chem 270: 9709–9716

    Article  CAS  PubMed  Google Scholar 

  13. Pepper MS et al. (1991) Vascular endothelial growth factor (VEGF) induces plasminogen activators and plasminogen activator inhibitor-1 in microvascular endothelial cells. Biochem Biophys Res Commun 181: 902–906

    Article  CAS  PubMed  Google Scholar 

  14. Gerber HP et al. (1998) Vascular endothelial growth factor regulates endothelial cell survival through the phosphatidylinositol 3′-kinase/Akt signal transduction pathway: requirement for Flk-1/KDR activation. J Biol Chem 273: 30336–30343

    Article  CAS  PubMed  Google Scholar 

  15. Harmey JH and Bouchier-Hayes D (2002) Vascular endothelial growth factor (VEGF), a survival factor for tumour cells: implications for anti-angiogenic therapy. Bioessays 24: 280–283

    Article  CAS  PubMed  Google Scholar 

  16. Tran J et al. (2002) A role for survivin in chemoresistance of endothelial cells mediated by VEGF. Proc Natl Acad Sci USA 99: 4349–4354

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Gerber HP et al. (2000) Complete inhibition of rhabdomyosarcoma xenograft growth and neovascularization requires blockade of both tumor and host vascular endothelial growth factor. Cancer Res 60: 6253–6258

    CAS  PubMed  Google Scholar 

  18. Shibuya M et al. (1990) Nucleotide sequence and expression of a novel human receptor-type tyrosine kinase gene (flt) closely related to the fms family. Oncogene 5: 519–524

    CAS  PubMed  Google Scholar 

  19. Kendall RL and Thomas KA (1993) Inhibition of vascular endothelial cell growth factor activity by an endogenously encoded soluble receptor. Proc Natl Acad Sci USA 90: 10705–10709

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Ebos JM et al. (2004) A naturally occurring soluble form of vascular endothelial growth factor receptor 2 detected in mouse and human plasma. Mol Cancer Res 2: 315–326

    CAS  PubMed  Google Scholar 

  21. Pan Q et al. (2007) Blocking neuropilin-1 function has an additive effect with anti-VEGF to inhibit tumor growth. Cancer Cell 11: 53–67

    Article  CAS  PubMed  Google Scholar 

  22. Veikkola T et al. (2001) Signalling via vascular endothelial growth factor receptor-3 is sufficient for lymphangiogenesis in transgenic mice. EMBO J 20: 1223–1231

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Achen MG et al. (2006) Targeting lymphangiogenesis to prevent tumour metastasis. Br J Cancer 94: 1355–1360

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Rak J et al. (2000) Oncogenes and tumor angiogenesis: differential modes of vascular endothelial growth factor up-regulation in ras-transformed epithelial cells and fibroblasts. Cancer Res 60: 490–498

    CAS  PubMed  Google Scholar 

  25. Kimbro KS and Simons JW (2006) Hypoxia-inducible factor-1 in human breast and prostate cancer. Endocr Relat Cancer 13: 739–749

    Article  CAS  PubMed  Google Scholar 

  26. Harris AL (2002) Hypoxia—a key regulatory factor in tumour growth. Nat Rev Cancer 2: 38–47

    Article  CAS  PubMed  Google Scholar 

  27. Pouyssegur J et al. (2006) Hypoxia signalling in cancer and approaches to enforce tumour regression. Nature 441: 437–443

    Article  CAS  PubMed  Google Scholar 

  28. Kurebayashi J et al. (2001) Hypoxia reduces hormone responsiveness of human breast cancer cells. Jpn J Cancer Res 92: 1093–1101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Hyder SM et al. (1998) Progestin regulation of vascular endothelial growth factor in human breast cancer cells. Cancer Res 58: 392–395

    CAS  PubMed  Google Scholar 

  30. Ruohola JK et al. (1999) Vascular endothelial growth factors are differentially regulated by steroid hormones and antiestrogens in breast cancer cells. Mol Cell Endocrinol 149: 29–40

    Article  CAS  PubMed  Google Scholar 

  31. Nakamura J et al. (1996) Estrogen regulates vascular endothelial growth/permeability factor expression in 7,12-dimethylbenz(a)anthracene-induced rat mammary tumors. Endocrinology 137: 5589–5596

    Article  CAS  PubMed  Google Scholar 

  32. Mueller MD et al. (2000) Regulation of vascular endothelial growth factor (VEGF) gene transcription by estrogen receptors alpha and beta. Proc Natl Acad Sci USA 97: 10972–10977

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Buteau-Lozano H et al. (2002) Transcriptional regulation of vascular endothelial growth factor by estradiol and tamoxifen in breast cancer cells: a complex interplay between estrogen receptors alpha and beta. Cancer Res 62: 4977–4984

    CAS  PubMed  Google Scholar 

  34. Stoner M et al. (2004) Estrogen regulation of vascular endothelial growth factor gene expression in ZR-75 breast cancer cells through interaction of estrogen receptor alpha and SP proteins. Oncogene 23: 1052–1063

    Article  CAS  PubMed  Google Scholar 

  35. Garvin S and Dabrosin C (2003) Tamoxifen inhibits secretion of vascular endothelial growth factor in breast cancer in vivo . Cancer Res 63: 8742–8748

    CAS  PubMed  Google Scholar 

  36. Gagliardi AR et al. (1996) Antiestrogens inhibit endothelial cell growth stimulated by angiogenic growth factors. Anticancer Res 16: 1101–1106

    CAS  PubMed  Google Scholar 

  37. Slamon DJ et al. (1987) Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235: 177–182

    Article  CAS  PubMed  Google Scholar 

  38. Piccart-Gebhart MJ et al. (2005) Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 353: 1659–1672

    Article  CAS  PubMed  Google Scholar 

  39. Wen XF et al. (2006) HER2 signaling modulates the equilibrium between pro- and antiangiogenic factors via distinct pathways: implications for HER2-targeted antibody therapy. Oncogene 25: 6986–6996

    Article  CAS  PubMed  Google Scholar 

  40. Klos KS et al. (2006) ErbB2 increases vascular endothelial growth factor protein synthesis via activation of mammalian target of rapamycin/p70S6K leading to increased angiogenesis and spontaneous metastasis of human breast cancer cells. Cancer Res 66: 2028–2037

    Article  CAS  PubMed  Google Scholar 

  41. Petit AM et al. (1997) 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 151: 1523–1530

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Pegram MD and Reese DM (2002) Combined biological therapy of breast cancer using monoclonal antibodies directed against HER2/neu protein and vascular endothelial growth factor. Semin Oncol 29: 29–37

    Article  CAS  PubMed  Google Scholar 

  43. Yen L et al. (2000) Heregulin selectively upregulates vascular endothelial growth factor secretion in cancer cells and stimulates angiogenesis. Oncogene 19: 3460–3469

    Article  CAS  PubMed  Google Scholar 

  44. Milanini-Mongiat J et al. (2002) Identification of two Sp1 phosphorylation sites for p42/p44 mitogen-activated protein kinases: their implication in vascular endothelial growth factor gene transcription. J Biol Chem 277: 20631–20639

    Article  CAS  PubMed  Google Scholar 

  45. Richard DE et al. (1999) p42/p44 mitogen-activated protein kinases phosphorylate hypoxia-inducible factor 1α (HIF-1alpha) and enhance the transcriptional activity of HIF-1. J Biol Chem 274: 32631–32637

    Article  CAS  PubMed  Google Scholar 

  46. Pages G et al. (2000) Stress-activated protein kinases (JNK and p38/HOG) are essential for vascular endothelial growth factor mRNA stability. J Biol Chem 275: 26484–26491

    Article  CAS  PubMed  Google Scholar 

  47. Gutierrez MC et al. (2005) Molecular changes in tamoxifen-resistant breast cancer: relationship between estrogen receptor, HER-2, and p38 mitogen-activated protein kinase. J Clin Oncol 23: 2469–2476

    Article  CAS  PubMed  Google Scholar 

  48. Huez I et al. (1998) Two independent internal ribosome entry sites are involved in translation initiation of vascular endothelial growth factor mRNA. Mol Cell Biol 18: 6178–6190

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Lang KJ et al. (2002) Hypoxia-inducible factor-1α mRNA contains an internal ribosome entry site that allows efficient translation during normoxia and hypoxia. Mol Biol Cell 13: 1792–1801

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Ciardiello F et al. (2001) Inhibition of growth factor production and angiogenesis in human cancer cells by ZD1839 (Iressa), a selective epidermal growth factor receptor tyrosine kinase inhibitor. Clin Cancer Res 7: 1459–1465

    CAS  PubMed  Google Scholar 

  51. Sini P et al. (2005) The antitumor and antiangiogenic activity of vascular endothelial growth factor receptor inhibition is potentiated by ErbB1 blockade. Clin Cancer Res 11: 4521–4532

    Article  CAS  PubMed  Google Scholar 

  52. Izumi Y et al. (2002) Tumour biology: herceptin acts as an anti-angiogenic cocktail. Nature 416: 279–280

    Article  CAS  PubMed  Google Scholar 

  53. Weidner N et al. (1992) Tumor angiogenesis: a new significant and independent prognostic indicator in early-stage breast carcinoma. J Natl Cancer Inst 84: 1875–1887

    Article  CAS  PubMed  Google Scholar 

  54. Horak ER et al. (1992) Angiogenesis, assessed by platelet/endothelial cell adhesion molecule antibodies, as indicator of node metastases and survival in breast cancer. Lancet 340: 1120–1124

    Article  CAS  PubMed  Google Scholar 

  55. Heimann R et al. (1996) Angiogenesis as a predictor of long-term survival for patients with node-negative breast cancer. J Natl Cancer Inst 88: 1764–1769

    Article  CAS  PubMed  Google Scholar 

  56. Blackwell KL et al. (2004) HER-2 gene amplification correlates with higher levels of angiogenesis and lower levels of hypoxia in primary breast tumors. Clin Cancer Res 10: 4083–4088

    Article  CAS  PubMed  Google Scholar 

  57. Gasparini G et al. (1995) Tumor angiogenesis predicts clinical outcome of node-positive breast cancer patients treated with adjuvant hormone therapy or chemotherapy. Cancer J Sci Am 1: 131–141

    CAS  PubMed  Google Scholar 

  58. Gasparini G et al. (1997) Prognostic significance of vascular endothelial growth factor protein in node-negative breast carcinoma. J Natl Cancer Inst 89: 139–147

    Article  CAS  PubMed  Google Scholar 

  59. Eppenberger U et al. (1998) Markers of tumor angiogenesis and proteolysis independently define high- and low-risk subsets of node-negative breast cancer patients. J Clin Oncol 16: 3129–3136

    Article  CAS  PubMed  Google Scholar 

  60. Toi M et al. (1994) Association of vascular endothelial growth factor expression with tumor angiogenesis and with early relapse in primary breast cancer. Jpn J Cancer Res 85: 1045–1049

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Linderholm B et al. (1998) Vascular endothelial growth factor is of high prognostic value in node-negative breast carcinoma. J Clin Oncol 16: 3121–3128

    Article  CAS  PubMed  Google Scholar 

  62. Foekens JA et al. (2001) High tumor levels of vascular endothelial growth factor predict poor response to systemic therapy in advanced breast cancer. Cancer Res 61: 5407–5414

    CAS  PubMed  Google Scholar 

  63. Linderholm B et al. (1999) Does vascular endothelial growth factor (VEGF) predict local relapse and survival in radiotherapy-treated node-negative breast cancer? Br J Cancer 81: 727–732

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Gasparini G et al. (1999) Clinical relevance of vascular endothelial growth factor and thymidine phosphorylase in patients with node-positive breast cancer treated with either adjuvant chemotherapy or hormone therapy. Cancer J Sci Am 5: 101–111

    CAS  PubMed  Google Scholar 

  65. Linderholm B et al. (2000) Correlation of vascular endothelial growth factor content with recurrences, survival, and first relapse site in primary node-positive breast carcinoma after adjuvant treatment. J Clin Oncol 18: 1423–1431

    Article  CAS  PubMed  Google Scholar 

  66. Ryden L et al. (2005) Tumor-specific expression of vascular endothelial growth factor receptor 2 but not vascular endothelial growth factor or human epidermal growth factor receptor 2 is associated with impaired response to adjuvant tamoxifen in premenopausal breast cancer. J Clin Oncol 23: 4695–4704

    Article  CAS  PubMed  Google Scholar 

  67. Ryden L et al. (2005) Tumor-specific VEGF-A and VEGFR2 in postmenopausal breast cancer patients with long-term follow-up: implication of a link between VEGF pathway and tamoxifen response. Breast Cancer Res Treat 89: 135–143

    Article  CAS  PubMed  Google Scholar 

  68. Konecny GE et al. (2004) Association between HER-2/neu and vascular endothelial growth factor expression predicts clinical outcome in primary breast cancer patients. Clin Cancer Res 10: 1706–1716

    Article  CAS  PubMed  Google Scholar 

  69. Svensson S et al. (2005) ERK phosphorylation is linked to VEGFR2 expression and Ets-2 phosphorylation in breast cancer and is associated with tamoxifen treatment resistance and small tumours with good prognosis. Oncogene 24: 4370–4379

    Article  CAS  PubMed  Google Scholar 

  70. Bando H et al. (2005) Association between intratumoral free and total VEGF, soluble VEGFR-1, VEGFR-2 and prognosis in breast cancer. Br J Cancer 92: 553–561

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Dales JP et al. (2005) Overexpression of hypoxia-inducible factor HIF-1α predicts early relapse in breast cancer: retrospective study in a series of 745 patients. Int J Cancer 116: 734–739

    Article  CAS  PubMed  Google Scholar 

  72. Bos R et al. (2003) Levels of hypoxia-inducible factor-1α independently predict prognosis in patients with lymph node negative breast carcinoma. Cancer 97: 1573–1581

    Article  PubMed  Google Scholar 

  73. Generali D et al. (2006) Hypoxia-inducible factor-1α expression predicts a poor response to primary chemoendocrine therapy and disease-free survival in primary human breast cancer. Clin Cancer Res 12: 4562–4568

    Article  CAS  PubMed  Google Scholar 

  74. Kronblad A et al. (2006) Hypoxia inducible factor-1α is a prognostic marker in premenopausal patients with intermediate to highly differentiated breast cancer but not a predictive marker for tamoxifen response. Int J Cancer 118: 2609–2616

    Article  CAS  PubMed  Google Scholar 

  75. Hillan KJ et al. (2003) The role of VEGF expression in response to bevacizumab plus capecitabine in metastatic breast cancer (MBC) [abstract #766]. Proc Am Soc Clin Oncol 22

  76. Deprimo SE et al. (2006) Effect of treatment with sunitinib malate, a multitargeted tyrosine kinase inhibitor, on circulating plasma levels of VEGF, soluble VEGF receptors 2 and 3, and soluble KIT in patients with metastatic breast cancer [abstract #578]. J Clin Oncol 24 (Suppl 18)

  77. Miller KD et al. (2005) E2100: A randomized phase III trial of paclitaxel versus paclitaxel plus bevacizumab as first-line therapy for locally recurrent or metastatic breast cancer [abstract]. Presented at the 41st Annual Meeting of the American Society of Clinical Oncology

  78. Wedam SB et al. (2006) Antiangiogenic and antitumor effects of bevacizumab in patients with inflammatory and locally advanced breast cancer. J Clin Oncol 24: 769–777

    Article  CAS  PubMed  Google Scholar 

  79. Bertolini F et al. (2006) The multifaceted circulating endothelial cell in cancer: towards marker and target identification. Nat Rev Cancer 6: 835–845

    Article  CAS  PubMed  Google Scholar 

  80. Rugo HS et al. (2006) Change in circulating endothelial cells (CEC) predicts progression free survival (PFS) in patients (pts) with hormone receptor positive metastatic breast cancer (MBC) receiving letrozole (L) and bevacizumab (B) [abstract #3039]. J Clin Oncol 24 (Suppl 18)

  81. Lu H et al. (2005) Association of genetic polymorphisms in the VEGF gene with breast cancer survival. Cancer Res 65: 5015–5019

    Article  CAS  PubMed  Google Scholar 

  82. Jin Q et al. (2005) Vascular endothelial growth factor polymorphisms in relation to breast cancer development and prognosis. Clin Cancer Res 11: 3647–3653

    Article  CAS  PubMed  Google Scholar 

  83. Sweeney CJ et al. (2001) The antiangiogenic property of docetaxel is synergistic with a recombinant humanized monoclonal antibody against vascular endothelial growth factor or 2-methoxyestradiol but antagonized by endothelial growth factors. Cancer Res 61: 3369–3372

    CAS  PubMed  Google Scholar 

  84. Browder T et al. (2000) Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer. Cancer Res 60: 1878–1886

    CAS  PubMed  Google Scholar 

  85. Miller KD et al. (2001) Redefining the target: chemotherapeutics as antiangiogenics. J Clin Oncol 19: 1195–1206

    Article  CAS  PubMed  Google Scholar 

  86. Hamano Y et al. (2004) Thrombospondin-1 associated with tumor microenvironment contributes to low-dose cyclophosphamide-mediated endothelial cell apoptosis and tumor growth suppression. Cancer Res 64: 1570–1574

    Article  CAS  PubMed  Google Scholar 

  87. Bocci G et al. (2003) Thrombospondin 1, a mediator of the antiangiogenic effects of low-dose metronomic chemotherapy. Proc Natl Acad Sci USA 100: 12917–12922

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Dupont J et al. (2004) Phase I and pharmacokinetic study of VEGF Trap administered subcutaneously to patients with advanced solid malignancies. In Proceedings of the American Society of Clinical Oncology: 2004 June 5–8; New Orleans

  89. Jain RK (2005) Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307: 58–62

    Article  CAS  PubMed  Google Scholar 

  90. Tozer GM et al. (2005) Disrupting tumour blood vessels. Nat Rev Cancer 5: 423–435

    Article  CAS  PubMed  Google Scholar 

  91. Sanborn R and Blanke CD (2005) Cyclooxygenase-2 inhibition in colorectal cancer: boom or bust? Semin Oncol 32: 69–75

    Article  CAS  PubMed  Google Scholar 

  92. Gasparini G et al. (2005) Angiogenic inhibitors: a new therapeutic strategy in oncology. Nat Clin Pract Oncol 2: 562–577

    Article  CAS  PubMed  Google Scholar 

  93. Miller KD 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: 792–799

    Article  CAS  PubMed  Google Scholar 

  94. Burstein H et al. (2005) Metronomic chemotherapy with and without bevacizumab for advanced breast cancer: a randomized phase II study. [abstract #4] Breast Cancer Res Treat 94 (Suppl 1): S6

    Google Scholar 

  95. Colleoni M et al. (2006) Metronomic low-dose oral cyclophosphamide and methotrexate plus or minus thalidomide in metastatic breast cancer: antitumor activity and biological effects. Ann Oncol 17: 232–238

    Article  CAS  PubMed  Google Scholar 

  96. Cobleigh MA et al. (2003) A phase I/II dose-escalation trial of bevacizumab in previously treated metastatic breast cancer. Semin Oncol 30: 117–124

    Article  CAS  PubMed  Google Scholar 

  97. Miller KD et al. (2005) Phase II study of SU11248, a multitargeted receptor tyrosine kinase inhibitor (TKI), in patients (pts) with previously treated metastatic breast cancer (MBC) [abstract #563]. J Clin Oncol 23 (Suppl 16): 563

    Article  Google Scholar 

  98. Miller KD et al. (2005) A multicenter phase II trial of ZD6474, a vascular endothelial growth factor receptor-2 and epidermal growth factor receptor tyrosine kinase inhibitor, in patients with previously treated metastatic breast cancer. Clin Cancer Res 11: 3369–3376

    Article  CAS  PubMed  Google Scholar 

  99. Jain RK et al. (2006) Lessons from phase III clinical trials on anti-VEGF therapy for cancer. Nat Clin Pract Oncol 3: 24–40

    Article  CAS  PubMed  Google Scholar 

  100. Pegram MCD et al. (2006) Phase II combined biological therapy targeting the HER2 proto-oncogene and the vascular endothelial growth factor using trastuzumab (T) and bevacizumab (B) as first line treatment of HER2-amplified breast cancer. In Proceedings of the San Antonio Breast Cancer Symposium: 2006 December 14–17; San Antonio

  101. Overmoyer B (2004) Phase II trial of neoadjuvant docetaxel with or without bevacizumab in patients with locally advanced breast cancer. In Proceedings of the San Antonio Breast Cancer Symposium: 2004 December 8–11; San Antonio

  102. Green MC et al. (2005) Weekly paclitaxel improves pathologic complete remission in operable breast cancer when compared with paclitaxel once every 3 weeks. J Clin Oncol 23: 5983–5992

    Article  CAS  PubMed  Google Scholar 

  103. Bottini A et al. (2006) Randomized phase II trial of letrozole and letrozole plus low-dose metronomic oral cyclophosphamide as primary systemic treatment in elderly breast cancer patients. J Clin Oncol 24: 3623–3628

    Article  CAS  PubMed  Google Scholar 

  104. Kerbel R and Folkman J (2002) Clinical translation of angiogenesis inhibitors. Nat Rev Cancer 2: 727–739

    Article  CAS  PubMed  Google Scholar 

  105. Greenberg DA and Jin K (2005) From angiogenesis to neuropathology. Nature 438: 954–959

    Article  CAS  PubMed  Google Scholar 

  106. Wood JM et al. (2000) PTK787/ZK 222584, a novel and potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, impairs vascular endothelial growth factor-induced responses and tumor growth after oral administration. Cancer Res 60: 2178–2189

    CAS  PubMed  Google Scholar 

  107. Bergsland E and Dickler MN (2004) Maximizing the potential of bevacizumab in cancer treatment. Oncologist 9 (Suppl 1): S36–S42

    Article  Google Scholar 

  108. Yang JC et al. (2003) A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 349: 427–434

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Johnson DH et al. (2004) Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol 22: 2184–2191

    Article  CAS  PubMed  Google Scholar 

  110. Jubb AM et al. (2006) Predicting benefit from anti-angiogenic agents in malignancy. Nat Rev Cancer 6: 626–635

    Article  CAS  PubMed  Google Scholar 

  111. Drevs J et al. (2005) Soluble markers for the assessment of biological activity with PTK787/ZK 222584 (PTK/ZK), a vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor in patients with advanced colorectal cancer from two phase I trials. Ann Oncol 16: 558–565

    Article  CAS  PubMed  Google Scholar 

  112. Yoshiji H et al. (1997) Vascular endothelial growth factor is essential for initial but not continued in vivo growth of human breast carcinoma cells. Cancer Res 57: 3924–3928

    CAS  PubMed  Google Scholar 

  113. Klement G et al. (2000) Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity. J Clin Invest 105: R15–R24

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Kerbel RS (2001) Clinical trials of antiangiogenic drugs: opportunities, problems, and assessment of initial results. J Clin Oncol 19 (Suppl): S45–S51

    Google Scholar 

  115. Huang J et al. (2004) Vascular remodeling marks tumors that recur during chronic suppression of angiogenesis. Mol Cancer Res 2: 36–42

    CAS  PubMed  Google Scholar 

  116. Casanovas O et al. (2005) Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. Cancer Cell 8: 299–309

    Article  CAS  PubMed  Google Scholar 

  117. Bergers G et al. (2003) Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. J Clin Invest 111: 1287–1295

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank Avon Breast Cancer Crusade, Breakthrough Breast Cancer, The Mary Jean Mitchell-Greene Foundation and Cancer Research UK for funding.

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Correspondence to Susana Banerjee or Lesley-Ann Martin.

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S Banerjee declared she has received a research grant from Novartis. L Martin has declared she has received a research grant from AstraZeneca and Novartis. M Dowsett declared he has been a Consultant for Novartis and Roche, he has been on speakers bureau for Novartis and Roche, and has received a research grant from Novartis. A Ashworth has declared he has no competing interests.

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Banerjee, S., Dowsett, M., Ashworth, A. et al. Mechanisms of Disease: angiogenesis and the management of breast cancer. Nat Rev Clin Oncol 4, 536–550 (2007). https://doi.org/10.1038/ncponc0905

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