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Angiogenesis Inhibition in Breast Cancer

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Abstract

Angiogenesis plays an essential role in tumor development, invasion, and metastasis. In preclinical models, agents that block the vascular endothelial growth factor (VEGF) pathway have been shown to effectively inhibit tumor angiogenesis and growth. Although antiangiogenic therapies, including anti-VEGF antibodies and tyrosine kinase inhibitors, have become important components of the standard of care for the treatment of many solid tumors, the results of clinical trials investigating the efficacy of antiangiogenic agents in breast cancer are contradictory. In this chapter, the importance of angiogenesis inhibition in breast cancer is discussed in light of recent clinical data.

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References

  1. Lorusso V. Bevacizumab in the treatment of HER2-negative breast cancer. Biologics. 2008;2:813–21.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Bareschino MA, Schettino C, Colantuoni G, Rossi E, Rossi A, Maione P, et al. The role of antiangiogenetic agents in the treatment of breast cancer. Curr Med Chem. 2011;18:5022–32.

    Article  CAS  PubMed  Google Scholar 

  3. Azam F, Mehta S, Harris AL. Mechanisms of resistance to antiangiogenesis therapy. Eur J Cancer. 2010;46:1323–32.

    Article  CAS  PubMed  Google Scholar 

  4. Gardlik R, Celec P, Bernadic M. Targeting angiogenesis for cancer (gene) therapy. Bratisl Lek Listy. 2011;112:428–34.

    CAS  PubMed  Google Scholar 

  5. Tammela T, Enholm B, Alitalo K, Paavonen K. The biology of vascular endothelial growth factors. Cardiovasc Res. 2005;65:550–63.

    Article  CAS  PubMed  Google Scholar 

  6. Ferrara N. Role of vascular endothelial growth factor in the regulation of angiogenesis. Kidney Int. 1999;56:794–814.

    Article  CAS  PubMed  Google Scholar 

  7. Liekens S, De Clercq E, Neyts J. Angiogenesis: regulators and clinical applications. Biochem Pharmacol. 2001;61:253–70.

    Article  CAS  PubMed  Google Scholar 

  8. Koutras AK, Starakis I, Lymperatou D, Kalofonos HP. Angiogenesis as a therapeutic target in breast cancer. Mini Rev Med Chem. 2012;12:1230–8.

    Article  CAS  PubMed  Google Scholar 

  9. Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971;285:1182–6.

    Article  CAS  PubMed  Google Scholar 

  10. Schneider BP, Miller KD. Angiogenesis of breast cancer. J Clin Oncol. 2005;23:1782–90.

    Article  CAS  PubMed  Google Scholar 

  11. Roland CL, Dineen SP, Lynn KD, Sullivan LA, Dellinger MT, Sadegh L, et al. Inhibition of vascular endothelial growth factor reduces angiogenesis and modulates immune cell infiltration of orthotopic breast cancer xenografts. Mol Cancer Ther. 2009;8:1761–71.

    Article  CAS  PubMed  Google Scholar 

  12. Viacava P, Naccarato AG, Bocci G, Fanelli G, Aretini P, Lonobile A, et al. Angiogenesis and VEGF expression in pre-invasive lesions of the human breast. J Pathol. 2004;204:140–6.

    Article  CAS  PubMed  Google Scholar 

  13. Bluff JE, Menakuru SR, Cross SS, Higham SE, Balasubramanian SP, Brown NJ, et al. Angiogenesis is associated with the onset of hyperplasia in human ductal breast disease. Br J Cancer. 2009;101:666–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Schneider BP, Radovich M, Sledge GW, Robarge JD, Li L, Storniolo AM, et al. Association of polymorphisms of angiogenesis genes with breast cancer. Breast Cancer Res Treat. 2008;111:157–63.

    Article  CAS  PubMed  Google Scholar 

  15. Guinebretière JM, Lê Monique G, Gavoille A, Bahi J, Contesso G. Angiogenesis and risk of breast cancer in women with fibrocystic disease. J Natl Cancer Inst. 1994;86:635–6.

    Article  PubMed  Google Scholar 

  16. Guidi AJ, Fischer L, Harris JR, Schnitt SJ. Microvessel density and distribution in ductal carcinoma in situ of the breast. J Natl Cancer Inst. 1994;86:614–9.

    Article  CAS  PubMed  Google Scholar 

  17. Weidner N, Semple JP, Welch WR, Folkman J. Tumor angiogenesis and metastasis – correlation in invasive breast carcinoma. N Engl J Med. 1991;324:1–8.

    Article  CAS  PubMed  Google Scholar 

  18. Kim KJ, Li B, Winer J, Armanini M, Gillett N, Phillips HS, Ferrara N. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature. 1993;362:841–4.

    Article  CAS  PubMed  Google Scholar 

  19. Inai T, Mancuso M, Hashizume H, Baffert F, Haskell A, Baluk P, et al. Inhibition of vascular endothelial growth factor (VEGF) signaling in cancer causes loss of endothelial fenestrations, regression of tumor vessels, and appearance of basement membrane ghosts. Am J Pathol. 2004;165:35–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Goel S, Duda DG, Xu L, Munn LL, Boucher Y, Fukumura D, et al. Normalization of the vasculature for treatment of cancer and other diseases. Physiol Rev. 2011;91:1071–121.

    Article  CAS  PubMed  Google Scholar 

  21. Wildiers H, Guetens G, De Boeck G, Verbeken E, Landuyt B, Landuyt W, et al. Effect of antivascular endothelial growth factor treatment on the intratumoral uptake of CPT-11. Br J Cancer. 2003;88:1979–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Manzoni M, Rovati B, Ronzoni M, Loupakis F, Mariucci S, Ricci V, et al. Immunological effects of bevacizumab-based treatment in metastatic colorectal cancer. Oncology. 2010;79:187–96.

    Article  CAS  PubMed  Google Scholar 

  23. Lu J-F, Bruno R, Eppler S, Novotny W, Lum B, Gaudreault J. Clinical pharmacokinetics of bevacizumab in patients with solid tumors. Cancer Chemother Pharmacol. 2008;62:779–86.

    Article  CAS  PubMed  Google Scholar 

  24. Dai F, Shu L, Bian Y, Wang Z, Yang Z, Chu W, Gao S. Safety of bevacizumab in treating metastatic colorectal cancer: a systematic review and meta-analysis of all randomized clinical trials. Clin Drug Investig. 2013;33:779–88.

    Article  CAS  PubMed  Google Scholar 

  25. Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350:2335–42.

    Article  CAS  PubMed  Google Scholar 

  26. Giantonio BJ, Catalano PJ, Meropol NJ, O’Dwyer PJ, Mitchell EP, Alberts SR, Eastern Cooperative Oncology Group Study E3200, et al. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol. 2007;25:1539–44.

    Article  CAS  PubMed  Google Scholar 

  27. Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006;355:2542–50.

    Article  CAS  PubMed  Google Scholar 

  28. Yang JC, Haworth L, Sherry RM, Hwu P, Schwartzentruber DJ, Topalian SL, et al. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med. 2003;349:427–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Perren TJ, Swart AM, Pfisterer J, Ledermann JA, Pujade-Lauraine E, Kristensen G, ICON7 Investigators, et al. A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med. 2011;365:2484–96.

    Article  CAS  PubMed  Google Scholar 

  30. Friedman HS, Prados MD, Wen PY, Mikkelsen T, Schiff D, Abrey LE, et al. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol. 2009;27:4733–40.

    Article  CAS  PubMed  Google Scholar 

  31. Tewari KS, Sill M, Long HJ, Ramondetta LM, Landrum LM, Oaknin A, et al. Incorporation of bevacizumab in the treatment of recurrent and metastatic cervical cancer: a phase III randomized trial of the Gynecologic Oncology Group. J Clin Oncol. 2013;31(Suppl):abstr 3.

    Article  Google Scholar 

  32. Gordon MS, Margolin K, Talpaz M, Sledge GW Jr, Holmgren E, Benjamin R, 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.

    Article  CAS  PubMed  Google Scholar 

  33. Margolin K, Gordon MS, Holmgren E, Gaudreault J, Novotny W, Fyfe G, 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.

    Article  CAS  PubMed  Google Scholar 

  34. Jayson GC, Mulatero C, Ranson M, Zweit J, Jackson A, Broughton L, European Organisation for Research and Treatment of Cancer (EORTC), et al. Phase I investigation of recombinant anti-human vascular endothelial growth factor antibody in patients with advanced cancer. Eur J Cancer. 2005;41:555–63.

    Article  CAS  PubMed  Google Scholar 

  35. Cobleigh MA, Langmuir VK, Sledge GW, Miller KD, Haney L, Novotny WF, et al. A phase I/II dose-escalation trial of bevacizumab in previously treated metastatic breast cancer. Semin Oncol. 2003;30(Suppl 16):117–24.

    Article  CAS  PubMed  Google Scholar 

  36. Sledge G, Miller K, Moisa C, Gradishar W. Safety and efficacy of capecitabine (C) plus bevacizumab (B) as first-line in metastatic breast cancer. J Clin Oncol. 2007;25(Suppl):abstr 1013.

    Google Scholar 

  37. Burstein HJ, Chen YH, Parker LM, Savoie J, Younger J, Kuter I, et al. VEGF as a marker for outcome among advanced breast cancer patients receiving anti-VEGF therapy with bevacizumab and vinorelbine chemotherapy. Clin Cancer Res. 2008;14:7871–7.

    Article  CAS  PubMed  Google Scholar 

  38. Perez EA, Hillman DW, Dentchev T, Le-Lindqwister NA, Geeraerts LH, Fitch TR, et al. North Central Cancer Treatment Group (NCCTG) N0432: phase II trial of docetaxel with capecitabine and bevacizumab as first-line chemotherapy for patients with metastatic breast cancer. Ann Oncol. 2010;21:269–74.

    Article  CAS  PubMed  Google Scholar 

  39. Smith IE, Pierga JY, Biganzoli L, Cortés-Funes H, Thomssen C, Pivot X, ATHENA Study Group, et al. First-line bevacizumab plus taxane-based chemotherapy for locally recurrent or metastatic breast cancer: safety and efficacy in an open-label study in 2,251 patients. Ann Oncol. 2011;22:595–602.

    Article  CAS  PubMed  Google Scholar 

  40. Smith I, Pierga JY, Biganzoli L, Cortes-Funes H, Thomssen C, Saracchini S, et al. Final overall survival results and effect of prolonged (≥1 year) first-line bevacizumab-containing therapy for metastatic breast cancer in the ATHENA trial. Breast Cancer Res Treat. 2011;130:133–43.

    Article  CAS  PubMed  Google Scholar 

  41. Fabi A, Russillo M, Ferretti G, Metro G, Nisticò C, Papaldo P, et al. Maintenance bevacizumab beyond first-line paclitaxel plus bevacizumab in patients with Her2-negative hormone receptor-positive metastatic breast cancer: efficacy in combination with hormonal therapy. BMC Cancer. 2012;12:482.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Bisagni G, Musolino A, Panebianco M, De Matteis A, Nuzzo F, Ardizzoni A, et al. The Breast Avastin Trial: phase II study of bevacizumab maintenance therapy after induction chemotherapy with docetaxel and capecitabine for the first-line treatment of patients with locally recurrent or metastatic breast cancer. Cancer Chemother Pharmacol. 2013;71:1051–7.

    Article  CAS  PubMed  Google Scholar 

  43. Militello L, Carli P, Di Lauro V, Spazzapan S, Scalone S, Lombardi D, et al. Bevacizumab as maintenance therapy (mBev) in metastatic breast cancer (MBC). J Clin Oncol. 2013;31(Suppl):abstr e22149.

    Google Scholar 

  44. Gligorov J, Doval D, Bines J, Alba E, Cortes P, Pierga JY, et al. Maintenance capecitabine and bevacizumab versus bevacizumab alone after initial first-line bevacizumab and docetaxel for patients with HER2-negative metastatic breast cancer (IMELDA): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014;15:1351–60.

    Article  CAS  PubMed  Google Scholar 

  45. Miller KD, Chap LI, Holmes FA, Cobleigh MA, Marcom PK, Fehrenbacher L, 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;23:792–9.

    Article  CAS  PubMed  Google Scholar 

  46. Miller K, Wang M, Gralow J, Dickler M, Cobleigh M, Perez EA, et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med. 2007;357:2666–76.

    Article  CAS  PubMed  Google Scholar 

  47. Miles DW, Chan A, Dirix LY, Cortés J, Pivot X, Tomczak P, et al. Phase III study of bevacizumab plus docetaxel compared with placebo plus docetaxel for the first-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2010;28:3239–47.

    Article  CAS  PubMed  Google Scholar 

  48. Chang TY, Dong YH, Lin C, Lin HH, Kuo SH, Lai C, et al. Does chemotherapy schedule matter when combining with bevacizumab? A stratified meta-analysis of randomized controlled trials. J Clin Oncol. 2014;32(suppl; abstr 1076):5s.

    Google Scholar 

  49. Miles DW, de Haas SL, Dirix LY, Romieu G, Chan A, Pivot X, et al. Biomarker results from the AVADO phase 3 trial of first-line bevacizumab plus docetaxel for HER2-negative metastatic breast cancer. Br J Cancer. 2013;108:1052–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Miles D, Cameron D, Bondarenko I, Manzyuk L, Alcedo JC, Lopez RI, et al. Bevacizumab plus paclitaxel versus placebo plus paclitaxel as first-line therapy for HER2-negative metastatic breast cancer (MERiDiAN): a double-blind placebo-controlled randomised phase III trial with prospective biomarker evaluation. Eur J Cancer. 2017;70:146–55.

    Article  CAS  PubMed  Google Scholar 

  51. Robert NJ, Diéras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, et al. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol. 2011;29:1252–60.

    Article  CAS  PubMed  Google Scholar 

  52. Brufsky AM, Hurvitz S, Perez E, Swamy R, Valero V, O’Neill V, et al. RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2011;29:4286–93.

    Article  CAS  PubMed  Google Scholar 

  53. von Minckwitz G, Puglisi F, Cortes J, Vrdoljak E, Marschner N, Zielinski C, et al. Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial. Lancet Oncol. 2014;15:1269–78.

    Article  CAS  Google Scholar 

  54. Vrdoljak E, Marschner N, Zielinski C, Gligorov J, Cortes J, Puglisi F, et al. Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer. Ann Oncol. 2016;27:2046–52.

    Article  CAS  PubMed  Google Scholar 

  55. Lang I, Brodowicz T, Ryvo L, Kahan Z, Greil R, Beslija S. Central European Cooperative Oncology Group, et al. Bevacizumab plus paclitaxel versus bevacizumab plus capecitabine as first-line treatment for HER2-negative metastatic breast cancer: interim efficacy results of the randomised, open-label, non-inferiority, phase 3 TURANDOT trial. Lancet Oncol. 2013;14:125–33.

    Article  CAS  PubMed  Google Scholar 

  56. Zielinski C, Láng I, Inbar M, Kahán Z, Greil R, Beslija S, et al. Bevacizumab plus paclitaxel versus bevacizumab plus capecitabine as first-line treatment for HER2-negative metastatic breast cancer (TURANDOT): primary endpoint results of a randomised, open-label, non-inferiority, phase 3 trial. Lancet Oncol. 2016;17:1230–9.

    Article  CAS  PubMed  Google Scholar 

  57. Inbar MJ, Lang I, Kahan Z, Greil R, Beslija S, Stemmer SM, et al. Central European Cooperative Oncology Group. Efficacy of first-line bevacizumab (BEV)-based therapy for metastatic triple-negative breast cancer (TNBC): subgroup analysis of TURANDOT. J Clin Oncol. 2013;31(Suppl):abstr 1040.

    Google Scholar 

  58. Rochlitz C, von Moos R, Bigler M, Zaman K, Anchisi S, Küng M, et al. SAKK 24/09: safety and tolerability of bevacizumab plus paclitaxel versus bevacizumab plus metronomic cyclophosphamide and capecitabine as first-line therapy in patients with HER2-negative advanced stage breast cancer-A multicenter, randomized phase III trial. J Clin Oncol. 2014;32(Suppl):abstr 518.

    Article  Google Scholar 

  59. Tredan O, Follana P, Moullet I, Cropet C, Trager-Maury S, Dauba J, et al. Arobase: a phase III trial of exemestane (Exe) and bevacizumab (BEV) as maintenance therapy in patients (pts) with metastatic breast cancer (MBC) treated in first line with paclitaxel (P) and BEV-A Gineco study. J Clin Oncol. 2014;32(Suppl):abstr 501.

    Article  Google Scholar 

  60. Trédan O, Follana P, Moullet I, Cropet C, Trager-Maury S, Dauba J, et al. A phase III trial of exemestane plus bevacizumab maintenance therapy in patients with metastatic breast cancer after first-line taxane and bevacizumab: a GINECO group study. Ann Oncol. 2016;27:1020–9.

    Article  PubMed  Google Scholar 

  61. Yen L, You XL, Al Moustafa AE, Batist G, Hynes NE, Mader S, et al. Heregulin selectively upregulates vascular endothelial growth factor secretion in cancer cells and stimulates angiogenesis. Oncogene. 2000;19:3460–9.

    Article  CAS  PubMed  Google Scholar 

  62. Bagheri-Yarmand R, Vadlamudi RK, Wang RA, Mendelsohn J, Kumar R. Vascular endothelial growth factor up-regulation via p21-activated kinase-1 signaling regulates heregulin-beta1-mediated angiogenesis. J Biol Chem. 2000;275:39451–7.

    Article  CAS  PubMed  Google Scholar 

  63. Laughner E, Taghavi P, Chiles K, Mahon PC, Semenza GL. HER2 (neu) signaling increases the rate of hypoxia-inducible factor 1alpha (HIF-1alpha) synthesis: novel mechanism for HIF-1-mediated vascular endothelial growth factor expression. Mol Cell Biol. 2001;21:3995–4004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Kumar R, Yarmand-Bagheri R. The role of HER2 in angiogenesis. Semin Oncol. 2001;28(Suppl 16):27–32.

    Article  CAS  PubMed  Google Scholar 

  65. Montero JC, Rodríguez-Barrueco R, Ocaña A, Díaz-Rodríguez E, Esparís-Ogando A, Pandiella A. Neuregulins and cancer. Clin Cancer Res. 2008;14:3237–41.

    Article  CAS  PubMed  Google Scholar 

  66. Konecny GE, Meng YG, Untch M, Wang HJ, Bauerfeind I, Epstein 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;10:1706–16.

    Article  CAS  PubMed  Google Scholar 

  67. Bhattacharjee RN, Timoshenko AV, Cai J, Lala PK. Relationship between cyclooxygenase-2 and human epidermal growth factor receptor 2 in vascular endothelial growth factor C up-regulation and lymphangiogenesis in human breast cancer. Cancer Sci. 2010;101:2026–32.

    Article  CAS  PubMed  Google Scholar 

  68. Le XF, Mao W, Lu C, Thornton A, Heymach JV, Sood AK, et al. Specific blockade of VEGF and HER2 pathways results in greater growth inhibition of breast cancer xenografts that overexpress HER2. Cell Cycle. 2008;7:3747–58.

    Article  CAS  PubMed  Google Scholar 

  69. Hurvitz S, Pegram M, Lin L, Chan D, Allen H, Dichmann R, et al. Final results of a phase II trial evaluating trastuzumab and bevacizumab as first line treatment of HER2-amplified advanced breast cancer. Cancer Res. 2009;69(24(Suppl)):3.

    Google Scholar 

  70. Martín M, Makhson A, Gligorov J, Lichinitser M, Lluch A, Semiglazov V, et al. Phase II study of bevacizumab in combination with trastuzumab and capecitabine as first-line treatment for HER-2-positive locally recurrent or metastatic breast cancer. Oncologist. 2012;17:469–75.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Schwartzberg LS, Badarinath S, Keaton MR, Childs BH. Phase II multicenter study of docetaxel and bevacizumab with or without trastuzumab as first-line treatment for patients with metastatic breast cancer. Clin Breast Cancer. 2014;14:161–8.

    Article  CAS  PubMed  Google Scholar 

  72. Zhao M, Pan X, Layman R, Lustberg MB, Mrozek E, Macrae ER, et al. A phase II study of bevacizumab in combination with trastuzumab and docetaxel in HER2 positive metastatic breast cancer. Investig New Drugs. 2014;32:1285–94.

    Article  CAS  Google Scholar 

  73. Rugo HS, Chien AJ, Franco SX, Stopeck AT, Glencer A, Lahiri S, et al. A phase II study of lapatinib and bevacizumab as treatment for HER2-overexpressing metastatic breast cancer. Breast Cancer Res Treat. 2012;134:13–20.

    Article  CAS  PubMed  Google Scholar 

  74. Falchook GS, Moulder S, Naing A, Wheler JJ, Hong DS, Piha-Paul SA, et al. A phase I trial of combination trastuzumab, lapatinib, and bevacizumab in patients with advanced cancer. Investig New Drugs. 2015;33:177–86.

    Article  CAS  Google Scholar 

  75. Gianni L, Romieu GH, Lichinitser M, Serrano SV, Mansutti M, Pivot X, et al. AVEREL: a randomized phase III trial evaluating bevacizumab in combination with docetaxel and trastuzumab as first-line therapy for HER2-positive locally recurrent/metastatic breast cancer. J Clin Oncol. 2013;31:1719–25.

    Article  CAS  PubMed  Google Scholar 

  76. Arteaga CL, Mayer IA, O’Neill AM, Swaby RF, Alpaugh RK, Yang XJ, et al. A randomized phase III double-blinded placebo-controlled trial of first-line chemotherapy and trastuzumab with or without bevacizumab for patients with HER2/neu-overexpressing metastatic breast cancer (HER2+ MBC): a trial of the Eastern Cooperative Oncology Group (E1105). J Clin Oncol. 2012;30(Suppl):abstr 605.

    Google Scholar 

  77. Miller KD, O’Neill A, Perez EA, Seidman AD, Sledge GW. A phase II pilot trial incorporating bevacizumab into dose-dense doxorubicin and cyclophosphamide followed by paclitaxel in patients with lymph node positive breast cancer: a trial coordinated by the Eastern Cooperative Oncology Group. Ann Oncol. 2012;23:331–7.

    Article  CAS  PubMed  Google Scholar 

  78. Miller K, O’Neill AM, Dang CT, Northfelt DW, Gradishar WJ, Goldstein LJ, et al. Bevacizumab (Bv) in the adjuvant treatment of HER2-negative breast cancer: final results from Eastern Cooperative Oncology Group E5103. J Clin Oncol. 2014;32(Suppl):abstr 500.

    Article  Google Scholar 

  79. Cameron D, Brown J, Dent R, Jackisch C, Mackey J, Pivot X, et al. Adjuvant bevacizumab-containing therapy in triple-negative breast cancer (BEATRICE): primary results of a randomised, phase 3 trial. Lancet Oncol. 2013;14:933–42.

    Article  CAS  PubMed  Google Scholar 

  80. Bell R, Brown J, Parmar M, Toi M, Suter T, Steger GG, et al. Final efficacy and updated safety results of the randomized phase III BEATRICE trial evaluating adjuvant bevacizumab-containing therapy in triple-negative early breast cancer. Ann Oncol. 2017;28:754–60.

    CAS  PubMed  Google Scholar 

  81. Slamon DJ, Swain SM, Buyse M, Martin M, Geyer CE, Im Y-H, et al. Primary results from BETH, a phase 3 controlled study of adjuvant chemotherapy and trastuzumab ± bevacizumab in patients with HER2-positive, node-positive or high risk node-negative breast cancer. Cancer Res. 2013;73(24 Suppl):abstr S1-03.

    Google Scholar 

  82. Greil R, Moik M, Reitsamer R, Ressler S, Stoll M, Namberger K, et al. Neoadjuvant bevacizumab, docetaxel and capecitabine combination therapy for HER2/neu-negative invasive breast cancer: efficacy and safety in a phase II pilot study. Eur J Surg Oncol. 2009;35:1048–54.

    Article  CAS  PubMed  Google Scholar 

  83. Rastogi P, Buyse ME, Swain SM, Jacobs SA, Robidoux A, Liepman MK, et al. Concurrent bevacizumab with a sequential regimen of doxorubicin and cyclophosphamide followed by docetaxel and capecitabine as neoadjuvant therapy for HER2- locally advanced breast cancer: a phase II trial of the NSABP Foundation Research Group. Clin Breast Cancer. 2011;11:228–34.

    Article  CAS  PubMed  Google Scholar 

  84. Kim HR, Jung KH, Im SA, Im YH, Kang SY, Park KH, et al. Multicentre phase II trial of bevacizumab combined with docetaxel-carboplatin for the neoadjuvant treatment of triple-negative breast cancer (KCSG BR-0905). Ann Oncol. 2013;24:1485–90.

    Article  CAS  PubMed  Google Scholar 

  85. Sánchez-Rovira P, Seguí MA, Llombart A, Aranda E, Antón A, Sánchez A, et al. Bevacizumab plus preoperative chemotherapy in operable HER2 negative breast cancer: biomarkers and pathologic response. Clin Transl Oncol. 2013;15:810–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. Bear HD, Tang G, Rastogi P, Geyer CE Jr, Robidoux A, Atkins JN, et al. Bevacizumab added to neoadjuvant chemotherapy for breast cancer. N Engl J Med. 2012;366:310–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Golshan M, Garber JE, Gelman R, Tung N, Smith BL, Troyan S, et al. Does neoadjuvant bevacizumab increase surgical complications in breast surgery? Ann Surg Oncol. 2011;18:733–7.

    Article  CAS  PubMed  Google Scholar 

  88. Kansal KJ, Dominici LS, Tolaney SM, Isakoff SJ, Smith BL, Jiang W, et al. Neoadjuvant bevacizumab: surgical complications of mastectomy with and without reconstruction. Breast Cancer Res Treat. 2013;141:255–9.

    Article  CAS  PubMed  Google Scholar 

  89. Bear HD, Tang G, Rastogi P, Geyer CE Jr, Liu Q, Robidoux A, et al. Neoadjuvant plus adjuvant bevacizumab in early breast cancer (NSABP B-40 [NRG Oncology]): secondary outcomes of a phase 3, randomised controlled trial. Lancet Oncol. 2015;16:1037–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. von Minckwitz G, Eidtmann H, Rezai M, Fasching PA, Tesch H, Eggemann H. German Breast Group, Arbeitsgemeinschaft Gynäkologische Onkologie–Breast Study Groups, et al. Neoadjuvant chemotherapy and bevacizumab for HER2-negative breast cancer. N Engl J Med. 2012;366:299–309.

    Article  Google Scholar 

  91. von Minckwitz G, Loibl S, Untch M, Eidtmann H, Rezai M, Fasching PA, et al. Survival after neoadjuvant chemotherapy with or without bevacizumab or everolimus for HER2-negative primary breast cancer (GBG 44-GeparQuinto). Ann Oncol. 2014;25:2363–72.

    Article  Google Scholar 

  92. Fasching PA, Loibl S, Hu C, Hart SN, Shimelis H, Moore R, et al. BRCA1/2 Mutations and Bevacizumab in the Neoadjuvant treatment of breast cancer: response and prognosis results in patients with triple-negative breast cancer from the GeparQuintoStudy. J Clin Oncol. 2018;23:JCO2017772285. https://doi.org/10.1200/JCO.2017.77.2285.

    Article  Google Scholar 

  93. Sikov WM, Berry DA, Perou CM, Singh B, Cirrincione CT, Tolaney SM, et al. Impact of the addition of carboplatin and/or bevacizumab to neoadjuvant once-per-week paclitaxel followed by dose-dense doxorubicin and cyclophosphamide on pathologic complete response rates in stage II to III triple-negative breast cancer: CALGB 40603 (alliance). J Clin Oncol. 2015;33:13–21.

    Article  CAS  PubMed  Google Scholar 

  94. Sikov WM, Berry DA, Perou CM, Singh B, Cirrincione CT, Tolaney SM, et al. Event-free and overall survival following neoadjuvant weekly paclitaxel and dose-dense AC +/− carboplatin and/or bevacizumab in triple-negative breast cancer: outcomes from CALGB 40603 (Alliance). Cancer Res. 2016;76(4 Suppl):abstr S2-05.

    Google Scholar 

  95. Chen XS, Yuan Y, Garfield DH, Wu JY, Huang O, Shen KW. Both carboplatin and bevacizumab improve pathological complete remission rate in neoadjuvant treatment of triple negative breast cancer: a meta-analysis. PLoS One. 2014;9:e108405.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  96. Earl HM, Hiller L, Blenkinsop C, Grybowicz L, Vallier A, Abraham J, et al. for ARTemis Investigators. ARTemis: a randomised trial of bevacizumab with neoadjuvant chemotherapy (NACT) for patients with HER2-negative early breast cancer-Primary endpoint, pathological complete response (pCR). J Clin Oncol. 2014;32(Suppl):abstr 1014.

    Article  Google Scholar 

  97. Earl HM, Hiller L, Dunn JA, Blenkinsop C, Grybowicz L, Vallier AL, et al. Disease-free and overall survival at 3.5 years for neoadjuvant bevacizumab added to docetaxelfollowed by fluorouracil, epirubicin and cyclophosphamide, for women with HER2 negative early breast cancer: ARTemis Trial. Ann Oncol. 2017;28:1817–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Rydén L, Stendahl M, Jonsson H, Emdin S, Bengtsson NO, Landberg G. 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. 2005;89:135–43.

    Article  PubMed  CAS  Google Scholar 

  99. Rydén L, Jirström K, Bendahl PO, Fernö M, Nordenskjöld B, Stål O, et al. 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. 2005;23:4695–704.

    Article  PubMed  CAS  Google Scholar 

  100. Forero-Torres A, Saleh MN, Galleshaw JA, Jones CF, Shah JJ, Percent IJ, et al. Pilot trial of preoperative (neoadjuvant) letrozole in combination with bevacizumab in postmenopausal women with newly diagnosed estrogen receptor- or progesterone receptor-positive breast cancer. Clin Breast Cancer. 2010;10:275–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Yardley DA, Raefsky E, Castillo R, Lahiry A, Locicero R, Thompson D, et al. Phase II study of neoadjuvant weekly nab-paclitaxel and carboplatin, with bevacizumab and trastuzumab, as treatment for women with locally advanced HER2+ breast cancer. Clin Breast Cancer. 2011;11:297–305.

    Article  CAS  PubMed  Google Scholar 

  102. Pierga JY, Petit T, Delozier T, Ferrero JM, Campone M, Gligorov J, et al. Neoadjuvant bevacizumab, trastuzumab, and chemotherapy for primary inflammatory HER2-positive breast cancer (BEVERLY-2): an open-label, single-arm phase 2 study. Lancet Oncol. 2012;13:375–84.

    Article  CAS  PubMed  Google Scholar 

  103. Pierga JY, Petit T, Levy C, Ferrero JM, Campone M, Gligorov J, et al. Pathological response and circulating tumor cell count identifies treated HER2+ inflammatory breast cancer patients with excellent prognosis: BEVERLY-2 survival data. Clin Cancer Res. 2015;21(6):1298–304.

    Article  CAS  PubMed  Google Scholar 

  104. Tabouret E, Bertucci F, Pierga JY, Petit T, Levy C, Ferrero JM, et al. MMP2 and MMP9 serum levels are associated with favorable outcome in patients with inflammatory breast cancer treated with bevacizumab-based neoadjuvant chemotherapy in the BEVERLY-2 study. Oncotarget. 2016;7:18531–40.

    Article  PubMed  PubMed Central  Google Scholar 

  105. Fernandez M, Calvo I, Martinez N, Herrero M, Quijano Y, Duran H, et al. Final results of neoadjuvant trial of bevacizumab (B) and trastuzumab (T) in combination with weekly paclitaxel (P) as neoadjuvant treatment in HER2-positive breast cancer: a phase II trial (AVANTHER). Cancer Res. 2012;72(Suppl):abstr P1-14-10.

    Google Scholar 

  106. Coudert B, Pierga JY, Mouret-Reynier MA, Kerrou K, Ferrero JM, Petit T, et al. Use of [(18)F]-FDG PET to predict response to neoadjuvant trastuzumab and docetaxel in patients with HER2-positive breast cancer, and addition of bevacizumab to neoadjuvant trastuzumab and docetaxel in [(18)F]-FDG PET-predicted non-responders (AVATAXHER): an open-label, randomised phase 2 trial. Lancet Oncol. 2014;15:1493–502.

    Article  CAS  PubMed  Google Scholar 

  107. Teng LS, Jin KT, He KF, Zhang J, Wang HH, Cao J. Clinical applications of VEGF-trap (aflibercept) in cancer treatment. J Chin Med Assoc. 2010;73:449–56.

    Article  CAS  PubMed  Google Scholar 

  108. Presta LG, Chen H, O’Connor SJ, Chisholm V, Meng YG, Krummen L, et al. Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders. Cancer Res. 1997;57:4593–9.

    CAS  PubMed  Google Scholar 

  109. Rudge JS, Holash J, Hylton D, Russell M, Jiang S, Leidich R, et al. VEGF Trap complex formation measures production rates of VEGF, providing a biomarker for predicting efficacious angiogenic blockade. Proc Natl Acad Sci U S A. 2007;104:18363–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Holash J, Davis S, Papadopoulos N, Croll SD, Ho L, Russell M, et al. VEGF-Trap: a VEGF blocker with potent antitumor effects. Proc Natl Acad Sci U S A. 2002;99:11393–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Huang J, Frischer JS, Serur A, Kadenhe A, Yokoi A, McCrudden KW, et al. Regression of established tumors and metastases by potent vascular endothelial growth factor blockade. Proc Natl Acad Sci U S A. 2003;100:7785–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Tew WP, Gordon M, Murren J, Dupont J, Pezzulli S, Aghajanian C, et al. Phase 1 study of aflibercept administered subcutaneously to patients with advanced solid tumors. Clin Cancer Res. 2010;16:358–66.

    Article  CAS  PubMed  Google Scholar 

  113. Lockhart AC, Rothenberg ML, Dupont J, Cooper W, Chevalier P, Sternas L, et al. Phase I study of intravenous vascular endothelial growth factor trap, aflibercept, in patients with advanced solid tumors. J Clin Oncol. 2010;28:207–14.

    Article  CAS  PubMed  Google Scholar 

  114. Isambert N, Freyer G, Zanetta S, You B, Fumoleau P, Falandry C, et al. Phase I dose-escalation study of intravenous aflibercept in combination with docetaxel in patients with advanced solid tumors. Clin Cancer Res. 2012;18:1743–50.

    Article  CAS  PubMed  Google Scholar 

  115. Van Cutsem E, Tabernero J, Lakomy R, Prenen H, Prausová J, Macarulla T, et al. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol. 2012;30:3499–506.

    Article  PubMed  CAS  Google Scholar 

  116. Sideras K, Dueck AC, Hobday TJ, Rowland KM Jr, Allred JB, Northfelt DW, et al. North central cancer treatment group (NCCTG) N0537: phase II trial of VEGF-trap in patients with metastatic breast cancer previously treated with an anthracycline and/or a taxane. Clin Breast Cancer. 2012;12:387–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Krupitskaya Y, Wakelee HA. Ramucirumab, a fully human mAb to the transmembrane signaling tyrosine kinase VEGFR-2 for the potential treatment of cancer. Curr Opin Investig Drugs. 2009;10:597–605.

    CAS  PubMed  Google Scholar 

  118. Spratlin J. Ramucirumab (IMC-1121B): monoclonal antibody inhibition of vascular endothelial growth factor receptor-2. Curr Oncol Rep. 2011;13:97–102.

    Article  CAS  PubMed  Google Scholar 

  119. Spratlin JL, Cohen RB, Eadens M, Gore L, Camidge DR, Diab S, et al. Phase I pharmacologic and biologic study of ramucirumab (IMC-1121B), a fully human immunoglobulin G1 monoclonal antibody targeting the vascular endothelial growth factor receptor-2. J Clin Oncol. 2010;28:780–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Mackey JR, Ramos-Vazquez M, Lipatov O, McCarthy N, Krasnozhon D, Semiglazov V, et al. Primary results of ROSE/TRIO-12, a randomized placebo-controlled phase III trial evaluating the addition of ramucirumab to first-line docetaxel chemotherapy in metastatic breast cancer. J Clin Oncol. 2015;33:141–8.

    Article  CAS  PubMed  Google Scholar 

  121. Patyna S, Laird AD, Mendel DB, O’farrell AM, Liang C, Guan H, et al. SU14813: a novel multiple receptor tyrosine kinase inhibitor with potent antiangiogenic and antitumor activity. Mol Cancer Ther. 2006;5(7):1774–82.

    Article  CAS  PubMed  Google Scholar 

  122. Chow LQ, Eckhardt SG. Sunitinib: from rational design to clinical efficacy. J Clin Oncol. 2007;25:884–96.

    Article  CAS  PubMed  Google Scholar 

  123. Murray LJ, Abrams TJ, Long KR, Ngai TJ, Olson LM, Hong W, et al. SU11248 inhibits tumor growth and CSF-1R-dependent osteolysis in an experimental breast cancer bone metastasis model. Clin Exp Metastasis. 2003;20:757–66.

    Article  CAS  PubMed  Google Scholar 

  124. Abrams TJ, Murray LJ, Pesenti E, Holway VW, Colombo T, Lee LB, et al. Preclinical evaluation of the tyrosine kinase inhibitor SU11248 as a single agent and in combination with “standard of care” therapeutic agents for the treatment of breast cancer. Mol Cancer Ther. 2003;2:1011–21.

    CAS  PubMed  Google Scholar 

  125. Faivre S, Delbaldo C, Vera K, Robert C, Lozahic S, Lassau N, et al. Safety, pharmacokinetic, and antitumor activity of SU11248, a novel oral multitarget tyrosine kinase inhibitor, in patients with cancer. J Clin Oncol. 2006;24:25–35.

    Article  CAS  PubMed  Google Scholar 

  126. Sweeney CJ, Chiorean EG, Verschraegen CF, Lee FC, Jones S, Royce M, et al. A phase I study of sunitinib plus capecitabine in patients with advanced solid tumors. J Clin Oncol. 2010;28:4513–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Robert F, Sandler A, Schiller JH, Liu G, Harper K, Verkh L, et al. Sunitinib in combination with docetaxel in patients with advanced solid tumors: a phase I dose-escalation study. Cancer Chemother Pharmacol. 2010;66:669–80.

    Article  CAS  PubMed  Google Scholar 

  128. Burstein HJ, Elias AD, Rugo HS, Cobleigh MA, Wolff AC, Eisenberg PD, et al. Phase II study of sunitinib malate, an oral multitargeted tyrosine kinase inhibitor, in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol. 2008;26:1810–6.

    Article  CAS  PubMed  Google Scholar 

  129. Kozloff M, Chuang E, Starr A, Gowland PA, Cataruozolo PE, Collier M, et al. An exploratory study of sunitinib plus paclitaxel as first-line treatment for patients with advanced breast cancer. Ann Oncol. 2010;21:1436–41.

    Article  CAS  PubMed  Google Scholar 

  130. Robert NJ, Saleh MN, Paul D, Generali D, Gressot L, Copur MS, et al. Sunitinib plus paclitaxel versus bevacizumab plus paclitaxel for first-line treatment of patients with advanced breast cancer: a phase III, randomized, open-label trial. Clin Breast Cancer. 2011;11:82–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Mayer EL, Dhakil S, Patel T, Sundaram S, Fabian C, Kozloff M, et al. SABRE-B: an evaluation of paclitaxel and bevacizumab with or without sunitinib as first-line treatment of metastatic breast cancer. Ann Oncol. 2010;21:2370–6.

    Article  CAS  PubMed  Google Scholar 

  132. Bergh J, Bondarenko IM, Lichinitser MR, Liljegren A, Greil R, Voytko NL, et al. First-line treatment of advanced breast cancer with sunitinib in combination with docetaxel versus docetaxel alone: results of a prospective, randomized phase III study. J Clin Oncol. 2012;30:921–9.

    Article  CAS  PubMed  Google Scholar 

  133. Cardoso F, Canon JL, Amadori D, Aldrighetti D, Machiels JP, Bouko Y, et al. An exploratory study of sunitinib in combination with docetaxel and trastuzumab as first-line therapy for HER2-positive metastatic breast cancer. Breast. 2012;21:716–23.

    Article  PubMed  Google Scholar 

  134. Barrios CH, Liu MC, Lee SC, Vanlemmens L, Ferrero JM, Tabei T, Pivot X, Iwata H, Aogi K, Lugo-Quintana R, Harbeck N, Brickman MJ, Zhang K, Kern KA, Martin M. Phase III randomized trial of sunitinib versus capecitabine in patients with previously treated HER2-negative advanced breast cancer. Breast Cancer Res Treat. 2010;121:121–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Crown JP, Diéras V, Staroslawska E, Yardley DA, Bachelot T, Davidson N, et al. Phase III trial of sunitinib in combination with capecitabine versus capecitabine monotherapy for the treatment of patients with pretreated metastatic breast cancer. J Clin Oncol. 2013;31:2870–8.

    Article  CAS  PubMed  Google Scholar 

  136. Wildiers H, Fontaine C, Vuylsteke P, Martens M, Canon JL, Wynendaele W, et al. Multicenter phase II randomized trial evaluating antiangiogenic therapy with sunitinib as consolidation after objective response to taxane chemotherapy in women with HER2-negative metastatic breast cancer. Breast Cancer Res Treat. 2010;123:463–9.

    Article  CAS  PubMed  Google Scholar 

  137. Yardley DA, Peacock NW, Peyton J, Shipley DL, Spigel S, Barton J, et al. Neoadjuvant sunitinib administered with weekly paclitaxel/carboplatin in patients with locally advanced triple-negative breast cancer: a Sarah Cannon Research Institute Phase I/II Trial. Cancer Res. 2011;71(24 Suppl):Abstract nr P3-14-29.

    Google Scholar 

  138. Ahlgren P, Thirlwell M, O’Regan R, Mormont C, Levesque L, Gaspo R, et al. An open-label study of sunitinib (SU) plus exemestane (E) in the first-line treatment of hormone receptor (HR)-positive metastatic breast cancer (MBC). J Clin Oncol. 2009;27(Suppl):abstr e12019.

    Google Scholar 

  139. Pilot/phase II randomised, double blind, placebo controlled multicenter study with biomarker evaluation of neoadjuvant exemestane in combination with sunitinib in post-menopausal women with hormone- sensitive, Her-2 negative primar breast cancer. ClinicalTrials.gov Identifier:NCT00931450.

  140. Strumberg D, Richly H, Hilger RA, Schleucher N, Korfee S, Tewes M, et al. Phase I clinical and pharmacokinetic study of the Novel Raf kinase and vascular endothelial growth factor receptor inhibitor BAY 43-9006 in patients with advanced refractory solid tumors. J Clin Oncol. 2005;23:965–72.

    Article  CAS  PubMed  Google Scholar 

  141. Wilhelm SM, Carter C, Tang L, Wilkie D, McNabola A, Rong H, et al. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. 2004;64:7099–109.

    Article  CAS  PubMed  Google Scholar 

  142. Wilhelm S, Chien DS. BAY 43-9006: preclinical data. Curr Pharm Des. 2002;8:2255–7.

    Article  CAS  PubMed  Google Scholar 

  143. Gianpaolo-Ostravage C, Carter C, Hibner B, Bankston D, Natero R, Monahan MC, et al. Anti-tumor efficacy of the orally active raf kinase inhibitor BAY 43-9006 in human tumor xenograft models. Proc Am Assoc Cancer Res. 2001;42:Abstr 4954.

    Google Scholar 

  144. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, SHARP Investigators Study Group, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378–90.

    Article  CAS  PubMed  Google Scholar 

  145. Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, TARGET Study Group, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007;356:125–34.

    Article  CAS  PubMed  Google Scholar 

  146. Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Staehler M, et al. Sorafenib for treatment of renal cell carcinoma: final efficacy and safety results of the phase III treatment approaches in renal cancer global evaluation trial. J Clin Oncol. 2009;27:3312–8.

    Article  CAS  PubMed  Google Scholar 

  147. Moreno-Aspitia A, Morton RF, Hillman DW, Lingle WL, Rowland KM Jr, Wiesenfeld M, et al. Phase II trial of sorafenib in patients with metastatic breast cancer previously exposed to anthracyclines or taxanes: North Central Cancer Treatment Group and Mayo Clinic Trial N0336. J Clin Oncol. 2009;27:11–5.

    Article  CAS  PubMed  Google Scholar 

  148. Bianchi G, Loibl S, Zamagni C, Salvagni S, Raab G, Siena S, et al. Phase II multicenter, uncontrolled trial of sorafenib in patients with metastatic breast cancer. Anti-Cancer Drugs. 2009;20:616–24.

    Article  CAS  PubMed  Google Scholar 

  149. Baselga J, Segalla JG, Roché H, Del Giglio A, Pinczowski H, Ciruelos EM, et al. Sorafenib in combination with capecitabine: an oral regimen for patients with HER2-negative locally advanced or metastatic breast cancer. J Clin Oncol. 2012;30:1484–91.

    Article  CAS  PubMed  Google Scholar 

  150. Baselga J, Zamagni C, Gómez P, Bermejo B, Nagai SE, Melichar B, et al. RESILIENCE: phase III randomized, double-blind trial comparing Sorafenib with Capecitabine versus Placebo with Capecitabine in locally advanced or metastatic HER2-negative breast cancer. Clin Breast Cancer. 2017;17:585–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Gradishar WJ, Kaklamani V, Sahoo TP, Lokanatha D, Raina V, Bondarde S, et al. A double-blind, randomised, placebo-controlled, phase 2b study evaluating sorafenib in combination with paclitaxel as a first-line therapy in patients with HER2-negative advanced breast cancer. Eur J Cancer. 2013;49:312–22.

    Article  CAS  PubMed  Google Scholar 

  152. Decker T, Overkamp F, Rösel S, Nusch A, Göhler T, Indorf M, et al. A randomized phase II study of paclitaxel alone versus paclitaxel plus sorafenib in second- and third-line treatment of patients with HER2-negative metastatic breast cancer (PASO). BMC Cancer. 2017;17:499.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  153. Isaacs C, Herbolsheimer P, Liu MC, Wilkinson M, Ottaviano Y, Chung GG, et al. Phase I/II study of sorafenib with anastrozole in patients with hormone receptor positive aromatase inhibitor resistant metastatic breast cancer. Breast Cancer Res Treat. 2011;125:137–43.

    Article  CAS  PubMed  Google Scholar 

  154. Mina LA, Yu M, Johnson C, Burkhardt C, Miller KD, Zon R. A phase II study of combined VEGF inhibitor (bevacizumab+sorafenib) in patients with metastatic breast cancer: Hoosier Oncology Group Study BRE06-109. Investig New Drugs. 2013;31:1307–10.

    Article  CAS  Google Scholar 

  155. Chen J, Tian CX, Yu M, Lv Q, Cheng NS, Wang Z, et al. Efficacy and safety profile of combining sorafenib with chemotherapy in patients with HER2-negative advanced breast cancer: a meta-analysis. J Breast Cancer. 2014;17:61–8.

    Article  PubMed  PubMed Central  Google Scholar 

  156. Tan QX, Qin QH, Lian B, Yang WP, Wei CY. Sorafenib-based therapy in HER2-negative advanced breast cancer: results from a retrospective pooled analysis of randomized controlled trials. Exp Ther Med. 2014;7:1420–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Ferrario C, Strepponi I, Esfahani K, Charamis H, Langleben A, Scarpi E, et al. Phase I/II trial of Sorafenib in combination with Vinorelbine as first-line chemotherapy for metastatic breast cancer. PLoS One. 2016;11:e0167906. https://doi.org/10.1371/journal.pone.0167906.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Yardley DA, Dickson N, Drosick D, Earwood C, Inhorn R, Murphy P, et al. Sorafenib Plus Ixabepilone as first-line treatment of metastatic HER2-negative breast cancer: a Sarah Cannon Research Institute phase I/II trial. Clin Breast Cancer. 2016;16:180–7.

    Article  CAS  PubMed  Google Scholar 

  159. Sonpavde G, Hutson TE. Pazopanib: a novel multitargeted tyrosine kinase inhibitor. Curr Oncol Rep. 2007;9:115–9.

    Article  CAS  PubMed  Google Scholar 

  160. Hurwitz HI, Dowlati A, Saini S, Savage S, Suttle AB, Gibson DM, et al. Phase I trial of pazopanib in patients with advanced cancer. Clin Cancer Res. 2009;15:4220–7.

    Article  CAS  PubMed  Google Scholar 

  161. Taylor SK, Chia S, Dent S, Clemons M, Agulnik M, Grenci P, et al. A phase II study of pazopanib in patients with recurrent or metastatic invasive breast carcinoma: a trial of the Princess Margaret Hospital phase II consortium. Oncologist. 2010;15:810–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Tan AR, Johannes H, Rastogi P, Jacobs SA, Robidoux A, Flynn PJ, et al. Weekly paclitaxel and concurrent pazopanib following doxorubicin and cyclophosphamide as neoadjuvant therapy for HER-negative locally advanced breast cancer: NSABP Foundation FB-6, a phase II study. Breast Cancer Res Treat. 2015;149(1):163–9.

    Article  CAS  PubMed  Google Scholar 

  163. de Jonge MJ, Hamberg P, Verweij J, Savage S, Suttle AB, Hodge J, et al. Phase I and pharmacokinetic study of pazopanib and lapatinib combination therapy in patients with advanced solid tumors. Investig New Drugs. 2013;31:751–9.

    Article  CAS  Google Scholar 

  164. Johnston SR, Gómez H, Stemmer SM, Richie M, Durante M, Pandite L, et al. A randomized and open-label trial evaluating the addition of pazopanib to lapatinib as first-line therapy in patients with HER2-positive advanced breast cancer. Breast Cancer Res Treat. 2013;137:755–66.

    Article  CAS  PubMed  Google Scholar 

  165. Cristofanilli M, Johnston SR, Manikhas A, Gomez HL, Gladkov O, Shao Z, et al. A randomized phase II study of lapatinib + pazopanib versus lapatinib in patients with HER2+ inflammatory breast cancer. Breast Cancer Res Treat. 2013;137:471–82.

    Article  CAS  PubMed  Google Scholar 

  166. Rosen LS, Kurzrock R, Mulay M, Van Vugt A, Purdom M, Ng C, et al. Safety, pharmacokinetics, and efficacy of AMG 706, an oral multikinase inhibitor, in patients with advanced solid tumors. J Clin Oncol. 2007;25:2369–76.

    Article  CAS  PubMed  Google Scholar 

  167. Coxon A, Bush T, Saffran D, Kaufman S, Belmontes B, Rex K, et al. Broad antitumor activity in breast cancer xenografts by motesanib, a highly selective, oral inhibitor of vascular endothelial growth factor, platelet-derived growth factor, and kit receptors. Clin Cancer Res. 2009;15:110–8.

    Article  CAS  PubMed  Google Scholar 

  168. De Boer RH, Kotasek D, White S, Koczwara B, Mainwaring P, Chan A, et al. Phase 1b dose-finding study of motesanib with docetaxel or paclitaxel in patients with metastatic breast cancer. Breast Cancer Res Treat. 2012;135:241–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Martin M, Roche H, Pinter T, Crown J, Kennedy MJ, Provencher L. TRIO 010 investigators, et al. Motesanib, or open-label bevacizumab, in combination with paclitaxel, as first-line treatment for HER2-negative locally recurrent or metastatic breast cancer: a phase 2, randomised, double-blind, placebo-controlled study. Lancet Oncol. 2011;12:369–76.

    Article  CAS  PubMed  Google Scholar 

  170. Choueiri TK. Axitinib, a novel anti-angiogenic drug with promising activity in various solid tumors. Curr Opin Investig Drugs. 2008;9:658–71.

    CAS  PubMed  Google Scholar 

  171. Wilmes LJ, Pallavicini MG, Fleming LM, Gibbs J, Wang D, Li KL, et al. AG-013736, a novel inhibitor of VEGF receptor tyrosine kinases, inhibits breast cancer growth and decreases vascular permeability as detected by dynamic contrast-enhanced magnetic resonance imaging. Magn Reson Imaging. 2007;25:319–27.

    Article  CAS  PubMed  Google Scholar 

  172. Rugo HS, Herbst RS, Liu G, Park JW, Kies MS, Steinfeldt HM, et al. Phase I trial of the oral antiangiogenesis agent AG-013736 in patients with advanced solid tumors: pharmacokinetic and clinical results. J Clin Oncol. 2005;23:5474–83.

    Article  CAS  PubMed  Google Scholar 

  173. Rugo HS, Stopeck AT, Joy AA, Chan S, Verma S, Lluch A, et al. Randomized, placebo-controlled, double-blind, phase II study of axitinib plus docetaxel versus docetaxel plus placebo in patients with metastatic breast cancer. J Clin Oncol. 2011;29:2459–65.

    Article  CAS  PubMed  Google Scholar 

  174. Morabito A, Piccirillo MC, Falasconi F, De Feo G, Del Giudice A, Bryce J, et al. Vandetanib (ZD6474), a dual inhibitor of vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR) tyrosine kinases: current status and future directions. Oncologist. 2009;14:378–90.

    Article  CAS  PubMed  Google Scholar 

  175. Wedge SR, Ogilvie DJ, Dukes M, Kendrew J, Chester R, Jackson JA, et al. ZD6474 inhibits vascular endothelial growth factor signaling, angiogenesis, and tumor growth following oral administration. Cancer Res. 2002;62:4645–55.

    CAS  PubMed  Google Scholar 

  176. Ciardiello F, Caputo R, Damiano V, Caputo R, Troiani T, Vitagliano D, et al. Antitumor effects of ZD6474, a small molecule vascular endothelial growth factor receptor tyrosine kinase inhibitor, with additional activity against epidermal growth factor receptor tyrosine kinase. Clin Cancer Res. 2003;9:1546–56.

    CAS  PubMed  Google Scholar 

  177. Holden SN, Eckhardt SG, Basser R, de Boer R, Rischin D, Green M, et al. Clinical evaluation of ZD6474, an orally active inhibitor of VEGF and EGF receptor signaling, in patients with solid, malignant tumors. Ann Oncol. 2005;16:1391–7.

    Article  CAS  PubMed  Google Scholar 

  178. Miller KD, Trigo JM, Wheeler C, Barge A, Rowbottom J, Sledge G, et al. 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. 2005;11:3369–76.

    Article  CAS  PubMed  Google Scholar 

  179. Boér K, Láng I, Llombart-Cussac A, Andreasson I, Vivanco GL, Sanders N, et al. Vandetanib with docetaxel as second-line treatment for advanced breast cancer: a double-blind, placebo-controlled, randomized Phase II study. Investig New Drugs. 2012;30:681–7.

    Article  CAS  Google Scholar 

  180. A randomised, double-blind, parallel- group, multicentre, phase II study to evaluate the safety and pharmacological activity of the combination of vandetanib (100 or 300 MG/ daily or placebo) with fulvestrant (loading dose), in postmenopausal advanced breast cancer patients. ClinicalTrials.gov Identifier: NCT00752986.

  181. Clemons MJ, Cochrane B, Pond GR, Califaretti N, Chia SK, Dent RA, et al. Randomised, phase II, placebo-controlled, trial of fulvestrant plus vandetanib in postmenopausal women with bone only or bone predominant, hormone-receptor-positive metastatic breast cancer (MBC): the OCOG ZAMBONEY study. Breast Cancer Res Treat. 2014;146:153–62.

    Article  CAS  PubMed  Google Scholar 

  182. Jost LM, Gschwind HP, Jalava T, Wang Y, Guenther C, Souppart C, et al. Metabolism and disposition of vatalanib (PTK787/ZK-222584) in cancer patients. Drug Metab Dispos. 2006;34:1817–28.

    Article  CAS  PubMed  Google Scholar 

  183. Banerjee S, A’Hern R, Detre S, Littlewood-Evans AJ, Evans DB, Dowsett M, et al. Biological evidence for dual antiangiogenic-antiaromatase activity of the VEGFR inhibitor PTK787/ZK222584 in vivo. Clin Cancer Res. 2010;16:4178–87.

    Article  CAS  PubMed  Google Scholar 

  184. Banerjee S, Zvelebil M, Furet P, Mueller-Vieira U, Evans DB, Dowsett M, et al. The vascular endothelial growth factor receptor inhibitor PTK787/ZK222584 inhibits aromatase. Cancer Res. 2009;69:4716–23.

    Article  CAS  PubMed  Google Scholar 

  185. Thomas AL, Morgan B, Horsfield MA, Higginson A, Kay A, Lee L, et al. Phase I study of the safety, tolerability, pharmacokinetics, and pharmacodynamics of PTK787/ZK 222584 administered twice daily in patients with advanced cancer. J Clin Oncol. 2005;23:4162–71.

    Article  CAS  PubMed  Google Scholar 

  186. A phase I/II study of PTK787 in combination with trastuzumab in patients with newly diagnosed HER2 overexpressing locally recurrent or metastatic breast cancer: Hoosier Oncology Group Trial BRE04–80. ClinicalTrials.gov Identifier: NCT00216047.

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Authors and Affiliations

  1. Medical Oncology Department, Altinbas University School of Medicine, Istanbul, Turkey

    Kerem Okutur

  2. Medical Oncology Department, Acibadem University School of Medicine, Istanbul, Turkey

    Gokhan Demir

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  1. Kerem Okutur
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  2. Gokhan Demir
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Editors and Affiliations

  1. Oncology Institute, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey

    Adnan Aydiner

  2. Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey

    Abdullah Igci

  3. Division of Surgical Oncology, Department of Surgery, University of Pittsburgh School of Medicine, Magee-Women’s Hospital of UPMC, Pittsburgh, PA, USA

    Atilla Soran

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Okutur, K., Demir, G. (2019). Angiogenesis Inhibition in Breast Cancer. In: Aydiner, A., Igci, A., Soran, A. (eds) Breast Disease. Springer, Cham. https://doi.org/10.1007/978-3-030-16792-9_34

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  • DOI: https://doi.org/10.1007/978-3-030-16792-9_34

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