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Trifluridine/tipiracil (FTD/TPI) is a novel oral formulation of two drugs with promising results in the treatment of metastatic colorectal cancer (mCRC).1 Trifluridine is a thymidine-based nucleoside analogue that, after intracellular phosphorylation, gets incorporated into DNA, causing DNA dysfunction.2 It was first identified by Callahan et al. in 1996 as an active impurity in the herbicide trifluralin, which […]

The Intriguing Role of Bevacizumab in Advanced Breast Cancer – The Search Continues

José Pablo Leone, Ricardo H Álvarez
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Published Online: May 15th 2012 European Oncology & Haematology, 2012;8(3):179-183 DOI: https://doi.org/10.17925/EOH.2012.08.3.179
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1

Abstract

Overview

Angiogenesis plays an important role in the biology of tumour progression and therapies that target the vascular endothelial growth factor (VEGF) pathways – ligands, receptors and co-receptors – have become an important treatment for many types of cancer. Bevacizumab, a monoclonal antibody against VEGF, was explored in several randomised Phase III studies conducted in patients with metastatic breast cancer. However, despite bringing improvements in progression-free survival, the use of bevacizumab has not been associated with improvements in overall survival. Further improvements in predictive biomarkers and the development of biology-driven Phase II trials will be critical to help us understand which patients would benefit the most from anti-angiogenic therapy.

Keywords

Bevacizumab, breast cancer, anti-angiogenesis, vascular endothelial growth factor

2

Article

Breast cancer continues to be a very prevalent disease worldwide. It is estimated that more than 39,000 women died of breast cancer in the US in 2011.1 Advances in the treatment of early-stage disease, including screening programmes for breast cancer detection and adjuvant systemic therapies, have improved outcomes for patients. Despite these improvements, however, many women ultimately develop metastatic breast cancer (MBC), which is essentially an incurable disease. The prognosis of patients with MBC has changed little over the past decade; the majority of patients succumb to their disease within two years of diagnosis.2–4 Novel treatments for patients with MBC are needed to improve the control of disease and prevent symptoms while minimising toxicity.

Role of Angiogenesis in Cancer Biology
In 1970, Folkman postulated that tumour progression might be dependent on angiogenesis – the formation of new blood vessels.5 The hypothesis was that a tumour cannot grow without blood supply and that, therefore, the inhibition of angiogenesis would be an important treatment for all cancers.

Angiogenesis is an important natural process of new blood vessel formation that occurs in the body, both in health and in disease.6 Thegeneration and growth of solid tumours depend on an intact vascular supply, which is stimulated by several pro-angiogenic factors. Changes in the finely balanced equilibrium between angiogenicstimulators and inhibitors that regulate angiogenesis are linked to a broad range of angiogenesis-dependent diseases, including both cancer and non-neoplastic diseases.7 Angiogenesis is now recognised as one of the key steps in the pathogenesis of cancer, regulating several events required for tumour development, invasion and metastasis.8,9

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References

  1. American Cancer Society, Cancer Facts and Figures 2011,
    Atlanta, Georgia, US: American Cancer Society, 2011.

  2. Greenberg PA, Hortobagyi GN, Smith TL, et al., Long-term
    follow-up of patients with complete remission following
    combination chemotherapy for metastatic breast cancer,
    J Clin Oncol, 1996;14:2197–205.

  3. Dawood S, Broglio K, Gonzalez-Angulo AM, et al., Trends in
    survival over the past two decades among white and black
    patients with newly diagnosed stage IV breast cancer,
    J Clin Oncol, 2008;26:4891–8.

  4. Chia SK, Speers CH, D’yachkova Y, et al., The impact of new
    chemotherapeutic and hormone agents on survival in a
    population-based cohort of women with metastatic breast
    cancer, Cancer, 2007;110:973–9.

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

  6. Alvarez RH, Guarneri V, Icli F, et al., Bevacizumab treatment
    for advanced breast cancer, Oncologist, 2011;16:1684–97.

  7. Carmeliet P, Jain RK, Angiogenesis in cancer and other
    diseases, Nature, 2000;407:249–57.

  8. Gasparini G, Prognostic value of vascular endothelial growth
    factor in breast cancer, Oncologist, 2000;5(Suppl. 1):37–44.

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

  10. Ellis LM, Epidermal growth factor receptor in tumor
    angiogenesis, Hematol Oncol Clin North Am, 2004;18:1007–21,viii.

  11. Heath VL, Bicknell R, Anticancer strategies involving the
    vasculature, Nat Rev Clin Oncol, 2009;6:395–404.

  12. Hanahan D, Folkman J, Patterns and emerging mechanisms
    of the angiogenic switch during tumorigenesis,
    Cell, 1996;86:353–64.

  13. Folkman J, Klagsbrun M, Angiogenic factors, Science,
    1987;235:442–7.

  14. Dameron KM, Volpert OV, Tainsky MA, Bouck N, Control of
    angiogenesis in fibroblasts by p53 regulation of
    thrombospondin-1, Science, 1994;265:1582–4.

  15. Ebos JM, Kerbel RS, Antiangiogenic therapy: impact on
    invasion, disease progression, and metastasis,
    Nat Rev Clin Oncol, 2011;8:210–21.

  16. Pàez-Ribes M, Allen E, Hudock J, et al., Antiangiogenic therapy
    elicits malignant progression of tumors to increased local
    invasion and distant metastasis, Cancer Cell, 2009;15:220–31.

  17. Desar IM, Mulder SF, Stillebroer AB, et al., The reverse side
    of the victory: flare up of symptoms after discontinuation of
    sunitinib or sorafenib in renal cell cancer patients. A report
    of three cases, Acta Oncol, 2009;48:927–31.

  18. Miles D, Harbeck N, Escudier B, et al., Disease course
    patterns after discontinuation of bevacizumab: pooled
    analysis of randomized phase III trials, J Clin Oncol,
    2011;29:83–8.

  19. Relf M, LeJeune S, Scott PA, et al., 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, 1997;57:963–9.

  20. 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;10:1706–16.

  21. Linderholm BK, Hellborg H, Johansson U, et al., Significantly
    higher levels of vascular endothelial growth factor (VEGF)
    and shorter survival times for patients with primary
    operable triple-negative breast cancer, Ann Oncol,
    2009;20:1639–46.

  22. Alvarez RH, Valero V, Hortobagyi GN, Emerging targeted
    therapies for breast cancer, J Clin Oncol, 2010;28:3366–79.

  23. Gerber HP, Ferrara N, Pharmacology and
    pharmacodynamics of bevacizumab as monotherapy or in
    combination with cytotoxic therapy in preclinical studies,
    Cancer Res, 2005;65:671–80.

  24. 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.

  25. Gianni L, Romieu G, Lichinitser M, et al., First results of
    AVEREL, a randomized phase III trial to evaluate
    bevacizumab (BEV) in combination with trastuzumab (H) +
    docetaxel (DOC) as first-line therapy for HER2-positive
    locally recurrent/metastatic breast cancer (LR/mBC),
    Cancer Res, 2011;71(Suppl. 24):S4–S8.

  26. 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.

  27. 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.

  28. 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;23:792–9.

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

  30. Miles DW, Chan A, Dirix LY, 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.

  31. Robert NJ, Diéras V, Glaspy J, 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.

  32. Gonzalez-Angulo AM, Hortobagyi GN, Optimal schedule of
    paclitaxel: weekly is better, J Clin Oncol, 2008;26:1585–7.

  33. Burstein HJ, Bevacizumab for advanced breast cancer: all
    tied up with a RIBBON? J Clin Oncol, 2011;29:1232–5.

  34. Gonzalez-Angulo AM, Hortobagyi GN, Ellis LM, Targeted
    therapies: peaking beneath the surface of recent
    bevacizumab trials, Nat Rev Clin Oncol, 2011;8:319–20.

  35. European Medicines Agency (EMA), EPAR (European public
    assessment report) summary for the public, Avastin,
    bevacizumab (EMA/349719/2011, EMEA/H/C/000582),
    November 2011. Available at:
    www.ema.europa.eu/docs/en_GB/document_library/
    EPAR_-_Summary_for_the_public/human/000582/
    WC500029260.pdf (accessed 23 May 2012).

  36. Smith IE, Pierga JY, Biganzoli L, et al., First-line bevacizumab
    plus taxane-based chemotherapy for locally recurrent or
    metastatic breast cancer: safety and efficacy in an openlabel
    study in 2,251 patients, Ann Oncol, 2011;22:595–602.

  37. Gray R, Bhattacharya S, Bowden C, et al., Independent
    review of E2100: a phase III trial of bevacizumab plus
    paclitaxel versus paclitaxel in women with metastatic breast
    cancer, J Clin Oncol, 2009;27:4966–72.

  38. Albain KS, Nag SM, Calderillo-Ruiz G, et al., Gemcitabine
    plus Paclitaxel versus Paclitaxel monotherapy in patients
    with metastatic breast cancer and prior anthracycline
    treatment, J Clin Oncol, 2008;26:3950–7.

  39. O’Shaughnessy J, Miles D, Vukelja S, et al., Superior survival
    with capecitabine plus docetaxel combination therapy in
    anthracycline-pretreated patients with advanced breast
    cancer: phase III trial results, J Clin Oncol, 2002;20:2812–23.

  40. Chan S, Romieu G, Huober J, et al., Phase III study of
    gemcitabine plus docetaxel compared with capecitabine
    plus docetaxel for anthracycline-pretreated patients with
    metastatic breast cancer, J Clin Oncol, 2009;27:1753–60.

  41. Hamilton A, Hortobagyi G, Chemotherapy: what progress in
    the last 5 years? J Clin Oncol, 2005;23:1760–75.

  42. Brufsky AM, Hurvitz S, Perez E, 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.

  43. Citeline, TrialTrove, 2012. Available at:
    https://informa.citeline.com

  44. Boneberg EM, Legler DF, Hoefer MM, et al., Angiogenesis
    and lymphangiogenesis are downregulated in primary
    breast cancer, Br J Cancer, 2009;101:605–14.

  45. Dudley AC, Tumor endothelial cells, Cold Spring Harb
    Perspect Med, 2012;2:a006536.

  46. Aird WC, Endothelial cell heterogeneity, Cold Spring Harb
    Perspect Med, 2012;2:a006429.

  47. Fojo T, Wilkerson J, Bevacizumab and breast cancer:
    the E2100 outlier, Lancet Oncol, 2010;11:1117–9.

3

Article Information

Disclosure

The authors have no conflicts of interest to declare.

Correspondence

Ricardo H Álvarez, Department of Breast Medical Oncology, Unit 1354, The University of Texas MD Anderson Cancer Center, PO Box 301439, Houston, Texas 77030-3721, US. E: ralvarez@mdanderson.org

Received

2012-03-12T00:00:00

4

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