Top

Published in:

01-02-2012 | Breast Cancer (KR Fox, Section Editor)

Bevacizumab in the Treatment of Metastatic Breast Cancer: Friend or Foe?

Authors: Alberto J. Montero, Mauricio Escobar, Gilberto Lopes, Stefan Glück, Charles Vogel

Published in: Current Oncology Reports | Issue 1/2012

Abstract

Metastatic breast cancer (MBC) is a major cause of death among women worldwide. Progress has been made in treating MBC with the advent of anti-estrogen therapies, potent cytotoxic agents, and monoclonal antibodies. Bevacizumab is a monoclonal antibody against circulating vascular endothelial growth factor (VEGF), which was approved in 2008 by the US Food and Drug Administration (FDA), for first-line treatment of HER-2 negative MBC in combination with paclitaxel. The FDA then reversed this decision in December 2010 by recommending removal of the MBC indication from bevacizumab, citing primarily safety concerns, and that these risks did not outweigh the ability of bevacizumab to significantly prolong progression-free survival. This decision was unexpected in the oncology community and remains controversial. This review looks at all available phase 3 data with bevacizumab in the MBC setting to determine whether the data support this decision by the FDA, and discusses the future of bevacizumab in breast cancer.

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(5 Suppl 16):117–24.PubMedCrossRef

Cohen MH, Gootenberg J, Keegan P, Pazdur R. FDA drug approval summary: bevacizumab plus FOLFOX4 as second-line treatment of colorectal cancer. Oncologist. 2007;12(3):356–61.PubMedCrossRef

Cohen MH, Gootenberg J, Keegan P, Pazdur R. FDA drug approval summary: bevacizumab (avastin) plus carboplatin and paclitaxel as first-line treatment of advanced/metastatic recurrent nonsquamous non-small cell lung cancer. Oncologist. 2007;12(6):713–8.PubMedCrossRef

Carmeliet P. Angiogenesis in life, disease and medicine. Nature. 2005;438(7070):932–6.PubMedCrossRef

Ferrara N. VEGF and the quest for tumour angiogenesis factors. Nat Rev Cancer. 2002;2(10):795–803.PubMedCrossRef

Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971;285(21):1182–6.PubMedCrossRef

Korpanty G, Sullivan LA, Smyth E, Carney DN, Brekken RA. Molecular and clinical aspects of targeting the VEGF pathway in tumors. J Oncol. 2010;2010:652320.PubMed

Yancopoulos GD, Davis S, Gale NW, Rudge JS, Wiegand SJ, Holash J. Vascular-specific growth factors and blood vessel formation. Nature. 2000;407(6801):242–8.PubMedCrossRef

Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science. 1989;246(4935):1306–9.PubMedCrossRef

10.

Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med. 2003;9(6):669–76.PubMedCrossRef

11.

Holmes K, Roberts OL, Thomas AM, Cross MJ. Vascular endothelial growth factor receptor-2: structure, function, intracellular signalling and therapeutic inhibition. Cell Signal. 2007;19(10):2003–12.PubMedCrossRef

12.

Ferrara N. Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev. 2004;25(4):581–611.PubMedCrossRef

13.

Jain RK. Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy. Nat Med. 2001;7(9):987–9.PubMedCrossRef

14.

Jain RK. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science. 2005;307(5706):58–62.PubMedCrossRef

15.

Duda DG, Jain RK, Willett CG. Antiangiogenics: the potential role of integrating this novel treatment modality with chemoradiation for solid cancers. J Clin Oncol. 2007;25(26):4033–42.PubMedCrossRef

16.

Ferrara N, Hillan KJ, Gerber HP, Novotny W. Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov. 2004;3(5):391–400.PubMedCrossRef

17.

Gray R, Bhattacharya S, Bowden C, Miller K, Comis RL. 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(30):4966–72.PubMedCrossRef

18.

• Martin M, Roche H, Pinter T, Crown J, Kennedy MJ, Provencher L, 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(4):369–76. This study showed that weekly paclitaxel plus bevacizumab had a median PFS of 11.5 months which was almost identical to that seen in E2100, versus 9.0 for paclitaxel, which was better than what was observed in the control arm in E2100. This study also showed that the oral anti-angiogenic agent motesanib when combined with paclitaxel was no better than placebo. PubMedCrossRef

19.

Ito Y, Aogi K, Masuda N, Ohno S, Oda T, Iwata H, et al. Efficacy of first-line bevacizumab (bev) combined with weekly paclitaxel (wPac) for HER2-negative metastatic breast cancer (MBC): results of a japanese phase II study (n = 120). J Clin Oncol. 2011;29(suppl; abst 1119).

20.

•• Valachis A, Polyzos NP, Patsopoulos NA, Georgoulias V, Mavroudis D, Mauri D. Bevacizumab in metastatic breast cancer: a meta-analysis of randomized controlled trials. Breast Cancer Res Treat. 2010;122(1):1–7. This meta-analysis shows that the addition of bevacizumab to chemotherapy offers meaningful improvement in PFS and ORR in MBC patients. No significant advantage was observed in OS with the addition of bevacizumab when pooling phase 3 data. PubMedCrossRef

21.

•• Smith IE, Pierga JY, Biganzoli L, Cortes-Funes H, Thomssen C, Pivot X, 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(3):595–602. This study showed in a real world oncology practice setting and in a very large number of women with metastatic breast cancer that combining bevacizumab with different types of chemotherapy was well tolerated and didn’t have greater toxicities than what were reported in the phase 3 trials. PubMedCrossRef

22.

•• Biganzoli L, Di Vincenzo E, Jiang Z, Lichinitser M, Shen Z, Delva R, et al. First-line bevacizumab-containing therapy for breast cancer: results in patients aged > =70 years treated in the ATHENA study. Ann Oncol. 2011 Mar 28. This study is the largest study to date evaluating the side effect profile of bevacizumab plus chemotherapy in older women (70 and older) with MBC. It shows that the combination of weekly paclitaxel and bevacizumab appeared to be particularly active in this patient population, with no additional safety signals.

23.

FDA begins process to remove breast cancer indication from avastin label [Internet]. U.S. Food and Drug Administration; 2010 [updated 12/16/2010. Available from: http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm237172.htm.

24.

Eskens FA, Verweij J. The clinical toxicity profile of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor (VEGFR) targeting angiogenesis inhibitors; a review. Eur J Cancer. 2006;42(18):3127–39.PubMedCrossRef

25.

Zhu X, Wu S, Dahut WL, Parikh CR. Risks of proteinuria and hypertension with bevacizumab, an antibody against vascular endothelial growth factor: systematic review and meta-analysis. Am J Kidney Dis. 2007;49(2):186–93.PubMedCrossRef

26.

Cortes J, O’Shaughnessy J, Loesch D, Blum JL, Vahdat LT, Petrakova K, et al. Eribulin monotherapy versus treatment of physician’s choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study. Lancet. 2011;377(9769):914–23.PubMedCrossRef

27.

Cortes J, Montero AJ, Gluck S. Eribulin mesylate, a novel microtubule inhibitor in the treatment of breast cancer. Cancer Treat Rev. 2011 May 6.

28.

Saad ED, Katz A, Hoff PM, Buyse M. Progression-free survival as surrogate and as true end point: insights from the breast and colorectal cancer literature. Ann Oncol. 2010;21(1):7–12.PubMedCrossRef

29.

Di Leo A, Bleiberg H, Buyse M. Overall survival is not a realistic end point for clinical trials of new drugs in advanced solid tumors: a critical assessment based on recently reported phase III trials in colorectal and breast cancer. J Clin Oncol. 2003;21(10):2045–7.PubMedCrossRef

30.

Cortazar P, Zhang JJ, Sridhara R, Justice RL, Pazdur R. Relationship between OS and PFS in metastatic breast cancer (MBC): review of FDA submission data. J Clin Oncol. 2011;29(suppl; abstr 1035).

31.

Jubb AM, Harris AL. Biomarkers to predict the clinical efficacy of bevacizumab in cancer. Lancet Oncol. 2010;11(12):1172–83.PubMedCrossRef

32.

Schneider BP, Wang M, Radovich M, Sledge GW, Badve S, Thor A, et al. Association of vascular endothelial growth factor and vascular endothelial growth factor receptor-2 genetic polymorphisms with outcome in a trial of paclitaxel compared with paclitaxel plus bevacizumab in advanced breast cancer: ECOG 2100. J Clin Oncol. 2008;26(28):4672–8.PubMedCrossRef

33.

Linderholm BK, Hellborg H, Johansson U, Elmberger G, Skoog L, Lehtio J, 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(10):1639–46.PubMedCrossRef

34.

Dowlati A, Gray R, Sandler AB, Schiller JH, Johnson DH. Cell adhesion molecules, vascular endothelial growth factor, and basic fibroblast growth factor in patients with non-small cell lung cancer treated with chemotherapy with or without bevacizumab–an eastern cooperative oncology group study. Clin Cancer Res. 2008;14(5):1407–12.PubMedCrossRef

35.

Ronzoni M, Manzoni M, Mariucci S, Loupakis F, Brugnatelli S, Bencardino K, et al. Circulating endothelial cells and endothelial progenitors as predictive markers of clinical response to bevacizumab-based first-line treatment in advanced colorectal cancer patients. Ann Oncol. 2010;21(12):2382–9.PubMedCrossRef

36.

Yang SX, Steinberg SM, Nguyen D, Wu TD, Modrusan Z, Swain SM. Gene expression profile and angiogenic marker correlates with response to neoadjuvant bevacizumab followed by bevacizumab plus chemotherapy in breast cancer. Clin Cancer Res. 2008;14(18):5893–9.PubMedCrossRef

37.

Denduluri N, Yang SX, Berman AW, Nguyen D, Liewehr DJ, Steinberg SM, et al. Circulating biomarkers of bevacizumab activity in patients with breast cancer. Cancer Biol Ther. 2008;7(1):15–20.PubMedCrossRef

38.

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(23):2335–42.PubMedCrossRef

39.

Montero AJ, Gluck S, Lopes Jr GD. The cost-effectiveness of bevacizumab in combination with paclitaxel in first-line treatment of patients with metastatic breast cancer. J Clin Oncol. 2011;29(suppl; abstr 6060).

40.

Dedes KJ, Matter-Walstra K, Schwenkglenks M, Pestalozzi BC, Fink D, Brauchli P, et al. Bevacizumab in combination with paclitaxel for HER-2 negative metastatic breast cancer: an economic evaluation. Eur J Cancer. 2009;45(8):1397–406.PubMedCrossRef

41.

Caplan AL. Will evidence ever be sufficient to resolve the challenge of cost containment? J Clin Oncol. 2011;29(15):1946–8.PubMedCrossRef

42.

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(26):2666–76.PubMedCrossRef

43.

Miles DW, Chan A, Romieu G, Dirix LY, Cortes J, Pivot X, et al. Randomized, double-blind, placebo-controlled, phase III study of bevacizumab with docetaxel or docetaxel with placebo as first-line therapy for patients with locally recurrent or metastatic breast cancer (mBC): AVADO. J Clin Oncol. 2008;26(43s).

44.

Robert NJ, Dieras 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(10):1252–60.PubMedCrossRef

45.

O’Shaughnessy JA, Brufsky AM. RiBBON 1 and RiBBON 2: phase III trials of bevacizumab with standard chemotherapy for metastatic breast cancer. Clin Breast Cancer. 2008;8(4):370–3.PubMedCrossRef

46.

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(4):792–9.PubMedCrossRef

47.

Brufsky A, Bondarenko I, Smirnov V, Hurvitz S, Perez E, Ponomarova O, 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 HER2-negative metastatic breast cancer. Cancer Res. 2009;69(24).

48.

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(24):2542–50.PubMedCrossRef

49.

Hurwitz HI, Fehrenbacher L, Hainsworth JD, Heim W, Berlin J, Holmgren E, et al. Bevacizumab in combination with fluorouracil and leucovorin: an active regimen for first-line metastatic colorectal cancer. J Clin Oncol. 2005;23(15):3502–8.PubMedCrossRef

50.

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(28):4733–40.PubMedCrossRef

51.

Escudier B, Pluzanska A, Koralewski P, Ravaud A, Bracarda S, Szczylik C, et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet. 2007;370(9605):2103–11.PubMedCrossRef

Title: Bevacizumab in the Treatment of Metastatic Breast Cancer: Friend or Foe?
Authors: Alberto J. Montero
Mauricio Escobar
Gilberto Lopes
Stefan Glück
Charles Vogel
Publication date: 01-02-2012
Publisher: Current Science Inc.
Published in: Current Oncology Reports / Issue 1/2012
Print ISSN: 1523-3790
Electronic ISSN: 1534-6269
DOI: https://doi.org/10.1007/s11912-011-0202-z

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 1/2012

Management of Brain Metastasis: Past Lessons, Modern Management, and Future Considerations

Neoadjuvant Clinical Trials for the Treatment of Primary Breast Cancer: The Experience of the German Study Groups

Treatment of Brain Metastases: Chemotherapy

Hypofractionated Radiation Therapy in the Treatment of Early-Stage Breast Cancer

Zoledronic Acid in the Treatment of Early-Stage Breast Cancer: Is There a Final Verdict?

The Role of Lapatinib in the Preoperative Therapy of Breast Cancer

Keynote webinar | Spotlight on antibody–drug conjugates in cancer