Elsevier

Cancer Treatment Reviews

Volume 38, Issue 6, October 2012, Pages 673-688
Cancer Treatment Reviews

Anti-Tumour Treatment
Controlling angiogenesis in breast cancer: A systematic review of anti-angiogenic trials

https://doi.org/10.1016/j.ctrv.2011.12.002Get rights and content

Abstract

Purpose

Angiogenesis is critical for tumor growth and a promising therapeutic target. This review will summarize and analyze data from clinical trials of anti-angiogenic agents in the treatment of breast cancer (BC).

Design

A systematic search of PubMed and conference databases was performed to identify reports of randomized clinical trials investigating specific anti-angiogenic agents in the treatment of BC.

Results and discussion

Phase III trials in advanced BC have demonstrated a reduction in the risk of disease progression (22–52%), improved response rates and net improvements in progression-free survival of 1.2 to 5.5 months, but no significant improvements in overall survival with the addition of bevacizumab to chemotherapy. Results of phase III trials in early breast cancer have been inconsistent. Bevacizumab-containing regimens have also been associated with higher overall adverse event rates compared to chemotherapy alone. Phase III trials of the tyrosine kinase inhibitor sunitinib were negative, while randomized phase II trials of sorafenib and pazopanib have improved some outcomes when combined with chemotherapy or targeted therapy compared to controls. In addition to expected vascular class safety signals, tyrosine kinase inhibitors show “off-target” side effects. Ongoing clinical trials evaluating combinatorial strategies based on biological synergies and translational studies identifying biological predictors of response will be crucial to establish meaningful clinical benefits in selected BC populations.

Conclusion

Most trials of anti-angiogenic agents in BC have reported improved response rate and progression-free survival but no increase in overall survival compared to chemotherapy alone. Optimizing the therapeutic indices of these agents is a focus of ongoing research and will be critical to their future development.

Introduction

Treatment of cancer using anti-angiogenic agents is based on several hypotheses: (i) there is a continuously expanding network of capillaries supplying nutrients and oxygen to support tumor growth; (ii) the process of angiogenesis can be blocked therapeutically without causing excessive host toxicity; and (iii) such therapeutic interventions will induce a state of tumor dormancy.1 It was initially thought that there would be a small number of tumor angiogenesis factors (TAFs) produced and secreted by tumor cells acting in a paracrine manner on the vascular endothelium of mature vessels to initiate angiogenesis. Thus a specific neutralizing anti-TAF antibody was hypothesized to have potential anti-angiogenic and therefore anti-tumor activity.1 The discovery of the vascular endothelial growth factor (VEGF) family of angiogenesis stimulators (VEGF-A, B, C, D and placental growth factor) and the development of several VEGF pathway-targeting agents have validated many of the principles of the anti-angiogenic treatment concept.2 These agents include antibodies to VEGF-A (“VEGF”) and its receptors, as well as a host of small molecule tyrosine kinase inhibitors (TKIs) that act intracellularly to target the catalytic function of vascular endothelial growth factor receptors (VEGFRs) expressed by endothelial cells.[2], [3], [4]

Clinical benefits of anti-angiogenic agents have been reported in colorectal cancer, non-small cell lung carcinoma[5], [6] and renal cell carcinoma7 and have led to the adoption of anti-angiogenic therapies for these diseases in many jurisdictions. Preclinical studies have confirmed that angiogenesis also plays a central role in breast cancer carcinogenesis and metastatic potential.[8], [9], [10], [11] The tumor microvessel density of breast cancers is known to be predictive of bone marrow micrometastases, recurrence and overall survival (OS),[12], [13], [14], [15] establishing angiogenesis as a potential therapeutic target for breast cancer.16 Our systematic review will analyze data from randomized clinical trials of anti-angiogenic agents in breast cancer, discuss possible factors limiting the impact of anti-angiogenic agents in metastatic breast cancer (MBC) and explore strategies for improving risk-to-benefit ratios.

Section snippets

Methods

English language reports of clinical trials investigating anti-angiogenic agents in the treatment of breast cancer were systematically identified through a search of PubMed (no limit to February 2010), American Society of Clinical Oncology (2007–2009) and American Society of Clinical Oncology Breast Cancer (2007–2009) databases (Fig. 1) using the search string: breast cancer AND angiogenesis (vascular, VEGF) AND inhibitors ([agents, treatment, therapy] OR [bevacizumab, pazopanib, axitinib,

Bevacizumab efficacy

Bevacizumab (Avastin®, Roche-Genentech) is a monoclonal antibody that binds and inactivates VEGF, thereby inhibiting VEGF-mediated angiogenesis. Initial phase II reports of bevacizumab showed modest single agent activity in the advanced setting with subsequent phase III trials suggesting improved activity when bevacizumab is administered in conjunction with chemotherapy.[16], [17], [18], [19], [20]

The AVF2119g trial combined bevacizumab with capecitabine (Xeloda®, Roche-Genentech) as

Bevacizumab safety and efficacy

Two randomized trials have evaluated the addition of bevacizumab to standard neo-adjuvant chemotherapy (Table 5).[45], [46], [47], [48] The phase III GeparQuinto trial randomized 1948 HER2-negative breast cancer patients to standard anthracycline-taxane neo-adjuvant chemotherapy and bevacizumab (15 mg/kg) or chemotherapy alone.[48], [49] The addition of bevacizumab did not significantly increase the pathological complete response rate (pCR; breast and axilla [ypT0, ypN0], 15% vs. 17.5% or pCR

Summary of efficacy and safety

There is a strong biological rationale supporting the addition of anti-angiogenics to chemotherapy in advanced breast cancer. Findings from four phase III clinical trials,[18], [19], [20], [21], [22], [23] three of which were placebo controlled, have shown that the addition of bevacizumab to first and second-line chemotherapy significantly reduces the risk of disease progression (22–52%) (Table 1). However, net improvements in median PFS observed in the placebo-controlled trials (1.2–2.9 months)

Conclusion

Randomized trials of anti-angiogenic agents combined with chemotherapy for MBC have generally demonstrated modest improvements in PFS relative to chemotherapy alone with no OS advantage and additive toxicities, highlighting the need to optimize the therapeutic index of this class of agents. Ongoing translational research, combinatorial strategies and identification of biological predictors of response will be critical to establishing a clear clinical benefit for anti-angiogenic agents in the

Role of funding source

This review was funded through an unrestricted educational grant from the Alberta Cancer Services Board. The sponsor had no role in review design; collection, analysis or interpretation of the data; in the writing of the manuscript; or in the decision to submit the manuscript for publication.

Conflict of interest statement

List of authors and acronyms: John R. Mackey (JRM), Robert S. Kerbel (RK), Karen A. Gelmon (KG), Deanna M. McLeod (DM), Stephen K. Chia (SC), Daniel Rayson (DR), Sunil K. Verma (SV), Loretta L. Collins (LC), Alexander H. G. Paterson (AP), André Robidoux (AR), Kathleen I. Pritchard (KP)

  • 1.

    Employment of Leadership Positions – JRM, none; RK, none; KG, none; DM, none; SC, none; DR, none; SV, none; LC, none; AP, none; AR, none; KP, none

  • 2.

    Consultant or Advisory Role –JRM, Esai, Roche, Eli Lilly; RK, Taiho

Acknowledgments

We thank Ilidio Martins and Deborah Card for their editorial and research contributions to this manuscript. We also thank the Alberta Health Services, Cancer Care for funding this review.

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