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Angiogenesis and breast cancer.

Introduction

For many years the mainstay of breast cancer management has been chemotherapy and hormone manipulation. However, while overall survival rates in breast cancer continue to improve, a significant number of patients, who appear to be disease free following adjuvant treatment, eventually relapse and die from metastatic disease. Thus, the aims of future drug development are to improve survival in the metastatic setting but also ultimately to prevent the development of metastatic disease following adjuvant treatment. Newer agents are constantly being developed with the aim of delivering more intelligent targeted' therapy. Recently, one class of drugs that has received much interest is the angiogenesis inhibitors.

Angiogenesis is the process of new blood vessel formation and has been implicated in the pathogenesis of both local tumour growth and the development of metastases. The vast majority of work investigating the potential therapeutic use of anti-angiogenic agents has focused on targeting the vascular endothelial growth factor (VEGF) and its receptors. VEGF and its receptors are overexpressed by a wide variety of solid organ malignancies including breast cancer. Furthermore, there are data suggesting that higher tumour levels of VEGF are predictive of a poorer response to systemic therapy in advanced breast cancer and are also an independent predictor of overall survival in node-positive patients following adjuvant treatment [1,2]. Targeting VEGF can be done at several levels including targeting the ligand itself, the extracellular domain of the receptor, or the internal receptor tyrosine kinase.

Bevacizumab: anti-VEGF antibody

Bevacizumab is a recombinant humanised monoclonal antibody directed against VEGF that has previously been shown to have clinical activity in metastatic colorectal, non-small-cell lung and renal cell cancers 3-5]. With regard to breast cancer, an initial Phase I/II trial assessed the safety and efficacy of bevacizumab in escalating doses ranging from 3 to 20 mg/kg administered intravenously (iv) every 2 weeks in 75 patients with previously treated metastatic breast cancer. Four patients discontinued study treatment because of an adverse event, while hypertension was reported in 17 (23%) patients. At the final assessment point on day 154, 12 of 75 patients (16%) had stable disease or an ongoing response [6].

Several smaller Phase II studies have been reported looking at the combination of bevacizumab with 'standard' chemotherapy agents including one which looked at the combination of bevacizumab (10 mg/kg iv on days 1 and 15) with weekly docetaxel (35 mg/[m.sup.2] iv on days 1, 8 and 15 of a 28-day cycle) as first- or second-line treatment in 27 patients with metastatic breast cancer [7]. The primary endpoints of the study were assessment of toxicity, overall response rate and progression-free survival. The most common grade 4 toxicities were pulmonary embolus, febrile neutropenia and infection. The overall response rate was 52% [95% confidence interval (CI), 32-71] and the median progression-free survival was 7.5 months (95% CI, 6.2-8.3). Other agents that have been studied in combination with bevacizumab include vinorelbine, letrozole and trastuzumab.

Recently, two randomised Phase III trials have been reported, again in the metastatic setting. The initial study was carried out on 462 women with metastatic breast cancer who had previously been treated with an anthracycline and a taxane. Patients were randomly assigned to receive either capecitabine monotherapy (2500 mg/[m.sup.2]/day twice daily on days 1 to 14 every 3 weeks) or capecitabine in combination with bevacizumab (15 mg/kg iv every 3 weeks) [8]. The addition of bevacizumab resulted in a significant increase in response rates (19.8% versus 9.1%; P = 0.001) but this was not associated with an improvement in median progression-free survival [4.17 and 4.86 months, respectively; hazard ratio (HR), 0.98; P = 0.85] or overall survival. There are several possible explanations for these results. Firstly, several different pro-angiogenic pathways are operating in advanced disease and thus blocking one pathway may not be effective and secondly, the testing of new drugs in patients who have failed two chemotherapy regimens may not be ideal.

A randomised Phase III study [Eastern Cooperative Oncology Group (ECOG) 2100] has been reported comparing paclitaxel alone (90 mg/[m.sup.2] iv on days 1, 8 and 15 of a 28-day cycle) with paclitaxel and bevacizumab (10 mg/kg iv on days 1 and 15) as first-line treatment in 722 patients with metastatic breast cancer. The primary endpoint for this study was progression-free survival. Patients who received the combination treatment had a progression-free survival of 11.4 months compared with 6.11 months for the patient group treated with paclitaxel alone (HR, 0.51; 95% CI, 0.43-0.62; P < 0.001) [9]. Furthermore, overall survival was improved in the group of patients who received bevacizumab, although this did not reach statistical significance. Thus, bevacizumab is the first anti-angiogenic agent that has been demonstrated to have clinical benefit in breast cancer. It should be reiterated that this trial was carried out in patients who had not received prior chemotherapy for their metastatic disease.

Currently further trials combining bevacizumab with different chemotherapy agents are taking place both in the metastatic and more recently in the adjuvant setting. The B017708 study is a randomised, double-blind, placebo-controlled Phase III trial comparing docetaxel (100 mg/[m.sup.2] iv every 3 weeks) with or without bevacizumab (at 7.5 or 15 mg/kg iv every 3 weeks) in previously untreated patients with metastatic breast cancer. The primary outcome measure of this trial will be progression-free survival.

Furthermore a multi-national Phase III study led by the Istituto Nazionale Tumori in Milan is currently being carried out to compare the efficacy and safety of bevacizumab (15 mg/kg iv every 3 weeks) with trastuzumab (8 mg/kg iv loading dose followed by 6 mg/kg every 3 weeks maintenance)/docetaxel (100 mg/[m.sup.2] iv every 3 weeks), versus trastuzumab/ docetaxel alone, as first-line treatment in patients with human epidermal growth factor receptor 2 (HER2)-positive locally recurrent or metastatic breast cancer. This study is being carried out following the report of initial data revealing a positive correlation between VEGF and HER2 expression in breast cancer together with the results of a Phase I trial that reported responses in five of nine (56%) patients treated with a combination of these antibodies [10,11]. The rationale for combining trastuzumab and bevacizumab is that an increase in VEGF expression may represent one mechanism by which tumour cells escape anti-HER2-targeted antibody therapy.

With regard to adjuvant studies, the Phase II ECOG E2104 trial exploring two potential strategies of incorporating bevacizumab has recently completed accrual. First, patients were enrolled into arm A, which gave bevacizumab (10 mg/kg iv) concurrently with an anthracycline (60 mg/[m.sup.2] doxorubicin) and cyclophosphamide (600 mg/[m.sup.2]) every 2 weeks for four cycles and then bevacizumab with a taxane (175 mg/[m.sup.2] paclitaxel) every 2 weeks for four cycles. Because this particular schedule might be expected to be associated with an increase in cardiac toxicity, further patients were enrolled into Arm B where patients completed the four cycles of anthracycline/cyclophosphamide combination first and then had bevacizumab added concurrently with their taxane for four cycles. For both arms bevacizumab was continued for a total duration of 1 year. The primary endpoint of this trial is cardiac dysfunction.

The National Cancer Institute is planning a large randomised Phase III adjuvant study (ECOG E5103) that will randomly assign patients to one of three arms. In basic terms, patients in Arm A will receive anthracycline plus taxane-based therapy alone. Patients in Arm B will receive the same chemotherapy with bevacizumab added concurrently with the chemotherapy, and patients in Arm C will have the same chemotherapy with bevacizumab, both concurrently and then for an additional six months of maintenance. The primary outcome measure in this study will be disease-free survival.

VEGF tyrosine kinase inhibitors

Although, in breast cancer, bevacizumab has been the most studied of the VEGF inhibitors several other agents are currently being explored. These include the VEGF receptor tyrosine kinase inhibitors sunitinib and sorafenib. One of the potential advantages these agents have over bevacizumab is that they interrupt multiple receptor tyrosine kinases and therefore may have greater clinical efficacy, although one might also expect greater toxicities.

Sunitinib

Sunitinib inhibits the VEGF, platelet-derived growth factor and FLT3 tyrosine kinases. A Phase II study recently reported objective response rates of 14% in patients with metastatic breast cancer who had previously received anthracycline and taxane therapy [12]. The drug was relatively well tolerated although 17% of patients required dose reductions with the most common toxicities being grade 3 neutropenia, diarrhoea, nausea, fatigue and hypertension. Ongoing Phase III trials are currently recruiting patients with advanced breast cancer to further investigate the potential role of sunitinib. The A6181094 trial is comparing treatment with sunitinib plus paclitaxel versus bevacizumab plus paclitaxel as first-line treatment for patients with metastatic breast cancer. This trial will compare the activity and safety of sunitinib combined with docetaxel versus docetaxel alone in patients with unresectable locally recurrent or metastatic breast cancer.

Sorafenib

Sorafenib has a similar but distinct tyrosine kinase inhibitor profile to sunitinib. However, a Phase II trial of sorafenib in third-line treatment in metastatic breast cancer demonstrated very modest clinical activity with a response in only one of 23 patients [13].

Axitinib

More recently, a Phase II study presented at the 2007 annual meeting of the American Society of Clinical Oncology examined the use of a VEGF receptor tyrosine kinase inhibitor, axitinib, in addition to docetaxel (80 mg/[m.sup.2]) in patients with previously untreated metastatic breast cancer [14]. Use of axitinib was associated with an increase in response rates (39.3% versus 23.2%; P = 0.038) with a borderline increase in time to progression (median 8.2 months versus 7 months; HR, 0.73; P = 0.052). A larger Phase III trial is planned.

Chemotherapy agents

Standard chemotherapy agents have also been demonstrated to have anti-angiogenic effects when administered at a lower more frequent dose. This method of dosing, also termed metronomic dosing, results in the death of endothelial cells within the tumour bed as opposed to direct killing of tumour cells. Low-dose oral methotrexate (2.5 mg twice a day on days 1 and 2 every week) with cyclophosphamide (50 mg daily) has been evaluated in patients previously treated for their metastatic breast cancer [15]. Among the 63 evaluable patients, there was an overall response rate of 19.0% (95% CI, 10.2-30.9). In this study the authors also measured serum VEGF levels and interestingly found that the median serum VEGF levels decreased for patients who had been on treatment for at least 2 months. This fall, however, did not appear to correlate with response because it was seen in both responders and non-responders.

Summary

Although anti-angiogenic agents have been shown to have clinical activity in breast cancer, many questions remain unanswered. Firstly, exactly which method of targeting angiogenesis will prove to be the most clinically effective is yet to be determined; for example, will targeting the VEGF pathway alone be better than using agents that target multiple pathways? Secondly, the exact combination of which anti-angiogenic agents and 'standard' treatment has the most clinical benefit is yet to be elucidated. Finally, the long-term safety of anti-angiogenic agents for patients receiving these drugs in an adjuvant setting is unknown as is the optimum duration of treatment.

References

[1.] Foekens JA, Peters HA, Grebenchtchikov N et al. High tumor levels of vascular endothelial growth factor predict poor response to systemic therapy in advanced breast cancer. Cancer Res, 2001, 61, 5407-5414.

[2.] Linderholm B, Grankvist K, Wilking N et al. Correlation of vascular endothelial growth factor content with recurrences, survival, and first relapse site in primary node-positive breast carcinoma after adjuvant treatment. J Clin Oncol, 2000, 18, 1423-1431.

[3.] Emmanouilides C, Sfakiotaki G, Androulakis N et al. Front-line bevacizumab in combination with oxaliplatin, leucovorin and 5-fluorouracil (FOLFOX) in patients with metastatic colorectal cancer: a multicenter phase II study. BMC Cancer, 2007, 7, 91.

[4.] Sandler A, Gray R, Perry MC et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med, 2006, 355, 2542-2550.

[5.] Yang JC, Haworth L, Sherry RM et al. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med, 2003, 349, 427-434.

[6.] Cobleigh MA, Langmuir VK, Sledge GW et al. A phase I/II dose-escalation trial of bevacizumab in previously treated metastatic breast cancer. Semin Oncol, 2003, 30, 117-124.

[7.] Ramaswamy B, Elias AD, Kelbick NT et al. Phase II trial of bevacizumab in combination with weekly docetaxel in metastatic breast cancer patients. Clin Cancer Res, 2006, 12, 3124-3129.

[8.] 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, 792-799.

[9.] Miller KD, Wang M, Gralow J et al. Randomized phase III trial of paclitaxel versus paclitaxel plus bavacizumab as first-line therapy for locally recurrent or metastatic breast cancer: a trial coordinated by the Eastern Cooperative Oncology Group (E2100). Breast Cancer Res Treat, 2005, 94 (suppl 1), Abstr. S6.

[10.] Konecny GE, Meng YG, Untch 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, 1706-1716.

[11.] Pegram M, Yeon C, Ku NC et al. Phase I combined biological therapy of breast cancer using two humanized monoclonal antibodies directed against HER2 proto-oncogene and vascular endothelial growth factor (VEGF). Breast Cancer Res Treat, 2004, 88 (suppl), Abstr. aS124.

[12.] Miller KD, Burstein HJ, Elias AD et al. (2005) Phase II study of SU11248, a multitargeted receptor tyrosine kinase inhibitor (TKI), in patients (pts) with previously treated metastatic breast cancer (MBC). J Clin Oncol, 23 (suppl 1), Abstr. 16S.

[13.] Moreno-Aspitia A, Hillman DW, Weisenfeld M et al. BAY 43-9006 as single oral agent in patients with metastatic breast cancer previously exposed to anthracycline and/or taxane. J Clin Oncol, 2006, 24 (suppl), Abstr. 18S.

[14.] Rugo HS, Stopeck A, Joy AA et al. A randomized double-blind phase II study of the oral tyrosine kinase inhibitor (TKI) axitin-Ib (AG-013736) in combination with docetaxel (DOC) compared to DOC plus placebo (PL) in metastatic breast cancer (MBC). Proc ASCO, 2007, 25, Abstr.1003.

[15.] Colleoni M, Rocca A, Sandri MT et al. Low-dose oral methotrexate and cyclophosphamide in metastatic breast cancer: antitumor activity and correlation with vascular endothelial growth factor levels. Ann Oncol, 2002, 13, 73-80.

Roopinder Gillmore and David Miles

Mount Vernon Hospital, Middlesex, UK

Correspondence to: David Miles, Mount Vernon Hospital, Rickmansworth Road, Northwood, Middlesex HA6 2RN, UK (email: david.miles@doctors.org.uk)
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Author:Gillmore, Roopinder; Miles, David
Publication:Advances in Breast Cancer
Geographic Code:1USA
Date:Jun 1, 2007
Words:2456
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