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. 2011 Mar;3(2):85–93. doi: 10.1177/1758834010397627

Bevacizumab in metastatic breast cancer: when may it be used?

Shari B Goldfarb 1, Clifford Hudis 2, Maura N Dickler 3,✉
PMCID: PMC3126041  PMID: 21789158

Abstract

Tumor angiogenesis, which is necessary for breast cancer growth, invasion and metastases, is regulated by pro-angiogenic factors such as vascular endothelial growth factor (VEGF). Bevacizumab is a recombinant humanized monoclonal antibody that targets VEGF. The addition of bevacizumab to chemotherapy has improved progression-free survival in the first- and second-line treatment of patients with advanced-stage breast cancer. In this article we review the clinical trials testing the utility of bevacizumab for the treatment of metastatic disease.

Keywords: bevacizumab, breast cancer, progression-free survival, vascular endothelial growth factor

Introduction

The development of novel biologic agents that specifically target growth factor–receptor signaling pathways has led to significant advances in breast cancer treatment. Vascular endothelial growth factor (VEGF) is a glycoprotein produced by both neoplastic and normal cells and it plays a major role in angiogenesis (new blood vessel formation) in both pathologic and physiologic conditions (i.e. tissue repair) [Ferrara, 1999]. In addition to regulating new blood vessel formation, VEGF also supports the maintenance of newly formed blood vessels and inhibits endothelial cell apoptosis. Therefore, VEGF became a target for pharmacological inhibition of tumor angiogenesis [Foekens et al. 2001; Linderholm et al. 2000, 1998]. Bevacizumab binds circulating VEGF, preventing the ligand from interacting with its receptor, thereby abrogating the biologic activity of VEGF [Presta et al. 1997]. Bevacizumab was the first anti-angiogenic drug to demonstrate efficacy in breast cancer and was granted ‘accelerated’ approval by the US Food and Drug Administration (FDA) in 2008 in combination with paclitaxel for the first-line treatment of metastatic, HER2-negative breast cancer. In this review article we discuss bevacizumab’s development as a treatment for advanced breast cancer.

Bevacizumab

Bevacizumab is composed of a human IgG backbone (93%) and an antigen-binding region derived from a murine monoclonal antibody (7%) [Presta et al. 1997]. Bevacizumab has a linear pharmacokinetic profile that is not affected by concurrent chemotherapy or endocrine therapy [Gordon et al. 2001]. The drug reaches a steady state at approximately 18 weeks. Bevacizumab also has a very long half life of approximately 21 days (range 11–50).

Bevacizumab monotherapy

The safety, efficacy, and pharmacokinetics of bevacizumab in patients with previously treated metastatic breast cancer was first evaluated in a phase I/II study [Cobleigh et al. 2003]. Bevacizumab was administered to 75 patients at escalating doses of 3, 10, and 20 mg/kg intravenously every 2 weeks. The overall response rate of bevacizumab monotherapy was 9.3%, with a 5.5 month median duration of response (range: 2.3–13.7 months). In addition, median time to progression was 2.4 months and median overall survival (OS) was 10.2 months.

Bevacizumab was generally well tolerated and the agent’s toxicity profile differed from those typically experienced with cytotoxic chemotherapy [Cobleigh et al. 2003]. Headache was the dose-limiting toxicity experienced at 20 mg/kg. Four patients treated with 20 mg/kg discontinued the study because of hypertensive encephalopathy, nephrotic syndrome, proteinuria, and headache associated with nausea and vomiting. Other bevacizumab-associated side effects included hypertension, myalgia, dyspnea, and asthenia. Two out of the 72 patients (2.8%) experienced proteinuria, and thrombotic events occurred in three patients. Given the toxicity from bevacizumab at 20 mg/kg, this study supported a recommended dose of 10 mg/kg intravenously every 2 weeks for the treatment of advanced breast cancer.

Bevacizumab and chemotherapy

Modest clinical benefits were seen with bevacizumab monotherapy and several preclinical studies suggested synergy between anti-angiogenic therapy and chemotherapy. Therefore, bevacizumab was studied in combination with a number of chemotherapeutic agents. Results from five large, randomized, phase III clinical trials have been reported and will be discussed below.

Bevacizumab and capecitabine

The first large, randomized, open-label, phase III study evaluated the safety and efficacy of capecitabine in combination with bevacizumab versus capecitabine alone [Miller et al. 2005]. The study was performed in 462 women with metastatic breast cancer who had previously received treatment with both taxanes and anthracyclines and either had recurrent breast cancer within 12 months of finishing adjuvant therapy or received one or two prior chemotherapy regimens for metastatic disease. All of the study participants received capecitabine 2500 mg/m2/day divided twice daily for 2 weeks followed by 1 week off therapy. Bevacizumab 15 mg/kg was administered intravenously every 3 weeks to all of the patients randomized to the experimental combination arm. The primary endpoint of the study was progression-free survival (PFS).

In this study of heavily pretreated women, bevacizumab in combination with capecitabine did not significantly improve PFS or OS compared with capecitabine alone [Miller et al. 2005]. In the capecitabine and bevacizumab cohort the median PFS was 4.86 months compared with 4.17 months in the capecitabine only arm (hazard ratio [HR] 0.98, 95% confidence interval [CI]: 0.77–1.25; p = 0.857). However, bevacizumab in addition to capecitabine increased the objective response rate from 9.1% to 19.8% (p = 0.001). The bevacizumab combination arm was mostly well tolerated; capecitabine-related toxicities such as diarrhea and hand–foot syndrome were not worsened by bevacizumab.

Bevacizumab-related toxicities included proteinuria, hypertension, and minor mucosal bleeding (grade 1 or 2 epistaxis). In the bevacizumab/capecitabine arm, 22.3% of patients had any-grade proteinuria versus 7.4% in the capecitabine-only arm. Likewise, 17.9% of patients in the combination arm had grade 3 hypertension compared with 0.5% in the single-agent capecitabine arm. Therapy for two patients was discontinued after they developed grade 3 proteinuria. Thromboembolic events and serious hemorrhage were uncommon and did not differ between treatment arms.

In this heavily pretreated patient population, the activity of bevacizumab may have been underestimated. The next randomized phase III trial evaluated bevacizumab in a relatively chemotherapy-naïve population of women, possibly addressing this limitation.

Bevacizumab and paclitaxel

The Eastern Cooperative Oncology Group (ECOG) performed a large, randomized, open-label, phase III trial evaluating bevacizumab in combination with weekly paclitaxel [Miller et al. 2007]. Preclinical evidence suggests that low-dose weekly paclitaxel has anti-angiogenic activity [Klauber et al. 1997; Belotti et al. 1996]; therefore, the combination of weekly paclitaxel and bevacizumab was selected for its dual angiogenic inhibition at a time when breast cancers may be critically dependent on VEGF. ECOG 2100 evaluated the safety and efficacy of bevacizumab in combination with weekly paclitaxel compared with paclitaxel alone as first-line therapy for 722 women with locally advanced or metastatic breast cancer. Patients randomized to the combination arm received bevacizumab at 10 mg/kg intravenously every 2 weeks, and all patients received paclitaxel at 90 mg/m2 weekly for 3 weeks followed by 1 week off. Study participants remained on therapy until unacceptable toxicity or progression of disease. Patients were eligible if they had no prior chemotherapy for metastatic breast cancer, and a disease-free interval of at least 1 year since they received adjuvant taxane therapy. Approximately 20% of patients had prior taxane therapy and two thirds of patients had received prior adjuvant chemotherapy. Patients were excluded from the study if they had significant heart disease, brain metastases or HER2-positive disease that was not previously treated with trastuzumab. Only 2.3% of the study population had breast cancer that overexpressed HER2.

PFS was the primary endpoint of the study. The addition of bevacizumab to paclitaxel significantly improved the median PFS from 5.9 to 11.8 months (p < 0.001) [Miller et al. 2007]. A higher overall response rate of 36.9% was seen in the combination arm compared with 21.2% in the single agent arm (p < 0.001). Despite the improved PFS and overall response rate, there was no difference in median OS between the two treatment arms.

Bevacizumab did not appear to worsen paclitaxel-related toxicities [Miller et al. 2007]. However, the bevacizumab treatment arm experienced more grade 3/4 proteinuria (3.5% versus 0%; p < 0.001), grade 3/4 hypertension (14.8% versus 0%; p < 0.001), headache (2.2% versus 0.0%, p = 0.008), and cerebrovascular ischemia (1.9% versus 0.0%, p = 0.02) than the paclitaxel monotherapy arm. There was no increase in thromboembolic events or episodes of congestive heart failure in the combination arm. Quality of life, measured by the Functional Assessment of Cancer Therapy (FACT)-general surveys and FACT-Breast Cancer questionnaires, was not different between treatment arms or timepoints. A subsequent independent review of E2100 was conducted, which showed a statistically significant improvement in both PFS and overall response rate, confirming the original study results [Gray et al. 2009]. The results of ECOG 2100 led to the FDA and European Medicines Agency (EMEA) approval (‘accelerated’ in the case of the FDA) of bevacizumab in combination with paclitaxel for the first-line treatment of metastatic breast cancer.

Bevacizumab and docetaxel

The AVADO (Avastin® and Docetaxel) study was a double-blind, placebo-controlled, randomized, phase III trial evaluating the efficacy of docetaxel with or without bevacizumab for first-line therapy in patients with metastatic HER2-negative breast cancer [Miles et al. 2010]. Between March 2006 and April 2007, patients were enrolled from 104 sites in 26 countries. More than 50% of patients had prior anthracycline-based therapy, 15% had prior taxane therapy and approximately two thirds of patients previously received chemotherapy for early stage breast cancer. At baseline, more than 80% of patients had measurable disease. Seven hundred and thirty six (736) women were randomized to one of three treatment arms including docetaxel 100 mg/m2 intravenously every 3 weeks with placebo versus docetaxel 100 mg/m2 with bevacizumab 7.5 mg/kg intravenously every 3 weeks versus docetaxel 100 mg/m2 with bevacizumab 15 mg/kg intravenously every 3 weeks.

Patients continued to receive treatment with docetaxel for a maximum of nine cycles or until the development of toxicity or disease progression. In the event of toxicity, dose reduction of docetaxel to 75 mg/m2 and/or 60 mg/m2 was permitted and early discontinuation of docetaxel was also allowed. Patients received bevacizumab maintenance therapy or placebo until disease progression. At the time of progression, all study participants were given the option to receive bevacizumab with their second-line chemotherapy. The primary endpoint of the trial was an unstratified PFS between the control arm and each bevacizumab-containing cohort. The study was not powered to detect a difference between the two doses of bevacizumab. Secondary endpoints were overall response rate, OS, safety, time to treatment failure, duration of response, and quality of life.

At a median follow up of 10.2 months, response rate and PFS were statistically significantly improved in both bevacizumab-containing arms compared with the placebo arm [Miles et al. 2010]. The median PFS was 8 months in the docetaxel monotherapy arm. The median PFS in the docetaxel/bevacizumab 7.5 mg/kg arm and 15 mg/kg arm were 9.0 months and 10.0 months, respectively. The unstratified HR for docetaxel and bevacizumab 7.5 mg/kg was 0.86 (0.72–1.04), p = 0.1163 and the unstratified HR for docetaxel and bevacizumab 15 mg/kg was 0.77 (0.64–0.93), p = 0.0061. Similarly, objective response rates were superior in both combination arms compared with the docetaxel-only arm, with 46.4% in the control arm, 55.2% (p = 0.0739) in the bevacizumab 7.5 mg/kg arm and 64.1% (p = 0.0003) in the bevacizumab 15 mg/kg arm. AVADO did not demonstrate a difference in OS between the treatment arms at a median follow up of 25 months; however, the study was not powered for an OS endpoint. The lack of an OS difference might also be attributable to the use of bevacizumab in subsequent lines of therapy and the impact of additional lines of therapy after progression of disease on this study [Miles et al. 2009]. However, AVADO confirmed the result of E2100, demonstrating an improvement in PFS and response rate when bevacizumab is combined with taxane chemotherapy for first-line treatment of advanced breast cancer.

The addition of bevacizumab had limited impact on docetaxel toxicity, and no new safety concerns were raised with regards to bevacizumab-associated toxicity [Miles et al. 2009]. The most common bevacizumab-related toxicity was grade 2 hypertension, which was seen in 7.2% of patients in the bevacizumab 7.5 mg/kg arm and 7.3% in the bevacizumab 15 mg/kg arm compared with 3.9% in the placebo arm. However, the incidence of grade 3 or 4 hypertension was low in all three cohorts. The rates of grade 3 or 4 proteinuria associated with bevacizumab (7.5 mg/kg and 15 mg/kg) were also quite low (0.8% and 2.0%). There was no difference in grade 3 or 4 bleeding, arterial or venous thromboembolic events or gastrointestinal perforations in the bevacizumab arms compared with the placebo arm. Grade 1 or 2 bleeding events were more prevalent in patients receiving docetaxel/bevacizumab compared with docetaxel alone.

Seven patients receiving anticoagulation at the beginning of the study were randomized to a bevacizumab-containing regimen [Wardley et al. 2009]. During the course of the study another 52 patients receiving bevacizumab were initiated on anticoagulation. In this group of 59 patients concurrently receiving bevacizumab and anticoagulation, the incidence of bleeding and thromboembolic events was not increased compared with patients in the control arm. However, the bleeding events and the number of anticoagulated patients were small. An exploratory analysis was also performed on 24 patients who developed brain metastasis during the course of study therapy [Dirix et al. 2009]. The use of bevacizumab in these patients was not associated with central nervous system (CNS) bleeding. There was no increased frequency of other grade 3 or 4 adverse events in patients with brain metastases being treated on either bevacizumab arm.

RIBBON-1

In an attempt to determine the optimal chemotherapy with which to combine bevacizumab, two recently performed phase III studies evaluated bevacizumab in combination with different standard chemotherapy agents for metastatic breast cancer. These trials partially address the possibility that the previously observed differences in efficacy with bevacizumab might be attributed to drug-specific synergy.

RIBBON-1 is an international, multicenter, randomized, placebo-controlled, phase III clinical trial evaluating bevacizumab in combination with chemotherapy for the first-line treatment of metastatic, HER2-negative breast cancer [O'Shaughnessy and Brufsky, 2008]. More than 1200 patients were randomized to chemotherapy in combination with bevacizumab or chemotherapy with placebo in a 2 : 1 ratio. Bevacizumab 15 mg/kg was administered intravenously every 3 weeks. The patient’s treating physician decided the type of chemotherapy and the range of options included a taxane (T, nab-paclitaxel, docetaxel), anthracycline (A), or capecitabine (Cape). The patients were prospectively analyzed in two groups, those that received either taxane or anthracycline-based chemotherapy and those that received capecitabine. The primary endpoint was PFS.

At a median follow up of 19.2 months in the T/A cohort and 15.6 months in the capecitabine cohort, there was a statistically significant improvement in PFS and response rate in the bevacizumab arms. In the T/A + bevacizumab arm the PFS was 9.2 months compared with 8.0 months in the T/A arm (p < 0.0001). In the capecitabine + bevacizumab cohort the PFS was 8.6 months compared with 5.7 months in the capecitabine arm (p < 0.0002). However, there was no statistically significant improvement in OS in the bevacizumab-containing arms. These results suggest that bevacizumab can be partnered with a number of chemotherapy regimens without impacting the efficacy of chemotherapy plus anti-VEGF therapy.

RIBBON-2: a second-line trial in metastatic breast cancer

RIBBON-2 is an international, multicenter, randomized, placebo-controlled, phase III clinical trial evaluating bevacizumab in combination with chemotherapy for the second-line treatment of metastatic, HER2-negative breast cancer [Brufsky et al. 2009]. All patients enrolled in the study were naïve to bevacizumab. Between February 2006 and June 2008, 684 women were randomized to receive standard second-line chemotherapy with bevacizumab or with placebo in a 2 : 1 ratio. The patient’s treating physician decided the type of second-line chemotherapy and the range of options included taxanes (weekly paclitaxel 90 mg/m2/week for 3 weeks followed by 1 week off therapy, paclitaxel 175 mg/m2 intravenously every 3 weeks, nab-paclitaxel 260 mg/m2 intravenously every 3 weeks or docetaxel 75–100 mg/m2 intravenously every 3 weeks), capecitabine 2000 mg/m2 on days 1–14 of a 21-day cycle, vinorelbine 30 mg/m2/week or gemcitabine 1250 mg/m2 on days 1 and 8 of a 21-day cycle. PFS was the primary endpoint of the study.

There was a statistically significant improvement in PFS and response rate in the bevacizumab-treated arms compared with the chemotherapy-only arms. PFS results were consistent across each chemotherapy cohort with the exception of the small vinorelbine subgroup of 76 patients. Bevacizumab in combination with chemotherapy had a PFS of 7.2 months versus a PFS of 5.1 months in the chemotherapy-alone cohort. The stratified HR was 0.78 (0.64–0.93), p < 0.0072. The addition of bevacizumab to chemotherapy also significantly improved the overall response rate from 29.6% to 39.5%, p = 0.0193. There was no significant difference in OS, but the data are still immature.

A meta-analysis of OS data from three trials of bevacizumab and first-line chemotherapy as treatment for patients with metastatic breast cancer was presented at the American Society of Clinical Oncology annual meeting in 2010 [O'Shaughnessy et al. 2010]. It reiterated that E2100, AVADO, and RIBBON-1 all have demonstrated significantly improved PFS for bevacizumab combined with different chemotherapies as first-line treatment for metastatic breast cancer. It also showed bevacizumab in combination with chemotherapy improved PFS regardless of sites of metastases, hormone receptor status, disease-free interval or prior adjuvant taxane use. The overall pooled PFS had a HR of 0.64 (0.57–0.71). The HR incorporates the entirety of the PFS curves and, therefore, may be a better measure than median PFS. The median PFS was 9.2 months in patients who received bevacizumab in combination with chemotherapy versus 6.7 months in the non-bevacizumab treated population. The overall response rate was 49% in the bevacizumab treated patients versus 32% in the chemotherapy only patients. In the pooled population, there was no statistically significant difference in OS. Therefore, this meta-analysis showed there is a statistically significant improvement in PFS, but no difference in OS with bevacizumab across three first-line studies and in a pooled analysis.

In summary, bevacizumab plus chemotherapy improves response rates and prolongs PFS when used as first- and second-line therapy for advanced breast cancer. However, bevacizumab has not improved OS in the individual studies currently reported. The relatively consistent improvement in PFS across these studies coupled with the lack of an OS benefit has raised questions regarding the general utility of PFS as a reliable surrogate for OS, and for the specific meaning and value of PFS prolongation using anti-angiogenic agents. In response, many investigators believe that tumor-angiogenic processes are likely more complicated than initially believed. Based on preclinical data, it is hypothesized that there may be a rebound effect or increased angiogenesis after discontinuing bevacizumab, which may help to explain the lack of impact on OS [Ebos et al. 2009]. Moreover, it is becoming evident that blockade of only one pathway in the signalling cascade is not as optimal as targeting two or more growth factor signalling pathways. Inhibiting multiple targets may be of greater clinical benefit to overcome resistance to monotherapy due to redundancy at the level of the VEGFR pathway and crosstalk between other signal transduction pathways.

On 20 July 2010 the Oncologic Drugs Advisory Committee (ODAC) of the FDA’s Center for Drug Evaluation and Research voted 12 to 1 against the use of bevacizumab in combination with chemotherapy for the first-line treatment of advanced breast cancer. Notably, in March 2008, the FDA had granted accelerated approval of bevacizumab for this indication contingent on additional data confirming the improvement in PFS and evidence that OS was not diminished with bevacizumab from ongoing clinical trials. On 17 December 2010, the FDA moved to revoke bevacizumab’s approval for breast cancer saying that its benefits do not outweigh its risks. It is expected that the manufacturer will request a hearing to review this decision.

Bevacizumab and endocrine therapy

Bevacizumab and letrozole

Estrogen is a potent modulator of angiogenesis under both pathologic and physiologic conditions [Morales et al. 1995]. The potent angiogenic effect of estradiol is demonstrated under normal conditions with the cyclical neovascularization of the female reproductive tract in premenopausal women [Losordo and Isner, 2001]. VEGF is the growth factor that mediates estrogen-induced angiogenesis [Kazi et al. 2005]. Estradiol increases VEGF expression in the rat uterus, leading to increased uterine edema and vascular permeability. Likewise, estrogen withdrawal, seen in oophorectomized animal models, decreases VEGF expression [Albrecht et al. 2003]. Similarly, in MCF-7 breast cancer cell lines [Takei et al. 2002], estrogen increased levels of VEGF expression and aromatase inhibition lowered VEGF in a hormone-dependent mouse model [Nakamura et al. 1996]. Data from a xenograft model shows the most compelling evidence for the relationship between endocrine regulation and angiogenesis [Jain et al. 1998]. It demonstrates tumor shrinkage and vascular regression after castration in a male mouse model of androgen-dependent breast cancer.

Despite an initial response to endocrine therapy, the majority of women with hormone-receptor positive metastatic breast cancer eventually become resistant to hormonal treatment [Jain et al. 1998]. In both adjuvant and metastatic breast cancer, retrospective studies indicate that elevated VEGF levels in breast tumor tissue are associated with decreased responsiveness to endocrine therapy [Manders et al. 2003; Linderholm et al. 2000]. Therefore, it was hypothesized that anti-VEGF therapy may delay or prevent resistance to endocrine therapy in patients with metastatic, hormone-receptor positive breast cancer. As a result, a feasibility study was performed combining endocrine therapy with bevacizumab.

Forty three postmenopausal women with locally advanced or metastatic hormone-receptor positive breast cancer received letrozole 2.5 mg orally in combination with bevacizumab 15 mg/kg intravenously every 3 weeks [Traina et al. 2009]. Prior use of a nonsteroidal aromatase inhibitor was allowed as long as the patient did not have progression of disease while on the therapy. Safety was the primary study endpoint and efficacy was a secondary endpoint. All study participants were monitored every 3 weeks for toxicity.

Letrozole in combination with bevacizumab was well tolerated. The most common treatment associated toxicities seen after a median of 13 cycles (range: 1–71 cycles) were hypertension (grades 2/3 in 19%/26%), proteinuria (grades 2/3, 14%/19%), headache (grades 2/3, 16%/7%), fatigue (grade 2/3, 19%/2%), and joint pain (grades 2/3, 19%/0%) [Traina et al. 2009]. After a median of 24.5 months (range 4–38 months) of treatment, 19% of patients (n = 8) experienced grade 3 proteinuria and all of them had hypertension. Three of these patients discontinued therapy because of proteinuria at 5, 12, and 26 months. Three patients remained on the protocol and were initiated on angiotensin-converting enzyme inhibitors and/or angiotensin receptor blockers with improvement of their proteinuria. The other two patients were removed from the study for disease progression. All eight patients with grade 3 proteinuria had hypertension (grades 2 and 3, 12.5% and 87.5%).

Efficacy was a secondary endpoint of the study. The median PFS was 17.1 months (95% CI: 8.5–26.2 months) [Traina et al. 2009]. Out of the 43 evaluable patients, 29 had stable disease (SD) for 24 weeks or longer. There were no complete responses, but four patients had a partial response as their best response on treatment. Therefore, the response rate was 9% (95% CI: 0.03–00.22) and the clinical benefit rate (PR + SD ≥ 24 weeks) was 77% (95% CI: 0.61–0.88). Six patients had SD for less than 24 weeks, but discontinued study therapy for reasons other than progression. The remaining four patients had progressive disease as best response.

Since the combination of letrozole and bevacizumab is feasible, a phase III trial of first-line endocrine therapy with or without bevacizumab is currently being performed through the Cancer and Leukemia Group B (CALGB 40503). Patients can receive either letrozole or tamoxifen based on physician preference.

Bevacizumab and anastrozole or fulvestrant

A noncomparative, two-arm, multicenter, phase II pilot study of anastrozole or fulvestrant with bevacizumab as first-line treatment of hormone-receptor positive metastatic breast cancer is ongoing [Yardley et al. 2009]. Postmenopausal patients who completed adjuvant hormonal therapy with an aromatase inhibitor at least 1 year ago or previously received tamoxifen were initiated on anastrozole 1 mg oral daily in combination with bevacizumab 10 mg/kg intravenously every 2 weeks. However, if patients had progression of disease on an aromatase inhibitor, were intolerant of aromatase inhibitors or completed adjuvant endocrine therapy with an aromatase inhibitor less than 1 year ago, they were given fulvestrant instead of anastrozole. Patients treated with fulvestrant received a loading dose of 500 mg intramuscularly (IM) on day 1 followed by fulvestrant 250 mg IM on days 15 and 28, and then subsequently every 28 days in combination with bevacizumab 10 mg/kg intravenously every 2 weeks. The primary endpoint of this study is PFS. The secondary endpoints include OS, response rate, toxicity, feasibility, and clinical benefit rate.

There are currently 25 patients in the anastrozole arm and 17 patients in the fulvestrant arm who are evaluable for response and toxicity. The median PFS is 16.3 months in patients receiving bevacizumab in combination with anastrozole [Yardley et al. 2009]. In the cohort of patients receiving bevacizumab and fulvestrant the median PFS has not yet been reached. The combination of bevacizumab with either anastrozole or fulvestrant is well tolerated and feasible. There were no grade 4 adverse events or unexpected toxicities. In this trial, so far there is a 2% rate of grade 3 proteinuria and a 12% rate of grade 3 hypertension. After a median number of four cycles, there is early evidence of an improved clinical benefit rate with endocrine therapy and bevacizumab. Further studies evaluating bevacizumab in combination with hormonal therapy are warranted.

Future directions

In the future, it is anticipated that bevacizumab may also be incorporated into adjuvant and neoadjuvant treatment regimens. Neoadjuvant trials are exploring the use of bevacizumab with metronomic low-dose cyclophosphamide and methotrexate, and with conventional chemotherapy. Studies are also assessing bevacizumab in patients with residual disease after neoadjuvant chemotherapy and surgery. There are several ongoing clinical trials evaluating bevacizumab in the adjuvant setting for breast cancer, which will be of particular interest given that there have been two negative adjuvant trials in colorectal cancer. ECOG 5103 is a phase III, randomized trial evaluating bevacizumab in the adjuvant setting in combination with anthracycline- and taxane-based chemotherapy for patients with lymph-node-positive or high-risk, lymph-node-negative breast cancer. BETH is a multicenter, phase III randomized trial comparing chemotherapy and trastuzumab with or without bevacizumab as adjuvant treatment for patients with HER2-positive, lymph-node-positive or high-risk lymph-node-negative breast cancer. BEATRICE is an ongoing open-label two-arm study where patients with triple-negative breast cancer are randomized to receive standard adjuvant chemotherapy ± bevacizumab.

Several other trials are ongoing which explore the use of bevacizumab in combination with novel agents that target signal transduction pathways. Randomized phase III studies are also evaluating bevacizumab in combination with anti-HER2 therapy and endocrine therapy. Bevacizumab doublets under investigation include bevacizumab with trastuzumab, pertuzumab, lapatinib, vorinostat, and letrozole to name just a few. Given bevacizumab’s manageable toxicity profile, it is an attractive addition to already established regimens for the treatment of breast cancer.

Other targeted therapies including VEGFR tyrosine kinase inhibitors (TKIs) such as sorafenib may also play a role in the treatment of breast cancer in the future. Sorafenib targets both angiogenesis and tumor cell proliferation through targets such as Raf kinase, KIT, Flt-3, and RET [Wilhelm et al. 2004]. Two recently performed phase two clinical trials evaluated sorafenib in the treatment of metastatic breast cancer [Baselga et al. 2009; Gradishar et al. 2009]. Sorafenib in combination with capecitabine compared with capecitabine alone significantly improved both PFS and response rate [Baselga et al. 2009]. Likewise, sorafenib in combination with paclitaxel versus paclitaxel alone improved time to progression [Gradishar et al. 2009]. However, there was no statistically significant difference in PFS between the sorafenib/paclitaxel arm and paclitaxel monotherapy. The PFS in this study was confounded by the 14% death rate in the sorafenib-treated arm. Many of these deaths were unrelated to treatment. Further studies are needed to better determine the role of sorafenib in the treatment of breast cancer.

Additional TKIs including sunitinib have been studied in women with locally advanced or metastatic breast cancer. A first-line study of weekly paclitaxel in combination with sunitinib versus weekly paclitaxel and bevacizumab was closed for futility after an independent data monitoring committee determined the study was unable to meet its primary endpoint of a superior PFS. Two additional phase III trials: first-line docetaxel ± sunitinib and second-line capecitabine ± sunitinib were also performed in patients with advanced breast cancer and did not meet their primary endpoints of improved PFS. Therefore, sunitinib is not a promising drug for the treatment of metastatic breast cancer.

Conclusion

The activity of anti-angiogenic agents exemplifies the bench-to-bedside paradigm. Bevacizumab, an anti-VEGF antibody, was the first anti-angiogenic therapy to show efficacy in breast cancer and is a promising addition to the myriad of already available breast cancer treatments. The effectiveness and manageable toxicity profile of bevacizumab support its use in combination with chemotherapy in the first- and second-line treatment of patients with metastatic breast cancer, and studies evaluating bevacizumab in combination with anti-HER2 and endocrine therapy are ongoing. The consistent improvement in PFS across these randomized, multicenter studies, but lack of an OS benefit suggests that either the drug is being applied suboptimally or there are as yet unidentified patient and/or tumor factors that could allow for improved patient selection. Further development of anti-angiogenic therapies is a critical goal in breast cancer medicine.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest statement

Shari Goldfarb has no conflict of interest. Clifford Hudis was paid as chair of the RIBBON 1 and 2 DSMB. Maura Dickler received payment for consulting with Genentech/Roche, Pfizer, Novartis, and Astra Zeneca.

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