Abstract
Tumor angiogenesis is an important step in breast cancer development, progression, invasion and metastasis. Proangiogenic factors such as VEGF regulate angiogenesis and are targets for drug development. Bevacizumab, an anti-VEGF antibody, has demonstrated significant clinical benefit in several solid tumors, including breast cancer. Its use in combination with either paclitaxel or docetaxel has prolonged progression-free survival and increased response rates in the first-line treatment of patients with metastatic breast cancer. This review article discusses the clinical trials establishing the use of bevacizumab for the treatment of advanced breast cancer.
Significant advances in breast cancer treatment have been made with the development of novel biologic therapies that specifically target growth factor-receptor signaling pathways. Bevacizumab (Avastin®) is a recombinant humanized monoclonal antibody that targets VEGF. VEGF, a glycoprotein produced by both normal and neo-plastic cells, plays a major role in the regulation of new blood vessel formation, known as angiogenesis, in physiologic (i.e., tissue repair) and pathologic conditions [1]. VEGF also inhibits endothelial cell apoptosis and supports maintenance of newly formed tumor vessels. The VEGF signal transduction pathway plays a key role in neovascularization, which is necessary for solid tumor growth, maintenance and metastases [2]. This article will review the role of bevacizumab therapy in the treatment of metastatic breast cancer.
VEGF receptor & pathways
The VEGF family is complex as there are several VEGF ligands and receptors that each have a specific binding preference [3]. VEGF ligands include VEGF-A, VEGF-B, VEGF-C, VEGF-D and placental growth factor (PIGF). Each VEGF ligand exists in multiple isoforms and has specific binding preferences for VEGF receptors. The VEGF receptors include VEGFR-1, VEGFR-2, VEGFR-3, neuropilin-1 and neuro-pilin-2. VEGFR-2 is most closely involved in solid tumor angiogenesis. The binding of VEGF to VEGFR-2 leads to receptor dimerization, tyrosine kinase phosphorylation and recruitment of intracellular signaling molecules that are responsible for survival, vascular permeability, migration and proliferation. Some of the signaling pathways triggered by this mechanism include AKT-PKB, eNOS, MAPK, FAK and paxillin, Ras–Raf–MEK–Erk and PLC-γ [4].
In addition to being one of the central growth factors responsible for tumor angiogenesis, VEGF has prognostic significance [5]. Several studies demonstrate an inverse relationship between VEGF expression and clinical outcome in breast cancer. In patients with early stage lymph node positive or negative breast cancer, elevated VEGF expression is associated with decreased disease-free and overall survival [6,7]. Therefore, VEGF is an appropriate target for the pharmacologic inhibition of tumor angiogenesis.
Bevacizumab
Bevacizumab is composed of a human IgG backbone (93%) and an antigen-binding complementarity-determining region derived from a monoclonal murine antibody (7%) [8]. Bevacizumab recognizes and neutralizes all isoforms of human VEGF-A [9]. Upon binding circulating VEGF, bevacizumab prevents the ligand from interacting with its receptor, thereby abrogating the biologic activity of VEGF [8].
Pharmacology
Bevacizumab has a linear pharmacokinetic profile that is not affected by concurrent use of chemo-therapy [10]. The drug's concentration increases with multiple doses and reaches steady state by approximately week 18. It also has a long terminal half-life of approximately 21 days (range: 11–50 days). Clearance of bevacizumab depends on a patient's gender, tumor burden and weight.
Bevacizumab monotherapy in metastatic breast cancer
A Phase I/II study was performed to evaluate the safety, efficacy and pharmacokinetics of bevacizumab in patients with previously treated metastatic breast cancer [11]. Bevacizumab was administered to 75 patients intravenously every 2 weeks at escalating doses of 3, 10 or 20 mg/kg. Four patients discontinued the study because of an adverse event at the dose-limiting toxicity of 20 mg/kg: hypertensive encephalopathy, nephrotic syndrome, proteinuria and headache associated with nausea and vomiting. Other bevacizumab-associated side effects that were identified include hypertension, asthenia, dyspnea and myalgia. In this study, the recommended dose of bevacizumab was 10 mg/kg intravenously every 2 weeks. Bevacizumab monotherapy had an overall response rate of 9.3% with a 5.5-month median duration of response (range: 2.3-13.7 months) [11]. There was a 2.4-month median time to progression and a 10.2-month median overall survival. Subsequently, clinical trials combining bevacizumab with chemotherapy were performed.
Combination therapy with bevacizumab in metastatic breast cancer
Capecitabine & bevacizumab
Bevacizumab has been combined with a myriad of chemotherapeutic agents in an attempt to improve efficacy. The first large, open-label, randomized Phase III trial evaluated the efficacy and safety of capecitabine alone versus capecitabine in combination with bevacizumab in 462 women with metastatic breast cancer [12]. The primary end point of the study was progression-free survival (PFS). All of the study participants were previously treated with taxanes and anthracyclines, and either had progression of disease within 12 months of completing adjuvant therapy or received one or two prior chemotherapy regimens for metastatic breast cancer. All of the women received capecitabine 2500 mg/m2/day divided twice-daily for 14 days followed by 1 week off therapy. Patients randomized to the experimental combination arm of the study received bevacizumab at 15 mg/kg intravenously every 3 weeks.
In this study of heavily pretreated women, capecitabine with bevacizumab did not significantly improve PFS. The median PFS in the capecitabine with bevacizumab cohort was 4.86 months compared with 4.17 months in the capecitabine-only arm [12]. There was also no difference in overall survival. However, capecitabine with bevacizumab improved the objective response rate from 9.1% to 19.8% (p = 0.001). Although the primary end point was not achieved, capecitabine in combination with bevacizumab was well-tolerated. Bevacizumab did not worsen capecitabine-associated toxicities, including diarrhea and hand-foot syndrome. Bevacizumab-associated toxicities included minor mucosal bleeding (Grade 1 or 2 epistaxis), hypertension and proteinuria. Grade 3 hypertension was observed in 17.9% of women in the combination arm versus 0.5% of women in the capecitabine-only arm. Proteinuria of any grade occurred in 22.3% of women treated with capecitabine/bevacizumab versus 7.4% treated with capecitabine alone. Two patients treated with bevacizumab developed Grade 3 proteinuria and, consequently, their therapy was discontinued. Serious hemorrhage and thromboembolic events were not increased in the combination arm.
Paclitaxel & bevacizumab
The extent of prior therapy in the initial study population was felt to obscure the activity of bevacizumab. It was hypothesized that more advanced stage or refractory breast cancer may develop redundant angiogenic pathways, making blockade of only one receptor or ligand insufficient for clinical benefit. Therefore, the next randomized Phase III study tested bevacizumab in a relatively chemonaive population of women.
A second large, randomized, open-label Phase III trial performed by the Eastern Cooperative Oncology Group (ECOG) – ECOG 2100 – evaluated the efficacy and safety of paclitaxel alone versus paclitaxel in combination with bevacizumab as first-line therapy for women with locally recurrent or metastatic breast cancer [13]. Preclinical evidence suggested that taxanes have antiangiogenic activity, which may be enhanced by low-dose, weekly administration [14]. 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. The primary end point of the study was PFS and one of the secondary end points was overall survival.
Patients were eligible for the study if they had untreated metastatic breast cancer, but prior adjuvant chemotherapy or hormonal therapy was permitted [13]. Adjuvant taxane therapy was allowed if a disease-free interval of at least 1 year had elapsed. Patients were excluded from the study if they had brain metastases, significant underlying heart disease or a nonhealing wound or fracture. Patients with HER-2 positive breast cancer could only be included in the study if they were previously treated with trastuzumab. HER-2 positive patients comprised only 2.3% of the study population.
A total of 722 women were enrolled in the study and received paclitaxel 90 mg/m2 intravenously each week for 3 weeks followed by 1 week off therapy [13]. More than half of the patients had received prior adjuvant chemotherapy, and approximately 17% of the patients had previous taxane therapy. Patients randomized to the experimental combination arm received bevacizumab 10 mg/kg intravenously every 2 weeks. Patients remained on therapy until progression of disease or unacceptable toxicity.
The paclitaxel/bevacizumab arm showed a significantly prolonged PFS with a median of 11.8 months versus 5.9 months in the paclitaxel only arm (p < 0.001) [13]. The addition of bevacizumab to paclitaxel also significantly improved the objective response rate from 21.2% to 36.9% (p = 0.001). Although there was no difference in median overall survival, the overall survival at 1 year was better in the bevacizumab-treated arm; 81.2 versus 73.4%, respectively (p = 0.01).
Paclitaxel in combination with bevacizumab was well-tolerated and bevacizumab did not appear to worsen paclitaxel-related toxicities [13]. The bevacizumab treatment arm had greater grade 3/4 hypertension (14.8 vs 0%; p < 0.001), grade 3/4 proteinuria (3.6 vs 0%; p < 0.001), cerebrovascular ischemia (1.9 vs 0%; p = 0.02), headache (2.2 vs 0%; p = 0.008), neuropathy (23.5 vs 17.7%; p < 0.05) and infection (9.3 vs 2.9%; p < 0.001) than the paclitaxel monotherapy arm. The results of this trial led to US FDA approval of bevacizumab for first-line treatment of metastatic breast cancer.
Docetaxel & bevacizumab
A double-blind, placebo-controlled, randomized Phase III trial compared docetaxel 100 mg/m2 intravenously every 3 weeks versus docetaxel 100 mg/m2 with either bevacizumab 7.5 mg/kg or bevacizumab 15 mg/kg intravenously every 3 weeks as first-line treatment in patients with locally recurrent or metastatic HER-2-negative breast cancer [15]. Patients continued to receive treatment with docetaxel for nine cycles or until the development of disease progression or toxicity. Dose reduction of docetaxel to 75 mg/m2 and/or 60 mg/m2 was permitted in the event of toxicity. Patients continued to receive maintenance placebo or bevacizumab until disease progression. The primary end point of the trial was PFS. Secondary end points were overall survival, overall response rate, safety, time to treatment failure, duration of response and quality of life.
A total of 736 women were enrolled in the study from 104 sites in 26 countries between March 2006 and April 2007 [15]. Approximately two-thirds of patients previously received chemotherapy for early-stage breast cancer. More than 50% of patients had prior anthracycline-based therapy and 15% had prior taxane treatment.
At baseline, more than 80% of patients had measurable disease. At a median follow-up of 11 months, PFS was statistically significant in both bevacizumab-containing arms compared with the placebo arm. In the control arm of docetaxel alone, the median PFS was 8 months. The median PFS in the docetaxel/bevacizumab 7.5 mg/kg arm and 15 mg/kg arm were 8.7 months and 8.8 months, respectively. The hazard ratios for PFS in the bevacizumab 7.5 mg/kg arm and 15 mg/kg arm were 0.79 (p = 0.03) and 0.72 (p = 0.01), respectively. Similarly, objective response rates were superior in both combination arms compared with the docetaxel only arm, with 44% in the control arm, 55% (p = 0.0295) in the bevacizumab 7.5 mg/kg arm and 63% (p = 0.0001) in the bevacizumab 15 mg/kg arm. Overall survival data are not yet mature, with cut-off for the final analysis set to occur 24 months after the last patient is enrolled. At the time of the present analysis, approximately 80% of patients were still alive and median overall survival had not been reached. Some limitations of this study include that it was not powered to compare two different doses of bevacizumab and many physicians discontinued docetaxel after six cycles owing to physician preference, but continued maintenance bevacizumab. It is unclear how such limitations may have impacted the results of the study.
This double-blind, placebo-controlled study confirms the benefit of adding bevacizumab to taxane chemotherapy for first-line treatment of locally recurrent or metastatic breast cancer [15]. This is the first placebo-controlled trial of bevacizumab in patients with breast cancer, in which adverse events were collected equally in both arms. This was not the case with E2100, since that was an open-label trial. The addition of bevacizumab had limited impact on the usual toxicity observed with docetaxel 100 mg/m2. 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 to 3.9% in the placebo arm. However, the incidence of grade 3 or more hypertension was low in all three groups. No new safety issues with bev-acizumab were detected. There was no difference in grade 3/4 bleeding, thromboembolic events or gastrointestinal perforations in the bevacizumab arms compared with the placebo arm. Grade ½ bleeding events were more prevalent in patients receiving docetaxel/bevacizumab compared with docetaxel alone.
A total of seven patients receiving anticoagulation therapy at the beginning of the study were randomized to a bevacizumab-containing regimen 16]. During the trial, another 52 patients receiving bevacizumab were initiated on anticoagulation therapy. In this group of 59 patients concurrently receiving anticoagulation and bevacizumab, 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 the study [17]. The use of bevacizumab in these patients was not associated with CNS bleeding. There was no increased frequency of other grade 3/4 adverse events in patients with brain metastasis being treated on either bevacizumab arm.
Additional Phase II trials tested the feasibility and efficacy of bevacizumab in combination with several other chemotherapy regimens. A Phase II trial studied bevacizumab in combination with nanoparticle albumin-bound (nab) paclitaxel given either weekly, every 2 weeks or every 3 weeks. Other trials explored the combination of nab–paclitaxel and gemcitabine [18], vinorelbine [19], and low-dose, repetitive, ‘metro-nomic’ chemotherapy with oral cyclophosphamide and methotrexate [20]. Preliminary data from these trials suggest the combinations are feasible and worthy of further study.
Two Phase III trials of bevacizumab in combination with standard chemotherapy for metastatic breast cancer were recently performed. In both trials patients were randomized to chemotherapy with bevacizumab or chemotherapy with placebo in a 2:1 ratio and the primary objective was PFS [21]. RiBBON 1 evaluated the clinical benefit of bevacizumab 15 mg/kg intravenously every 3 weeks in the first-line setting in over 1200 patients [22]. The results were confirmatory and demonstrated an improvement in PFS when bevacizumab was administered in combination with chemotherapy. Chemotherapy included a range of options such as capecitabine, a taxane (T; nab–paclitaxel or docetaxel), or an anthracycline (A). At a median follow-up of 15.6 months in the capecitabine cohort and 19.2 months in the T plus A cohort, there was a statistically significant improvement in PFS and response rate in the bevacizumab arm. PFS was 5.7 versus 8.6 months (p = 0.0002) for capecitabine plus bevacizumab and was 8.0 versus 9.2 months (p < 0.0001) for T/A plus bevacizumab. However, there was no impact on overall survival.
RiBBON 2 is currently evaluating bevacizumab in the second-line setting in combination with several chemotherapy regimens for metastatic breast cancer [21]. The RiBBON 2 trial will evaluate the safety and efficacy of bevacizumab with PFS as the primary end point.
Based on the previously performed studies, bevacizumab does not improve overall survival. However, it prolongs PFS and increases response rates when used as first-line therapy for metastatic breast cancer. It is hypothesized that there is a potential rebound effect after discontinuing bevacizumab, which may help explain why no difference in overall survival is seen [23]. Moreover, it is becoming evident that blockade of only one pathway in the signaling cascade is not as optimal as targeting two or more growth factor signaling pathways. Therefore, bevacizumab is being studied in combination with other targeted and endocrine therapies.
Bevacizumab with endocrine therapy
Letrozole & bevacizumab
Estrogen is a potent modulator of angiogenesis under both physiologic and pathologic conditions [24]. The cyclical neovascularization of the female reproductive tract in premenopausal women is one of the few active sites of angiogenesis in adult organisms under normal conditions and suggests a potent angiogenic effect of estradiol [25]. Estrogen-induced angio-genesis is mediated by VEGF [26]. Estradiol increases VEGF expression in the rat uterus, leading to increased vascular permeability and uterine edema. In oophorectomized animal models, estrogen withdrawal reduces VEGF expression [27]. Similarly, in MCF-7 breast cancer cell lines, estrogen increased levels of VEGF [28], and aromatase inhibition lowered VEGF expression in a hormone-dependent mouse model [29]. The most compelling evidence for the relationship between angiogenesis and endocrine regulation derives from xenograft data, in which castration in a male mouse model of androgen-dependent breast cancer led to tumor shrinkage and vascular regression [30].
The majority of patients with metastatic breast cancer become resistant to endocrine therapy despite a good initial response [30]. Retrospective studies indicate that high VEGF levels in breast tumor tissue are associated with decreased responsiveness to endocrine therapy in both the adjuvant and metastatic settings [7,31]. It was hypothesized that in patients with hormone-receptor positive metastatic breast cancer, anti-VEGF therapy may delay or prevent resistance to endocrine therapy. Therefore, it seemed reasonable to combine bevacizumab with endocrine therapy for the treatment of breast cancer.
A feasibility study of bevacizumab and letrozole was performed in postmenopausal, hormone receptor-positive women with locally advanced or metastatic breast cancer [32,33]. A total of 43 women were given bevacizumab 15 mg/kg intravenously every 3 weeks in combination with letrozole 2.5 mg orally daily. Prior use of a nonsteroidal aromatase inhibitor was permitted as long as the patient did not have progression of disease while on the endocrine therapy. The primary study end point was safety and patients were monitored for toxicity every 3 weeks.
The combination of bevacizumab and letrozole appeared to be well-tolerated. After a median of 13 cycles (range: 1–68 cycles), the most common drug-related toxicities included fatigue (grade 2/3, 19/2%), proteinuria (grades 2/3, 14/19%), joint pain (grades 2/3, 19/0%), hypertension (grades 2/3, 19/26%) and headache (grades 2/3, 16/7%) [32–34]. Hemorrhage was rare (grades 2/3, 2/2%). Grade 3 proteinuria, observed in 19% of patients (n = 8), developed after a median of 24.5 months (range: 4–38 months) of therapy. Three of these patients discontinued study therapy because of proteinuria.
Efficacy was a secondary end point of the study. Out of the 43 evaluable patients, 29 had stable disease (SD) for 24 weeks or longer. There was a response rate of 9% (95% CI: 0.03–00.22) with four patients having a partial response (PR) as best response on treatment. There were no complete responses observed. Therefore, the clinical benefit rate (PR + SD ≥24 weeks) was 77% (95% CI: 0.61–60.88). The median PFS was 17.1 months (95% CI: 8.5–26.2); which compares favorably to PFS rates (∼9 months) in prior trials. 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 the best response.
Anastrozole or fulvestrant & bevacizumab
A multicenter, Phase II, noncomparative, two-arm pilot of bevacizumab with anastrozole or fulvestrant as first-line treatment of hormone-receptor-positive metastatic breast cancer is currently ongoing [35]. If postmenopausal patients previously received tamoxifen or completed adjuvant endocrine therapy with an aromatase inhibitor at least 1 year prior, they were started on anastrozole 1 mg orally each day in combination with bevacizumab 10 mg/kg intravenously every 2 weeks. If patients completed adjuvant aromatase inhibitor therapy less than 1 year ago, were intolerant of aromatase inhibitors, or had progression of disease on aromatase inhibitors, they were offered fulvestrant instead of anastrozole. Patients treated with fulvestrant received a loading dose of 500 mg intramuscularly on day 1 followed by fulvestrant 250 mg intramuscularly on days 15 and 28, and then subsequently every 28 days in combination with bevacizumab. The primary end point of this trial was time to disease progression. Secondary end points are overall response rate, overall survival, clinical benefit rate, feasibility and toxicity.
In patients receiving anastrozole and bevacizumab, the median PFS was 16.3 months [34]. The fulvestrant and bevacizumab median PFS has not yet been reached. There is also early evidence of an improved clinical benefit rate with endocrine therapy in combination with bevacizumab after a median number of four cycles. The combination of anastrozole or fulvestrant with bevacizumab is well-tolerated and feasible. There was a 12% rate of grade 3 hypertension and a 2% rate of grade 3 proteinuria. There were no unexpected toxicities or grade 4 adverse events. Further studies evaluating endocrine therapy in combination with bevacizumab are warranted. The Cancer and Leukemia Group B (CALGB) is performing a randomized, Phase III trial of first-line endocrine therapy with or without bevacizumab. Patients receive either letrozole or tamoxifen based on physician preference.
Bevacizumab & other targeted therapies
In addition to studying bevacizumab in combination with chemotherapy and endocrine therapy, bevacizumab is also being tested with other novel treatments that target growth factor signaling pathways. VEGF expression has been linked to HER-2 overexpression in numerous preclinical and clinical studies [36,37]. Overexpression of HER-2 leads to increased expression of VEGF at the mRNA and protein levels
Trastuzumab & bevacizumab
A Phase I, open-label, dose-escalation trial of bevacizumab in combination with trastuzumab was performed to determine the appropriate doses for these biologic agents when given in combination [39]. Of the nine patients who were treated on this study, five patients had clinical responses with minimal toxicity, including one patient with previous progression of disease on trastuzumab. Coadministration of bevacizumab and trastuzumab did not alter the pharmacokinetics of either agent.
Subsequently, a Phase II study of bevacizumab 10 mg/kg intravenously every 2 weeks and trastuzumab 4 mg/kg loading dose followed by 2 mg/kg intravenously weekly was performed. The study evaluated the efficacy and safety of the antibody combination for first-line treatment of HER-2-overexpressing metastatic breast cancer [40]. Approximately 50% of the study patients had received prior neoadjuvant or adjuvant chemotherapy and 50% had previous endocrine therapy. An interim analysis of the first 37 patients showed an overall response rate of 54%. The most common adverse events seen with the combination of antibodies were hypertension, headache, grade ½ elevation of liver function tests, epistaxis and fatigue. Baseline and posttreatment LVEF were measured in all of the subjects. Adverse cardiac events were noted in 13 out of the first 30 patients enrolled in the study. A total of seven patients had grade 1 events, five patients had grade 2 and one patient had a grade 4 cardiac toxicity. It was determined that the coadministration of bevacizumab and tras-tuzumab is efficacious and feasible, but close cardiac surveillance should be performed.
Further studies are exploring the use of bevacizumab in combination with trastuzumab. Currently, there is an ongoing randomized, Phase III, placebo-controlled trial of first-line chemotherapy and trastuzumab with or without bevacizumab in patients with HER-2/neu overexpressing metastatic breast cancer. In addition, a randomized trial of adjuvant chemotherapy plus trastuzumab versus adjuvant chemotherapy plus trastuzumab and bevacizumab in HER-2 positive, node-positive or high-risk node-negative breast cancer is ongoing (BETH trial).
Lapatinib & bevacizumab
Lapatinib is a potent and specific reversible, small molecule, oral, dual tyrosine kinase inhibitor of both HER-2 and EGFR with less known cardiac toxicity than trastuzumab. Therefore, a Phase II, open-label, 52-patient, single-arm study was performed to evaluate the efficacy and safety of lapatinib in combination with bevacizumab [41]. Lapatinib 1500 mg orally daily and bevacizumab 10 mg/kg intravenously every 2 weeks were administered to patients with locally advanced or metastatic HER-2/neu-overexpressing breast cancer. The primary end point was PFS at week 12 and secondary end points included overall response rate, clinical benefit rate, overall PFS and safety.
Most patients (96%) had received prior cytotoxic chemotherapy and prior trastuzumab (90%). Study participants were heavily pretreated before enrollment with a median of four previous chemotherapy regimens (range: 0-13) and a median prior exposure to trastuzumab of 84.1 weeks (range: 5.3-434.3) [41]. Lapatinib coadministered with bevacizumab had a 11- week PFS of 69.2% and a median PFS of 24.7 weeks. The clinical benefit rate was 30.8%. Coadministration of lapatinib and bevacizumab was well-tolerated. The most common adverse events reported were diarrhea (81%), rash (62%), fatigue (48%), bleeding (49%), nausea (51%) and headache (40%). Grade 3 diarrhea was only observed in 2% of study patients. Five patients were noted to have asymptomatic decreases in LVEF, but no patients developed symptomatic congestive heart failure.
Conclusion
Bevacizumab, an anti-VEGF antibody, is well-tolerated and a promising addition to the myriad of already available breast cancer treatments. The efficacy and manageable toxicity profile of bevacizumab support its use in combination with chemotherapy in the first-line setting for locally recurrent or metastatic breast cancer. Bevacizumab was the first anti-angiogenic agent to show efficacy in breast cancer. Ongoing studies are also evaluating VEGFR tyrosine kinase inhibitors such as sunitinib and sorafenib.
Future perspective
After ECOG 2100, bevacizumab was approved by the FDA and European Medicines Agency for the first-line treatment of metastatic breast cancer. 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. ECOG 5103 is a Phase III, randomized trial evaluating bevacizumab in the adjuvant setting in combination with anthra-cycline- and taxane-based chemotherapy for patients with lymph node-positive or high risk, lymph node-negative breast cancer. Randomized Phase III studies are also evaluating bevacizumab in the second-line setting, in combination with endocrine therapy, and in combination with anti-HER2 therapy. Bevacizumab's manageable toxicity profile makes it an attractive addition to already established regimens for the treatment of breast cancer.
Executive summary
Bevacizumab (Avastin®) is a recombinant humanized monoclonal antibody that targets VEGF.
The VEGF signal transduction pathway plays a key role in neovascularization, which is necessary for solid tumor growth, maintenance and metastases.
Bevacizumab has a linear pharmacokinetic profile that is not affected by chemotherapy.
The concentration increases with multiple doses and reaches a steady state by approximately 18 weeks.
Bevacizumab has a long terminal half-life of approximately 21 days (range: 11–50 days).
Clearance of bevacizumab depends on the patient's gender, tumor burden and weight.
Capecitabine with bevacizumab improved the objective response rate from 9.1 % to 19.8% (p = 0.001).
Progression-free survival was significantly prolonged with first-line weekly paclitaxel in combination with bevacizumab with a median of 11.8 versus 5.9 months with paclitaxel alone (p < 0.001).
There was no difference in median overall survival in the paclitaxel/bevacizumab arm versus the paclitaxel-alone arm, but the 1-year survival was better in the bevacizumab-treated arm, 81.2% versus 73.4% (p = 0.01).
Hazard ratios for progression-free survival in the docetaxel/bevacizumab 7.5 mg/kg arm and docetaxel/bevacizumab 15 mg/kg arm were 0.79 (p = 0.03) and 0.72 (p = 0.01), respectively.
Hypertension.
Proteinuria (the development of proteinuria, hypertension and epistaxis may influence compliance when bevacizumab is used long term in women with metastatic breast cancer).
Epistaxis.
Delayed wound healing.
Arterial and venous thromboembolic events.
Cerebrovascular accidents.
Myocardial infarctions.
Reversible posterior leukoencephalopathy syndrome.
Dosage for first-line treatment of metastatic breast cancer: bevacizumab 10mg/kg intravenously every 2 weeks or bevacizumab 15 mg/kg intravenously every 3 weeks.
Footnotes