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University of California, San Francisco, Comprehensive Cancer Center, San Francisco, California, USA
Correspondence: Hope S. Rugo, M.D., University of California, San Francisco, Comprehensive Cancer Center, 1600 Divisidero Avenue, 2nd Floor, San Francisco, California 94115, USA. Telephone: 415-353-7618; Fax: 415-353-9571; e-mail: hope.rugo{at}ucsfmedctr.org
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LEARNING OBJECTIVES
Top
Learning Objectives
Abstract
Introduction
VEGF as a Target...
Bevacizumab in Breast Cancer
Conclusions
References
After completing this course, the reader will be able to:
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ABSTRACT |
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TopLearning ObjectivesAbstractIntroductionVEGF as a Target...Bevacizumab in Breast CancerConclusionsReferences |
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Preclinical studies have shown that the humanized monoclonal antibody to VEGF, bevacizumab (AvastinTM; Genentech, Inc., South San Francisco, CA), can reduce tumor angiogenesis and inhibit the growth of solid tumors, either alone or in combination with chemotherapy. As a single agent or added to vinorelbine, bevacizumab has produced encouraging results in phase II clinical trials in patients with refractory metastatic breast cancer. When added to capecitabine chemotherapy in a phase III trial, bevacizumab produced a greater response rate, but did not prolong progression-free survival. This may reflect the late disease stage and poor prognostic factors in the patient population. A large, ongoing, phase III, cooperative group trial is evaluating the effect of bevacizumab in combination with paclitaxel as first-line therapy for metastatic disease. The adverse effect profile of bevacizumab differs from that of cytotoxic chemotherapy and includes hypertension, proteinuria, thrombosis, and epistaxis.
Key Words. Bevacizumab • Breast cancer • Monoclonal antibodies • Vascular endothelial growth factor
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INTRODUCTION |
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TopLearning ObjectivesAbstractIntroductionVEGF as a Target...Bevacizumab in Breast CancerConclusionsReferences |
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Significant advances in the use of targeted biological therapies with novel mechanisms of action over the past several years have changed, and continue to influence, treatment for patients with cancer. For example, trastuzumab is a humanized monoclonal antibody that selectively targets the extracellular domain of the human epidermal growth factor receptor-2 (HER2), which is overexpressed in 15%-25% of breast tumors, owing to amplification of the erbB-2 gene [1].
Trastuzumab has been shown to provide significant clinical benefits to patients with HER2-positive metastatic breast cancer when administered as monotherapy [2, 3]. It has also offered better response rates when combined with chemotherapy than chemotherapy alone [4]. A variety of new targets are being explored, and a wide variety of agents, with a broad range of activities, are in clinical trials. It is hoped that targeted therapeutics will allow better disease control with less toxic therapy and, in the future, in combination with molecular or protein profiling, individualize care for specific cancers.
The formation of new blood vessels (neovascularization/angiogenesis) is needed for the growth and invasiveness of primary tumors [5] and plays an important role in metastatic growth [6]. Owing to this critical role in cancer growth and metastasis, tumor-related angiogenesis has become an attractive target for anticancer therapy. Vascular endothelial growth factor (VEGF) is the ligand for the VEGF receptor 2, and has emerged as a key potential target for the pharmacological inhibition of tumor angiogenesis [7].
This review discusses current data and the future potential of bevacizumab (rhuMAb VEGF; AvastinTM; Genentech Inc.; South San Francisco, CA), a recombinant humanized monoclonal antibody to VEGF [8], in the treatment of breast cancer. Bevacizumab is currently being investigated in a range of tumor types. A recent, randomized clinical trial showed significantly better survival, with modest toxicity, in patients treated with bevacizumab and standard first-line chemotherapy for metastatic colorectal cancer, compared with standard chemotherapy alone. That study confirmed the importance of targeting angiogenesis as part of the treatment of cancer.
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VEGF AS A TARGET IN BREAST CANCER |
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TopLearning ObjectivesAbstractIntroductionVEGF as a Target...Bevacizumab in Breast CancerConclusionsReferences |
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VEGF is expressed in the majority of tumor types, including breast cancer [9]. A study by Brown and colleagues found a high degree of expression of VEGF mRNA and protein in invasive ductal carcinoma, metastatic ductal carcinoma, and comedo-type ductal carcinoma in situ, with relatively lower expression in lobular carcinoma [10].
All tumors examined in a study of 64 primary breast cancers expressed at least six different angiogenic growth factors [11]. VEGF was the most abundant, although other angiogenic factors, including thymidine phosphorylase and transforming growth factor (TGF)-ß1, were also expressed at high levels. These data suggest that VEGF may be the rate-limiting factor in the tumor-related switch to an angiogenic phenotype that is critical for growth and metastasis.
VEGF gene expression is upregulated by a number of stimuli, including nitric oxide, various growth factors, loss of tumor-suppressor genes such as p53, and activation of oncogenes such as ras, v-src, and HER2. VEGF mRNA and/or protein production can also be stimulated by estrogens and progestins, as shown in human breast cancer cells in vitro [12, 13] and in 7,12-dimethylbenzanthracene-induced rat mammary tumors in vivo [14].
Evidence suggests that the HER2 and VEGF signaling pathways are interlinked at the molecular level in human breast cancer and lead, ultimately, to cell proliferation [15]. Preliminary data have shown that upregulation of VEGF expression occurs in HER2-overexpressing breast cancer cells. This may contribute to the switch to an aggressive angiogenic phenotype observed in HER2-positive disease. In view of this observed interaction, it may be logical to combine anti-HER2 and anti-VEGF treatment approaches for the treatment of HER2-overexpressing breast cancers.
A range of studies has examined the relationship between VEGF expression and clinical outcome in breast cancer. In general, they have concluded that VEGF leads to worse relapse-free and overall survival rates in patients with early-stage breast cancer [16]. The largest of those trials showed that VEGF was an independent prognostic marker in both node-positive and node-negative breast cancers [17]. In patients with metastatic breast cancer, VEGF overexpression led to larger tumors, negative steroid-receptor status, p53 mutations, and poor tumor differentiation. Basic fibroblast growth factor (bFGF) overexpression led to smaller tumors and negative nodal status. Foekens et al. evaluated tumor levels of VEGF in 845 patients. They found that high tumor levels of VEGF led to breast tumors resisting chemotherapy with FAC (fluorouracil/doxorubicin/cyclophosphamide) or CMF (cyclophosphamide/mitoxantrone/fluorouracil) and hormonal therapy with tamoxifen [18].
Quantitative studies of tumor vascularization have indicated that intratumoral microvessel density (MVD) within hotspots of high vessel concentrations may also be a significant and independent prognostic indicator in both node-negative and node-positive breast cancers [7, 19–22]. A retrospective study of 328 primary breast cancer patients by Toi et al. [20] showed close association between greater MVD and VEGF expression.
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BEVACIZUMAB IN BREAST CANCER |
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TopLearning ObjectivesAbstractIntroductionVEGF as a Target...Bevacizumab in Breast CancerConclusionsReferences |
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Kim and colleagues demonstrated suppression of tumor growth by A.4.6.1 in vivo [23]. Following the injection of human rhabdomyosarcoma, glioblastoma multiforme, or leiomyosarcoma cell lines into nude mice, A.4.6.1 inhibited tumor growth and reduced the density of blood vessels in the tumor. However, no inhibitory effect was seen on the growth rate of tumor cells in vitro.
Another study investigated whether VEGF inhibition with an anti-VEGF monoclonal antibody could reduce tumor interstitial fluid pressure (IFP) [24]. Increased IFP, a marker of permeability, is thought to cause poor delivery of large therapeutic molecules to solid tumors [25]. That study treated athymic nude mice bearing xenografts of human glioblastoma multiforme (U87) or colon adenocarcinoma (LS174T) with either A.4.6.1 or combined A.4.6.1 and radiation, under normoxic and hypoxic conditions. A.4.6.1 alone inhibited the growth of both xenograft types, and this inhibition led to a significant reduction in tumor vascular density and a small increase in the number of apoptotic cells. IFP decreased by over 70% in both types of tumor, and partial oxygen tension increased significantly in the U87 tumors. Combined radiation/A.4.6.1 treatment induced a tumor growth delay that was greater than additive in U87 tumors but generally only additive in LS174T tumors. In both tumor types, the growth delay induced by A.4.6.1 occurred under both normoxic and hypoxic conditions, implying that inhibition of VEGF can compensate for the resistance to radiation induced by hypoxia [24].
Preclinical studies have also combined bevacizumab with chemotherapeutic agents. In murine breast cancer models (MCF-7, ZR-75, and SK-BR-3), twice-weekly intraperitoneal administration of A.4.6.1 at a dose of 200 µg significantly suppressed angiogenic activity in all tumor types [26]. Doxorubicin alone also reduced the growth rate of MCF-7 cells but did not affect angiogenesis significantly. In contrast, doxorubicin with A.4.6.1 significantly reduced tumor regression, so that viable tumor cells could not be detected in some animals at the end of the 2-week observation period. This strongly supports the view that neutralization of VEGF with bevacizumab, in combination with conventional cytotoxic agents, could be a promising treatment for metastatic breast cancer.
Endothelial-cell stimulation with VEGF and bFGF protected endothelial cells from the antiangiogenic properties of docetaxel, but protection was lost when bevacizumab was coadministered with docetaxel, both in vitro and in vivo [27].
Clinical Trials
Phase I Studies and Extension Study
Two phase I clinical trials of bevacizumab have been reported. In the first trial, bevacizumab was administered to 25 patients with refractory solid tumors at doses ranging from 0.1–10 mg/kg [28] over 6 weeks. In the second trial, bevacizumab, at a dose of 3 mg/kg, was administered in combination with chemotherapy to 12 patients with advanced cancer [29]. Those trials showed that bevacizumab can be administered safely, without dose-limiting toxicities, at doses up to 10 mg/kg, and that it can be combined with chemotherapy without apparent synergistic toxicity.
All patients who completed 6–12 months of therapy in the phase I/II trials of bevacizumab were given the opportunity to participate in an ongoing extension study [30]. Of 52 patients with advanced solid tumors, 28 received bevacizumab for 1 year or more. The dosage of bevacizumab ranged from 5–15 mg/kg every 2 or 3 weeks. The majority of patients treated for 1 year had an observation period off therapy for up to 6 months, but were able to restart bevacizumab at progression. Sixteen patients progressed on or before the observation period and restarted bevacizumab. The median duration of treatment was 14 months (range 11–36 months) and, at the time of reporting these results, a median survival time had not been reached (range 17 months to >40 months, with 20 patients alive).
Safety results obtained from the extension study indicate that the adverse event profile of bevacizumab when used long term differs from that seen with cytotoxic chemotherapy. Bevacizumab was generally well tolerated, with no unexpected adverse events observed after 1 year of therapy. The only significant events that occurred during the extension study were thromboembolic episodes (five cases of deep vein thrombosis). Grade 2/3 hypertension developed in three patients, and grade 1 proteinuria occurred in one patient. There were also two gastrointestinal bleeds (grades 2 and 4) in patients who had colorectal cancer. Overall, the data obtained from the extension study suggest that some patients who progress after 6–12 months of bevacizumab, with or without chemotherapy, may benefit from retreatment.
Phase II Studies
A phase II, two-center, open-label clinical trial of bevacizumab monotherapy produced encouraging results in patients with breast cancer. That study treated 75 patients with metastatic breast cancer with bevacizumab at escalating doses of 3 mg/kg (n = 18), 10 mg/kg (n = 41), and 20 mg/kg (n = 16) administered intravenously every other week [31]. The majority of patients (83%) had infiltrating ductal carcinoma, and 96% had received prior anthracycline- or taxane-based therapy for metastatic disease. Twenty-one of the 75 (28%) patients were HER2 positive and 47 (63%) were HER2 negative. Twelve of the 75 patients (16%) completed the 6-month trial and received all 13 scheduled doses of bevacizumab. The median number of doses of bevacizumab administered was six and the median duration of treatment was 70 days.
Objective responses were documented in 7 of 75 (9.3%, 6.7% confirmed) patients (Table 1
). The median duration of confirmed response was 5.5 months (range 2.3–13.7 months), with one ongoing partial response at 10 months. At the final tumor assessment on day 154, 12 of 75 (16%) patients had stable disease or an ongoing response. In the 10-mg/kg group, 17% of patients had stable disease or better at day 154, and 7% were stable at 1 year. Thus, the optimal dosage of bevacizumab in that trial was found to be 10 mg/kg every other week, and toxicity was deemed to be acceptable, as only four patients (5.3%) stopped bevacizumab because of adverse events.
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A phase II trial of bevacizumab with vinorelbine is examining patients with metastatic breast cancer. Key eligibility criteria include prior chemotherapy with one or two regimens for metastatic breast cancer (including trastuzumab for HER2-positive disease) and disease progression within 1 year of adjuvant chemotherapy. Patients receive treatment with bevacizumab at a dose of 10 mg/kg every 2 weeks and vinorelbine at a dose of 25 mg/m2/week (adjusted for neutrophil count) until either the disease progresses or they experience undue toxicity. That trial has observed 17 responses (one complete and 16 partial) among 55 patients (31% objective response rate [ORR]). Overall, bevacizumab with vinorelbine was well tolerated, and toxicity analyses indicate only minor occurrences of hypertension, proteinuria, and epistaxis and one instance of pericardial effusion. No major bleeding events or thrombotic events were noted, and other side effects were consistent with the historic experience of the use of vinorelbine [32].
Phase III Studies
The bevacizumab phase III clinical trial for breast cancer was an open-label, randomized, comparative trial in which previously treated patients with metastatic breast cancer were randomized to treatment with either capecitabine alone or capecitabine plus bevacizumab [33]. From November 2000 to March 2002, 462 patients entered the study. The bevacizumab dosage was 15 mg/kg once every 3 weeks. Capecitabine was given at the U.S. Food and Drug Administration-approved dose of 2,500 mg/m2 in two divided doses for 2 out of every 3 weeks, with appropriate dose reductions for toxicity. Eligibility included resistance to both anthracyclines and taxanes and one or two prior chemotherapy regimens for metastatic disease. Patients with evidence of disease progression within 1 year of adjuvant therapy containing both an anthracycline and a taxane were also eligible. This very-poor-prognosis group of patients represented about 20% of the patients in the trial. HER2-positive patients were excluded unless they had received prior trastuzumab therapy. Also excluded were patients with significant proteinuria.
Although adding bevacizumab to capecitabine produced a highly statistically significant greater ORR (19.8% versus 9.1%), the primary end point of the study, there was no effect on progression-free survival (PFS). Responses to bevacizumab tended to be short and were, therefore, not translated into improved PFS times, which were equivalent at 4.9 months in the combination arm and 4.2 months in the capecitabine-alone arm. No increases in capecitabine-related toxicities or serious adverse events were noted in the bevacizumab arm, and the pattern of bevacizumab-related adverse events was similar to that seen in phase II trials.
The apparent low response with bevacizumab plus capecitabine combination therapy points to a need for preclinical studies on bevacizumab/chemotherapy combinations to determine additive, synergistic, or even negative interactions between specific agents. It has been suggested that, instead of using standard high-dose cyclic regimens, chemotherapy should be given in smaller and more frequent doses (metronomic chemotherapy) when used with an antiangiogenic agent [34, 35]. Although capecitabine provides a longer duration and continuous exposure to cytotoxic therapy than standard 3-week cyclic chemotherapy, effectiveness may be limited by differences in absorption and metabolism among individuals.
Another study [36] examined over 200 tumor blocks for expression of VEGF by immunohistochemistry. It found no association between expression and response or failure to respond, and the degrees of expression were similar in the two groups. These data are limited by the minority of samples represented in the analysis. Future studies will need to prioritize the collection of tumor blocks and obtain frozen tissue for marker analysis to help determine potential subtypes for treatment with bevacizumab.
A variety of factors, including trial design and biologic differences, may have contributed to the failure to reach the primary end point of this trial. Sixty percent of breast tumor biopsies have been shown to produce VEGF as their sole proangiogenic factor at their first diagnosis, but other proangiogenic factors, such as bFGF and TGF-ß1, are produced in the later stages of disease [11]. This implies that a VEGF-specific inhibitor, such as bevacizumab, might be less effective in late-stage than in early-stage disease. Furthermore, the patients in the trial had poor prognoses, as defined by resistance to both anthracyclines and taxanes. It is probably unrealistic to expect an increase in time to progression in a trial that included a large proportion of patients who had failed within 12 months of previous adjuvant anthracycline- and taxane-based therapy. There may be significant heterogeneity in breast cancer in terms of response to antiangiogenic therapy, similar to known differences in response based on hormone-receptor or HER2/neu status. At this time, it does not appear that expression of VEGF will be a determinant of response, and prospective trials must examine other factors. These trials include the ongoing Eastern Cooperative Oncology Group (ECOG) study comparing paclitaxel plus bevacizumab with paclitaxel alone as first-line therapy for metastatic breast cancer. In that trial, a variety of correlative studies will be performed on tissue blocks. This aims to elucidate possible markers of response.
Using a targeted therapy such as bevacizumab in an unselected population may also be problematic as, if patients are unscreened, treatment effect may be diluted to the point of being invisible. In the future, studies that enroll only patients identified as being most likely to respond to a specific agent or combination will look at targeted treatments. Had trastuzumab been studied in an unselected patient population, it is highly unlikely that its antitumor effects and survival benefits with chemotherapy would have been discovered. In addition, future trials must focus on a less heavily treated patient population, with both lower disease burdens and resistance to therapy. Both clinical trials that demonstrated a survival benefit from a novel targeted agent in combination with chemotherapy compared with chemotherapy alone (trastuzumab in breast cancer and bevacizumab in colorectal cancer) targeted patients with previously untreated metastatic disease. In addition, the schedules of administration in the phase II studies in breast cancer and the phase III studies in colorectal cancer were similar— 10 mg/kg every 2 weeks versus 15 mg/kg every 3 weeks, respectively. Although pharmacokinetics suggest that every-3-week dosing should result in the same serum level as the lower dose every 2 weeks, more frequent dosing may be more effective for this novel agent. For a more detailed discussion of dosage, patient selection, and tolerability issues see Bergsland and Dickler [37].
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CONCLUSIONS |
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TopLearning ObjectivesAbstractIntroductionVEGF as a Target...Bevacizumab in Breast CancerConclusionsReferences |
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Bevacizumab has shown promising efficacy and was well tolerated as a single agent in phase II clinical trials in metastatic breast cancer. A phase III study showed a lack of benefit of bevacizumab with capecitabine, compared with capecitabine alone, in progression-free survival. This may reflect the late disease stage and poor prognostic factors of the patient population, as well as the choice of chemotherapy regimen. The contribution of other proangiogenic factors to breast cancer progression and the heterogeneity of VEGF expression in breast cancer indicate that a more focused approach to the use of anti-VEGF therapy may be beneficial.
It was suggested recently that angiogenesis occurs at the very earliest stages of tumor development, when perhaps only 100–300 tumor cells are present. This suggests that antiangiogenic treatments may be most effective in micrometastatic disease, before visible metastatic disease is identified. For example, coinjection of a soluble VEGF receptor with tumor cells can inhibit subsequent angiogenesis and tumor growth in rodent models. This led to the suggestion that anti-VEGF treatments could inhibit tumor growth most effectively before the onset of angiogenesis [38, 39].
A number of ECOG trials of bevacizumab in breast cancer are under way. One is investigating the benefits of bevacizumab with paclitaxel as first-line therapy for metastatic breast cancer. Combinations of bevacizumab with biologic agents, including trastuzumab and erlotinib, an inhibitor of the HER1 (epidermal growth factor receptor) tyrosine kinase, are also being evaluated.
Further studies are warranted to determine the potential of bevacizumab in breast cancer, particularly in earlier stage disease, and methods of selecting patients who would benefit optimally from anti-VEGF therapy are urgently needed.
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ACKNOWLEDGMENT |
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TopLearning ObjectivesAbstractIntroductionVEGF as a Target...Bevacizumab in Breast CancerConclusionsReferences |
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REFERENCES |
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TopLearning ObjectivesAbstractIntroductionVEGF as a Target...Bevacizumab in Breast CancerConclusionsReferences |
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