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Targeted therapies in breast cancer.

Introduction

Targeted therapies are evolving constantly, with the aim of limiting toxicity while selectively acting against cancer cells. The main targets at present are the human epidermal growth factor receptors 1 (HER1) and 2 (HER2), tyrosine kinase inhibitors and angiogenesis. Here we present some of the evidence supporting the use of various targeted agents, as well as future prospects in this field.

HER2

Trastuzumab

Approximately 25% of breast cancers over-amplify the HER2/neu gene (by fluorescence in situ hybridisation) or overexpress HER2 receptors (3+ by immunohistochemistry). This confers a more aggressive phenotype and worse prognosis. Trastuzumab is a humanised monoclonal antibody (immunoglobulin G1 type) targeted against the extracellular domain of HER2. It has revolutionised the management of patients with HER2-positive breast cancer.

In a study of 84 patients with metastatic breast cancer (MBC) that overexpressed HER2, single-agent trastuzumab as first-line therapy yielded an overall response rate (ORR) of 35% [1]. In those patients who had been pretreated with chemotherapy, single-agent trastuzumab resulted in an ORR of 18% [2].

In a study of 469 patients, the addition of trastuzumab to chemotherapy led to increased overall survival (OS), prolonged time to progression (TTP) and higher ORR compared to chemotherapy alone [3]. It was also noted in this study that the combination of trastuzumab with an anthracycline resulted in significant cardiotoxicity, compared to a trastuzumab/taxane combination. Many studies have been conducted to evaluate trastuzumab in combination with other cytotoxic agents including docetaxel [4], paclitaxel [5], capecitabine [6], vinorelbine [7] and gemcitabine [8], all with favourable results.

Combination chemotherapy regimens alongside trastuzumab have also been the subject of research. A Phase III study randomly assigned 196 patients with HER2-positive MBC to receive either trastuzumab and paclitaxel, or trastuzumab, paclitaxel and carboplatin. There was a significant increase in ORR and progression-free survival (PFS), but this came with an increase in grade 4 neutropenia [9].

With such encouraging results in advanced disease, research was undertaken to establish the value of trastuzumab in the adjuvant and neoadjuvant settings. The Herceptin Adjuvant (HERA) study showed significant reduction in the number of events (recurrence, contralateral disease, metastatic disease and death) in HER2-positive patients who received trastuzumab for a year following chemotherapy after surgery for early breast cancer, compared to those who did not [hazard ratio (HR), 0.54] [10]. Several other large studies have shown similar benefits of trastuzumab in the adjuvant setting [11-13].

Despite the huge impact that trastuzumab has had in both the adjuvant and metastatic settings, questions remain as to what to do with patients who progress on or after trastuzumab, the optimum duration of treatment in the adjuvant setting, and whether this agent should be given concurrently or sequentially with chemotherapy. Many of these questions will be answered as more data are collected not only from ongoing studies but also from new research.

Lapatinib

Lapatinib is an orally active competitive inhibitor of both HER1 and HER2 tyrosine kinases. A Phase III study comparing capecitabine and lapatinib with capecitabine alone in 321 patients with advanced HER2-positive breast cancer refractory to trastuzumab showed a significant increase in the TTP in the combination arm (36.9 versus 19.7 weeks; HR, 0.51; P<0.001) without significant additional toxicity [14].

As it is a small molecule, it was hypothesised that lapatinib, in contrast to trastuzumab, may be able to breach the blood-brain barrier in patients with brain metastases. A Phase II study of lapatinib in 39 patients with progressive or relapsed central nervous system disease was conducted. Lapatinib failed to show significant activity, but on volumetric analysis there was a trend towards a response. On the basis of this study, a larger multicentre study is to be carried out using volumetric analysis to assess response of brain metastases to lapatinib [15].

In view of the tolerability and efficacy of this orally active agent, studies are under way to evaluate its efficacy in the adjuvant setting.

Pertuzumab

Pertuzumab is a humanised monoclonal antibody that binds to HER2 and inhibits the dimerisation of HER2 with other members of the HER family, thus inhibiting cell survival pathways important in neoplastic transformation and progression [16]. The results of a Phase II study designed to assess the activity of pertuzumab in patients with metastatic breast cancer and low expression of HER2 were unfortunately not very encouraging, with only six of 78 patients achieving a response or sustained stable disease [17].

Xenograft studies suggested that the combination of pertuzumab and trastuzumab may have a synergistic effect [18]. A recently presented Phase II study to assess the use of this combination of antibodies in patients with metastatic breast cancer who had progressed on trastuzumab, showed extremely encouraging results with six of 33 patients achieving an objective response, and a further seven patients having sustained stable disease [19].When this study is finally published, it may provide us with an answer as to what to do with patients who progress on trastuzumab.

Epidermal growth factor receptor

The epidermal growth factor receptor (EGFR) is a member of the tyrosine kinase group of growth factor receptors. Following the binding of ligands such as the epidermal growth factor (EGF) to its receptor, activation of signal transduction pathways can lead to changes in cellular proliferation and differentiation. EGFR is highly expressed in breast cancer, particularly in hormone-resistant disease [20]. Targeting EGFR and its downstream signalling pathways will provide useful anti-tumour targeted therapies, as discussed below.

Gefitinib

Gefitinib is an oral compound that inhibits the tyrosine kinase activity of EGFR. Preclinical studies have demonstrated anti-tumour activity against breast cancer cells expressing varying degrees of EGFR and high levels of ErbB2. Phase I studies have shown anti-tumour activity and stable disease in patients with breast cancer [21].

A Phase II study was conducted to evaluate the response rate of gefitinib 500 mg/day in advanced breast cancer, as well as the pharmacodynamic effects of gefitinib on the tumour [22]. Of the 31 patients in the study, 12 (38.7%) had stable disease which included three (9.7%) with recurrent breast cancer that stabilised for more than 6 months. Gefitinib was well tolerated and the common adverse events were grade 1/2 gastrointestinal and skin disorders [22].

A Phase II study evaluating gefitinib with docetaxel as first-line therapy in metastatic breast cancer showed an overall response of 54% [95% confidence interval (CI), 45-75%] where five patients (12%) achieved complete response and 17 (42%) achieved partial response [23].

In another Phase II trial with gefitinib and docetaxel as first-line treatment, one of 33 patients showed complete response and 12 had a partial response. Overall objective response was 39.4%(95% CI, 22.9-57.9%).Median duration of clinical benefit was 10.9 months (95% CI, 6-17.6 months). In this study, patients received 250 mg gefitinib once a day and docetaxel 75mg/[m.sup.2] every 3 weeks. It appears that gefitinib as monotherapy has low anti-tumour activity but in combination with docetaxel is an active regimen in first-line metastatic breast cancer [24]. Further studies need to be carried out to determine which subsets of patients would benefit from EGFR inhibition.

Erlotinib

Erlotinib is an EGFR tyrosine kinase inhibitor that has shown anti-tumour activity in human cancer cell lines including non-small cell lung cancer and head and neck cancers [25].

A Phase I study looking at escalating doses of continuous erlotinib with weekly trastuzumab demonstrated some anti-tumour activity at a dose of 150 mg/day. The most common toxicities were grade 1/2 diarrhoea and rash [26].

The combination of erlotinib with weekly docetaxel was assessed in a Phase II study in previously untreated recurrent and/or metastatic breast cancer. In total, 31 patients were enrolled and best clinical response in the 20 evaluable patients showed that 11 patients achieved a partial response, seven had stable disease and two had progressive disease. Overall survival was 71% at 12 months and 42% at 24 months [27]. The combination of docetaxel and erlotinib has shown promising results and Phase III trials would be required to evaluate the efficacy of this further.

Cetuximab

Cetuximab is a humanised monoclonal antibody directed against EGFR that competes with ligand binding to the EGFR. This results in an efficient blockade of tumour-promoting downstream signalling pathways [28]. Preclinical studies have demonstrated that EGFR is overexpressed in oestrogen receptor-, progesterone receptor- and HER2-negative breast cancer.

A Phase II study was conducted in which patients were randomly assigned to receive cetuximab alone (400mg/[m.sup.2], then 250mg/[m.sup.2] weekly), with carboplatin [area under the curve (AUC) 2, for 3 of 4 weeks] added on disease progression, or cetuximab and carboplatin throughout. Cetuximab alone was better tolerated but showed low anti-tumour activity in this subtype of breast cancer. The primary endpoint was objective response (partial response plus complete response). The cetuximab alone arm showed a partial response of 6% and stable disease of 4%. The cetuximab and carboplatin arm showed objective response of 18% and stable disease of 9% [29].

A Phase II trial of irinotecan and cetuximab in patients with metastatic breast cancer who had received previous taxane- or anthracycline-based chemotherapy, showed that although tolerability was acceptable, there was minimal anti-tumour activity in this group of patients [30].

Angiogenesis

Neo-angiogenesis is a hallmark of cancer and is vital for tumour progression, invasion and metastases. In fact, tumours are unable to exceed 2 mm in diameter without recruiting a novel blood supply through the manipulation of pro- and anti-angiogenic factors and the cancer stromal environment. The regulation of angiogenesis is intricate, involving a complex interplay of growth factors, hormones, oncogenes, tumour suppressor genes and environmental cues such as hypoxia. In breast cancer, a role for the steroid hormone oestrogen and members of the EGF family EGFR1 and erbB2/HER2 in tumour neo-vasculature has also emerged [31,32]. However, the pro-angiogenic vascular endothelial growth factor (VEGF) family is increasingly a focus of drug development for targeted breast cancer therapy.

The glycoprotein VEGF family and its receptors are highly overexpressed in multiple human cancers including breast cancer. The VEGF family comprises at least seven related glycoprotein factors, the best characterised being VEGFA/VEGF which has five isoforms [33]. Two related receptors facilitate VEGF signalling: VEGFR1 (Flt-1) which is thought to act as a decoy receptor and VEGFR2 (KDR) which mediates the pro-angiogenic signal. VEGF acts to promote extracellular matrix degradation and supports the growth, invasion and survival of both endothelial and tumour cells. VEGF overexpression is an early step in breast cancer, apparent at the pre-invasive carcinoma in situ stage [34]. Invasive tumours with overexpression of VEGF are associated with poor patient prognosis and treatment resistance [35,36]. The rationale for anti-angiogenic agents is: (1) to turn off the 'angiogenic switch' and thereby target early disease and micro-metastasis before tumour vasculature is established; and (2) to 'normalise' aberrant tumour vasculature in advanced disease, thus optimising cytotoxic drug delivery.

Bevacizumab

Bevacizumab is a humanised monoclonal antibody to VEGFA. It directly binds and neutralises VEGFA preventing receptor activation. In preclinical models, a murine bevacizumab precursor inhibited tumour growth and angiogenesis. A Phase I trial of the humanised antibody in pre-treated metastatic breast cancer determined an optimal dosing schedule of 10 mg/kg with a 6.7% confirmed response rate and a median response duration of 5.5 months [37]. Early studies also suggested a potential synergistic action of anti-angiogenic and anti-HER2 therapy [31]. A Phase II trial with 37 patients demonstrated a 54% response rate for combined treatment in patients with HER2-positive breast cancer [38]. One responsive patient had previously progressed on single-agent trastuzumab. A Phase III study is now in progress to evaluate this effect further.

A number of Phase III trials have assessed the efficacy of bevacizumab combined with chemotherapy. Significant side effects associated with bevacizumab include grade 3/4 hypertension, proteinuria and bleeding. Miller et al. evaluated bevacizumab plus capecitabine versus capecitabine alone in a heavily pretreated patient group with metastatic breast cancer [39,40]. In this study, there was no significant increase in PFS. In another Phase III trial, comparing weekly paclitaxel and bevacizumab to chemotherapy alone in the first-line metastatic setting, there was a statistically significant increase in PFS in the combination group (11.4 versus 6.11 months; P<0.001). However, there was no statistically significant overall survival benefit in the bevacizumab group [41].

Small tyrosine kinase inhibitors

Small tyrosine kinase inhibitors block the kinase-mediated signalling of the VEGF receptor, thereby indirectly inhibiting downstream effects of the VEGF pathway. The benefits of these agents include oral bioavailability and multiple molecular targets potentially enhancing anti-tumour activity.

Sunitinib targets VEGFR, platelet-derived growth factor receptor (PDGFR) and stem cell factor receptor (kit), in addition to others. A very recent study has shown activity of sunitinib in an open-label, single-arm trial in patients with metastatic breast cancer previously treated with anthracyclines or taxanes [42]. Sunitinib achieved an 11% overall response rate with median overall survival of 38 weeks. The authors commented that response was prominent among patients with triple-negative and HER2-positive breast cancers. Toxicities included grade 3 neutropenia (39%), diarrhoea (56%), fatigue (49%) and hypertension (17%).

Sorafenib is a tyrosine kinase inhibitor that appears to have both anti-proliferative and anti-angiogenic properties mediated by the combined action on the Raf pathway, VEGFR and PDGFR. Significant increases in overall survival shown in metastatic solid tumours such as renal cell carcinoma have led to trials in advanced breast cancer. However, a Phase II study in patients with metastatic breast cancer yielded a response from only one of 23 patients enrolled [43].

Although demonstrating promising signs of disease modulation, particularly when combined with cytotoxic or biological agents, there appears to be significant scope for further optimisation of antiangiogenic therapy in breast cancer. Ongoing trials to assess the efficacy of anti-angiogenic agents in the adjuvant and neoadjuvant setting may delineate whether the stage of disease is important for improving disease targeting. In addition, the combination of anti-angiogenic agents with hormonal therapy and HER2 antagonists may allow further individualised therapy for each breast cancer patient.

Conclusion

New targeted agents are continually being developed, and existing agents are being evaluated in early phase studies. Ongoing research will guide us regarding combinations of targeted agents and efficacy with chemotherapy. With each new drug, questions arise as to sequencing and timing, which can only be answered with clinical trials.

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Rahul Peck (1), Bihani Kularatne (1) and Ciara O'Brien (2)

(1) Department of Medical Oncology, The Christie Hospital NHS Foundation Trust, Manchester, UK

(2) Paterson Institute for Cancer Research, Manchester, UK

Correspondence to: Rahul Peck Department of Medical Oncology, The Christie Hospital NHS Foundation Trust, Wilmslow Road, Manchester, M20 4BX, UK (email: rahul.peck@christie.nhs.uk)
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Title Annotation:Feature Article
Author:Peck, Rahul; Kularatne, Bihani; O'Brien, Ciara
Publication:Advances in Breast Cancer
Article Type:Report
Geographic Code:4EUUK
Date:Jun 1, 2008
Words:3839
Previous Article:Breast imaging: digital mammography.
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