Metastatic breast cancer (MBC) remains incurable in most patients; the goals of treatment are to optimize quality of life, manage symptoms and prolong survival. A wide array of agents is available for the treatment of MBC, including endocrine therapies, cytotoxic chemotherapy (Table 1) and targeted biological agents. Treatment choice is influenced by a large number of factors 1, and careful consideration is required to strike a balance between the benefits of treatment and the associated side effects.

Despite the variety of agents currently available for the treatment of MBC, median survival remains 2 to 3 years, indicating considerable unmet need and the necessity for improvement. This review summarizes recent data for novel agents, either in development or recently approved for use in MBC, that have the potential to improve treatment outcomes for patients with human epidermal growth factor receptor 2 (HER2)-negative disease.

Recommendations support the use of endocrine treatment as first-line therapy in patients with hormone-sensitive MBC 12. Tamoxifen is approved for the treatment of MBC and has long been considered the 'gold standard' of therapy for hormone-sensitive disease in premenopausal or postmenopausal patients. However, this agent is associated with some serious side effects, including thromboembolic events and uterine cancer, both occurring predominantly in women aged 50 years or older 3.

More recently developed endocrine therapies, including the third-generation aromatase inhibitors (anastrozole, letrozole and exemestane) and the selective oestrogen receptor down-regulator fulvestrant, are at least as effective as tamoxifen but have improved tolerability 45678. The aromatase inhibitors are recommended as first-line therapy for postmenopausal women with hormone receptor-positive MBC; however, tamoxifen remains a valuable therapeutic option 12. Treatment options for premenopausal patients include tamoxifen and ovarian function suppression (using a luteinizing hormone-releasing hormone agonist) or a combination of both 12.

Fulvestrant is recommended for second-line therapy after failure of tamoxifen and for third-line therapy after failure of tamoxifen and aromatase inhibitors. Other third-line agents that are used after other options have failed include progestins, androgens or high-dose oestrogens 12. The increasing use of selective oestrogen receptor modulators and aromatase inhibitors in the adjuvant setting may limit their utility in the treatment of relapsed disease, and data on rechallenging with these agents are limited.

Cytotoxic chemotherapy is the treatment modality of choice for patients with aggressive or symptomatic visceral disease, a short disease-free interval since adjuvant treatment, hormone receptor-negative disease, endocrine therapy-refractory hormone receptor-positive disease, or rapidly progressive hormone receptor-positive disease.

Anthracyclines and taxanes, used as single agents or in combination, are the most popular cytotoxic agents for the treatment of MBC 1. Partly because of the increasing use of these agents in the adjuvant setting, an issue currently facing physicians is the choice of treatment in patients with anthracycline-resistant or taxane-resistant disease. Agents including capecitabine and vinorelbine have demonstrated clinical benefit as monotherapy and combination therapy in such patients. Gemcitabine and ixabepilone have demonstrated clinical benefit only when used in combination with taxanes and capecitabine, respectively 1.

The term 'triple-negative' breast cancer (TNBC) refers to a subgroup of patients whose tumours do not express HER2 or hormone receptors. Gene expression analysis has defined five distinct subtypes of breast cancer, with predictive and prognostic implications 9. One of these, the basal-like subtype, shares numerous clinical and pathological features with the triple-negative phenotype, but – although there is significant overlap between the two groups – they are not synonymous 10.

Although patients with TNBC show some sensitivity to taxane and anthracycline-based regimens, they generally are at greater risk for early systemic recurrence and poorer survival than are their non-TNBC counterparts 1112. Interestingly, recent clinical trial data indicate that adjuvant tandem high-dose chemotherapy may be more effective than standard-dose therapy in improving 5-year event-free survival and overall survival in patients with the triple-negative phenotype 13.

Recent evidence suggests that TNBC may have increased susceptibility to platinum-based therapies relative to other breast cancers, and this has revived interest in their use 1415. Triple-negative tumours are known to have reduced levels of the DNA repair protein BRCA1, increasing their sensitivity to the DNA-damaging effects of platinum compounds 16. Further information on this subject is expected from an ongoing phase III trial (NCT00532727), which is comparing platinum therapy (carboplatin) with taxane therapy (docetaxel) in patients with triple-negative MBC. The estimated completion date of this trial, which aims to recruit around 400 patients, is 2012.

For a tumour to survive and grow, it needs to develop and maintain a network of blood vessels. Angiogenesis, the growth of new blood vessels, is therefore regarded as a key target for the development of new therapeutic strategies for breast cancer, as well as many other cancer types. A number of agents have been developed to inhibit the vascular endothelial growth factor (VEGF) pathway, which plays a key role in both normal and tumour angiogenesis (Table 3). To date, the most successful strategies have been based on direct inhibition of the VEGF ligand with a specific monoclonal antibody, or inhibition of the VEGF receptor using small-molecule tyrosine kinase inhibitors (TKIs).

The epidermal growth factor receptors (EGFRs) are a family of transmembrane proteins that trigger intracellular pathways responsible for cell growth via tyrosine kinase activation. Four receptors have been identified and given the acronym HER (human epidermal growth factor receptor): EGFR/HER1, HER2/neu, HER3 and HER4.

The development of trastuzumab, an antibody against HER2 (Table 4), significantly improved the outcome for patients with HER2 over-expressing breast cancer, and is now a widely recognized treatment option in this patient group. Indeed, combination therapy with trastuzumab plus chemotherapy is the current standard first-line treatment for HER2-positive MBC, and breast cancer patients are routinely tested to determine their HER2 status. A recent retrospective analysis revealed that some patients with HER2-negative disease may also benefit from the addition of trastuzumab to their chemotherapy regimen 45. Response to trastuzumab in these patients may be linked to polysomy of chromosome 17 46.

EGFR over-expression has been noted in some breast tumours, most frequently in the basal subtype 47, and has been linked to poor prognosis 48. However, EGFR expression is not a reliable marker of response to EGFR inhibitors, and EGFR status is not yet routinely tested in breast cancer 49.

Lapatinib is a dual inhibitor of EGFR and HER2 (Table 4) and is approved in combination with capecitabine for second-line or later-line treatment (after anthracyclines and taxanes) of patients with HER2-positive disease who have received prior trastuzumab therapy. However, lapatinib appears to offer little, if any, benefit to patients with HER2-negative disease. In a large phase III study investigating the combination of lapatinib and paclitaxel versus placebo and paclitaxel, the lapatinib combination failed to show any benefit over paclitaxel alone in patients with HER2-negative disease 50.

The EGFR inhibitor erlotinib (Table 4) is an effective treatment for patients with pancreatic or non-small-cell lung cancer; however, its efficacy in MBC remains unclear. In a phase II trial, single-agent erlotinib had minimal activity in heavily pretreated patients with MBC, with only one partial response and three cases of stable disease (≥ 12 weeks) among 69 treated patients 51. In another phase II study of 37 patients receiving erlotinib with the anti-angiogenic agent bevacizumab, one partial response was reported and four patients achieved stable disease (>9 months) 52. Another study suggests that greater clinical success may be achieved by combining erlotinib with gemcitabine, yielding a 14% response rate 53. Further phase II trials with erlotinib in MBC are ongoing.

In a phase II study, patients with triple-negative MBC received combination therapy with the EGFR inhibitor cetuximab (Table 4) and carboplatin 54. In arm 1 of the trial, patients were treated with single-agent cetuximab until disease progression, and then carboplatin was added; patients in arm 2 received combination therapy throughout. The ORR was low in both arms but favoured combination therapy (arm 1: 6%; arm 2: 18%). Adverse events occurred more frequently in the combination arm, most commonly rash, fatigue and nausea. Phase II studies of cetuximab in combination with other agents in MBC are ongoing.

A phase II study of single-agent gefitinib (Table 4) in 58 patients with taxane-pretreated and anthracycline-pretreated MBC produced an ORR of only 1.7% 55. Gefitinib was well tolerated, but it was not efficacious as a single agent in this setting. Two randomized phase II trials of gefitinib in combination with docetaxel also produced disappointing results 5657: one showed no efficacy benefit, but increased toxicity versus docetaxel alone, and the other was closed early due to treatment-related toxicity. Development of gefitinib in breast cancer has been discontinued.

Considerable interest has been expressed in modulation of resistance to endocrine therapies by concomitant inhibition of the EGFR pathway 58. Preclinical studies have shown that combining fulvestrant with gefitinib may result in greater antitumour activity than fulvestrant alone in patients with hormone receptor-positive advanced breast cancer 5960. It is hoped that ongoing trials will determine whether concomitant targeting of the EGFR pathway will delay the onset of resistance to fulvestrant in this setting 61. Another ongoing phase III trial is examining the effect of letrozole with or without lapatinib in patients with hormone receptor-positive MBC.

Overall, the success of EGFR inhibitors in MBC has been mixed. Although trastuzumab remains an agent of choice for patients with HER2-positive disease, there remains a lack of treatment options for patients with HER2-negative disease, and new therapeutic options for this patient population are required.

Mammalian target of rapamycin (mTOR) is a serine/threonine-protein kinase that is vital to the regulatory mechanisms of cell growth. mTOR inhibitors that have been, or are being, studied in breast cancer include sirolimus, temsirolimus, everolimus and deforolimus (Table 5).

The most promising data in this class have been reported from studies of temsirolimus; data with other agents remain limited. An ORR of 9.2% was reported in a phase II study of 106 patients with MBC receiving temsirolimus 62, whereas in another phase II study there was an improvement in PFS in postmenopausal women with locally advanced or MBC receiving temsirolimus combined with letrozole 63. In a preliminary analysis of this study, median PFS in patients receiving temsirolimus plus letrozole was 13.2 months, as compared with 11.6 months in patients who received letrozole alone. A phase III randomized, double-blind study that planned to evaluate this combination further has been discontinued.

A number of phase I and II studies are planned or ongoing investigating everolimus in combination with chemotherapy, endocrine agents, or erlotinib 64. Although further clinical study of these agents is required, the downstream location of mTOR in relation to activated receptor tyrosine kinases, plus the relatively mild toxicity profile of these agents, makes them attractive clinical candidates for the treatment of patients with MBC.

The Ras/Raf/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) signalling cascade conveys mitogenic input to the cell nucleus through sequential phosphorylation, controlling growth regulatory functions 65. Although Ras mutations are infrequent in breast cancers, this signalling pathway is known to play a role in endocrine therapy resistance 66. Preclinical studies combining endocrine agents with farnesyl transferase inhibitors, which target this pathway, have reported synergistic effects 6667. Therefore, drugs that inhibit the Ras/Raf/MEK/ERK pathway may have important clinical ramifications for breast cancer therapy 65. A phase II trial of two doses of the farnesyl transferase inhibitor tipifarnib (Table 5) in patients with MBC reported response rates at 6 months of 10% and 14%, and stable disease in 15% and 9% of patients 68. Further studies combining tipifarnib with chemotherapy and endocrine agents are ongoing.

Poly-ADP ribose polymerase (PARP) is a nuclear enzyme that is involved in repairing DNA damage, and it is activated when damage of the type caused by chemotherapy and/or radiotherapy occurs 69. Targeting PARP may prevent tumour cells from repairing DNA, a mechanism by which they develop drug resistance. Indeed, PARP inhibitors may make tumour cells more sensitive to cancer therapies 707172. As PARP inhibition appears to be particularly effective against BRCA1-deficient or BRCA2-deficient cells, PARP inhibitors may be particularly useful for the treatment of hereditary cancer with BRCA mutations 7374. Several PARP inhibitors are currently being investigated in phase II trials in patients with MBC, including KU-59436, BSI-201 and AG-14699 (Table 5). Of note, BSI-201 is currently undergoing evaluation in a multicentre, open-label, randomized phase II trial in 120 patients with triple-negative MBC. Patients receive gemcitabine plus carboplatin, either alone or in combination with BSI-201; intriguing data were presented at ASCO 2009 (O'Shaughnessy et al., unpublished data) with final analysis expected in 2010.

Although there are many agents available for the treatment of MBC, long-term responses are infrequent and prognosis remains poor. Increasing use of anthracyclines and taxanes for early breast cancer may have reduced the usefulness of these highly active agents in the metastatic setting. Patients with HER2-negative tumours are unlikely to benefit from therapy with trastuzumab or lapatinib, and treatment options are more limited for patients with triple-negative tumours. Further study of platinum therapy and the epothilone ixabepilone in these patients is required to determine their value in this setting.

Phase III clinical data suggest that bevacizumab may be a valuable treatment option for patients with HER2-negative MBC. Given the success of this anti-angiogenic approach, further investigation of VEGF receptor TKIs in this patient group is warranted.

In conclusion, several agents have shown promising results in clinical trials of patients with HER2-negative MBC. The new biological agents offer the potential to provide additive and synergistic therapeutic effects when used in combination with chemotherapy, and will potentially offer improved outcomes for MBC patients in the next few years.

CNS: central nervous system; EGFR: epidermal growth factor receptors; ERK: extracellular signal-regulated kinase; HER2: human epidermal growth factor receptor 2; HR: hazard ratio; MBC: metastatic breast cancer; MEK: mitogen-activated protein kinase kinase; mTOR: mammalian target of rapamycin; ORR: overall response rate; PARP: Poly-ADP ribose polymerase; PFS: progression-free survival; RR: response rate; TKI: tyrosine kinase inhibitor; TNBC: triple-negative breast cancer; VEGF: vascular endothelial growth factor.

DWM has received honoraria from Roche, GSK and Sanofi Aventis for invited presentations and advisory boards.

This article is part of a review series on Recent advances in systemic therapy, edited by Paul Ellis.

Other articles in the series can be found online athttp://breast-cancer-research.com/series/bcr_systemic_therapy