Problems
We are currently facing a changing scenario. Continued improvements in cancer treatments are achieving better control of systemic disease, not only in breast cancer but also in other neoplasms such as lung, kidney, colon and melanoma. The development of better imaging studies is permitting detection of subclinical disease and better control of systemic disease. These and other factors are leading to more patients being diagnosed with brain and other CNS metastatic disease.

Nowhere does this seem more true than for patients with HER-2-positive breast cancer receiving trastuzumab treatment, as CNS metastases are becoming the most important site of progression and limitation of quality of life and survival.³⁸

Nevertheless, for many patients standard treatments only offer a median six months’ survival with few prospective trials conducted for the treatment of brain metastasis of breast cancer. Most studies of novel agents excluded women with known brain metastasis, and the majority of published trials of brain metastasis treatment have grouped different histological types of tumours together as one.^4,38

Perspectives
There is a clear, unmet need to improve the therapeutic option for patients with CNS metastatic disease, specifically for patients with HER-2-positive breast cancer. The advent of active targeted therapies and antiangiogenesic agents has the potential to bring a new perspective to the treatment of CNS disease.

Small Molecules

Dual Kinase Inhibitors
The epidermal growth factor (EGF) or ErbB receptors are members of the receptor tyrosine kinase superfamily. There are four ErbB receptor family members: ErbB1 (EGFR, HER-1), ErbB2 (HER-2/neu), ErbB3 (HER3) and ErbB4 (HER-4).³⁹ These receptors are situated at the cell membrane and have an extracellular ligand-binding region, a transmembrane region and a cytoplasmic tyrosine kinase domain. Ligand binding to the receptors results in receptor homo- and/or hetero-dimerisation, activating the intrinsic kinase domain and leading to phosphorylation of specific tyrosine residues within the cytoplasmic tail and, finally, to the activation of a variety of intracellular signalling pathways that promote cell growth, proliferation, differentiation and migration.39 Interactions between ErbB receptors allows ErbB2 – which has no kinase activity but is the preferred dimerisation partner for all the other ErbB receptors – to participate in effective signalling.⁴⁰

Amplification of HER-2 is seen in 25–30% of breast cancers and is associated with a statistically significant shortening in disease-free and overall survival.¹³ Overexpression of ErbB1 occurs in a similar proportion of breast cancers, although it is less clear in what proportion expression confers biological activity (and thus the potential for therapeutic intervention).¹⁹

A number of agents directed against individual ErbB receptors have been approved for clinical use in human cancer and can broadly be separated into two main groups. Humanised monoclonal antibodies are directed against the extracellular domain of the receptor, such as trastuzumab, and small-molecule tyrosine kinase inhibitors, such as gefitinib, bind to the ATP-binding site of the intracellular tyrosine kinase domain of the receptor.⁴⁰

Molecular pathways can be both adaptable and redundant. It is thus unlikely that therapy focusing on a single target will achieve durable disease control for most patients. The ErbB receptor family members follow this paradigm, in that they are known to be interdependent, preferentially functioning as dimmers to induce signal transduction and malignant transformation.41 This is supported by the clinical observation that cancers concomitantly overexpressing EGFR and HER-2 have a worse outcome than those that overexpress either receptor alone.^42,43 There is therefore increasing evidence in support of developing effective therapies that concurrently inhibit two or more receptors.

HER-2 overexpression has been shown to activate and potentiate EGFR signalling, and combined inhibition of EGFR and HER-2 results in greater tumour growth inhibition. Pre-clinical data with breast cancer cell lines and animal models resulted in superior antitumour activity utilising a dual ErbB approach rather than single-receptor targeting, suggesting that the addition of EGFR blocking could overcome trastuzumab resistance.¹⁹ In these studies, the combined use of trastuzumab with gefitinib, erlotinib or lapatinib was compared with the activity of trastuzumab alone. A phase II study with gefitinib and trastuzumab was unfortunately terminated early with no effect seen.¹⁹

Most interest has been centred on agents that produce dual inhibition from one molecule such as lapatinib, but there is still room for developing combinations of single agents in order to attain full blockade of both receptors, which might not be efficiently obtained from a single molecule since the toxicity of blocking one receptor may hinder dose escalation to achieve complete blockade of the combined receptor.¹⁹

Lapatinib
Lapatinib is a potent, reversible, selective dual inhibitor of EGFR and HER-2 kinases, and has demonstrated growth inhibition in both in vitro and in vivo models overexpressing these receptors.⁴⁴ Toxicology studies supported the clinical development of the oral use of lapatinib with minimal side effects.⁴⁵ Lapatinib acts intracellularly and directly targets the tyrosine kinase domain, preventing downstream signalling events.¹⁹

Early clinical studies have reported significant activity, with phase II studies in advanced or metastatic breast cancer showing a response rate of 22% in trastuzumab-refractory patients⁴⁶ and 24% in patients treated with lapatinib in first line.⁴⁷

Clinical trials have been carried out with lapatinib for the treatment of brain metastasis because it is a small molecule able to penetrate the blood–brain barrier.¹⁹ At the American Society of Clinical Oncology Annual Meeting in 2006, Winer and colleagues presented a phase II study involving lapatinib in the treatment of breast cancer patients with progressive brain metastasis despite prior treatment with radiotherapy and/or surgery. These patients were evaluated for objective response according to Response Evaluation Criteria In Solid Tumours (RECIST), with MRI and positron emission tomography (PET) as imaging studies. The study goal was to observe four objective responses – only two, however, were observed in their sample of 39 patients, and overall the median time to progression (TTP) was three months (95% confidence interval (CI) 2.04–3.68) with a median overall survival time of 6.6 months.⁴⁸ However, anecdotal evidence suggests that more patients than just these two benefited from the intervention, which has led to larger studies to more precisely determine the activity of this agent for these patients, including the multicentre phase II study, NCT00263588. This study has closed to accrual and the results are eagerly awaited. With a similar design, the study registered as NCT00098605 and sponsored by Dana Farber Institute is also presently closed to accrual (see www.clinicaltrials.gov).⁴⁹

A pivotal phase III study with lapatinib was conducted in patients with metastatic HER-2-positive breast cancer already treated with trastuzumab, anthracyclines and taxanes. The goal was to compare the use of the combination lapatinib and capecitabine with capecitabine alone. It is interesting to observe that in the first report of this study, the number of women presenting CNS metastasis as first-site progression during this treatment was only four in the combined treatment group compared with 11 in the monotherapy group. While this difference did not reach statistical significance by Fisher’s exact test (p=0.10), it suggests that lapatinib might be able to help prevent this devastating complication of HER-2-positive breast cancer.⁵⁰ Updated clinical data are expected soon.

The Tykerb® Evaluation After Chemotherapy trial is enrolling patients. The objective of this trial is to determine whether adjuvant therapy with lapatinib for one year will improve disease-free survival in women with early-stage ErbB2-overexpressing breast cancer that has not previously received trastuzumab. Results for lapatinib use versus placebo will also be compared for the rate of CNS recurrence.¹⁹ In a similar way, the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation trial will explore the relative efficacy of adjuvant trastuzumab and lapatinib, as well as their use in sequence and concomitantly. The incidence of brain metastasis and, consequently, the possible efficacy of these drugs in its prevention will also be evaluated.

The concurrent use of lapatinib and radiation has not previously been evaluated in humans, but the experience with gefitinib (ErbB1 inhibitor) in patients with non-small-cell lung cancer suggested that this agent could be useful in the treatment of brain metastasis.⁵¹ The results of the use of lapatinib in this group of patients remain to be proved. A real need exists for drugs capable of crossing the blood–brain barrier with significant activity against brain metastasis, and other agents can also fit this requirement.