A systematic review of dual targeting in HER2-positive breast cancer

Background

Human epidermal growth factor receptor 2 (HER2) is overexpresed in 15–20% of all breast cancers. Treatment with trastuzumab has led to an improved outcome and prolonged survival of HER2-positive breast cancer patients and today the drug is established as standard of care in both the adjuvant and metastatic settings. However, trastuzumab resistance is common and a major focus in the treatment of HER2-positive breast cancer has been developing therapeutic agents to either potentiate the effect of trastuzumab or to target cells which have become resistant to trastuzumab. The present review addresses efficacy and toxicity of dual targeting in HER2-positive breast cancer.

Materials and methods

A computer-based literature search was carried out using PubMed; data reported at international meetings and clinicaltrials.gov was included.

Results

This paper describes efficacy and safety of lapatinib, pertuzumab or trastuzumab-DM1 in combination with trastuzumab in the (neo)adjuvant and metastatic settings. Furthermore, combinations of trastuzumab and drugs targeting the downstream pathway are described.

Conclusion

Dual blockade is likely to represent a substantial advance for patients with HER2-positive breast cancer. However, the relevant subpopulation remains to be defined and side effects including cardiotoxicity might be a limiting factor to the use. There is an urgent need for prospective biomarker-driven trials to identify patients for whom dual targeting is cost-effective.     

Therapeutic approaches for HER2-positive brain metastases: Circumventing the blood–brain barrier

We aim to summarize data from studies of trastuzumab in patients with human epidermal growth factor receptor 2 (HER2)–positive metastatic breast cancer (MBC) and brain metastasis and to describe novel methods being developed to circumvent the blood–brain barrier (BBB). A literature search was conducted to obtain data on the clinical efficacy of trastuzumab and lapatinib in patients with HER2-positive MBC and brain metastasis, as well as the transport of therapeutic molecules across the BBB. Trastuzumab-based therapy is the standard of care for patients with HER2-positive MBC. Post hoc and retrospective analyses show that trastuzumab significantly prolongs overall survival when given after the diagnosis of central nervous system (CNS) metastasis; this is probably attributable to its control of extracranial disease, although trastuzumab may have a direct effect on CNS disease in patients with local or general perturbation of the BBB. In patients without a compromised BBB, trastuzumab is thought to have limited access to the brain, because of its relatively large molecular size. Several approaches are being developed to enhance the delivery of therapeutic agents to the brain. These include physical or pharmacologic disruption of the BBB, direct intracerebral drug delivery, drug manipulation, and coupling drugs to transport vectors. Available data suggest that trastuzumab extends survival in patients with HER2-positive MBC and brain metastasis. Novel methods for delivery of therapeutic agents into the brain could be used in the future to enhance access to the CNS by trastuzumab, thereby improving its efficacy in this setting.     

Dual human epidermal growth factor receptor 2 blockade for the treatment of HER2-positive breast cancer

The introduction of trastuzumab into clinical practice changed the natural course of HER2-positive breast cancer. Currently, treatment with trastuzumab represents the standard of care for HER2-positive breast cancer and this treatment has been approved in the adjuvant, neoadjuvant, and metastatic settings. Besides trastuzumab, two other anti-HER2 agents—lapatinib and pertuzumab—have been approved for the treatment of HER2-positive advanced breast cancer. Strong biologic data support the concept of dual HER2 blockade, with different anti-HER2 agents demonstrating complementary mechanisms of action. Several neoadjuvant and metastatic studies performed in HER2-positive breast cancer using dual HER2 blockade have been proven to outperform anti-HER2 monotherapies. These dual combinations of agents represent a promising therapeutic strategy that is now reaching clinical practice. In this review we describe the results of studies utilizing dual blockade in patients with HER2-positive breast cancer.     

Randomized phase II study of lapatinib plus capecitabine or lapatinib plus topotecan for patients with HER2-positive breast cancer brain metastases

Approximately one-third of patients with advanced, HER2-positive breast cancer develop brain metastases. A significant proportion of women experience central nervous system (CNS) progression after standard radiation therapy. The optimal treatment in the refractory setting is undefined. This study evaluated the toxicity and efficacy of lapatinib in combination with chemotherapy among patients with HER2-positive, progressive brain metastases. Patients with HER2-positive breast cancer with progressive brain metastases after trastuzumab and cranial radiotherapy were included. The primary endpoint was CNS objective response, defined as a ≥50% volumetric reduction of CNS lesion(s) in the absence of new or progressive CNS or non-CNS lesions, or increasing steroid requirements. The study was closed early after 22 of a planned 110 patients were enrolled due to excess toxicity and lack of efficacy in the lapatinib plus topotecan arm. The objective response rate (ORR) in the lapatinib plus capecitabine arm was 38% (exact 95% confidence interval [CI] 13.9–68.4). No responses were observed in the lapatinib plus topotecan arm. Although the study was stopped prior to full enrollment, some promising indications of CNS activity were noted for lapatinib plus capecitabine. The combination of lapatinib plus topotecan was not active and was associated with excess toxicity.     

HER2-positive,trastuzumab-resistant metastatic esophageal cancer presenting with brain metastasis after durable response to dual HER2 blockade: a case report

We here report a case of a patient diagnosed with human epithelial growth factor receptor 2 (HER2)-amplified esophageal adenocarcinoma. The patient responded well to trastuzumab-based chemotherapy initially, but progressed with liver metastases. Her treatment was then switched to dual HER2 blockade with both trastuzumab and lapatinib in combination with capecitabine. She tolerated therapy and responded remarkably well with radiographic resolution of liver metastases. Unfortunately, she developed multiple brain metastases in the absence of extracranial progression. Discordant negative expression of HER2 and subclonal mutations in brain lesions were discovered, which, at least in part, explained her brain metastases in the presence of capecitabine and lapatinib, as both agents are known to be able to cross the blood brain barrier. The potential mechanism for dual HER2 blockade is discussed in the context of HER2-positive, trastuzumab-resistant, advanced esophageal cancer. The incidence of brain metastasis in advanced gastro-esophageal cancer has been reported to be extremely low, but is expected to increase with more effective systemic therapy. The intratumoral heterogeneity between the metastases, local recurrences and the primary tumor is definitely noteworthy.     

Impact of anti-HER2 therapy on overall survival in HER2-overexpressing breast cancer patients with brain metastases

Background:

Trastuzumab-based therapy after diagnosis of brain metastases (BM) may improve survival due to prolonged systemic disease control. We investigated whether lapatinib may yield additional survival benefit.

Methods:

Eighty patients with BM from HER2-positive breast cancer were identified. Karnofsky Performance Score (KPS) of at least 70 was required. We included a control group of 37 patients treated before 2003, when continuation of trastuzumab after diagnosis of BM was not yet recommended. Remainders received either trastuzumab or lapatinib and trastuzumab (either concomitantly or sequentially) with or without chemotherapy.

Results:

Median overall survival (OS) in patients receiving trastuzumab after diagnosis of BM was 13 months; corresponding numbers were 9 months in patients treated with chemotherapy, and 3 months with radiotherapy alone. Median OS was not reached in the lapatinib group. Addition of lapatinib prolonged OS over trastuzumab alone (P=0.002). After correction for potential confounders, lapatinib therapy remained an independent positive predictor for survival (HR 0.279; P=0.012).

Interpretation:

This retrospective single-centre study suggests that the introduction of lapatinib improved survival in patients with BM from HER2-positive breast cancer. Patients with KPS ⩾70 may benefit when treated with lapatinib in addition to trastuzumab after completion of local therapy.     

Complete response in HER2+ leptomeningeal carcinomatosis from breast cancer with intrathecal trastuzumab

Trastuzumab, a monoclonal antibody against the HER2 receptor, is a major breakthrough in the treatment of HER2+ breast cancer. However, its high molecular weight precludes it from crossing the intact blood–brain barrier, making the central nervous system a sanctuary to HER2+ breast cancer metastases. We prospectively assessed functional outcome and toxicity of administering trastuzumab directly into the cerebrospinal fluid of a patient with leptomeningeal carcinomatosis (LC) and brain metastases from HER2+ breast cancer that had already been treated with other intrathecal chemotherapy, with no benefit. Upon signed informed consent, weekly lumbar puncture with administration of trastuzumab 25 mg was begun to a 44 year-old women with metastatic breast cancer (lymph node, bone, lung, and liver involvement) previously treated with tamoxifen, letrozole, anthracyclines, taxanes, capecitabine, intravenous trastuzumab, and lapatinib. She received 67 weekly administrations of intrathecal trastuzumab with marked clinical improvement and no adverse events. She survived 27 months after LC diagnosis. A complete leptomeningeal response, with no evidence of leptomeningeal metastasis at necropsy, was achieved. We believe that intrathecal trastuzumab administration should be prospectively evaluated to confirm clinical activity and optimize dose, schedule, and duration of treatment.     

Dual HER2-targeted approaches in HER2-positive breast cancer

Approximately 15–20% of all breast cancers are human epidermal growth factor receptor 2 (HER2) positive, with clinical studies having validated the HER2 receptor tyrosine kinase pathway as an important therapeutic target. Presently, two HER2-targeted therapies are approved by the Food and Drug Administration for treatment of HER2-positive breast cancer: the HER2-targeted humanized monoclonal antibody trastuzumab and the small-molecule tyrosine kinase inhibitor lapatinib. Despite use of these HER2-targeted agents, many patients still experience disease progression. For this reason, numerous new agents and therapeutic strategies are under investigation. Based on preclinical data suggesting synergistic effects from dual therapy targeting HER2, clinical trials that test the effects of combining anti-HER2 agents have been conducted and are ongoing. Here, we review recently presented data from several clinical trials, which indicate that the strategy of combining HER2 blockade therapies can offer greater clinical efficacy, with adverse effects of varying degrees. Specifically, we review new data reported at the 2010 San Antonio Breast Cancer Symposium (SABCS 2010), including the phase II NeoSphere and phase III NeoALTTO clinical trials, and data from three clinical trials reported at the 2011 American Society of Clinical Oncology (ASCO 2011) meeting. Together these trials elucidate the potential role of combining trastuzumab with lapatinib or pertuzumab. We also discuss additional ongoing studies that will help further define the role of dual HER2 blockade therapies and its impact on clinical practice.     

Lapatinib and breast cancer: current indications and outlook for the future

Lapatinib is an oral dual erbB 1/2 tyrosine kinase inhibitor that inhibits human EGF receptor 2 (HER2) and blocks the EGF receptor. Studies have shown that in patients with metastatic HER2-positive breast cancer that is resistant to trastuzumab, the addition of lapatinib to capecitabine improves progression-free survival and appears to lengthen overall survival. Furthermore, lapatinib has been studied in patients with involvement of the CNS and has been associated with stable disease and some responses. Its combination with letrozole provided an improvement in progression-free survival compared with single-agent letrozole in women with hormone receptor-positive, HER2-positive metastatic breast cancer. More recently, data suggested that the combination of lapatinib with trastuzumab significantly improves overall survival in women with metastatic breast cancer compared with single-agent lapatinib. Current indications in the USA for the use of lapatinib are for the treatment of metastatic HER2-positive breast cancer, both in combination with capecitabine in patients who have received taxane, anthracycline and traztuzumab, and in combination with letrozole for postmenopausal patients with hormone receptor- and HER2-overexpressing breast cancer. Common side effects of lapatinib include diarrhea and rash. Studies to date have found a less than 2% risk for cardiotoxicity, although most cardiac events that occurred during the studies were not attributed to lapatinib. It is important to consider that most of the patients in existing studies had already been treated with trastuzumab with no significant cardiotoxicity; therefore, future studies will show how trastuzumab-naive patients tolerate lapatinib. Ongoing research is evaluating the role of lapatinib in the adjuvant setting as a single agent or in combination with trastuzumab.     

A case of HER2-positive breast cancer receiving lapatinib+capecitabine chemotherapy with ventriculoperitoneal shunting for hydrocephalus associated with brain metastases

In patients with HER2-positive breast cancer, cerebral metastasis sometimes occurs even if the breast tumor and liver/lung metastasis are controlled with trastuzumab. We encountered a case of HER2-positive breast cancer with cerebral metastasis presenting with hydrocephalus, in which VP shunting was successful, enabling continued treatment with lapatinib+capecitabine and improvement of the patient's QOL. VP shunting relieved the symptoms of the brain metastasis, including headache and vomiting, which was damaging for the patient. In addition, the efficacy of lapatinib for the treatment of cerebral metastasis in HER2-positive breast cancer has been reported. In our case of HER2-positive breast cancer with brain metastasis that presented with hydrocephalus, VP shunting relieved the symptoms and improved the QOL of the patient, enabling treatment with lapatinib+capecitabine to be continued.     

Clinical recommendations for the use of lapatinib ditosylate plus capecitabine for patients with advanced or metastatic HER2-positive breast cancer

Primary and acquired resistance to trastuzumab pose a therapeutic challenge when treating patients with HER2 (erbB-2)-positive locally advanced or metastatic breast cancer (MBC). The recent introduction of lapatinib (Tykerb/Tyverb, GlaxoSmithKline, Brentford, UK) provides a new management option for such patients. A prospective, randomized phase III clinical trial has confirmed that lapatinib in combination with capecitabine extends time to progressive disease in HER2-positive MBC, compared with capecitabine alone in patients with disease progression despite prior anthracycline, taxane and trastuzumab therapy. Preliminary data also indicate that lapatinib may exert a beneficial effect on brain metastases, a common sanctuary site for HER2-positive breast cancer following trastuzumab treatment. The tolerability of lapatinib is commensurate with that of other erbB family tyrosine kinase inhibitors and no significant new adverse events have emerged following its introduction into clinical practice. In particular, no additive cardiotoxicity has been observed when lapatinib is prescribed after trastuzumab therapy. Based on the published literature and supplemented by clinical experience, this article provides practical management recommendations for the use of lapatinib plus capecitabine in patients with MBC. Issues addressed include patient selection, baseline evaluation and monitoring for clinical benefit. The minimization and management of adverse events is also discussed in detail, particularly the dermatological and gastrointestinal effects, which are the most clinically significant side-effects of lapatinib therapy. Further recommendations cover the minimization of drug interactions, anticipated dosing alterations and the optimal employment of oral anticancer regimens.     

Trastuzumab et lapatinib dans la prise en charge du cancer du sein HER2 positif

HER2-positive breast cancers, i.e., with an overexpression of the HER2-protein in immunohistochemistry and/or with anHER2gene amplification, account for 10% to 26% of breast cancers. The surexpression of this tyrosine kinase receptor is often associated with a poor prognosis. However, the use of HER2-targeted therapy has considerably changed the management and the prognosis of these patients, both in metastatic and adjuvant settings. The first available molecule was trastuzumab (Herceptin®, Roche), a humanized monoclonal antibody specifically directed against the extracellular domain of the HER2-receptor. Recently, lapatinib (Tyverb®, Glaxosmithkline) has been approved for the metastatic HER2-positive breast cancers only. This molecule inhibits the intracellular tyrosine kinase domains of both HER1- and HER2-receptors, explaining a different toxicity compared to trastuzumab. We present an overview of the different possible associations in the metastatic setting between the trastuzumab on one part and the lapatinib on the other part and the hormonotherapy or the chemotherapy. Data regarding cardiotoxicity and the use of the HER2-targeted therapy in the management of brain metastases are also reviewed. Finally, the phase III studies involving trastuzumab in the adjuvant setting are detailed.     

Treatment of Her2-Positive Breast Cancer: What’s on the Horizon

Almost 30% of all breast cancers are noted to overexpress human epidermal growth factor receptor 2 (Her2), an epidermal growth factor receptor that is part of the HER family of tyrosine kinases. Her2 exerts its effect by forming heterodimers with other HER family members, resulting in the activation of a number of signaling pathways that are important for tumor progression and survival. Her2 overexpression has been linked with a more aggressive breast cancer phenotype and with decreased survival in patients with Her2-positive tumors. Trastuzumab and lapatinib are approved targeted agents for treatment of Her2-overexpressing breast cancer. The use of trastuzumab in this patient population resulted in phenomenal responses and paved the way for use of molecularly targeted therapies in the treatment of many other cancers. However, despite the tremendous progress attained, disease progression, even with trastuzumab and lapatinib treatment, is inevitable in metastatic breast cancer. Thus, research efforts have focused on finding alternative therapies to trastuzumab and lapatinib for the treatment of Her2-positive breast cancer. Efforts aimed at understanding the mechanism of action of trastuzumab and lapatinib and the causes of resistance have led to the identification of several promising agents for the treatment of patients with Her2-positive breast cancer.     

Trastuzumab treatment in patients with breast cancer and metastatic CNS disease

Background: Patients with metastatic central nervous system (mCNS) disease progression from breast cancer have a poor prognosis and often develop associated neurological complications. Human epidermal growth factor receptor 2 (HER2)-positivity status increases the risk of developing mCNS disease. Trastuzumab is an mAb that targets HER2 and is known to extend survival across all stages of HER2-positive breast cancer.Design: This review considers evidence from preclinical and clinical studies examining the value of continuing trastuzumab treatment in patients who develop mCNS disease. A wealth of data from clinical studies showed that trastuzumab prolonged survival in patients with mCNS disease, compared with no trastuzumab treatment, by effectively controlling their non-CNS disease. Trastuzumab has also been shown to penetrate an impaired blood–brain barrier to a limited degree, such as during radiotherapy, and intrathecal delivery of trastuzumab to the central nervous system (CNS) has shown promise. Research efforts are focussing on improving the delivery of trastuzumab to the CNS.Conclusion: Evidence indicates that patients with mCNS disease from HER2-positive breast cancer should continue to receive trastuzumab to control HER2-positive metastases outside the CNS and receive established therapies to control the mCNS disease.     

Dose-Reduced Trastuzumab Emtansine: Active and Safe in Acute Hepatic Dysfunction

Breast cancer is the most common cancer in women worldwide. The majority of deaths attributed to breast cancer are a result of metastatic disease, and 30% of early breast cancers (EBC) will develop distant disease. The 5-year survival of patients with metastatic disease is estimated at 23%. Breast cancer subtypes continue to be stratified histologically on oestrogen, progesterone and human epidermal growth factor-2 (HER2) receptor expression. HER2-positive breast cancers represent 25% of all breast cancer diagnoses. The therapies available for metastatic breast cancer (MBC) are expanding, in particular within the field of HER2-positive disease, with the approval of trastuzumab, pertuzumab, lapatinib and trastuzumab emtansine (TDM-1). Recently, TDM-1 has been shown to improve progression-free survival in HER2 MBC when compared to capecitabine and lapatinib in clinical studies. Its main toxicities are deranged liver function tests and thrombocytopenia. There have also been cases of acute liver failure. Therefore, its use in acute hepatic dysfunction, to our knowledge, has been neither studied nor reported. We report a patient with progressive HER2-positive MBC who had previously responded to multiple HER2-targeted therapies that presented with acute hepatic dysfunction. She was treated with dose-reduced TDM-1 safely, with clear evidence of rapid biochemical, clinical and radiological response. This allowed dose escalation of TDM-1, and the patient maintains an ongoing response.Key Words: Human epidermal growth factor-2, Metastatic breast cancer, Hepatic dysfunction, Trastuzumab emtansine     

Biological subtypes and survival outcomes in breast cancer patients with brain metastases (study of the anatolian society of medical oncology)

Background: The aim of this study is to determine the relationship between the survival outcomes and biological subtype in breast cancer patients with brain metastases. Methods: We retrospectively evaluated clinical data from 422 breast cancer patients with brain metastases between 2001 and 2011 from referral centers in Turkey. The study population was divided into four biological subtypes according to their hormone receptor status and HER2 expression. Results: Systemic treatment prolonged median overall survival (OS) after brain metastases in the entire group (14 vs. 3.2 months, p < 0.001). It also prolonged median OS after brain metastases in the triple negative (7.5 vs. 1.6 months, p = 0.010) and luminal A (14.3 vs. 7.1 months, p = 0.003) subgroups. The median OS for untreated patients, chemotherapy and/or hormonal therapy receiving patients, and chemotherapy and/or hormonal therapy plus targeted therapy receivers was 2, 5.8, and 17.7 months, respectively (p < 0.001), in the HER2-overexpressing subgroup. In the luminal B subgroup, it was 3.7, 5.3, and 15.4 months, respectively (p = 0.003). Conclusions: The use of systemic therapy improves OS after brain metastases in all biological subgroups. Targeted therapies also improve OS after brain metastases in HER2-positive patients. The combined use of targeted therapies and lapatinib are superior to single use and trastuzumab, respectively, in these patients.     

Lapatinib monotherapy in patients with relapsed, advanced, or metastatic breast cancer: efficacy, safety, and biomarker results from Japanese patients phase II studies

Background:

HER2-positive metastatic breast cancer (MBC) relapsing after trastuzumab-based therapy may require continued HER2 receptor inhibition to control the disease and preserve the patients'' quality-of-life. Efficacy and safety of lapatinib monotherapy was evaluated in Japanese breast cancer patients after trastuzumab-based therapies.

Methods:

In studies, EGF100642 and EGF104911 evaluated the efficacy and safety of oral lapatinib given 1500 mg once daily in patients with advanced or MBC. All patients progressed on anthracyclines and taxanes; HER2-positive patients had also progressed on trastuzumab.

Results:

For HER2-positive tumours (n=100), objective response rate was 19.0% (95% confidence interval (CI): 11.8–28.1) and clinical benefit rate (CBR) was 25.0% (95% CI: 16.9–34.7). One out of 22 HER2-negative tumour was documented as complete response (n=22). The median time-to-progression (TTP) in the HER2-positive and HER2-negative groups was 13.0 and 8.0 weeks (P=0.007); median overall survival was 58.3 and 40.0 weeks, respectively. The most frequent adverse event was diarrhoea. TTP and CBR were significantly associated with HER2 expression. Patients with tumours harbouring an H1047R PIK3CA mutation or low expression of PTEN derived clinical benefit from lapatinib.

Conclusion:

Lapatinib monotherapy had shown anti-tumour activity in Japanese patients with HER2-positive MBC that relapsed after trastuzumab-based therapy, including those with brain metastases. Patients benefiting from lapatinib may have biomarker profiles differing from that reported for trastuzumab.     

Thérapeutiques dans le cancer du sein métastatique HER2-positif : présent et futur

HER2-positive breast cancer accounts for 20 to 25% of breast cancers. The surexpression of this tyrosine-kinase receptor is often associated with a poor prognosis. However, the management and the outcome of these patients have changed these last ten years with trastuzumab. Despite the encouraging results obtained with this humanized monoclonal antibody directed against the HER2-receptor, used alone or in association with chemotherapy in metastatic patients, progression under trastuzumab are usually observed and resistances to this treatment are described. Thus, many other monoclonal antibodies and tyrosine-kinase inhibitors emerged. These therapeutics, used alone or in association with chemotherapy or trastuzumab have variable properties: anti-HER2 and anti-EGFR such as lapatinib, pertuzumab and neratinib; anti-EGFR such as erlotinib and gefitinib; antiangiogenesis (bevacizumab, pazopanib); anti-mTOR pathway (temsirolimus, everolimus) or inhibitor of HSP90 (tanespimycine). In this paper, we present an overview on validated targeted therapies and those which are currently under investigation and seem promising in first line or after progression under trastuzumab. Data regarding cardiotoxicity and the use of trastuzumab under particular clinical circumstances (brain metastases, pregnancy) are also reviewed.     

Lapatinib: A competitor or companion to trastuzumab?

Trastuzumab (Herceptin), a monoclonal antibody against HER2 has established itself as the treatment paradigm of HER2-overexpressing breast cancer. Its success, however, has been tempered by its sequelae. In particular, most tumours become resistant to trastuzumab through a variety of mechanisms. Furthermore, there is both an increased incidence of cardiac dysfunction and a worrying pattern of CNS metastasis associated with trastuzumab. To manage these concerns, many new treatments targeting HER2 have been developed. Of these emerging therapies, the dual tyrosine kinase receptor inhibitor against EGFR and HER2, lapatinib (Tyverb/Tykerb) has shown the most promise to date. Encouraging early results in vitro have now been reproduced in phase II/III clinical trials, both as lapatinib monotherapy and synergistically with other established therapeutic regimes, including trastuzumab itself. Trial results suggest it may be of considerable benefit to patients with trastuzumab-resistant tumours and may play a role in the reduction of CNS relapses. In addition, lapatinib is well-tolerated and unlike trastuzumab, minimal cardiac dysfunction has been documented. A number of trials are underway to assess whether lapatinib will oust trastuzumab from its pole position in the management of HER2-positive breast cancer or whether their combination will prove to be superior to either therapy alone.     

New challenges and opportunities in the management of brain metastases in patients with ErbB2-positive metastatic breast cancer

The introduction of trastuzumab for the treatment of tumors that overexpress ErbB2 (also known as HER2) has contributed significantly to recent improvements in systemic therapy for advanced breast cancer. The advances in systemic therapy have highlighted an increasing prevalence of central nervous system involvement in patients with ErbB2-positive breast cancer and a consequent need for new treatment options for brain metastases. Just as ErbB2-targeted systemic therapy has given rise to this challenge, so too could targeted therapy represent an opportunity to meet it. This Review considers the potential for targeted therapy to facilitate effective management of brain metastases in patients with ErbB2-positive breast cancer, and discusses in particular the data currently available in this setting for lapatinib, an orally available small-molecule tyrosine kinase inhibitor of ErbB1 and ErbB2.