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.     

Lapatinib plus letrozole for postmenopausal patients with advanced HER2+/HR+ breast cancer

Lapatinib is an oral, small-molecule dual inhibitor of human EGF receptor 1 (EGFR/erbB1) and 2 (HER2/erbB2). Lapatinib has recently been approved, in combination with capecitabine, for the treatment of HER2-positive metastatic breast cancer patients failing trastuzumab therapy. Data from clinical trials are consistently showing the key role of this agent in the management of HER2-positive disease. Moreover, interesting data are suggesting a key role of lapatinib in enhancing endocrine responsiveness and/or restoring endocrine sensitivity in hormone receptor-positive disease. The present article will summarize the main data leading to the clinical development of the combination of lapatinib and the aromatase inhibitor letrozole.     

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.     

The emerging role of Lapatinib in HER2-positive breast cancer

In breast cancer, overexpression of HER2 is associated with an aggressive tumor phenotype and poor prognosis. Lapatinib has demonstrated benefit in combination with capecitabine in patients with HER2-positive locally advanced and metastatic breast cancer that has progressed after prior treatment with an anthracycline, a taxane, and trastuzumab. It has also demonstrated benefit with paclitaxel in patients with metastatic disease not previously treated with chemotherapy. This review discusses results from clinical trials suggesting an advantage with the use of lapatinib with other treatment modalities in the setting of metastatic and locally advanced disease.     

Intermediate to highly suspicious calcification in breast lesions: a radio-pathologic correlation

Targeted therapies against the human epidermal growth factor receptor HER2, have led to revolutionary strides in breast cancer research and treatment. Clinical therapeutic decisions in the treatment of patients with HER2 positive metastatic breast cancer are based on appropriate patient selection, the clinical situation, and data related to the available therapeutic agents trastuzumab and lapatinib. Trastuzumab was the first agent tested and approved in 1996 as single agent for patients with chemotherapy-refractory disease, and in combination with paclitaxel as first-line treatment. This intravenous humanized monoclonal antibody is directed against the extracellular domain of the HER2 protein. Lapatinib, an oral small molecule tyrosine kinase inhibitor has more recently become available (in 2007), approved for used in combination with capecitabine for patients with HER2 positive metastatic disease that has progressed on trastuzumab. Important questions and controversies still remain and are reviewed, including patient selection for anti-HER2 treatment of metastatic disease based on HER2 testing, dose scheduling of trastuzumab, duration of therapy, tolerability, role of lapatinib and clinical significance of trastuzumab resistance and efficacy. Ongoing trials designed to maximize the therapeutic ratio of these agents, are also discussed.     

Combined chemotherapy with molecular-targeted agent for breast cancer

Molecular-targeted agents, trastuzumab, lapatinib or bevacizumab, demonstrated efficacy in patients with breast cancer. Trastuzumab exhibited efficacy and safety for HER2-positive metastatic breast cancer, in single usage or in combination with paclitaxel, docetaxel or vinorelbine. Trastuzumab is also useful in an adjuvant setting in HER2-positive early breast cancer. However, it is not clear whether concurrent or sequential treatment is superior. Lapatinib combined with capecitabine showed efficacy against HER2-positive metastatic breast cancer. It was suggested that the combination with lapatinib and paclitaxel was effective. Bevacizumab combined with paclitaxel revealed efficacy for metastatic breast cancer. These molecular-targeted agents play an important role in treatment of breast cancer.     

Trastuzumab as first-line therapy in HER2-positive metastatic breast cancer patients

Trastuzumab is a humanized monoclonal antibody against the extracellular domain of hEGF receptor-2 (HER2). Trastuzumab in combination with chemotherapy has proven efficacy in treating both early and metastatic HER2-positive breast cancer. In the metastatic setting, the addition of trastuzumab to chemotherapy is associated with a statistically significant longer time to disease progression, higher rate of objective response and improvement in overall survival. Trastuzumab efficacy is not influenced by hormone receptor status, but differences in median overall survival exist between HER2-positive and HER2-negative states. Reassessment of the benefit of re-exposing patients with metastatic breast cancer to trastuzumab following relapse in the adjuvant setting is necessary. Ongoing research into new HER2-targeted therapies and trials involving combination anti-HER2 drug therapy without chemotherapy show promise. This review is focused on the available results obtained with the use of trastuzumab in the subset of HER2-positive breast cancer patients with metastatic disease.     

Emerging approaches for treating HER2-positive metastatic breast cancer beyond trastuzumab

Because metastatic breast cancer (MBC) is incurable in most cases, the goals of treatment are improvement in quality of life, management of symptoms, and prolonged survival. The human epidermal growth factor receptor 2 (HER2) is overexpressed in up to 30% of breast tumors, and before the development of HER-targeted therapy, HER2 positivity was predictive of poorer clinical outcomes. Trastuzumab and pertuzumab (anti-HER2 monoclonal antibodies), lapatinib (a small molecule inhibitor of HER2 and the epidermal growth factor receptor [EGFR]) are approved for treating HER2-positive MBC in the United States. Although trastuzumab plus chemotherapy is currently regarded as the first-line standard of care for HER2-positive MBC, it is not without shortcomings; these include its association with certain adverse events (e.g. cardiotoxic effect) and development of resistance. A number of investigational agents that target HER2 and other members of that receptor family are in clinical development for patients with HER2-positive MBC whose disease has progressed on trastuzumab. In addition, in an effort to overcome treatment resistance, clinical trials are evaluating combination therapy (investigational HER-targeted agents with trastuzumab or lapatinib). This review discusses recently completed and ongoing phase II and III clinical trials of investigational HER-targeted agents in the setting of trastuzumab-progressive, HER2-positive MBC.     

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.     

Cardiac toxicity of ErbB2-targeted therapies: what do we know?

The potential for cardiac toxicity in association with targeted biologic agents was first observed with trastuzumab, a monoclonal antibody that targets the ErbB2/HER2 receptor. In the pivotal trial of trastuzumab in ErbB2-positive metastatic cancer, an increased incidence of serious cardiac events was observed, particularly when trastuzumab was administered in combination with anthracyclines. The ErbB2 receptor is expressed on cardiomyocytes, in addition to tumor tissue, where it exerts a protective effect on cardiac function; thus, interference with ErbB2-signaling may block this protective effect. However, in contrast to anthracycline-induced cardiac toxicity, trastuzumab-related cardiac dysfunction does not appear to increase with cumulative dose or to be associated with ultrastructural changes in the myocardium and is generally reversible. When used in adjuvant regimens for the treatment of ErbB2-positive early-stage breast cancer, trastuzumab has been shown to significantly improve disease-free and overall survival. The incidence of class III/IV congestive heart failure (CHF) ranged from 0.4%-3.8% in the major adjuvant trastuzumab trials. More recently, small-molecule tyrosine kinase inhibitors such as lapatinib have been investigated for the treatment of ErbB2-positive metastatic breast cancer. In a comprehensive analysis of cardiac safety data from all lapatinib trials completed to date, which included 3558 healthy volunteers and patients with a variety of solid cancers on 43 trials, the overall incidence of left ventricular ejection fraction declines was 1.6%, with 0.2% of patients experiencing symptomatic CHF. Risk factors that might predict for cardiac dysfunction with ErbB2-targeted therapy are actively under investigation and will aid in the identification of at-risk populations and in the development of strategies for risk minimization in the future. It is important to note that, while careful cardiac monitoring is required for all patients receiving ErbB2-targeted therapy in any disease setting, the overall impact of these agents on the outcomes of patients with ErbB2-positive breast cancer has been dramatic and positive.     

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     

Trastuzumab emtansine: a unique antibody-drug conjugate in development for human epidermal growth factor receptor 2-positive cancer

Trastuzumab emtansine (T-DM1) is a human epidermal growth factor receptor (HER2)-targeted antibody-drug conjugate, composed of trastuzumab, a stable thioether linker, and the potent cytotoxic agent DM1 (derivative of maytansine), in phase III development for HER2-positive cancer. Extensive analysis of T-DM1 in preclinical studies has shown that T-DM1 combines the distinct mechanisms of action of both DM1 and trastuzumab, and has antitumor activity in trastuzumab- and lapatinib-refractory experimental models. Clinically, T-DM1 has a consistent pharmacokinetics profile and minimal systemic exposure to free DM1, with no evidence of DM1 accumulation following repeated T-DM1 doses. Although a few covariates were shown to affect interindividual variability in T-DM1 exposure and clearance in population-pharmacokinetics analyses, the magnitude of their effect on T-DM1 exposure was not clinically relevant. Phase I and phase II clinical trials of T-DM1 as a single agent and in combination with paclitaxel, docetaxel, and pertuzumab have shown clinical activity and a favorable safety profile in patients with HER2-positive metastatic breast cancer. Two randomized phase III trials of T-DM1 are recruiting patients: EMILIA (NCT00829166) is evaluating T-DM1 compared with lapatinib plus capecitabine, and MARIANNE (NCT01120184) is evaluating T-DM1 plus placebo versus T-DM1 plus pertuzumab versus trastuzumab plus a taxane. Additional combinations of T-DM1 (for example, with GDC-0941) and additional disease settings (early-stage HER2-positive breast cancer) are also under investigation. Data from the phase III trials and other studies of T-DM1-containing agents are eagerly awaited.     

HER2 overexpressing metastatic breast cancer

Opinion statement More than 40,000 women in the United States die each year from metastatic breast cancer. Elucidation of HER2 and its role in malignant transformation has helped define a subset of aggressive breast cancer that may be relatively resistant to non-anthracycline-based therapies and hormonal agents, but responds to targeted molecular therapy. Trastuzumab, an antibody against HER2, has proven effective as single agent therapy in women with HER2 overexpressed metastatic breast cancer. Moreover, in combination with chemotherapy, trastuzumab has been shown to delay disease progression and improve overall survival for women with HER2-positive advanced breast cancer. The combination of chemotherapy and trastuzumab is emerging as a standard of care in women with HER2 overexpressed metastatic breast cancer. Several combination regimens using trastuzumab with taxanes, vinca alkaloids, or platinum compounds have demonstrated efficacy in first- and second-line treatment settings. However, the development of anthracycline-based combinations has been limited by concerns of related cardiotoxicity. Newer multi-agent regimens are in development. The optimal combination, duration, and sequence of trastuzumab therapy remain unknown in patients with HER2-positive metastatic disease. The role of continuing treatment after disease progression is also unclear. Evidence from some retrospective analyses suggest HER2-positive tumors are relatively resistant to tamoxifen and perhaps more responsive to aromatase inhibitors, although such data are inconclusive. HER2 status should not be used routinely for clinical decision making regarding hormonal therapy options. Several ongoing trials are attempting to address these and other issues related to HER2 testing to select the most appropriate candidates for these emerging therapies. While many questions remain, the treatment of HER2 overexpressing metastatic breast cancer is rapidly evolving, and represents a new approach to treatment in oncology.     

Promises borne out in clinical studies

This article reviews lapatinib clinical trials in patients with HER2 (ErbB2)-positive breast cancer, and is a report of a presentation from a symposium at the ECCO 14 congress in 2007.Promising clinical results have been achieved to date with lapatinib, an oral, intracellular, dual-targeted small molecule inhibitor of EGFR (ErbB1) and HER2 in patients with HER2-positive metastatic breast cancer. Lapatinib has shown impressive activity in HER2-positive metastatic breast cancer, both first-line and in heavily pretreated patients whose disease has progressed following prior treatment in the metastatic setting with taxanes, anthracyclines and trastuzumab. Lapatinib has also demonstrated activity in inflammatory breast cancer, a particularly aggressive form of the disease. Lapatinib is generally well tolerated, with the most common adverse events being diarrhoea and rash, which can be effectively managed with proactive guidelines.In conclusion, these data demonstrate that lapatinib is a promising new agent in the fight against HER2-positive breast cancer.     

Does lapatinib,a small-molecule tyrosine kinase inhibitor,constitute a breakthrough in the treatment of breast cancer?

ErbB/HER receptor or its signal transduction pathway is an attractive therapeutic target for breast cancer. Lapatinib, an orally administered dual inhibitor of ErbB1 (EGFR) and ErbB2 (HER2) receptor tyrosine kinases has shown promising results for metastatic breast cancer (MBC). Lapatinib exhibited activity against trastuzumab-refractory MBC and showed an acceptable adverse event profile such as transient mild rash, diarrhea and nausea. The addition of lapatinib to capecitabine resulted in significantly prolonged time to progression. Large randomized trials using lapatinib following chemotherapy and surgery are ongoing for early stage HER2-overexpressing breast cancer. Various combinations with agents such as paclitaxel, aromatase inhibitors, or other molecular targeted agents are currently being investigated in clinical trials. If these approaches overcome the limitations of trastuzumab, lapatinib will become an effective treatment option for breast cancer in the near future.     

新型抗Her-2药物T-DM1

T-DM1是新型抗体-药物偶联物,具有曲妥珠单抗类似的生物活性,可特异性的将强效抗微管药物DM1释放至Her-2过表达的肿瘤细胞内。T-DM1单药疗效优于拉帕替尼联合卡培他滨,有望成为Her-2阳性晚期乳腺癌的标准二线治疗药物。比较T-DM1与曲妥珠单抗联合紫杉类药物一线治疗晚期乳腺癌的试验正在进行中。该药是继曲妥珠单抗之后又一种全新的抗Her-2药物。美国FDA正式批准T-DM1作为治疗Her-2阳性晚期乳腺癌患者的药物。      

Challenges in the treatment of ErbB2 (HER2)-positive breast cancer

This article reviews the challenges and future options in the treatment of ErbB2- positive metastatic breast cancer. It summarizes a presentation from a symposium that was held at the ECCO 14 congress in 2007.Despite great progress in the management of ErbB2-positive metastatic breast cancer, significant challenges remain in these patients. Many patients do not respond to trastuzumab-containing regimens or develop progressive disease within 1 year. Continuing trastuzumab in these patients has yet to show proven clinical benefit in prospective studies. Several targeted agents have been developed to overcome the limitations of current targeted therapy for ErbB2-positive breast cancer. One such agent, lapatinib, was recently approved in Europe in combination with capecitabine in patients previously treated with trastuzumab in the metastatic setting. The intracellular site of action of lapatinib may underlie substantial clinical benefit.Based on available data to date, novel ErbB2-targeted therapies may hold significant promise in the management of ErbB2-positive metastatic breast cancer.     

Pertuzumab in combination with trastuzumab and docetaxel for HER2-positive metastatic breast cancer

Overexpression of HER2 – found in approximately 15–20% of all breast cancers – is a negative prognostic factor. Although trastuzumab significantly improves the prognosis of HER2-positive breast cancer, half of the patients with metastatic breast cancer experience disease progression within 1 year. Pertuzumab is a novel HER2-targeted humanized monoclonal antibody that binds to the dimerization domain of HER2 and acts synergically with trastuzumab in inhibiting tumor progression. The CLEOPATRA trial demonstrated that adding pertuzumab to trastuzumab plus docetaxel significantly prolonged progression-free survival and overall survival without increasing severe adverse events. Conclusively, pertuzumab was approved by the US FDA in June 2012 for use in combination with trastuzumab and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer. Furthermore, various clinical trials to evaluate the efficacy and safety of pertuzumab combined with other cytotoxic agents are ongoing at present. Thus, pertuzumab has been becoming important for the treatment of patients with HER2-positive metastatic breast cancer.     

Beyond trastuzumab: novel therapeutic strategies in HER2-positive metastatic breast cancer

The use of trastuzumab, a monoclonal antibody that targets the human epidermal growth factor receptor 2 (HER2) alteration present in 25 to 30% of breast cancers, has been associated with improved survival outcomes in both the adjuvant and metastatic settings. However, despite the robust clinical efficacy of trastuzumab in HER2-positive metastatic breast cancer (MBC), primary and secondary resistance remains a clinical challenge. Although lapatinib has demonstrated modest activity in this setting, trials reported to date have yet to demonstrate improvements in overall survival with its use. Novel therapeutic strategies to circumvent trastuzumab resistance are warranted, and agents targeting the HER, vascular endothelial growth factor, heat shock protein 90, phosphoinositide 3 kinase/Akt/mammalian target of rapamycin, and insulin-like growth factor-1 receptor pathways represent rational approaches in the management of HER2-positive disease. In this review, early-phase and emerging trial data surrounding the use of these promising agents in HER2-positive MBC will be discussed.     

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.