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.     

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.     

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.     

A systematic review of trastuzumab and lapatinib in the treatment of women with brain metastases from HER2-positive breast cancer

Patients with HER2-positive breast cancer are living still longer and increasingly experiencing brain metastases. Current HER2-targeted therapies have limited potential to cross the blood–brain-barrier. We performed a systematic review to investigate data on HER2-targeting therapies in the treatment of brain metastases in breast cancer. We searched PUBMED for all human studies published 1998–2012 using the following search terms: breast neoplasm/cancer, human epidermal growth factor receptor 2/HER2, ErbB2, trastuzumab, lapatinib, brain/cerebral neoplasm/metastases and blood–brain barrier. We identified few and mostly small clinical studies. Study designs were very heterogeneous making comparisons on endpoints difficult. Overall survival for patients treated with trastuzumab varied from 8 to 25 months and 5.5 to 11 months for patients receiving lapatinib. The majority of studies were retrospective thus possibly biasing data. Only three studies were identified comparing trastuzumab to lapatinib. Conclusively, no solid data exist on how to treat patients with HER2-positive disease and brain metastases. Although continuous HER2-blockade is recommended by international consensus guidelines, it is still not evident which HER2-targeting agent should be preferred when brain metastases occur. The choice of chemotherapy to accompany the blockade is not obvious and we do not know if dual is better than single blockade. Further clinical trials are urgently needed.     

Response to dual HER2 blockade in a patient with HER3-mutant metastatic breast cancer

BackgroundHER3 activating mutations have been shown in preclinical models to be oncogenic and ligand-independent, but to depend on kinase-active HER2.Patients and methodsWhole-exome sequencing of the primary HER2-negative breast cancer and its HER2-negative synchronous liver metastasis from a 46-year-old female revealed the presence of an activating and clonal HER3 G284R mutation.ResultsHER2 dual blockade with trastuzumab and lapatinib as third-line therapy led to complete metabolic response in 2 weeks and confirmed radiological partial response after 8 weeks. Following the resection of the liver metastasis, the patient remains disease-free 40 weeks after initiation of the HER2 dual blockade therapy. Immunohistochemical analysis demonstrated a substantial reduction of phospho-rpS6 and phospho-AKT in the post-therapy biopsy of the liver metastasis.DiscussionThis is the first-in-man evidence that anti-HER2 therapies are likely effective in breast cancers harboring HER3 activating mutations.     

Clinical outcomes in patients who received lapatinib plus capecitabine combination therapy for HER2-positive breast cancer with brain metastasis and a comparison of survival with those who received trastuzumab-based therapy: a study by the Anatolian Society of Medical Oncology

Purpose

In this study, we investigated the effect of lapatinib plus capecitabine treatment in HER2-positive breast cancer patients with brain metastasis.

Methods

Of 405 metastatic breast cancer patients with brain metastases at referral centers in Turkey, 46 were treated with lapatinib plus capecitabine only after the development of brain metastasis. Patients who only received trastuzumab-based therapy after the development of brain metastases were accepted as the historic control group for survival analyses (n = 65). Patients who received both drugs consecutively or sequentially were excluded from the analyses (n = 34).

Results

Median age among 46 patients who received lapatinib plus capecitabine therapy was 45 years (27–76), and median time for development of brain metastases was 11.9 months (0–69 months). Twenty-six out of 38 patients who received lapatinib plus capecitabine and had extracranial metastasis showed partial response or stable diseases (68.4 %). Grade 3-4 toxicity was observed in eight patients (17.3 %). Median overall survival (OS) in patients treated with lapatinib plus capecitabine was significantly increased compared to that in patients treated with trastuzumab-based therapy (19.1 vs. 12 months, respectively, p = 0.039). The incidence of cerebral death was slightly decreased in patients who received lapatinib plus capecitabine compared to those who received trastuzumab-based therapy (32 vs. 43.4 %, p = 0.332). In the multivariate analysis, lapatinib plus capecitabine therapy remained an independent positive predictor for survival [odds ratio (OR), 0.57; p = 0.02].

Discussion

Although this retrospective multicenter study had several limitations, the results suggest that undergoing lapatinib plus capecitabine therapy after the diagnosis of brain metastasis may further improve survival compared to undergoing only trastuzumab-based therapy.     

Two cases of HER2-positive advanced or metastatic breast cancer, responding to lapatinib and capecitabine

The first patient was a 59-year-old woman who was diagnosed with invasive scirrhous carcinoma. The tumor was estrogen receptor (ER)-positive, progesterone receptor (PgR)-positive, and human epidermal growth factor receptor 2 (HER2)-positive. The patient was treated with adjuvant chemotherapy and endocrine therapy after surgery. Liver metastases developed 5 years after surgery. She was treated with trastuzumab combined with vinorelbine, paclitaxel, or docetaxel. The liver metastases increased in size, 9 years after surgery, and she was treated with lapatinib and capecitabine. The efficacy of chemotherapy was judged as a partial response. The second patient was a 74-year-old woman who was diagnosed with invasive ductal carcinoma in 2005. The tumor was ER-negative, PgR-positive, and HER2-positive; she was treated with trastuzumab and paclitaxel. She developed dyspnea in January 2010. Chest radiograph showed increased lung metastases and left pleural effusion; she was treated with lapatinib and capecitabine. Lung metastases decreased and left pleural effusion disappeared after the first cycle of chemotherapy. The efficacy of chemotherapy was judged as a partial response.     

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.     

SRT联合拉帕替尼治疗HER2阳性乳腺癌脑转移疗效及预后分析

目的 探讨立体定向放射治疗(Stereotactic radiotherapy,SRT)联合拉帕替尼治疗HER2阳性乳腺癌脑转移的疗效及预后。方法 回顾性分析91例HER2阳性乳腺癌脑转移患者接受拉帕替尼靶向治疗的同时接受全脑放疗或SRT的情况,其中42例患者接受SRT的同时进行拉帕替尼联合卡培他滨治疗(SRT组),另外49例患者采用全脑放疗同时进行拉帕替尼联合卡培他滨治疗(全脑放疗组)。评价其疗效和毒性,定期随访,并行多因素Cox回归分析其预后相关因素。结果 放疗结束后1月SRT组脑部病灶客观缓解率为92.86%(39/42),全脑放疗组客观缓解率为77.55%(38/49),SRT组优于全脑放疗组(χ²=4.070,P=0.044)。SRT组和全脑组12个月受照射肿瘤病灶无进展生存率分别为95.20%及83.10%, SRT组优于全脑放疗组(χ²=10.851,P=0.001)。 SRT组无颅内转移生存率与全脑放疗组无统计学差异(P＞0.05)。SRT组和全脑放疗组1年生存率分别为85.70%和69.40%,2年生存率分别为66.70%和55.10%,两组中位生存期分别为31.56个月和25.00个月,SRT组优于全脑放疗组(P=0.002)。多因素Cox回归分析结果表明无颅外转移(HR=0.527,95% CI:0.290~0.957,P=0.035),颅内病灶≤3个(HR=2.457,95% CI:1.223~4.933,P=0.012),放疗方式SRT(HR=1.746,95% CI:1.055~2.888,P=0.030)是HER2阳性乳腺癌脑转移放疗预后的独立保护因素。结论 SRT联合拉帕替尼在局部控制率以及生存率上优于全脑放疗联合拉帕替尼。颅内病灶个数少、无颅外转移灶和放疗方式是HER2阳性乳腺癌脑转移治疗的良好预后因素。     

A case of breast cancer liver metastases responding to lapatinib and capecitabine therapy

We report a 55-year-old female with liver metastases from breast cancer who responded to lapatinib and capecitabine combination therapy as third-line. She was diagnosed as invasive ductal carcinoma (T1cN1M0, stage IIA). Biomarker of breast cancer was negative hormone receptor (ER-, PgR-) and overexpression of HER2(HercepTest 3+). We started preoperative chemotherapy with weekly paclitaxel followed by FEC100. Then mastectomy with axillary dissection was performed. Histopathology of the breast and lymph nodes showed complete disappear of invasive cancer cells( pCR, grade 3). We performed her adjuvant therapy with trastuzumab after surgery. The liver metastases developed 5 months after surgery. We treated her in trasutumab combined with vinorelbine, and followed by docetaxel during one year and four months. Because liver metastases re-grew during the combination therapy with trastuzumab, we switched to lapatinib and capecitabine combination therapy. After four months of administration, abdominal CT revealed liver metastases were remarkably reduced in size. The efficacy of chemotherapy lasted for eight months.     

Drug Insight: intracellular inhibitors of HER2--clinical development of lapatinib in breast cancer

Targeting the human epidermal growth factor receptor type 2 (HER2) in breast cancer patients whose tumors overexpress HER2 has been clearly demonstrated to be effective in clinical trials with the monoclonal antibody trastuzumab. Not all patients, however, respond to trastuzumab therapy. Lapatinib is an oral receptor tyrosine kinase inhibitor that targets HER2 and the EGFR. Preclinical data reveal that lapatinib has activity in trastuzumab-resistant cell lines as well as synergistic activity with trastuzumab. In a pivotal phase III trial, a combination of lapatinib and capecitabine significantly decreased the risk of disease progression relative to capecitabine alone in women with HER2-positive advanced or metastatic breast cancer previously treated with anthracyclines, taxanes, and trastuzumab. Other trials are evaluating lapatinib in inflammatory breast cancer--for which encouraging data have been reported--in combination with hormone therapy, in combination with trastuzumab, and as an adjunct to adjuvant therapy for early-stage disease. Notably, lapatinib has not been associated with serious or symptomatic cardiotoxicity in clinical trials. It can cross the blood-brain barrier and might therefore have a role in preventing central-nervous-system progression. These features make lapatinib an ideal agent to evaluate more fully in HER2-positive metastatic and early-stage breast cancer.     

Ki-67 index as a prognostic factor of subsequent lapatinib-based therapy in HER2-positive metastatic breast cancer with resistance to trastuzumab

Prognostic factor analysis has been conducted to determine whether the parameters of clinical data and biomarkers would predict differential progression-free survival (PFS) or overall survival (OS) from lapatinib-based therapy in patients with primary or acquired resistance to trastuzumab. Treatment with lapatinib plus capecitabine for HER2-positive metastatic breast cancer (MBC) with primary or acquired resistance to trastuzumab was analyzed retrospectively. Tumor biomarkers, which came from the biopsies before the starting of lapatinib therapy, were evaluated by immunohistochemistry (IHC). Prognostic factors related to PFS or OS of the lapatinib therapy were assessed by univariate and multivariate analysis. Ki-67 index and liver metastases were the significant prognostic factors for predicting PFS of subsequent lapatinib therapy in the univariate analysis and the multivariate analysis. The risk for disease progression in patients who had a Ki-67 index < 40% was 59% less than that in patients had Ki-67 ≥ 40 (HR = 0.41, 95% CI, 0.23–0.74, P = 0.003). TTP of prior trastuzumab therapy, liver metastases, and the number of metastatic sites were three independent prognostic factors of subsequent lapatinib therapy. Ki-67 index was the significant prognostic factors for predicting PFS of the subsequent second line targeted therapy in patients with trastuzumab resistance.     

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.     

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.     

Retreatment with trastuzumab-based therapy after disease progression following lapatinib in HER2-positive metastatic breast cancer

BackgroundPreclinical data suggest that treatment with lapatinib reinduces sensitivity to trastuzumab in human epidermal growth factor receptor 2(HER2)-positive breast cancer cells.Patients and methodsBetween January 2007 and November 2010, 179 HER2-positive metastatic breast cancer patients were treated with lapatinib and capecitabine at nine Italian institutions. We evaluated the clinical outcome of 69 patients (38.5%) retreated with trastuzumab after lapatinib progression.ResultsVisceral metastases were identified in 51 (74%) and brain metastases in 16 patients (23%). All patients were pretreated with both trastuzumab- and lapatinib-based therapy. We observed with retreatment with trastuzumab-based therapy: 1 complete remission (2%), 18 partial remission (29%) and 10 stable disease ≥6 months (14%) and 47% of clinical benefit (CB). Median duration of response was 8.1 months [95% confidence interval (CI) 5.5–10.7]. No unexpected toxic effects occurred. At a median follow-up of 13 months, median progression-free survival was 4.9 months (95% CI 4.2–5.6) and overall survival (OS) 19.4 months (95% CI 14.0–25.0). Median OS was longer for patients experiencing CB (not reached versus 13.4 months for patients without CB, P = 0.002). Brain involvement was associated with lower median OS (17.3 versus 23.3 months for patients without brain disease; P = 0.021).ConclusionRetreatment with trastuzumab-based therapy showed CB in 47% of patients progressing during lapatinib-based therapy, leading to a prolonged OS.     

Cardiac toxicity in breast cancer patients treated with dual HER2 blockade

Although dual HER2 blockade shows promising results in patients with HER2‐positive breast cancer it is unclear whether this treatment strategy increases the risk for cardiac adverse events. We conducted a meta‐analysis of randomized trials to investigate the risk of cardiac adverse events when a combination of anti‐HER2 therapies compared to anti‐HER2 monotherapy. We searched Medline, the Cochrane library, as well as the electronic abstract databases of the major international congresses' proceedings to identify randomized trials that evaluated the administration of anti‐HER2 monotherapy (lapatinib or trastuzumab or pertuzumab) versus anti‐HER2 combination (pertuzumab plus trastuzumab or trastuzumab plus lapatinib) therapy in breast cancer. The trials were considered eligible if the only systematic difference between the study arms was the type of anti‐HER2 therapy used. Study outcomes were the congestive heart failure (CHF) grade ≥3 and left ventricular ejection fraction (LVEF) decline <50% or more than 10% from baseline. Six trials were considered eligible. Overall incidence results for CHF in the combined anti‐HER2 therapy and the anti‐HER2 monotherapy were 0.88% (95% CI: 0.47–1.64%) and 1.49% (95% CI: 0.98–2.23%). The incidence of LVEF decline was 3.1% (95% CI: 2.2–4.4%) and 2.9% (95% CI: 2.1–4.1%), respectively. The OR of CHF between anti‐HER2 combination and monotherapy was 0.58 (95% CI: 0.26–1.27, p‐value= 0.17) while the OR of LVEF decline was 0.88 (95% CI: 0.53–1.48, p‐value= 0.64). This meta‐analysis provides evidence supporting comparable cardiac toxicity between anti‐HER2 combination therapy and anti‐HER2 monotherapy.     

Clinical outcome of patients with brain metastases from HER2-positive breast cancer treated with lapatinib and capecitabine

BackgroundIn the present study, we investigated the clinical outcome of patients with brain metastases (BMs) from human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC) treated with lapatinib and capecitabine (LC).MethodsOf 81 HER2+ metastatic BC patients treated with LC at two Italian institutions, 30 patients with BMs eligible for the analysis were identified. All patients were pretreated with trastuzumab for metastatic disease. No patients had received prior lapatinib and/or capecitabine.ResultsMedian age was 45 years (range 24–75) and 26 of 30 patients (86.7%) had received prior cranial radiotherapy. In the 22 patients with BMs evaluable for response, 7 partial responses (31.8%) and 6 disease stabilizations (27.3%) were observed. Overall, the median brain-specific progression-free survival was 5.6 months (95% confidence interval 4.4–6.8). Patients treated with LC had a median overall survival (from the time of development of BMs) significantly longer compared with 23 patients treated with trastuzumab-based therapies only beyond brain progression (27.9 months versus 16.7 months, respectively, P = 0.01).ConclusionsLC is active for BMs from HER2+ BC in patients not pretreated with either lapatinib or capecitabine. The introduction of LC after the development of BMs may further improve survival compared with trastuzumab-based therapies only beyond brain progression.     

Management of HER2-Positive Breast Cancer for a Young Patient with Visceral Crisis—The Adjuvant Role of Lifestyle Changes

The safety profile and effectiveness of existing anti-HER2-targeted therapies have not been evaluated in patients with breast cancer and visceral crisis. We report the case of a 26-year-old woman who was diagnosed with advanced HER2-positive breast cancer and initially treated with curative intent therapy in a neoadjuvant setting, using Trastuzumab and Pertuzumab in combination with Docetaxel; her cancer recurred two years later, with liver metastases and pulmonary lymphangitic carcinomatosis, causing visceral crisis. Furthermore, the patient’s clinical status worsened when she developed respiratory failure, hepatomegaly and a severe hepatocytolysis. Since the patient was free of disease more than six months, we started with Paclitaxel half dose because of the hepatic dysfunction, and we gradually reintroduced Trastuzumab and then Pertuzumab. In the meantime, the patient changed her lifestyle by increasing her consumption of fresh fruits and vegetables and fiber and reducing her intake of processed meat, dairy and sugar. As a result, the patient showed a significant improvement in her respiratory symptoms and liver tests in less than two months. Imaging reevaluation showed partial remission of liver metastases and pulmonary lymphangitic carcinomatosis. She underwent seven months of dual anti-HER2 blockade before relapsing cerebrally. Our results suggest that the sequential combination therapy with Trastuzumab, Pertuzumab and Paclitaxel presented in this study, associated with a healthy lifestyle, may be a good management for recurrent HER2-positive breast cancer with pulmonary visceral crisis and severe liver dysfunction.     

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, a dual inhibitor of EGFR and HER2, has synergistic effects with 5-fluorouracil on esophageal carcinoma

Epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) amplification occurs in over 30% of esophageal carcinomas. Combination therapies with EGFR and HER2-targeting agents and cytotoxic agents are considered a potential therapeutic option for esophageal cancer. We evaluated the antitumor effects of lapatinib, a dual tyrosine kinase inhibitor which simultaneously inhibits EGFR and HER2, 5-fluorouracil (5-Fu) alone and in combination on esophageal cancer cells. The antiproliferative activity of lapatinib, 5-Fu and lapatinib plus 5-Fu was measured by MTT assay and the combination index (CI) values were calculated. Additionally, cell cycle distribution of lapatinib alone and the combination with 5-Fu were detected by flow cytometry analysis. Annexin?V-FITC and propidium iodide stain were used for analyzing the apoptotic cells after cells were treated with either agent alone or in combination. The EGFR and HER2 activated signaling pathways were monitored by western blotting. The combination of lapatinib and 5-Fu synergistically inhibited cell proliferation and exhibited an enhanced proapoptotic effect on esophageal cancer cells. The potentiation effect of combined treatment was associated with downregulation of EGFR and HER2 signaling pathways because data from western blot analysis showed that lapatinib in combination with 5-Fu markedly reduced the phosphorylation of EGFR and HER2, and inhibited the activation of downstream signaling molecules, such as AKT and ERK. A significant G1 arrest was also observed in cell cycle analysis after exposing cells to lapatinib, however, combination with 5-Fu did not enhance G1 arrest. These results indicate that the combination of the lapatinib and 5-Fu is a promising treatment option for esophageal carcinoma with HER2 amplification.