Bouchalova Katerina, Cizkova Magdalena, Cwiertka Karel, Trojanec Radek, Friedecky David, Hajduch Marian
Laboratory of Experimental Medicine, Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University Olomouc and University Hospital Olomouc, Czech Republic.
Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2010 Dec;154(4):281-8. doi: 10.5507/bp.2010.043.
Breast cancer treatment trends are currently based on tailored therapies using tumor and patient biomarkers. Lapatinib is the first dual inhibitor of HER1 (EGFR, ErbB1) and HER2 (ErbB2, Neu) tyrosine kinases to be used in clinical practice. However, only HER2 is currently used for therapy indications and new predictors for the treatment with lapatinib are sought.
This minireview focuses on lapatinib and its role in breast cancer treatment. Preclinical and clinical studies as well as pharmacological characteristics are briefly reviewed while the focus is on efficacy assessment including predictive factors for therapy outcome.
Lapatinib (Tykerb/Tyverb) was Food and Drug Administration (FDA) approved in 2007 for use in combination with capecitabine for the treatment of HER2-positive advanced or metastatic breast cancer in patients who had received previous treatment (including anthracycline, taxane and trastuzumab containing regimens) and in 2010 for use in combination with letrozole for postmenopausal women with hormonal receptor positive and HER2- positive metastatic breast cancer. In contrast to trastuzumab (Herceptin), lapatinib is orally administered and it targets both HER2 and HER1 receptors. As a synthetic and oral tyrosine kinase inhibitor (TKI), it is convenient, cheaper and easier to produce than monoclonal antibodies. The recommended dosage is not dependent on body weight either. Lapatinib plasma level measurement could be an approach to tailored therapy for further optimizing the dose and prolonging this efficient therapy. New lapatinib response predictors are being evaluated. At this time, only HER2 amplification/overexpression is used to choose lapatinib therapy candidates. Further studies on concurrent HER1 fluorescent in situ hybridization (FISH)/immunohistochemistry (IHC) assessment and/or microarray analyses may produce new data on the predictive role of the HER1 (EGFR) gene/protein. PTEN loss and PIK3CA gene mutations are other markers that may predict lapatinib poor response.
乳腺癌治疗趋势目前基于使用肿瘤和患者生物标志物的个体化疗法。拉帕替尼是首个用于临床实践的HER1（表皮生长因子受体，ErbB1）和HER2（ErbB2，Neu）酪氨酸激酶双重抑制剂。然而，目前仅HER2用于治疗指征，并且正在寻找拉帕替尼治疗的新预测指标。
本综述聚焦于拉帕替尼及其在乳腺癌治疗中的作用。简要回顾了临床前和临床研究以及药理学特性，重点是疗效评估，包括治疗结果的预测因素。
拉帕替尼（泰立沙/Tyverb）于2007年被美国食品药品监督管理局（FDA）批准与卡培他滨联合用于治疗先前接受过治疗（包括含蒽环类、紫杉烷类和曲妥珠单抗的方案）的HER2阳性晚期或转移性乳腺癌患者，并于2010年被批准与来曲唑联合用于激素受体阳性且HER2阳性转移性乳腺癌的绝经后女性。与曲妥珠单抗（赫赛汀）不同，拉帕替尼是口服给药，并且靶向HER2和HER1受体。作为一种合成的口服酪氨酸激酶抑制剂（TKI），它比单克隆抗体更方便、更便宜且易于生产。推荐剂量也不依赖于体重。测量拉帕替尼血浆水平可能是一种个体化治疗方法，可进一步优化剂量并延长这种有效治疗。正在评估新的拉帕替尼反应预测指标。目前，仅HER2扩增/过表达用于选择拉帕替尼治疗候选者。关于同时进行HER1荧光原位杂交（FISH）/免疫组织化学（IHC）评估和/或微阵列分析的进一步研究可能会产生关于HER1（表皮生长因子受体）基因/蛋白预测作用的新数据。PTEN缺失和PIK3CA基因突变是其他可能预测拉帕替尼反应不佳的标志物。
