Cameron David A, Stein Steven
DA Cameron is Professor of Medical Oncology and NCRN Director at the NCRN Co-ordinating Centre, Leeds, UK.
Nat Clin Pract Oncol. 2008 Sep;5(9):512-20. doi: 10.1038/ncponc1156. Epub 2008 Jul 1.
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.
在肿瘤过度表达人表皮生长因子受体2（HER2）的乳腺癌患者中，使用单克隆抗体曲妥珠单抗进行临床试验已明确证明靶向HER2是有效的。然而，并非所有患者都对曲妥珠单抗治疗有反应。拉帕替尼是一种口服受体酪氨酸激酶抑制剂，可靶向HER2和表皮生长因子受体（EGFR）。临床前数据显示，拉帕替尼在对曲妥珠单抗耐药的细胞系中有活性，并且与曲妥珠单抗具有协同活性。在一项关键的III期试验中，对于先前接受过蒽环类药物、紫杉烷类药物和曲妥珠单抗治疗的HER2阳性晚期或转移性乳腺癌女性患者，拉帕替尼与卡培他滨联合使用相对于单独使用卡培他滨显著降低了疾病进展风险。其他试验正在评估拉帕替尼在炎性乳腺癌中的应用——已有令人鼓舞的数据报道——与激素疗法联合使用、与曲妥珠单抗联合使用，以及作为早期疾病辅助治疗的辅助药物。值得注意的是，在临床试验中拉帕替尼尚未与严重或有症状的心脏毒性相关联。它可以穿过血脑屏障，因此可能在预防中枢神经系统进展方面发挥作用。这些特性使拉帕替尼成为在HER2阳性转移性和早期乳腺癌中进行更全面评估的理想药物。
