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首页> 外文期刊>Expert opinion on pharmacotherapy >New protein kinase inhibitors in breast cancer: Afatinib and neratinib
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New protein kinase inhibitors in breast cancer: Afatinib and neratinib

机译：乳腺癌中的新型蛋白激酶抑制剂：阿法替尼和那拉替尼

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Introduction: Human epidermal growth factor receptor (HER) 2 is overexpressed in 20-25% of breast cancers, and has historically been a poor prognostic marker. The introduction of trastuzumab, the first fully humanized monoclonal antibody targeting HER2, has drastically changed the outcomes of metastatic breast cancers. However, despite initial response, most patients develop resistance. Recent data suggest that strategies targeting more than one member of HER family may circumvent trastuzumab resistance and confer synergistic effects. Areas covered: Following a literature search on PubMed, national meetings and clinicaltrials.gov using 'afatinib', 'neratinib', 'HER2' and 'breast cancer' as keywords, we critically analyzed the different HER2-targeted therapies for their drug development and evidence-based therapeutic strategies. Afatinib and neratinib, two second-generation tyrosine kinase inhibitors (TKIs) that irreversibly inhibit more than one HER family member, are being actively investigated in clinical trials either as monotherapy or in combination. We reviewed the efficacy and optimal use of these agents in various settings, such as systemic therapy for advanced breast cancer including brain metastases, and neoadjuvant therapy in early-stage breast cancer. Expert opinion: HER2-targeted therapies have been widely used and greatly improved the outcome of HER2-positive breast cancer. Despite the accelerated advancement in recent years, several crucial questions remain unanswered, such as how to treat a prior resistance or affect a sanctuary site, that is, CNS metastasis. The novel next-generation TKIs, afatinib and neratinib, were rationally designed to overcome the resistance by targeting multiple HER family members and irreversibly binding the targets. In spite of the encouraging results of the afatinib and neratinib monotherapies, they have not been proven more efficacious in the combination therapies yet, even though multicenter international trials are still ongoing. The key tasks in the future are to study resistance pathways, design novel strategies to more efficiently test combinations for synergistic effects and identify biomarkers and novel imaging tools to guide individualized therapies.
机译：简介：人类表皮生长因子受体（HER）2在20％至25％的乳腺癌中过表达，并且历来是不良的预后指标。曲妥珠单抗（第一种靶向HER2的完全人源化单克隆抗体）的引入已彻底改变了转移性乳腺癌的结局。但是，尽管有最初的反应，但大多数患者仍会产生抵抗力。最新数据表明，针对HER家族中一个以上成员的策略可能会规避曲妥珠单抗的耐药性并产生协同效应。涵盖的领域：在使用“ afatinib”，“ neratinib”，“ HER2”和“乳腺癌”作为关键词对PubMed，全国会议和Clinicaltrials.gov进行文献搜索之后，我们针对其药物开发和治疗方法，严格分析了针对HER2的不同靶向疗法。循证治疗策略。阿法替尼和那拉替尼是两种不可逆地抑制一个以上HER家族成员的第二代酪氨酸激酶抑制剂（TKI），正在临床试验中以单一疗法或联合疗法的形式进行积极研究。我们审查了这些药物在各种情况下的功效和最佳使用，例如针对包括脑转移在内的晚期乳腺癌的全身治疗以及早期乳腺癌的新辅助治疗。专家意见：靶向HER2的疗法已被广泛使用，并大大改善了HER2阳性乳腺癌的预后。尽管近年来发展迅速，但仍未回答几个关键问题，例如如何治疗先前的耐药性或如何影响避难所，即中枢神经系统转移。新型的下一代TKIs afatinib和neratinib经过合理设计，可以通过靶向多个HER家族成员并不可逆地结合靶标来克服耐药性。尽管afatinib和neratinib单一疗法取得了令人鼓舞的结果，但尽管多中心国际试验仍在进行中，但尚未证明它们在联合疗法中更有效。未来的关键任务是研究耐药性途径，设计新颖的策略以更有效地测试组合的协同作用，并识别生物标志物和新颖的成像工具来指导个体化治疗。

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