ERBB2 AMPLIFICATION

高达20%的乳腺癌中可见Her2（erbb2）扩增，发现时与侵袭性疾病和不良预后有关。曲妥珠单抗首次在化疗进展的HER2阳性转移性乳腺癌（MBC）中获得了相当大的成功，并被批准用于治疗。尽管如此，这些转移癌在曲妥珠单抗治疗下仍有进展，并对包括酪氨酸激酶抑制剂在内的其他形式的治疗进行了研究。拉帕替尼是ErbbB1和ErbB2中酪氨酸激酶活性的可逆抑制剂，阿法替尼是所有4种ErbB形式的不可逆抑制剂，在曲妥珠单抗进展的Her2-MBC中具有活性。有趣的是，曲妥珠单抗本身在治疗曲妥珠单抗进展的HER2 MBC方面仍然有效。Lux乳腺1试验比较了以tki为基础的治疗（阿法替尼）与以trastuzumab为基础的治疗进展中的her2-mbc的疗效，Lux乳腺3试验探讨了在Her2-mbc背景下应用tki治疗难以治疗脑转移。在这两个病例中，TKI都没有更有效的效果，使得将来成功地用TKI替代曲妥珠单抗治疗进展中的her2-mbc似乎不太可能。相反，在这种疾病背景下，tkis的一个潜在作用在临床前研究中被揭示，表明tki和曲妥珠单抗的作用具有协同作用，而拉帕替尼或阿法替尼联合曲妥珠单抗的临床试验表明，双重HER2阻断可能是一种有效的治疗方法。用Pertuzumab而不是tki在Her2-mbc中阻断Her2双抗体，最近在克利奥帕特拉试验中也显示了强有力的结果。HER2的过度表达是新辅助治疗乳腺癌的靶点，也已成功地靶向胃癌。
Her2 (ERBB2) amplifications are seen in up to 20% of breast cancers and were associated with aggressive disease and poor prognosis when discovered. Trastuzumab first found considerable success, and was approved for treatment, in HER2 positive metastatic breast cancer (MBC) which had progressed under chemotherapy. These metastatic cancers nonetheless progressed under trastuzumab, and other forms of therapy were studied for next line treatments, including tyrosine kinase inhibitors. Lapatinib, a reversible inhibitor of tyrosine kinase activity in ErbB1 and ErbB2, and afatinib, an irreversible inhibitor of all 4 ErbB forms were shown to have activity in trastuzumab-progressed HER2 MBC. Interestingly trastuzumab itself also turned out to remain effective in treatment of trastuzumab-progressed HER2 MBC. The LUX-Breast 1 trial compared a TKI-based treatment (afatinib) to a trastuzumab-based treatment of trastuzumab-progressed HER2 MBC, and the LUX-Breast 3 trial addressed TKI application in the context of HER2 MBC with difficult to treat brain metastases. In neither of these cases was the TKI more effective, making successful future replacement of trastuzumab-based therapy with a TKI in trastuzumab-progressed HER2 MBC seem unlikely. Instead, a potential role for TKIs in this disease context is revealed in preclinical work suggesting synergism between TKI and trastuzumab action, and clinical trials with lapatinib or afatinib combined with trastuzumab indicate that dual HER2 blockade may be an effective therapy. Dual antibody HER2 blockade with pertuzumab instead of TKI in HER2 MBC has also recently shown strong results in the CLEOPATRA trial. HER2 overexpression is targeted in neoadjuvant breast cancer treatment, and has also been successfully targeted in gastric cancer.