University of Tennessee Cancer Institute, Memphis, TN, USA.
Clin Breast Cancer. 2012 Feb;12(1):19-29. doi: 10.1016/j.clbc.2011.07.001. Epub 2011 Sep 8.
Breast cancer is the most common type of cancer among women and the second leading cause of cancer death in the United States. Metastatic breast cancer is considered incurable, and treatment is aimed at palliating symptoms, achieving remission, and prolonging survival. Treatment options for metastatic disease vary based on tumor surface markers and clinical factors in an individual patient and include cytotoxic chemotherapy, hormonal therapy, biological therapy, or some combination of these. An important molecular determinant of therapy is the human epidermal growth factor receptor 2 (HER2) positivity of the tumor, which affects response to HER2-targeted treatment. HER2 is a member of the human epidermal growth factor receptor family of receptor tyrosine kinases, also known as the HER family, which activates signaling that promotes tumorigenic cellular processes such as proliferation and evasion of apoptosis. Several targeted agents, including monoclonal antibodies and tyrosine kinase inhibitors that inhibit one or more HER family receptors have been developed that affect signaling through this pathway. Some of these, such as trastuzumab and lapatinib, have been approved for breast cancer treatment. Resistance to therapy is a challenge that limits the duration of benefit achieved with these agents. Therefore, combinations of HER family-targeted agents with other therapies such as cytotoxic agents, hormonal therapy, or inhibitors of other cellular pathways, are being developed to exploit synergy and overcome resistance mechanisms. Here we review the HER family-targeted agents currently approved or in development for HER2-positive metastatic breast cancer with a focus on strategies to overcome tumor resistance.
乳腺癌是女性中最常见的癌症类型，也是美国癌症死亡的第二大主要原因。转移性乳腺癌被认为是不可治愈的，治疗旨在缓解症状、实现缓解和延长生存。转移性疾病的治疗选择取决于肿瘤表面标志物和个体患者的临床因素，包括细胞毒性化疗、激素治疗、生物治疗或这些治疗的某些组合。治疗的一个重要分子决定因素是肿瘤的人表皮生长因子受体 2（HER2）阳性，这影响了对 HER2 靶向治疗的反应。HER2 是受体酪氨酸激酶的人表皮生长因子受体家族的成员，也称为 HER 家族，它激活信号传导，促进肿瘤发生的细胞过程，如增殖和逃避细胞凋亡。已经开发出几种靶向药物，包括单克隆抗体和酪氨酸激酶抑制剂，这些药物抑制一个或多个 HER 家族受体，从而影响该途径的信号传导。其中一些，如曲妥珠单抗和拉帕替尼，已被批准用于乳腺癌治疗。对治疗的耐药性是一个挑战，限制了这些药物的获益持续时间。因此，正在开发针对 HER 家族的药物与其他疗法（如细胞毒性药物、激素治疗或其他细胞途径的抑制剂）的组合，以利用协同作用并克服耐药机制。在这里，我们回顾了目前批准或正在开发用于 HER2 阳性转移性乳腺癌的 HER 家族靶向药物，重点介绍了克服肿瘤耐药性的策略。
