Chemotherapy-Resistant Metastatic Breast Cancer
Chemotherapy-Resistant Metastatic Breast Cancer
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DOI：
10.1007/s11864-012-0184-6
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发表时间：
2012-06-01
影响因子：
4.3
通讯作者：
Nabell, Lisle
中科院分区：
文献类型：
--
作者：
Marquette, Carrie;Nabell, Lisle
在整个21（st）世纪，乳腺癌仍然是女性中最常见的癌症，并且治疗策略的发展继续突出了我们对癌症发展的发病机制和对治疗的抗性的理解方面所取得的进展。尽管在乳腺癌治疗方面取得了重大进展，但对化疗药物的耐药性仍然是治疗成功的一个持续障碍。30多年前首次使用的蒽环类药物和最近在治疗药物中增加的紫杉烷类药物是新诊断和复发乳腺癌的组成部分。不幸的是，沿着其他成分的联合化疗转移性乳腺癌，这些药物最终成为无效的控制疾病。随着耐药表型的出现，肿瘤被认为是耐药的-通常是多药耐药（MDR）。已经确定了许多过程可以成为临床耐药性的基础;观察结果主要来自人类癌细胞系的体外实验室研究。公认的耐药机制包括转运蛋白三磷酸腺苷结合盒（ABC）超家族表达的改变、DNA修复途径的改变、细胞靶点的突变、对凋亡途径启动的耐药和组成性激活信号通路的发展。随着我们对耐药机制的理解的扩展，选择特定于癌症表型的特定药物或药物组合的能力将变得更加具体。这些进展的例证是报告了在三阴性乳腺癌中使用较新的微管靶向药物（如艾日布林和伊沙匹隆）的益处;这些药物可能对常见的耐药途径不太敏感。同样地，在受体串扰中交叉的试剂的组合使用，例如雌激素受体和雷帕霉素的哺乳动物靶标（mTOR）之间，已经证明了抗肿瘤作用的协同作用。最近关于依维莫司与依维莫司联合使用的报告在这方面显示出很大的希望。对于患有HER 2阳性疾病的患者，曲妥珠单抗和研究药物（如帕妥珠单抗）的联合方法似乎导致HER 2信号传导的更完全阻断，并改善无进展生存期。因此，随着我们对乳腺癌信号通路相互联系的理解的提高，合理设计适当的化疗方案和延迟出现耐药性的能力将得到提高。
Remaining the most common cancer in women through the 21(st) century, breast cancer and the development of treatment strategies continue to highlight advances made in our understanding of the pathogenesis of cancer development and resistance to therapies. Despite significant progress in the treatment of breast cancer, resistance to chemotherapeutic agents remains a consistent obstacle in terms of treatment success. Anthracyclines, first used over 30 years ago, and the more recent addition of taxanes to the treatment armamentarium are integral components for both newly diagnosed and recurrent breast cancer. Unfortunately, along with other constituents of combination chemotherapy for metastatic breast cancer, these agents ultimately become ineffective in controlling disease. With the emergence of a resistant phenotype, tumors are deemed to be drug resistant - frequently multidrug resistant (MDR). A number of processes have been identified that can underlie clinical drug resistance; observations stemming largely from in vitro laboratory-based studies in human cancer cell lines. Recognized mechanisms of resistance include altered expression of the adenosine triphosphate-binding cassette (ABC) superfamily of transporters, alteration in DNA repair pathways, mutations in cellular targets, resistance to initiation of the apoptotic pathway and the development of constitutively activated signaling pathways. As our understanding of mechanisms of resistance expands, the ability to select specific drugs or drug combinations specific to the phenotype of the cancer will become more specific. Illustrative of these advancements are the reported benefits from the use of newer microtubule-targeting agents in triple negative breast cancer, such as eribulin and ixabepilone; drugs which may be less susceptible to common pathways of drug resistance. Likewise, the combination usage of agents which intersect in receptor crosstalk, such as between the estrogen receptor and the mammalian target of rapamycin (mTOR), have demonstrated synergy in antitumor effects. The recent report of exemestane used in combination with everolimus, have shown great promise in this regard. For patients with HER2 positive disease, a combination approach with trastuzumab and investigational agents such as pertuzumab appear to result in a more complete blockage of HER2 signaling, and improved progression free survival. Thus, as our understanding of the interconnectedness of signaling pathways in breast cancer improves, the ability to rationally design appropriate chemotherapy regimens and delay emerging resistance will improve.