Faculty of Medicine, Imperial College London, South Kensington Campus, London SW7 2AZ, UK.
Neuroscience Solution to Cancer Research Group, Department of Life Sciences, Faculty of Natural Sciences, Sir Alexander Fleming Building, Imperial College London, South Kensington Campus, London SW7 2AZ, UK.
Cancer Treat Rev. 2018 Jan;62:110-122. doi: 10.1016/j.ctrv.2017.11.003. Epub 2017 Nov 13.
Triple negative breast cancer (TNBC) is a complex and aggressive subtype of breast cancer which lacks oestrogen receptors, progesterone receptors and HER2 amplification, thereby making it difficult to target therapeutically. In addition, TNBC has the highest rates of metastatic disease and the poorest overall survival of all breast cancer subtypes. Resultantly, development of targeted therapies for TNBC is urgently needed. Recent efforts aimed at molecular characterisation of TNBCs have revealed various emerging therapeutic targets including PARP1, receptor and non-receptor tyrosine kinases, immune-checkpoints, androgen receptor and epigenetic proteins. Key successes include that of the PARP inhibitor, olaparib, which prolonged progression-free survival in a trial of BRCA-mutated breast cancer and for which clinical approval (in this setting) appears imminent. Nevertheless, the heterogeneity of TNBC has limited the clinical benefits of many trialled therapies in 'unselected' patients. Further, drug resistance develops following use of many targeted monotherapies due to upregulation of compensatory signalling pathways. In this review, we evaluate the current status of investigational targeted treatments and present evidence for the role of novel biomarkers and combination therapies in increasing response rates and circumventing drug-induced resistance. Additionally, we discuss promising novel targets in metastatic TNBC identified through preclinical and/or epidemiological studies.
三阴性乳腺癌(TNBC)是一种复杂且侵袭性的乳腺癌亚型,缺乏雌激素受体、孕激素受体和 HER2 扩增,因此难以进行治疗性靶向。此外,TNBC 的转移性疾病发生率最高,所有乳腺癌亚型中总体生存率最差。因此,迫切需要开发针对 TNBC 的靶向治疗方法。最近,针对 TNBC 的分子特征的研究努力揭示了各种新的治疗靶点,包括 PARP1、受体和非受体酪氨酸激酶、免疫检查点、雄激素受体和表观遗传蛋白。关键的成功包括 PARP 抑制剂奥拉帕利,它在 BRCA 突变型乳腺癌的试验中延长了无进展生存期,并且似乎即将获得临床批准(在这种情况下)。然而,TNBC 的异质性限制了许多试验治疗方法在“未选择”患者中的临床获益。此外,由于补偿性信号通路的上调,许多靶向单药治疗后会产生耐药性。在这篇综述中,我们评估了目前正在研究的靶向治疗方法的现状,并提出了新型生物标志物和联合治疗在提高反应率和避免药物诱导耐药方面的作用的证据。此外,我们还讨论了通过临床前和/或流行病学研究确定的转移性 TNBC 中具有前景的新型靶点。
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