AlFakeeh A, Brezden-Masley C
Division of Hematology/Oncology, St. Michael's Hospital, University of Toronto, Toronto, ON.
King Fahad Medical City, Comprehensive Cancer Centre, Riyadh, Saudi Arabia.
Curr Oncol. 2018 Jun;25(Suppl 1):S18-S27. doi: 10.3747/co.25.3752. Epub 2018 Jun 13.
Endocrine therapy, a major modality in the treatment of hormone receptor (hr)-positive breast cancer (bca), has improved outcomes in metastatic and nonmetastatic disease. However, a limiting factor to the use of endocrine therapy in bca is resistance resulting from the development of escape pathways that promote the survival of cancer cells despite estrogen receptor (er)-targeted therapy. The resistance pathways involve extensive cross-talk between er and receptor tyrosine kinase growth factors [epidermal growth factor receptor, human epidermal growth factor receptor 2 (her2), and insulin-like growth factor 1 receptor] and their downstream signalling pathways-most notably pi3k/akt/mtor and mapk. In some cases, resistance develops as a result of genetic or epigenetic alterations in various components of the signalling pathways, such as overexpression of her2 and erα co-activators, aberrant expression of cell-cycle regulators, and mutations. By combining endocrine therapy with various molecularly targeted agents and signal transduction inhibitors, some success has been achieved in overcoming and modulating endocrine resistance in hr-positive bca. Established strategies include selective er downregulators, anti-her2 agents, mtor (mechanistic target of rapamycin) inhibitors, and inhibitors of cyclin-dependent kinases 4 and 6. Inhibitors of pi3ka are not currently a treatment option for women with hr-positive bca outside the context of clinical trial. Ongoing clinical trials are exploring more agents that could be combined with endocrine therapy, and biomarkers that would help to guide decision-making and maximize clinical efficacy. In this review article, we address current treatment strategies for endocrine resistance, and we highlight future therapeutic targets in the endocrine pathway of bca.
内分泌治疗是激素受体（HR）阳性乳腺癌（BCA）治疗的主要方式，已改善了转移性和非转移性疾病的治疗效果。然而，BCA内分泌治疗的一个限制因素是耐药性，这是由于逃逸途径的发展导致的，尽管有针对雌激素受体（ER）的治疗，但这些途径仍能促进癌细胞存活。耐药途径涉及ER与受体酪氨酸激酶生长因子[表皮生长因子受体、人表皮生长因子受体2（HER2）和胰岛素样生长因子1受体]及其下游信号通路之间广泛的相互作用，最显著的是PI3K/AKT/mTOR和MAPK。在某些情况下，耐药性是由信号通路各组分的基因或表观遗传改变引起的，如HER2和ERα共激活因子的过表达、细胞周期调节因子的异常表达以及突变。通过将内分泌治疗与各种分子靶向药物和信号转导抑制剂联合使用，在克服和调节HR阳性BCA的内分泌耐药性方面已取得了一些成功。既定策略包括选择性ER下调剂、抗HER2药物、mTOR（雷帕霉素作用靶点）抑制剂以及细胞周期蛋白依赖性激酶4和6的抑制剂。目前，PI3KA抑制剂在临床试验之外并非HR阳性BCA女性的治疗选择。正在进行的临床试验正在探索更多可与内分泌治疗联合使用的药物，以及有助于指导决策和最大化临床疗效的生物标志物。在这篇综述文章中，我们阐述了内分泌耐药性的当前治疗策略，并强调了BCA内分泌途径中的未来治疗靶点。
