Clinical efforts to combine endocrine agents with targeted therapies against epidermal growth factor receptor/human epidermal growth factor receptor 2 and mammalian target of rapamycin in breast cancer
Clinical efforts to combine endocrine agents with targeted therapies against epidermal growth factor receptor/human epidermal growth factor receptor 2 and mammalian target of rapamycin in breast cancer
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DOI：
10.1158/1078-0432.ccr-05-2125
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发表时间：
2006-02-01
影响因子：
11.5
通讯作者：
Johnston, SRD
中科院分区：
文献类型：
--
作者：
Johnston, SRD
通过克服从头或获得性耐药来提高内分泌治疗的益处仍然是系统性乳腺癌治疗的一个重要目标。在阐明雌激素受体阳性的乳腺癌细胞逃避内分泌治疗的分子途径方面继续取得进展。随着对表皮生长因子受体(EGFR)和人EGFR2在雌激素受体信号串扰激活中作用的认识日益加深，针对这些受体的小分子酪氨酸激酶抑制剂与内分泌药物结合时，是否具有相加或协同作用的研究已成为研究的重点。磷脂酰肌醇-3-羟基激酶/Akt通路的激活也与对他莫昔芬或雌激素剥夺的抵抗有关，临床前研究表明，雷帕霉素拮抗剂替西罗莫司的哺乳动物靶点可以恢复乳腺癌细胞的内分泌敏感性。芳香酶抑制剂与EGFR/人EGFR2酪氨酸激酶抑制剂或雷帕霉素拮抗剂的哺乳动物靶点相结合的随机II期试验已经在新辅助和晚期乳腺癌环境中完成。使用这两种方法的更大规模的III期试验现在正在进行中，并已被用来检测与单独的内分泌治疗相比，这两种方法中的任何一种是否可以显着延长疾病进展的时间。这些正在进行的研究的分子和临床结果的相关性对于建立适当的生物学变量来选择那些可能从这种联合方法中受益最大的患者将是重要的。
Enhancing the benefit of endocrine therapy by overcoming de novo or acquired resistance remains an important goal in systemic breast cancer therapy. Progress continues to be made in elucidating the molecular pathways by which estrogen receptor-positive breast cancer cells escape from endocrine therapy. The increasing recognition of the roles of epidermal growth factor receptor (EGFR) and human EGFR2 in cross-talk activation of estrogen receptor signaling has led to studies aimed at identifying whether small-molecule tyrosine kinase inhibitors targeted against these receptors give additive or synergistic effects when combined with endocrine agents. Activation of the phosphatidylinositol-3-OH kinase/Akt pathway has also been associated with resistance to either tamoxifen or estrogen deprivation, and preclinical studies have shown that the mammalian target of rapamycin antagonist temsirolimus can restore endocrine sensitivity in breast cancer cells. Randomized phase II trials of aromatase inhibitors combined with EGFR/human EGFR2 tyrosine kinase inhibitors or mammalian target of rapamycin antagonists have been completed in both the neoadjuvant and advanced breast cancer settings. Larger phase III trials with both approaches are now in progress and have been powered to detect whether either strategy can significantly prolong time to disease progression compared with endocrine therapy alone. The correlation of molecular and clinical results from these ongoing studies will be important to establish appropriate biological variables for selecting those patients who may benefit most from this combined approach.