Medical Oncology & Breast Unit, A. Perrino Hospital, Brindisi, Italy.
Crit Rev Oncol Hematol. 2012 Nov;84(2):243-51. doi: 10.1016/j.critrevonc.2012.03.004. Epub 2012 Apr 10.
Endocrine therapy is the most important systemic therapy for hormone receptor positive breast cancer; however, some patients with ER+ breast cancer show intrinsic resistance to endocrine therapy, whereas others develop acquired resistance. Preclinical models have shown that endocrine resistance is associated with enhanced expression of membrane growth factor pathways or activation of various intracellular pathways involved in signal transduction and cell survival. Despite encouraging preclinical data, clinical trials investigating the combination of endocrine therapy with trastuzumab or the TKIs gefitinib, erlotinib and lapatinib have yielded varied results. This may be related to some limitations in the studies conducted so far: lack of appropriate patient selection and stratification based on previous endocrine exposure and/or sensitivity; lack of identification of a molecular biomarker; lack of appropriate clinical endpoints in the trial design. More promising results come from clinical studies which have focused on novel agents such as the mTOR inhibitor everolimus. The two randomized trials (BOLERO-2 and TAMRAD) evaluating everolimus±endocrine therapy in a selected subgroup of HR-positive metastatic breast cancer patients have demonstrated a significant improvement in progression free survival for the combination compared to the endocrine therapy alone. The data reported so far show that the combination of target agents with endocrine therapy is effective in overcoming acquired resistance in patients with hormone receptor positive metastatic breast cancer. However, this therapeutic strategy is not yet a standard treatment for this patients. Application of more rigorous trial design, tumor and patient selection criteria will be important to better understand the complexity of endocrine resistance.
内分泌治疗是激素受体阳性乳腺癌最重要的全身治疗方法；然而，一些 ER+乳腺癌患者对内分泌治疗表现出内在耐药性，而另一些患者则产生获得性耐药性。临床前模型表明，内分泌耐药与膜生长因子途径的表达增强或参与信号转导和细胞存活的各种细胞内途径的激活有关。尽管有令人鼓舞的临床前数据，但内分泌治疗联合曲妥珠单抗或 TKIs 吉非替尼、厄洛替尼和拉帕替尼的临床试验结果不一。这可能与迄今为止进行的研究中的一些局限性有关：缺乏基于先前内分泌暴露和/或敏感性的适当患者选择和分层；缺乏鉴定分子生物标志物；临床试验设计中缺乏适当的临床终点。更有希望的结果来自于专注于新型药物的临床研究，如 mTOR 抑制剂依维莫司。两项评估依维莫司±内分泌治疗在 HR 阳性转移性乳腺癌患者选定亚组中的随机试验（BOLERO-2 和 TAMRAD）表明，与单独内分泌治疗相比，联合治疗在无进展生存期方面有显著改善。迄今为止报告的数据表明，靶向药物联合内分泌治疗在克服激素受体阳性转移性乳腺癌患者获得性耐药方面是有效的。然而，这种治疗策略尚未成为此类患者的标准治疗方法。应用更严格的试验设计、肿瘤和患者选择标准对于更好地理解内分泌耐药的复杂性将非常重要。
