Dr Osborne：有多种方式，关键是我们需要阻断如AP-1这样的生长因子途径。当应用内分泌治疗时，雌激素受体（ER）被阻断，而一些生长因子途径会被激活，其中之一即为AP-1。但PI3K/AKT途径也存在激活，这个途径可以磷酸化ER以及它的共激活剂，比如AIB1。因此，在这些患者中，通过一个受体拮抗剂或PI3K/AKT抑制剂来抑制生长因子途径是有效的。最后，或许最好的治疗方式是去除ER，这样我们就无需担心它被激活或者起到其他的作用。我们现有的抗雌激素治疗方式之一为氟维司群，有很好的效果，它可以下调ER但不会完全去除它。

 

　　我们与贝勒的O’Malley博士合作发现，有一种基因在ER自身的表达中起到重要作用。这个基因与ER的启动子区结合，增加了ER信使RNA的合成。如果阻断那个途径，将不再生成ER。如果该方法与氟维司群联用，仍然能够降解ER。这将使细胞中ER的数量进一步降低。

 

　　我们对此非常乐观并将进行一项临床试验，使用这个具有表观遗传活性的抑制剂来阻断ER的合成，并与氟维司群联用来加速ER降解。目前，已有部分1期或2期，甚至有时是3期的乳腺癌患者在接受初始治疗后获得治愈。但对于转移性乳腺癌患者，目前我们还无法实现治愈。我们的目标是让这些患者在尽可能保证良好生活质量的情况下持续存活。如果我们能延长内分泌治疗的应用并推迟像化疗这样毒性更大的治疗，就能使患者受益。在我治疗的转移性乳腺癌患者中有十年持续缓解并且从未接触过化疗的。我想随着更多新的治疗办法的出现，我们将有能力进一步延长她们的生存期。

 

　　Oncology Frontier: Similar to the blockage of AP-1 which is referred in your research， are there any other ways to potentiate endocrine therapy and overcome resistance? What are the implications for overcoming endocrine therapy resistance in the clinical practice?

 

　　Dr Osborne: There are several ways. The key is that we have to block growth factor pathways like AP-1， which can become activated when you block estrogen receptor (ER) with endocrine therapy. One of those is AP-1 but there is also activation of the PI3kinase/AKT pathway， which can phosphorylate estrogen receptor and its coactivators like AIB1. Therefore， inhibiting the growth factor pathway either by a receptor antagonist or a PI3kinase/AKT inhibitor would be effective in those patients. Finally， maybe the best therapy of all would be a therapy that gets rid of the estrogen receptor so you don’t have to worry about it being activated or playing another role.

 

 

　　Dr Osborne：肿瘤活检可以告诉我们是否有ER表达。如果活检质量高，我们还可以得知是否存在ER突变，这是耐药的另一个原因。但是你也可以不用肿瘤活检，可以采用新的办法--使用血样，即液体活检的方法。你可以测量来自循环血液中的肿瘤DNA来研究ER或其他基因是否发生突变。如果它们发生突变，那么这通常意味着患者会对我们的标准内分泌治疗产生抵抗，你需要采取其他措施，比如应用大剂量的他莫昔芬或大剂量的氟维司群。有数据显示这些药物在这种情况下可能会起作用。

 

　　Oncology Frontier: According to your research， many patients with recurrent ER positive breast tumors progressing on one type of ER-targeted treatment still benefit from sequential endocrine treatments that target ER by a different mechanism. Therefore， biopsies of recurrent lesions are needed to assess the changes of ER. However， biopsies from metastatic sites are challenging， are there any more feasible and convenient ways to assess the status of ER?

 

　　Dr Osborne: Biopsying the tumor will tell you if it is still there. If you have a good biopsy， it can tell you if there is mutant estrogen receptor， which is another cause of resistance. But there are new ways where you don’t need to biopsy the tumor and a blood sample can be used. This is called a liquid biopsy. You can measure the DNA coming from the tumor in the circulating blood and determine if estrogen receptor or other genes are mutated. If they are， then that usually means it is resistant to our standard endocrine therapies and you will need to do something else， such as high doses of tamoxifen or high doses of fulvestrant. There are some data that those may work in those circumstances.

 

　　《肿瘤瞭望》：抗HER-2治疗会使ER重新表达，Bcl-2表达上升。这对临床实践有何指导意义？

 

　　Dr Osborne: 这意味着如果肿瘤的ER及HER-2均为阳性，当阻断HER-2时，细胞中的ER数量会增加，重新开始信号传导。如果阻断了HER-2但ER起主导作用，此时肿瘤将会对HER-2治疗产生抵抗。我们可以通过同时应用内分泌治疗来应对这一问题。关键就在于需要同时阻断HER-2以及ER。

 

　　Oncology Frontier: According to your report， anti-HER2 therapy could result in the ER reexpression and Bcl2 upregulation. What are the guiding significance for clinical practice?

 

　　Dr Osborne：That means that if you have a tumor that is both ER-positive and HER2-positive， when you block HER2， the amount of estrogen receptor in the cell goes up and starts signaling again. If you are blocking HER2 but estrogen receptor takes over as the driver， now you have resistance to HER2 therapy. You can get around that by using simultaneous endocrine therapy to block the estrogen receptor. The take home message is that you need to block both HER2 and estrogen receptor at the same time.

 

　　《肿瘤瞭望》：今年您将继续担任圣安东尼奥乳腺癌会议的主席，今年有什么内容值得期待的吗？

 

　　Dr Osborne：我们正处于接收摘要的过程中，并在评审今年的会议将呈现怎样的内容，所以现在我无法说得非常具体。但是可以肯定的是，这将是一届非常有趣的会议。我已经听说部分重要的临床试验刚刚结束，并将在会上呈现试验结果。我确信这将是一个非常好的会议，我们会在将来的一到两个月更多地了解它。

 

　　Oncology Frontier: You were the President of last year’s San Antonio Breast Cancer Symposium and again this year. What can we look forward to at this year’s symposium?

 

　　Dr Osborne: We are just in the process of getting abstracts in to review to see what will be presented so I can’t say specifically just now. But I am sure it will be an interesting meeting. I have heard some of the important trials that are just finishing now will be presented there. I am sure it will be a good meeting and we will know more about it in a month or two.