Oncology Frontier: Could you tell us about the new developments in metastatic breast cancer and how to integrate these data into clinical practice?

　　《肿瘤瞭望》：转移性乳腺癌有何最新进展，如何将这些研究成果应用于临床？

　　Dr Rugo: There are many new data sets for HER2-positive disease. There is pertuzumab in the first-line setting. There is T-DM1， the monoclonal trastuzumab antibody that is linked to a derivative of maytansine， a tubulin toxin. That’s a fascinating drug and is now approved as second-line therapy. Both those have shown improved survival over the standard. We have new hormone therapies that are emerging on top of the approval of everolimus in the BOLERO-2 trial that showed improved progression-free survival with a non-significant 4.4 month improvement in overall survival in patients whose hormone receptor positive cancers were progressing on a non-steroidal aromatase inhibitor. They received exemestane and everolimus. We are looking at ways to try and improve tolerance of that combination regimen to reduce toxicity with steroid mouthwash and with patient and physician education. The new hormonal therapies that are being evaluated that we are encouraged by include PI3 kinase inhibitors， both pan-PI3 kinase inhibitors and alpha-specific and combinations of PI3 kinase inhibitors with other targeted agents that may improve response to hormone therapy such as the new cyclin-dependent kinase 4/6 inhibitors. There are three different pharmaceutical companies with fascinating agents. Palbocyclib is the farthest ahead with two phase III trials that have already completed accrual in combination with hormone therapy. LEE011 is the other drug from Novartis that is being studied both by itself with hormone therapy and in combination with hormone therapy and the PI3 kinase inhibitor， BYL719. There is a third agent， abemaciclib from Lilly that has single agent efficacy and is starting a phase II single agent trial. It has a slightly different toxicity profile. These agents are all fairly well tolerated which is intriguing. There is the pan-PI3 kinase inhibitor， buparlisib， being studied in combination with fulvestrant. Those trials， called the BELLE trials， are very far ahead and we should see results in the not-too-distant future. The neoadjuvant setting is looking at these new agents as well. For triple-negative disease， there is a lot of interest in immune-modulating drugs. PD-1 and PD-L1 inhibitors have already demonstrated limited single agent efficacy in triple-negative breast cancers so we will see what happens. We are seeing results from other immune-modulators such as the macrophage inhibitors that we are working on as well as other agents. There is an interest in trying to screen tumors for specific genomic abnormalities and then targeting them with specific targeted agents like fibroblast growth factor receptor inhibitors or agents that block other pathways. In terms of hormone therapy， there are drugs called HDAC inhibitors or histone deacetylase inhibitors and drug entinostat also has breakthrough status from the FDA from a phase II study and is in a phase III study with exemestane. There are a few other agents out there that are interesting and studies are ongoing. There is a targeted chemotherapy agent targeted with an antibody which is being studied in triple-negative breast cancer. So there is a lot going on right now and we are really excited about seeing some new data in the next few years that will help us move forward. We also hope that some day there will be a PARP inhibitor approved for the treatment of BRCA-associated breast and ovarian cancer. Recently， the FDA’s advisory group， ODAC， recommended against the approval of olaparib， one of the first PARP inhibitors to be studied and approved for ovarian cancer， because the data wasn’t clean enough. But there are a bunch of studies going on with a number of different companies with very potent PARP inhibitors， so we hope to see approval of at least one of those drugs in the not-too-distant future. I think the FDA is working hard at mechanisms to try and make drugs accessible to patients as early as possible. There is compassionate use， for example， for some of the PARP inhibitors and some of the CDK4/6 inhibitors. This accelerated drug approval process of drugs that look promising allows the companies to provide information to the FDA much more quickly and to have the drugs monitored as they are going along. We haven’t yet seen it result in earlier approvals but hope that it will. The neo-adjuvant approach also， which is being studied in a number of trials including the I-SPY 2 trial network， hopefully will also result in earlier drug approval for promising agents in specific populations of patients and with specific tumors that will most likely benefit from that treatment.

　　Rugo教授：关于HER-2阳性乳腺癌有很多新试验数据。在一线治疗范畴有帕妥珠单抗。另外，T-DM1，微管蛋白毒素美登素衍生物偶联的曲妥珠单抗，是一种很有前景的药物，现在被批准用于二线治疗。这两种药物都显示出比标准治疗更好的生存获益。

　　我们还有新的激素治疗方案，例如已经获批的依维莫司，BOLERO-2试验显示，依维莫司治疗激素受体阳性的、经非甾体类芳香化酶抑制剂治疗后进展的癌症患者，能延长无进展生存期，延长总生存期（4.4个月，但无统计学意义）。这些患者接受了依美西坦和依维莫司治疗。我们正在设法改善这一联合方案的耐受性，如类固醇漱口以减轻毒性以及医患教育等。

　　还有一些新的激素治疗正处于评估中，也给了我们很大鼓舞，即PI3激酶抑制剂，包括PI3激酶非特异抑制剂、α-特异性抑制剂、以及与其他可以改善激素治疗效果的靶向药物，如细胞周期依赖激酶（CDK）-4/6抑制剂等的联合应用。目前有三家不同的制药公司在开发CDK-4/6。Palbocyclib率先通过了两项Ⅲ期试验，并完成了与激素治疗的联合应用。LEE011，来自诺华制药公司，其单独、与激素治疗联合以及与PI3激酶抑制剂BYL719联合的试验都正在进行。第三种药物是礼来公司研发的abemaciclib，单药治疗有效，II期单药试验刚刚开始。其毒副反应与其他两种药物略有不同。吸引人的是，这些药物都有相当好的耐受性。一种PI3激酶非特异抑制剂，buparlisib，其与氟维司琼联合治疗的试验（BELLE系列试验）正在开展，这些试验是非常前沿的，在不远的将来我们就能看到试验结果。新辅助治疗方案也在关注这些药物。

　　对于三阴性乳腺癌的治疗，在免疫调节剂方面有很多进展。现已证明，PD-1和PD-L1抑制剂对三阴性乳腺癌有一定的单药药效，因此我们拭目以待。其他免疫调节剂如我们正在研究的巨噬细胞抑制剂和其他药物。有研究尝试筛查具有特殊基因组异常的肿瘤，然后使用特异性靶向药物，例如纤维组织母细胞因子受体抑制剂或是阻断其他通路的药物进行靶向治疗。就激素治疗而言，有一些叫做组蛋白去乙酰化酶抑制剂的药物，如恩替诺特也已经通过Ⅱ期试验，联合依美西坦的Ⅲ期试验也在进行中，已获得FDA批准。还有其他几种药物也都很令人感兴趣，相关试验正在进行中。其中一种为针对见于三阴性乳腺癌的一种抗体的靶向化疗药物。

　　所以目前有很多在研药物，在未来若干年将会有一些新结果帮助我们继续发展，对此我们倍感振奋。我们也希望有一天会有DNA修复酶PARP抑制剂被批准用于BRCA基因相关的乳腺癌和卵巢癌。近来，FDA顾问组肿瘤药物咨询委员会（ODAC）建议不批准首批DNA修复酶抑制剂之一奥拉帕尼在卵巢癌中的应用，因为相关数据不够清楚。但是有很多不同公司正在进行强效的PRAP抑制剂研发，所以我们希望看到在不远的将来至少有一种此类药物通过批准。我认为FDA正在制度上做努力，以让药物尽早在患者身上投入使用。有一些富有同情心的应用，例如，某些PARP抑制剂和某些CDK-4/6抑制剂。这加快了药物审批程序，让医药公司将那些有希望的药物信息尽快提供给FDA，并让药物接受监测。我们还没看到更快审批的发生，不过我们希望这能早日成真。很多试验正在对新辅助治疗方案进行研究，其中包括I-SPY2研究网络，希望可以让药物更快获得批准，使那些最可能获益的特定肿瘤患者得到治疗。