Oncology Frontier: What is the current standard of care for metastatic HER2-positive breast cancer?

　　《肿瘤瞭望》：转移性HER-2阳性乳腺癌的标准治疗是什么？

　　Dr Gradishar: For HER2-positive metastatic breast cancer， we are fortunate to have different， very effective options for treating patients. We have seen improvements in outcomes as a result of the use of these agents. Quite some time ago now， we saw the introduction of trastuzumab and then subsequently lapatinib， which we use less frequently today. More importantly， we have seen the introduction of drugs like pertuzumab and TDM-1 (ado-trastuzumab) and we have found that with these kinds of drugs， we have been able to incrementally and significantly improve outcomes for patients with metastatic disease， and specifically survival. At least in the United States， most patients receive trastuzumab as a component of their adjuvant therapy. If there is recurrence， we usually start with a trastuzumab-based regimen as per the CLEOPATRA-like studies – trastuzumab/pertuzumab and a taxane. We try to continue that course as long as patients appear to be responding with the aim that chemotherapy is truncated and the antibodies continue if the patient continues to respond， thus avoiding some of the toxicity of the chemotherapy. Inevitably， patients do progress， and when that occurs， typically， the next step is to use TDM-1. TDM-1 is also proven to be effective and generally very well tolerated by patients. If disease progression continues at that point， we have a number of different options. Those include different chemotherapy agents in combination with trastuzumab， consideration for lapatinib with capecitabine， or even in selected patients， the combination of trastuzumab and lapatinib. The path forward is also looking at a number of different agents that may or may not become available in the coming years for patients who develop refractory disease. These include drugs like neratinib， which we have some data on although not yet approved and other agents looking at the HER2 pathway that we might have access to for those patients who develop disease progression despite the agents I have mentioned.

　　Dr Gradishar: 对于HER-2阳性的转移性乳腺癌，非常幸运的是，在治疗这类患者时，我们有着不同的并且非常有效的治疗方式，并且我们也看到，这些药物的应用提高了治疗效果。曲妥珠单抗已经成功研发了很长时间，随后又出现了我们现在相对较少应用的拉帕替尼。更重要的是，我们看到了类似帕妥珠单抗及TDM-1这样的药物的出现。通过应用这些药物，我们可以逐渐地并且显著地改善出现转移的这类患者的治疗效果，特别是生存时间。至少在美国，大多数患者都将曲妥珠单抗作为辅助治疗的一部分。

　　如果是复发病例，我们通常会启动以曲妥珠单抗为基础的治疗方案，就像CLEOPATRA这类研究一样，使用曲妥珠单抗/帕妥珠单抗并联合紫杉醇。只要患者产生应答我们会尽可能地维持靶向药物的疗程，这样如果患者能持续应答，就可以缩短化疗而维持靶向药物，从而避免化疗的某些毒性反应。不可避免的是，患者会出现进展，当进展出现时，代表性的下一步治疗通常是应用TDM-1。TDM-1也被证明有效，并且通常可以被较好耐受。如果疾病在那时出现进展，我们有很多不同的治疗选择。这些治疗选择包括化疗药物联合曲妥珠单抗，拉帕替尼联合卡培他滨，或者甚至可以在合适的患者中联合使用曲妥珠单抗和拉帕替尼。对有着难治性疾病的患者来说，我们还在探索很多不同的药物，这些药物在未来的日子里可能会被应用但也可能失败。如来那替尼，该药目前有一些数据但尚未被批准使用，还有其他作用于HER-2通路的药物，它们为那些虽然应用了前面提到的药但仍出现疾病进展的患者带来了新的治疗选择。

　　Oncology Frontier: The NCCN Guidelines for invasive breast cancer treatment have just been updated and you are the Chairman of that committee. What are the key updates in the endocrine therapy part of those guidelines?

　　《肿瘤瞭望》：您是NCCN乳腺癌指南专家组主席，在最新更新的2016年第2版NCCN指南中，内分泌治疗方面有哪些重要更新？

　　Dr Gradishar: The endocrine therapy treatment options for hormone receptor positive metastatic disease have also evolved. What we have seen， particularly with metastatic disease， is that rather than giving monotherapy or single agent  endocrine therapy， we have seen the introduction of other agents such as mTOR inhibitors like everolimus， or more recently， the CDK4/6 inhibitors like palbociclib. The data has demonstrated most recently with palbociclib is that in conjunction with an anti-hormone therapy， either as first- or second-line therapy (typically with an aromatase inhibitor in the first-line and for those who had received an aromatase inhibitor but not received palbociclib， it would be with fulvestrant)， there is an enhanced clinical outcome. The time to disease progression was significantly improved favoring the combination. Furthermore， the drug palbociclib， although expensive， is generally very well tolerated by patients. For those patients who progress after receiving palbociclib， we can also use the mTOR inhibitor everolimus in conjunction with an aromatase inhibitor such as exemestane， and that too shows an incremental improvement in outcomes. The issue that we face as we start to develop these somewhat more complicated endocrine-based regimens is that the toxicity profile of endocrine therapy changes a little bit. We start to see some hematologic toxicity with palbociclib. With mTOR inhibitors， we see a number of events such as skin rashes， fatigue and so on. So it does change the nature of the expectations some patients might have with these combinations compared to standard monotherapy. Again， as we go forward， there are a number of other agents that are in development including alternative CDK4/6 inhibitors. We heard about abemaciclib at this meeting. We may hear more about ribociclib as we go forward， so I think we are going to be able to enhance the number of options patients with ER-positive disease have.

　　Dr Gradishar: 对于激素受体阳性的转移性乳腺癌来说，内分泌治疗也有了进步。尤其是对于转移性乳腺癌来说，因为出现了像依维莫司这样的mTOR抑制剂或是最近出现的像帕布昔利布这样的CDK4/6抑制剂，我们可以不再单一应用单个内分泌治疗药物。无论是一线或是二线内分泌治疗药物（代表性的一线药物芳香化酶抑制剂，对于那些接受过芳香化酶抑制剂但并未接受帕布昔利布治疗的患者可以联合氟维司群），都会改善临床治疗效果。联合应用使得出现疾病进展的时间大大延长。并且帕布昔利布这样的药物虽然价格昂贵，但通常可以被患者较好耐受。对于那些接受了帕布昔利布治疗之后出现进展的患者，我们也可以应用mTOR抑制剂依维莫司联合依西美坦这样的芳香化酶抑制剂，它同样可以改善治疗效果。在我们开始使用这些更复杂的以内分泌治疗为基础的方案时，我们所面临的问题是内分泌治疗的毒性反应谱发生了一些改变。应用帕布昔利布时可能出现血液毒性，应用mTOR抑制剂时，很多患者出现皮疹、疲劳等症状。因此相比于标准的单药治疗，联合用药确实会改变一些患者对于它的期望。此外，在我们不断研究的过程中，还有大量的其他种类药物在不断发展，包括可替代的CDK4/6抑制剂。在这次会议上出现了abemaciclib这个药物，未来我们还将对ribociclib有更多认识，因此我认为我们有能力为雌激素受体阳性的乳腺癌患者提供更多的治疗选择。

　　Oncology Frontier: Immunotherapy is a very hot topic in the field of oncology. What progress has there been in this regard in the breast cancer setting， including any progress with biomarkers?

　　《肿瘤瞭望》目前免疫治疗是肿瘤领域的热点。在乳腺癌领域免疫治疗及相关生物标志物有哪些重要进展？

　　Dr Gradishar：肿瘤免疫学确实是一个非常热门的领域，但近来在乳腺癌领域免疫治疗并不十分热门。它在黑色素瘤、肺癌以及一些其他疾病中特别受关注，在这些疾病中，免疫治疗被证实可以真正改善患者的预后，特别是免疫检查点抑制剂。在乳腺癌中有一些数据，治疗效果相当平庸，但是我们已经进入原理论证阶段，开始认识到这些药物对乳腺癌患者有抗癌效应。同样，利用肿瘤浸润淋巴细胞来研究肿瘤，我们不仅了解到哪些患者可以对治疗产生应答，哪些患者更容易对治疗产生反应，以及根据免疫细胞浸润推测预后。我们也在研究其他的肿瘤标志物，来提示哪些患者可以最大程度地从这些治疗策略中获益。至少在乳腺癌领域，肿瘤免疫学还处在一个非常初级的阶段。非常坦白地讲，随着我们在研究道路上不断前进，不太可能有哪种药物（就像化疗药物）能彻底根除乳腺癌。我们可能会发现，联合应用不同的肿瘤免疫相关药物包括免疫检查点抑制剂、NK细胞、疫苗及其他策略，无论是同时应用还是序贯给药，都可以加强药物的抗肿瘤效应。我要指出的是，这并不意味着化疗或其他药物可以从此不再应用。我仅仅认为，这些治疗可以使治疗方式更为复杂、更为连续、更有希望个体化，从而我们可以针对每一个患者以及患者的每个肿瘤来个体化制定治疗策略。

　　Dr Gradishar: The whole notion of immuno-oncology has been a really hot area， not as much in breast cancer in recent times， but particularly in melanoma， lung cancer and some other diseases where it has been proven to really improve outcomes for patients， particularly the checkpoint inhibitors. We have some data in breast cancer. It is fairly modest at this point， but we are starting to see proof-of-principle that these agents can have an anti-tumor effect in patients with breast cancer. We are also learning that by interrogating the tumor with tumor infiltrating lymphocytes， we not only get a sense of who may respond， who is more likely to respond and what the prognosis may be based on the infiltration of immune cells. We are also interrogating tumors for other markers that may suggest a certain signature in those patients most likely to benefit from these strategies. At least in breast cancer， we are in the very early stages of immuno-oncology. Quite frankly， as we go forward， it is unlikely that any one of these agents (just like any chemotherapy agent) is going to eradicate the disease. What we may find is that using a combination of different immuno-oncology agents including checkpoint inhibitors and NK cells， vaccines and other strategies， either combined or in sequence， will enhance the anti-tumor effect. I should point out that this doesn’t mean chemotherapy or other agents will go away. I simply think they will make the approach to treating patients much more complex and sequential and hopefully individualized so we are tailoring therapy to each patient and each patient’s tumor.