Oncology Frontier: So of all of those drugs being developed， which would you say was the most exciting and your favorite?

　　《肿瘤瞭望》：在这些已经研发的药物中，对你来说，哪种药物是最令人鼓舞并看好的？

　　Dr Chan: Fifteen percent of patients have HER2 positive breast cancer. In the HER2 arena， we have been very spoilt in the last few years to have had large randomized trials establishing the efficacy of new anti-HER2 agents such as T-DM1 and pertuzumab. T-DM1 is a molecule that is interesting in that it is really utilizing the targeting ability of trastuzumab as a monoclonal antibody but linking it in a very fine-tuned way with a very small dose of a cytotoxic and then using the trastuzumab as a carrier molecule to deliver that cytotoxic to the HER2 positive breast cancer cells. Your readers should be familiar with the published results of both the EMILIA and THERESA trials that have established T-DM1 as an effective drug in that HER2 setting. My problem with a lot of these anti-HER2 drugs， apart from T-DM1， pertuzumab， lapatinib (which many specialists around the world will be familiar with as an oral tyrosine kinase inhibitor)， and other TKIs being explored looking at neratinib and afatinib， is that once a lot of them have been established as being effective， the issue is access. I was fortunate to have just done a review of cancer care delivery in three of the largest nations in the world， China， India and Russia， and I know full well that these new anti-HER2 agents are not going to be used in any patients in the same way as trastuzumab (which is readily available to most first-world patients) is only available to a minority of early HER2-positive breast cancer patients. In the HER2-negative space， there is a lot of excitement. For the triple-negative patients who account for about 15% of breast cancers， unfortunately the early interest in looking at PARP inhibitors has yet to be developed and there are a number of agents being evaluated in the neo-adjuvant and metastatic setting. Again， once these are shown to be effective， I would hope that they are translated into the clinical arena in a way that is affordable and available to all women with triple-negative disease. There are a number of other areas that need to be improved on in triple-negative disease， because the data that we have at the moment is that PARP inhibitors are effective particularly for the triple-negative breast cancers that are related to BRCA mutation. We know that there are other types of non-BRCA mutation-related triple-negative disease and that opens up a whole new arena of research to identify agents that will be effective for that. Then we have the large numbers of luminal cancers that make up 60-65% of breast cancers. For luminal A’s we probably have reached one of the peaks in terms of delivery of treatment as these tend to be endocrine-responsive tumors which are associated with a better prognosis and I am not aware of a large body of research being specifically done in luminal A’s because these patients do so well at the moment. For luminal B’s， which are those patients who are generally thought to be endocrine-responsive but with a high level of de novo resistance to endocrine therapy or subsequently develop resistance to both selective estrogen receptor modulators like tamoxifen and the aromatase inhibitors， this group of patients that constitute almost half of our breast cancers is really the population which I want to look at for new novel agents appearing. There are a lot of data looking at PI3 kinase inhibitors， CD4/6 inhibitors and mTOR inhibitors， so I think it is going to be exciting to know that we have these effective agents that are accessible and have a duration of response. These new biologics have a whole range of toxicities that we as clinicians have to be familiar with such as skin toxicities， neural toxicities (because many of these agents cross the blood-brain barrier and can cause mood disturbances) and hypersensitivity reactions with skin and lung toxicities. Once we know they are effective in large trials， we are also going to have to do well-conducted trials to evaluate predictors of these toxicities and importantly， designing interventions or preventative strategies so that these toxicities don’t lead to these effective agents having to be stopped.

　　Chan博士：15%的乳腺癌患者为HER-2阳性。在HER-2阳性的乳腺癌研究中，近年来值得我们骄傲的是经过大宗随机试验确立了新的HER-2受体拮抗剂例如T-DM1和帕妥珠单抗。T-DM1具有曲妥珠单抗的靶向作用，同时又以一种非常巧妙的方式偶联了很小剂量的细胞毒药物，利用曲妥珠单抗作为载体，而将细胞毒药物传递入HER-2阳性的肿瘤细胞。读者应该很熟悉EMILIA和THERESA这两个试验的结果，它们确立了T-DM1为治疗HER-2阳性乳腺癌的有效药物。现在有很多抗HER-2受体的药物，比如T-DM1、帕妥珠单抗、拉帕替尼（全球很多专家都熟知的口服酪氨酸激酶抑制剂），和其他一些正在开发的酪氨酸激酶抑制剂如来那替尼、阿法替尼，我所担心的是这些药物被证实有效的同时，其可获得性如何。最近，我有幸受邀写一篇关于给予癌症患者关怀的综述，主要针对的是世界上最大的三个国家，包括中国，印度和俄罗斯。虽然曲妥珠单抗目前已在第一世界的大多数国家中使用，而在这三个国家中只有一小部分HER-2阳性的早期乳腺癌患者接受该药物治疗，因此我很清楚这些新的HER-2拮抗剂也很难应用到每一个患者身上。

　　HER-2阴性乳腺癌方面，也有很多令人鼓舞的研究结果。例如在所有乳腺癌病例中比例约占15%的三阴性乳腺癌，尽管对于早期PARP抑制剂的研究兴趣未能继续，但在新辅助治疗和转移性肿瘤中有很多药物处于评估中。一旦这些药物被证实有效，我希望可以尽快转化为临床应用，而且是所有三阴性乳腺癌患者都能得到并负担得起的。对于三阴性乳腺癌的研究仍有许多领域有待开拓，目前的研究显示PARP抑制剂对其中BRCA突变的患者十分有效。还有许多其他类型的非BRCA突变三阴性乳腺癌，都是需要研发相关药物的新领域。

　　同样也有许多luminal型乳腺癌，大约占患者的60%~65%。luminal A型乳腺癌的治疗方面已经达到一定高度，这些患者对内分泌治疗有效，通常预后较好。据我所知，由于luminal A型乳腺癌治疗反应好，目前针对该型患者的研究不多。luminal B型乳腺癌患者原则上对内分泌治疗敏感，但该型乳腺癌对内分泌治疗的原发耐药或继发对选择性雌激素受体调节剂如三苯氧胺和芳香酶抑制剂同时耐药的发生率高，该类患者几乎占乳腺癌患者的一半，需要开发一些新的治疗药物。有许多研究针对PI3激酶抑制剂，CD4/6受体抑制剂和mTOR受体抑制剂，因此这些药物在临床上使用并产生持续应答将是十分激动人心的事。作为临床医生，我们需要熟悉这些生物制剂的药理毒性，如皮肤毒性、神经毒性（因为这些生物制剂中的大多数可以透过血脑屏障，引起情绪波动），以及皮肤和肺毒性引起的超敏反应等。一旦这些生物制剂在大型临床试验中证实有效，我们需要制订全面的试验来筛选预测毒性的指标，更重要的是设计干预措施或预防措施，以免这些药物的毒性作用影响这些有效生物制剂的继续使用。