早期HER-2阳性乳腺癌个体化辅助治疗

　　中美早期HER-2阳性乳腺癌个体化辅助治疗现状

　　早期乳腺癌抗HER-2个体化治疗体现在几个方面：抗HER-2治疗联合的化疗方案、抗HER-2治疗的疗程、抗HER-2治疗的药物选择等。由于目前对于HER-2阳性乳腺癌，还没有可以预测患者接受曲妥珠单抗辅助治疗的获益程度的分子标志物，因此Winer教授表示，个体化治疗主要依赖于疾病的分期：“疾病分期对于预测最终的复发风险非常重要……对于极早期乳腺癌或2期、3期等不同分期的乳腺癌，我们给予的化疗方案多少有所不同。当然，还要依赖药物的副作用特点，患者是否能够耐受或是愿意耐受。”

　　邵志敏教授介绍了中国的情况，目前在中国，对于早期HER-2乳腺癌的辅助治疗，主要参照指南执行，包括NCCN指南和St Gallen共识。个体化治疗真正应依赖的应该是特定的分子标志物，而在当前主要依赖于病理参数，如淋巴结、肿瘤大小、HER-2和ER的状态。例如，对于HER-2阳性乳腺癌患者，如果肿瘤大小超过当前的推荐值，如1 cm，就会建议这类患者接受曲妥珠单抗联合化疗。但由于费用问题，近70%的患者没有进行靶向治疗。“HER-2患者的预后很大程度上依赖于抗HER-2治疗，（靶向治疗应用的不充分）导致中美的HER-2阳性乳腺癌患者的预后也有很大差异。”

　　Krop教授进一步补充道：“早期HER-2阳性乳腺癌的治疗可能是当前在乳腺癌中进步最大的领域。绝大部分患者若能得到曲妥珠单抗等抗HER-2药物的治疗，结局很好。现在的目标是双重的——尽量减小低危患者的治疗副作用以及进一步改善高危患者的预后”。

　　三位教授表示，要实现上述目标，包括改善中国及其他中低收入地区的成本限制问题，一方面需要继续开发更新的治疗方案和药物，帮助提高化疗和HER-2治疗的疗效，一方面则是要努力寻找生物标志物，从而了解哪些患者仅通过HER-2靶向治疗就可获得成功，哪些患者不需要太多化疗。

　　低危患者“退一步”以取得更大进步

　　为说明对于不同疾病负荷和临床特征的患者如何给予个体化治疗，专家们以ATP试验对之加以了解释。ATP试验于2015年年初正式发表于《新英格兰医学杂志》，作为该研究的参与者，Krop教授和Winer教授均表示，这是个体化治疗的好例子。

　　Krop教授指出，当前对于相对低危的HER-2阳性乳腺癌，标准治疗尚不明确。一般认为，全面的多药化疗联合曲妥珠单抗对于这类患者而言，是过度治疗，因此也带来了过多的毒性。“因此通过利用肿瘤的生物学特性，找到那些对曲妥珠单抗非常敏感的肿瘤患者，我们有望充分利用曲妥珠单抗的作用，而减少化疗的量。这个研究正好显示，对于肿瘤较小、淋巴结阴性的患者而言，少量的化疗（紫杉治疗12周）联合曲妥珠单抗（1年）治疗就能得到很好的结果，同时毒性非常小”。

　　Winer教授则表示，这个试验的表现“远远超出了预期”，试验人群的复发率非常低。更重要的是，这项研究并不像很多人以为的那样，局限在肿瘤很小的人群中，“实际上，一半的受试者的肿瘤介于1.1 cm和3 cm，大部分为1~2 cm。”Winer教授反复提到，希望未来肿瘤医生可以更“聪明”，对于某些患者，可以“退一步”，不给予化疗，而主要使用靶向治疗。在他看来，ATP就是一个何时可以“退一步”的好例子。“至少在美国，这项研究已经改变了临床实践。”

　　此外现在Krop教授等在做进一步“退一步”的尝试，即ATTEMPT研究，使用靶向性更强的药物T-DM1治疗这些低危患者，以进一步降低毒性。

　　双靶向辅助治疗前景

　　双靶向药物的联合也是HER-2阳性乳腺癌个体化治疗的一个表现。然而，令很多人惊讶且失望的是，ALTTO研究显示，拉帕替尼联合曲妥珠单抗和化疗相比于曲妥珠单抗联合化疗，在应用于辅助治疗时似乎并不能改善预后，反而增加毒性。Krop教授认为，“既然已经有一个样本量很大的、很好的研究得到了清晰的数据……那么当前拉帕替尼联合曲妥珠单抗的方案在早期疾病领域再无用武之地。”

　　Winer教授也指出，“尽管一些研究明确显示，拉帕替尼和曲妥珠单抗在转移性乳腺癌中是有效的方案，但联用化疗后，这种方法是否更有效并不清楚。在新辅助治疗领域也是如此，新辅助治疗领域是非常复杂的，有多种原因可能导致新辅助治疗的结果不转化为辅助治疗时的获益。”

　　但需要指出的是，拉帕替尼联合曲妥珠单抗双靶向辅助治疗的失败并不能否定其他双靶向药物组合。Winer教授和Krop教授表示，其他HER-2靶向治疗药物的联合，例如曲妥珠单抗和帕妥珠单抗的联合，即双重阻断，其机制不同。

　　“目前大家在非常乐观地等待APHINITY试验的结果。这个乐观不是因为这是在新辅助治疗领域，而在很大程度上是因为帕妥珠单抗在转移性乳腺癌中表现出来的惊人的生存获益，而这是拉帕替尼所不具备的。”

　　当然，几位教授并不排除可能存在能从拉帕替尼联合曲妥珠单抗治疗中获益的特殊肿瘤患者，但当前并无合适的生物标志物能够鉴别这类人群。

　　早期HER-2阳性乳腺癌的个体化新辅助治疗

　　在新辅助治疗方案的选择上，Winer教授提醒大家，要注意方案是否能获得长期获益。一些方案在短期内表现出优势，能减少乳房切除率、缩小外科手术的范围等。“但如果一种方案最终不能有助于预防疾病的长期复发，就很难引起人们在新辅助治疗中加以应用的兴趣。”以拉帕替尼联合曲妥珠单抗为例，该方案不改善长期结局，也不改善乳腺癌的缓解率或其他短期结局指标，因此在新辅助治疗领也没有应用的价值。

　　在美国，帕妥珠单抗已被批准用于新辅助治疗。根据来自新辅助治疗试验的结果和CLEOPATRA研究所展示的惊人的生存获益，将帕妥珠单抗用于新辅助治疗已经可行，而根据APHINITY试验的结果，未来还将有显著的改变。

　　Krop教授则介绍了在新辅助治疗应用中生物标志物的探索情况。目前已经认识到，HER-2阳性乳腺癌也不是单一一种疾病，同样由多种不同亚型组成，各亚型间对靶向治疗和化疗的应答有一定区别，特别是在使用病理学缓解作为终点评估时，区别更加明显。其中有些肿瘤可能具有特定的免疫标签（免疫细胞浸润），对HER-2靶向治疗和化疗的应答最好，这给未来的治疗提供了一些线索。

　　转移性HER-2阳性乳腺癌的个体化治疗

　　中美治疗方案比较

　　目前在中国，由于帕妥珠单抗、T-DM1等药物尚未上市。因此在转移性HER-2阳性乳腺癌的治疗方面，可选择的余地不大。一线治疗方案可选择曲妥珠单抗联合不同化疗方案或拉帕替尼和卡培他滨。邵教授表示，T-DM1的注册试验将在明年年初展开。“我们正在努力，通过自己的工作来证实其疗效，将新药的最新发展引入到中国，用于我们的HER-2阳性乳腺癌患者。”

　　而在美国，对于大部分HER-2阳性的转移性乳腺癌患者，推荐的一线治疗方案是联合应用化疗、曲妥珠单抗和帕妥珠单抗，这是基于CLEOPATRA试验的结果。该研究比较了多西他赛、曲妥珠单抗联合安慰剂或帕妥珠单抗，结果显示加用帕妥珠单抗使生存期显著延长近16个月，同时，加用帕妥珠单抗所增加的毒性相对轻微，因此在美国，基于帕妥珠单抗的方案事实上已经成为大部分患者的标准治疗。

　　在二线治疗方面，美国当前的标准二线治疗是T-DM1单药。T-DM1为曲妥珠单抗-emtansine，是一种由HER-2靶向抗体曲妥珠单抗与细胞毒性药物和微管抑制剂DM1物理耦联而成的药物。Winer教授介绍道：“如果患者在二线治疗时没有用过T-DM1，如使用了曲妥珠单抗联合其他化疗或曲妥珠单抗联合拉帕替尼，有证据支持三线治疗使用T-DM1能够获益”。T-DM1已成为帕妥珠单抗和曲妥珠单抗治疗后疾病进展的大部分患者的标准治疗。其有效性优于卡培他滨和拉帕替尼方案。

　　Krop教授进一步介绍了T-DM1的安全性。他表示，T-DM1的副作用问题较小，没有化疗药物的很多常见毒性，不会引起脱发、不会导致严重的中性粒细胞减少或中性粒细胞缺乏。主要副作用有乏力和胃肠道副作用，与其他化疗药物相比，通常都很轻微。需要在随访中注意的是，该药可引起3级或以上的血小板减少，发生率约10%，还可导致转氨酶升高，5%或6%的患者出现显著升高，不过通常是一过性的，一般没有症状，减少药物剂量可改善。从患者的角度上讲，这是一个能很好耐受的药物。

　　真实世界数据的意义和应用挑战

　　在Winer教授看来，在讨论真实世界数据时，也是在讨论大数据，讨论的是经验性临床实践。几位教授都认为，真实世界数据和大数据作为对临床试验的补充无疑是有价值的，有助于了解在真实世界中药物是如何应用的，以及结局如何。如Winer教授就认为这些数据的最大价值是评估可能的长期结局，例如看看接受了曲妥珠单抗治疗的HER-2阳性乳腺癌患者在10年后有多大比例发生了心衰，HER-2阳性转移性乳腺癌中脑转移的准确发生率等。

　　但参加临床试验的患者人群显然有别于真实世界中未经选择的患者，而且真实世界数据或大数据中有很多干扰和潜在偏倚，数据质量不高，有时无法控制所有的潜在偏倚。如美国的SEER医疗数据库能够提供大家一些与治疗和结局相关的信息，但详细内容相比临床试验中要简陋得多。如Winer教授所说，“我认为我们需要牢记的是，它不是临床试验的替代品，有了真实世界数据不等于可以不做临床试验。我们在解释这种情况下的治疗方案时，会引入偏倚，而且很难纠正。在拥有足够数据的情况下，我们至少可以生成假设，并由此衍生出更小的但是更有效的临床试验。”

　　总之，对真实世界数据的探索和开发才刚刚开始，还需要更多的努力。随着更准确的电子病历记录和高级的分析程序的应用，以及如邵教授的团队等研究者正在开展的相关基础工作，真实世界数据的质量将不断提高。“前进只会带来获益！”

访谈原文

　　Oncology Frontier : Today we have the honor of doing a short interview. I would like to do a brief introduction of our honored guests. Professor Shao is the Director of the Breast Cancer Institute in Shanghai Cancer Center. We have Professor Winer from Dana Farber Institute. He is the director of Breast Oncology and we also have Professor Krop from Dana Farber. He is the director of the Breast Cancer Program and the Clinical Research Committee.

　　《肿瘤瞭望》：The management of breast cancer has entered into an era of molecular classification where the various therapy regimens have been established for patients with corresponding molecular subtype. But the regimen is not inflexible; fine-tuning is necessary given the specific patient.  That is what we call personalized treatment. Today we are greatly honored by inviting three prestigious figures in breast cancer field to answer our questions. In treatment of breast cancer such as early stage cancer， what factors will affect personalized treatment?

　　《肿瘤瞭望》：乳腺癌的管理进入到了分子分型时代，针对不同分子分型的患者建立起不同类型的治疗方案。但治疗方案绝不是一成不变的，需要根据患者的具体情况来对方案做出细调，这也就是我们所说的个体化治疗。今天很荣幸邀请到三位权威的乳腺癌专家，一起来谈一谈HER-2阳性乳腺癌患者的个体化治疗。在早期乳腺癌治疗时，哪些因素可能影响个体治疗？

　　Dr. Winer: For HER 2 positive breast cancer unfortunately we do not have biomarkers that predict greater or lesser benefit from adjuvant trastuzumab. In terms of personalizing treatment， we really are left personalizing based on the stage of the disease， so we give somewhat different chemotherapy regimens for patients with very early stage disease versus patients who have for example， stage 2 and stage 3 breast cancer. Also based on the side effect profile that the patient is either able to tolerate or wiling to tolerate. We have different regimens that have somewhat different side effects and in that way we can also personalize treatment. We hope that there will be a time in the future where in fact we can be a little smarter than we are today. We can back off on chemotherapy in some patients and use primarily targeted therapy but in order to get there and in order to back off on some of the chemotherapy we are going to have to get pretty creative in terms of how we do the clinical trials.

　　Winer教授：对于HER-2阳性乳腺癌，很不幸还没有什么生物标志物可以帮助我们预测患者从曲妥珠单抗辅助治疗中的获益会更大还是更小。就个体化治疗而言，我们主要是依赖于疾病的分期，因此对于极早期乳腺癌或2期、3期乳腺癌等不同分期的患者，我们给予的化疗方案多少有所不同。当然，还要依赖药物的副作用特点，患者是否能够耐受或是愿意耐受。不同方案的副作用多少是不同的，这样也是在进行个体化治疗。我们希望未来我们能够更加“聪明”，对于某些患者，可以“退一步”，不给予化疗，而主要使用靶向治疗。而要实现这一点，在临床试验的开展上，我们需要更加富有创新性。

　　Dr. Shao : Yes just to add to what Dr. Winer said， but in HER 2 positive patients right now we have to based on their molecular targets， for example HER 2， if the tumor size is more than what is recommended right now – for one side it is 1 centimeter， the patients will probably be recommended for anti HER 2 treatment which is with trastuzumab and chemotherapies. Also we probably know that we have some markers or the signatures to predict how is the HER 2 treatment has effect or not but it is still in the trials right now. Giving the trastuzumab they do not have too many side effects， particularly in the heart， but this is still a minus. For the HER 2 positive breast cancer patients right now， if the patients they can receive the trastuzumab then we all recommend it but in China it is still a big difference between China and the United States where it is cost effective. In the United States I know it is all covered by the insurance but in China most of the provinces are not covered by insurance so even in Shanghai， it still is a big cost. In our hospital we only have 35% patients who receive adjuvants. That is a big difference because in the HER 2 positive breast cancers the prognosis is really based on the anti HER 2 treatment.

　　邵志敏教授：没错。我想补充的是，目前对于HER-2阳性患者，我们不得不依赖患者的分子靶点。例如，如果肿瘤大小超过当前的推荐值，如1 cm。我们可能会建议这类患者接受曲妥珠单抗抗HER-2治疗联合化疗。现在也有一些标志物或标签可能能预测抗HER-2治疗是否有效，但还限于临床试验范畴。曲妥珠单抗的副作用并不多，主要是在心脏方面，这是它的弱点。目前在中国，对于HER-2阳性乳腺癌患者，如果患者能够使用曲妥珠单抗，我们都会推荐应用该药，但中美之间，在成本效益方面仍有很大的差异。据我所知，在美国，医疗保险完全覆盖该药的费用，但在中国，该药在很多省份都未进入医保，因此即使在上海，治疗仍需一大笔费用。在我们医院，只有35%的患者接受辅助治疗。由于HER-2患者的预后很大程度上依赖于抗HER-2治疗，因此在中美的HER-2阳性乳腺癌患者之间，结局有很大差异？

　　Dr. Krop : The treatment in early stage HER 2 positive disease is probably the area in breast cancer that we have made the most progress. Most people now do quite well particularly if they have access to drugs like trastuzumab. Our goal now is as Dr. Winer suggested is two fold. One is to try to decrease the side effects of treatment for those patients with lower risk disease and the other is for the relatively small population who has very high risk disease， how can we still improve them further. In terms of the high-risk disease area， we are still trying to develop newer drugs which may help make chemotherapy and HER 2 directed therapy work better， like other signal transduction inhibitors and other immune therapies. For the lower risk patients， again， what we are really trying to do is cut down on toxicity and one way to do that is to try to identify with biomarkers who can be treated successfully with HER 2 targeted therapies alone and who does not need as much chemotherapy. That has been difficult but there have been a number of clinical trials on going that are trying to tease out some of those biomarkers. What Professor Shao was pointing out in terms of the cost， again， if we can identify biomarkers of who needs less therapy then perhaps we can use our HER 2 therapies， our expensive therapies， and concentrate it on those patients who are going to derive the most benefit. I think a lot of this can be improved if we can determine more precisely the characteristics of cancers and how they respond and do not respond to treatment. That is where we are trying to go to better personalize our therapies.

　　Krop教授：早期HER-2阳性乳腺癌的治疗可能是当前在乳腺癌中进步最大的领域。绝大部分患者若能得到曲妥珠单抗等抗HER-2药物的治疗，结局很好。如Winer博士提到的，我们现在的目标是双重的：一个是在低危人群中尽量减少治疗的副作用，另一个是对于风险很高的相对较少的患者，如何进一步改善他们的预后。

　　对于高危患者，我们仍在努力开发更新的药物，其他信号转导抑制剂和其他免疫治疗，希望能帮助提高化疗和HER-2治疗的疗效。对于低危患者，我们真正在做的是减少毒性，方法之一是寻找生物标志物，从而了解哪些患者仅通过HER-2靶向治疗就可获得成功，哪些患者不需要太多化疗。这个过程很难，但已经有很多临床试验在开展，试图梳理出一些生物标志物。邵志敏教授指出了费用的问题，一样地，如果我们能找到生物标志物，就能找到一种治疗方案的特定获益人群。我想，如果我们能更为精准地了解癌症的特征和对治疗是否应答、如何应答，上述很多问题都能得到改善。这是为实现更好的个体化治疗而需要达到的。

　　Oncology Frontier : Earlier in this year， the APT trial published in the New England Journal of Medicine demonstrated that specific patients who use either trastuzumab and paclitaxel as adjuvant therapy can have favorable survival outcome. This should be a perfect example of personalized treatment. Professor Winer and Professor Krop have all participated in APT. Can you please give us your comments on the outcomes of this trial?

　　《肿瘤瞭望》：今年年初正式发表于NEJM的APT研究提示，对于特定患者，单用曲妥珠单抗和紫杉醇单药辅助治疗即可达到很好的生存结局，这应该就是个体化治疗的一个非常好的例子。Winer教授和Kan教授都参与了APT试验，请二位分别评价一下这个研究？

　　Professor Krop : Well I do think this is an example of personalized medicine in which we identified patients who were relatively low risk with HER 2 positive disease and there was no clear standard treatment for these patients and our general sense was that giving them comprehensive multi-agent chemotherapy and trastuzumab was probably too much treatment and therefore too much toxicity. Taking advantage of the biologic characteristics of this cancer which we knew were very sensitive to trastuzumab we could hopefully cut down on the amount of chemotherapy and exploit the benefits of transtuzumab and this trial which used a small amount of chemotherapy and trastuzumab did show that in the patient with smaller， node negative cancers， that outcomes were very good and toxicity was fairly low when given just a small amount of chemotherapy， just 12 weeks of paclitaxel， with a year of trastuzumab. We think this was a nice proof of concept that identifying a population that is sensitive to HER 2 directed therapy can do very well with less chemotherapy. What we are now trying to do currently is to try to even cut back further on toxicity by using it as a more targeted therapy， T-DM 1 in these low risk patients.

　　Krop教授：我的确认为这是个体化治疗的范例。对于相对低危的HER-2阳性乳腺癌，当前没有明确的标准治疗，我们一般认为，全面的多药化疗联合曲妥珠单抗对于这类患者而言，是过度治疗，因此也带来了过多的毒性。因此通过利用肿瘤的生物学特性，找到那些对曲妥珠单抗非常敏感的肿瘤患者，我们有望充分利用曲妥珠单抗的作用，而减少化疗的量。这个研究正好显示，对于肿瘤较小、淋巴结阴性的患者而言，少量的化疗（紫杉治疗12周）联合曲妥珠单抗（1年）治疗，就能得到很好的结果，同时毒性非常小。我想这也是一个很好的证据，它证实，对HER-2靶向治疗敏感的?巳菏褂媒仙俚幕埔材芑竦煤芎玫慕峁?我们现在在做进一步“退一步”的尝试，使用靶向性更强的治疗T-DM1治疗这些低危患者，以进一步降低毒性。

　　Professor Winer: So when we designed the trial we had hoped that it would show an acceptable result and we had defined an acceptable result as a recurrence rate of less than 5% at 3 years. As it turned out the trial far out performed what we expected meaning that the number of recurrences was very very small and in fact if you look at distant recurrences only there were 2 distant recurrences in those first 3 years of 406 patients who were on the trial. It is also important to point out that the trial was not just for patients who had tumors less than 1 centimeter. It has been interpreted by some people as being a trial for patients who had the smallest of all cancers， actually half of the tumors were between 1.1 centimeters and 3 centimeters， most were in the 1 to 2 centimeter range. I think that this really is an example of a situation where we are able to back off， we knew we could not do a randomized trial for a whole range of reasons and rather than do nothing， we actually launched a study and it worked out quite well. At least in the United States， this has really changed clinical practice.

　　Winer教授：在我们设计这项试验时，我们希望它能展示出一个能够让人接受的结果，我们将这个结果设定为3年复发率小于5%。结果显示，试验的表现远远超出了我们的预期，复发率非常低，在研究纳入的406例患者中，前3年仅有2例出现远期复发。还有重要的一点需要指出，即这个试验并不只包括肿瘤＜1 cm的患者。有些学者在解读这项试验时，把它认作是在肿瘤极小的患者中进行的。但实际上，一半的受试者的肿瘤介于1.1 cm和3 cm，大部分为1~2 cm。我认为这是一个何时可以“退一步”的好例子。我们早就知道不可能开展一项纳入了所有因素的随机试验，但与袖手旁观相比，我们开展了一项试验，而这项试验开展得非常成功。至少在美国，这项研究已经改变了临床实践。

　　Oncology Frontier : The next question is that Professor Shao， in China how can we provide personalized treatment for patients with early stage breast cancer and are there some cases or trials involved in adjuvant and neo adjuvant therapy?

　　《肿瘤瞭望》：在中国，早期乳腺癌抗HER-2治疗的个体化是如何开展的，有无辅助或新辅助个体化治疗的例子或临床试验？

　　Professor Shao  : Yes right now for early breast cancer treatment in China， for example with adjuvants， is really based on the guidelines. Even the NCCN guidelines on this and the St. Gallen consensus because really right now we are talking about personalized treatment and it really depends on certain molecular markers and the major thing right now is still on the pathological parameters for example nodes， tumor size， HER 2， ER status， so it is really based on these factors to guide our treatment. Also in our clinical practice right now we all still have some localized or we also attend multi-center clinical trials. But this is really based on the study you designed to try to approve one treatment over another treatment. Right now in China， the majority of patients is still treated with the guidelines but we have a small amount of patients who attend clinical trials to try to improve our results.

　　邵志敏教授：当前在中国，对于早期乳腺癌的辅助治疗，主要参照指南执行，包括NCCN指南和St Gallen共识。现在我们讨论的是个体化治疗，它真正应该依赖于特定的分子标志物，而目前主要依赖于病理参数，如淋巴结、肿瘤大小、HER-2和ER的状态，这些因素指导着我们的治疗。在我们的临床实践中，我们自己开展或参与了一些多中心临床试验。不过要证明一种治疗优于另一种治疗，与试验设计有很大关系。在中国，大部分患者是按照指南治疗，也有少量患者参与临床试验，尝试改善预后。

　　Oncology Frontier : Our first question is that in adjuvant and non adjuvant therapy， no matter what the technique is we all wish that we had some highly sensitive and specific molecular biomarkers to predict the treatment response or prognosis. Professor Winer and Professor Shao， what should we do， can you comment on this.

　　《肿瘤瞭望》：无论是辅助治疗还是新辅助治疗，我们总是希望有一些敏感性好的、特异性高的分子标志物来帮助我们判断患者的治疗应答或预后。在这一方面几位教授有什么经验吗？

　　Professor Winer  : Well unfortunately we do not have high risk specific biomarkers other than HER 2. We continue to look for them， we continue to look for biomarkers that will allow us to determine， for example， which patients might benefit from the addition of drugs like pertuzumab， which patients might be able to do well with a shorter course of antibody therapy， which patients might benefit from a whole range of other agents. It has been surprising how much we have looked at here from the early adjuvant trials and how little we have been able to come up with. As has been said， I think at least at this point in time we have to base our treatment decisions on the presence or absence of HER 2 and then on patient preferences and the stage of disease. Stage of disease turns out to be very very important in terms of predicting the ultimate risk of having a recurrence which is really what we are trying to prevent.

　　Winer教授：很不幸，除了HER-2外，我们没有其他的高危特异性生物标志物。我们还在继续寻找能给我们提供帮助的生物标志物，例如，告诉我们哪些患者可能从添加帕妥珠单抗等药物中获益，不同的患者是否需要不同的疗程，哪些患者可能从其他的药物中获益等。从早期辅助治疗的试验中，我们看到了很多可能，但能够实现的却很少，这很不可思议。如之前谈到的，我想至少在目前，我们不得不根据HER-2的表达情况以及患者倾向性和疾病分期，来进行治疗决策。疾病分期对于预测最终的复发风险非常重要，而复发是我们要千方百计预防的。

　　Professor Krop  : So we certainly have not identified single markers that are highly predictive of response to therapy particularly with HER 2 but it is starting to be some progress and one of the ways as you suggested， was looking at neo adjuvant trials in which we can develop a lot of tissue as part of a trial and incorporate that with how patients do pathologically after targeted therapy. Some of those studies are starting to yield some interesting results. We now know that HER 2 positive disease is actually， when looked at with genomic techniques， is actually made up of several different sub types and these actually respond somewhat differently to targeted therapy and chemotherapy particularly when you are using pathologic response as your endpoint. I think one of the more intriguing results from those studies is that tumors that seem to have an immune signature to them probably because they are somewhat antigenic and they have developed infiltrates of immune cells， seem to respond best to HER 2 targeted therapy and chemotherapy and that may give us clues in the future in terms of whether we can take advantage of that and use therapies to stimulate the immune system， particularly in those cancers. I think there are some intriguing data that are just starting to come out and we hope that that will pay off in the future but certainly right now we do not have anything that we can use clinically to guide therapy decisions.

　　Krop教授：我们还没有发现能高效预测治疗应答（特别是HER-2靶向治疗）的单一标志物，但已经获得了一些进展。其中之一是在新辅助试验中，试验中我们可以获得很多组织，从病理上分析靶向治疗后患者的变化。其中部分试验已经得到了一些有意思的结果。通过遗传学技术，现在我们知道，HER-2阳性乳腺癌实际上也是由多种不同亚型组成的，它们对靶向治疗和化疗的应答是有一定区别的，特别是使用病理学缓解作为终点时（区别更加明显）。我想，其中比较值得关注的一个结果是，似乎具有某种免疫标签的肿瘤——可能是由于具有某种抗原性，因而出现了免疫细胞的浸润——对HER-2靶向治疗和化疗的应答最好，这在未来我们如何利用这一点上提供了一些线索，可以使用刺激免疫系统的治疗，特别是对于这类肿瘤。我想，现在还有很多有意思的结果刚刚涌现，希望将来能获得成功，但在目前还没有能够用于临床指导治疗决策的标志物。

　　Professor Winer: Can I just make one more comment. The one other area that is probably worth paying attention to relates to hormone receptor status. There we know that anti HER 2 therapies are effective in both ER negative and ER positive breast cancer but there is at least some suggestion that the combination of anti hormonal therapy and anti HER 2 therapy could be of particular benefit in those patients with hormone receptor positive disease. There was a pre-operative clinical trial conducted by a group at Baylor that looked at the use of anti HER 2 therapy with anti hormonal therapy with somewhat surprisingly favorable results.

　　Winer教授：我想补充一点。还有一点值得注意，即激素受体状态。HER-2靶向治疗对ER阳性和ER阴性乳腺癌都有效，但至少有迹象显示，对于激素受体阳性的患者，联合抗激素治疗和HER-2靶向治疗格外有效。Baylor大学中的一个研究组曾进行了一项术前应用的临床试验，观察抗HER-2治疗与内分泌治疗的效果，得到了非常好的结果。

　　Oncology Frontier : Professor Shao do you have any comments you can share with us on this question?

　　《肿瘤瞭望》：邵教授，在这个问题上您有什么意见可以和我们分享？

　　Professor Shao : Yes I think that right now there are new techniques that are still trying to find all the biomarkers just as Dr. Winer has said in the presentation. He has given us clues that right now we are not looking for not only one single gene or one single marker but we are looking for the pathway of multi-gene authorizations that may be an effector of one treatment. For example right now in HER 2 positive breast cancer， we are looking for the mutation for the HER 2 genes. In particular we have found HER 2 and even the HER 2 mutation rates for positive is only like 2.8% but whenever the patient relapses with a metastases with HER 2 treatment， the metastatic site of the HER 2 mutation rates will go up to 30% or 40% which means HER 2 mutation in HER 2 positive breast cancer patients with HER 2 mutation may be one mechanism of the HER treatment resistance. In this particular patient with HER 2 mutations， we may use different mechanisms of HER 2 treatment. Right now all the new techniques are looking for this in HER 2 positive breast cancers. As Dr. Winer also suggested， in different pathways for example the HER 2 pathways or the downstream of the ER they have a crosstalk. If we block one way， it may work. That is why all the clinical trials that designed different are looking for， hopefully in one or two years in the future this may work.

　　邵志敏教授：现在有一些新的技术可以发现所有的生物标志物，如Winer教授在演讲中提到的（OncoMap）。他告诉我们，当前我们并不仅仅是需找一个基因或是一个标志物，而是需找多个基因控制的通路，可能是某种治疗的效应分子。例如，对于HER-2阳性乳腺癌，我们在寻找HER-2基因的突变。特别的，我们发现（最初）HER-2甚至是HER-2突变阳性率只有2.8%，但当患者在抗HER-2治疗后出现复发转移时，转移位点的HER-2突变率将升高到30%或40%，这意味着有HER-2突变的HER-2阳性乳腺癌患者中，HER-2突变可能是HER治疗耐药的机制之一。对于这类携带HER-2突变的特殊患者，我们可能需要使用不同作用机制的HER-2靶向治疗。当前所有的技术都在探索这一点。如Winer博士提到的，例如HER-2通路或ER的下游通路存在交叉。如果我们阻断其中一个，可能会有效。这就是为什么要设计不同的临床试验加以寻找。希望未来一两年能取得成功。

　　Oncology Frontier : The ALTTO clinical trials have shown that trastuzumab combined with lapatinib is not better than using trastuzumab in some cases. Professor Winer and Professor Shaw， how do you see the future of double combination when treated with trastuzumab and combined with lapatinib?

　　《肿瘤瞭望》：ALTTO研究告诉我们，曲妥珠单抗联合拉帕替尼并不优于单用曲妥珠单抗，您如何看待其他双联组合，如曲妥珠单抗联合帕妥珠单抗的前景？

　　Professor Krop: I think many of us were a little surprised and disappointed that the combination of lapatinib and trastuzumab along with chemotherapy did not seem to improve outcomes in the adjuvant setting compared to chemotherapy and trastuzumab alone because the data from the neo adjuvant setting did suggest that combining trastuzumab and lapatinib would be beneficial and we know that that is true in the metastatic setting. I think because we now have clear data from a very nicely done study with a large number of patients that demonstrates pretty clearly that the combination does not improve outcomes and it is associated with additional toxicity that right now there is really no role for that combination in the early disease setting. Now just as we have talked about with a lot of the other questions， I think that there certainly may be specific cancers that benefit from that combination and hopefully as an analysis of the ALTTO trial tumor samples is ongoing that we will be able to learn whether there are particular cancers that seem to benefit more but right now without any good biomarker there really is not a role for using the combination of lapatinib and trastuzumab. There are other combinations of HER 2 directed therapies such as trastuzumab and pertuzumab that may be another approach to this so called dual blockade paradigm. Certainly with trastuzumab and lapatinib I do not think that there is a clinical role any time soon.

　　Krop教授：拉帕替尼联合曲妥珠单抗和化疗相比于曲妥珠单抗联合化疗，在应用于辅助治疗时似乎并不能改善预后，这令很多人惊讶且失望，毕竟，来自新辅助治疗的数据提示，联合曲妥珠单抗和拉帕替尼能给患者带来pCR的提高，而且在转移性乳腺癌领域也有阳性数据。我想，既然已经有一个样本量很大的、开展得很好的研究得到了清晰的数据，明确显示联合治疗并不改善结局，反而增加毒性，那么当前这种联合方案在早期疾病领域再无用武之地。不过就像我们之前讨论的很多问题一样，我想一定存在能从拉帕替尼联合曲妥珠单抗治疗中获益的特殊肿瘤患者。针对ALTTO试验的肿瘤样本的分析目前正在进行，我们有望知道，是否存在这样的特殊人群。但当前，在没有任何好的生物标志物的情况下，二者的联合着实没有意义。其他HER-2靶向治疗药物的联合，例如曲妥珠单抗和帕妥珠单抗的联合，即所谓的双重阻断，是另外一种方法。

　　Professor Winer : I would tend to agree that there may be a sub group of patients who ultimately would benefit from the 2 drugs， from a combination of trastuzumab and lapatinib. We do not know who those people are. In retrospect， I think that it is probably too bad and while its always not fair to look at this issue in retrospect but in retrospect the way the ALTTO study was designed was probably not optimal. We probably would have been far better off looking at a two-armed trial with a larger number of patients in each of those two arms so that we can actually look at subsets more effectively instead of having a more complex four arm trial. I think part of the problem though is that although lapatinib and trastuzumab in the metastatic setting in some studies is clearly an effective regime， whether or not it is more effective when added to chemotherapy is unclear; it is not in the neo adjuvant setting. The neo adjuvant setting is a tricky area and there are a number of reasons why neo adjuvant results may not translate into benefiting the adjuvant arena. I do think that it certainly raises a caution about dual-blockage but it in no way suggests that other anti-HER 2 therapies when combined with trastuzumab will not be useful. I think we are all waiting for the results from the APHINITY trial and quite optimistically waiting on results. A large part of that optimism is not because of the neo adjuvant trials but because of the dramatic impact of pertuzumab in the metastatic setting on survival and those are data we never had for lapatinib.

　　Winer教授：我同意可能有一部分亚组患者最后能曲妥珠单抗联合拉帕替尼中获益。但我们不知道他们是谁。回顾的话，我想可能会更糟，从回顾性角度看待这个问题一般是不公平的，但回头来看，ALTTO试验的设计方式可能是不合理的。我们可能应该进行一个双臂的、各组纳入了更多患者的试验，这样更有利于我们有效地观察各亚组的情况，而不是开展一个复杂的四臂试验。尽管如此，我想部分问题是，尽管一些研究明确显示，拉帕替尼和曲妥珠单抗在转移性乳腺癌中是有效的方案，但联用化疗后，这种方法是否更有效并不清楚，而且也不是在新辅助治疗领域。新辅助治疗领?蚴欠浅８丛拥模卸嘀衷蚩赡艿贾滦赂ㄖ瘟频慕峁蛔ㄖ瘟剖钡幕褚妗Ｎ蚁胝獾娜犯刈瓒咸岢隽司妫皇撬灯渌鸋ER-2靶向治疗药物联合曲妥珠单抗也无效。我们都在等待，而且是非常乐观地在等待APHINITY试验的结果。这个乐观不是因为这是在新辅助治疗领域，而在很大程度上是因为帕妥珠单抗在转移性乳腺癌中表现出来的惊人的生存获益，而这是拉帕替尼所不具备的。

　　Oncology Frontier  : Furthermore， neo adjuvant therapy have been used in more and more patients， and are suited to the earlier and earlier cancer stages. What are the prospects of double targeting in neo adjuvant therapy for HER 2 positive breast cancer patients?

　　《肿瘤瞭望》：此外，目前新辅助治疗的应用人群越来越广，适应疾病分期也越来越早，双靶向治疗在HER-2阳性乳腺癌新辅助治疗领域有何前景？

　　Dr. Winer  : There is no role for lapatinib and trastuzumab in the neo adjuvant setting because it does not improve long term outcome and to my knowledge has not been shown to improve rates of breast cancer remission or any other short term outcome measure. In terms of pertuzumab， in the United States and I believe in Europe at the moment， pertuzumab has been approved in the neo adjuvant setting. I think in Europe it is actually in ER negative patients but I am not absolutely sure of this but I think it is the case. Whether or not that is available in European countries is another question. In the United States， based on the data from the neo adjuvant trials and based on the dramatic survival advantage from CLEOPATRA， neo adjuvant pertuzumab is available and it is something that is used that will change dramatically depending on the results of the APHINITY study. In my mind， the main reason we give neo adjuvant therapy is for long term benefits. We take advantage of the fact that in the short term it may allow us to decrease the mastectomy rate， decrease the extent of surgery， but if a regimen ultimately does not help prevent disease recurrence long term it would be hard to get too excited about using them in the neo adjuvant setting.

　　Winer教授：在新辅助治疗领域，拉帕替尼联合曲妥珠单抗没有意义，因为它不改善长期结局，而且据我所知，也不改善乳腺癌的缓解率或其他短期结局指标。在美国，帕妥珠单抗已被批准用于新辅助治疗，我想在欧洲目前也是如此。（可能更准确地说，是在ER阴性患者中，不过我不是非常肯定。在欧洲国家它是否获得了批准是另外一个问题。）在美国，根据来自新辅助治疗试验的结果和CLEOPATRA研究所展示的惊人的生存获益，将帕妥珠单抗用于新辅助治疗已经是可行的，而根据APHINITY试验的结果，这还将有显著的改变。在我看来，进行新辅助治疗的主要原因是为获得长期获益。我们可以利用它在短期减少乳腺切除率、缩小外科手术的范围等的作用，但如果一种方案最终不能有助于预防疾病的长期复发，就很难引起人们在新辅助治疗中加以应用的兴趣。

　　Oncology Frontier : Thank you， my next question is for HER-2 positive metastatic breast cancer， which regimen is commonly used in first line and second line treatment scenario and strategy?

　　《肿瘤瞭望》：对于HER-2 阳性的转移性乳腺癌，您目前惯常选择哪种一线治疗和二线治疗方案？

　　Dr. Krop  : In the United States， for the majority of patients with first line HER 2 positive disease the recommendations are to use the combination of chemotherapy， trastuzumab， and pertuzumab and that is based on the data that Dr. Winer just mentioned which was a CLEOPATRA study which compared a docetaxel， trastuzumab with either placebo or pertuzumab showing what we have learned recently is a dramatic improvement in survival of almost 16 months with the addition of pertuzumab. Based on this survival benefit and the fact that for the most part pertuzumab adds relatively mild toxicities to chemotherapies and trastuzumab， but based on this combination of survival benefits and reasonable toxicity profile that this pertuzumab based regimen really is the standard for most patients in the United States.

　　Krop教授：在美国，对于大部分HER-2阳性的乳腺癌患者，推荐的方案是联合应用化疗、曲妥珠单抗和帕妥珠单抗，这是基于刚才Winer博士提到的CLEOPATRA试验的结果。该研究比较了多西他赛、曲妥珠单抗联合安慰剂或帕妥珠单抗，结果显示加用帕妥珠单抗使生存期显著延长近16个月。根据这一生存获益以及对绝大部分患者来说，在化疗和曲妥珠单抗基础上加用帕妥珠单抗所增加的毒性相对轻微，因此在美国，基于帕妥珠单抗的方案事实上已经成为大部分患者的标准治疗。

　　Dr. Winer: Do you want to add about the first line?

　　Winer教授：您在一线治疗上有何补充？

　　Dr. Shao  : In China right now， we do not have too much choice because we only have two anti HER 2 drugs in the market. It is one transtuzumab and the second is lapatinib. Whenever the first line treatment will be， we have two choices， one is trastuzumab changed with a different chemotherapy or lapatinib and capecitabine， so that is two that we can use. We do not have pertuzumab， we do not have the T-DM 1， so we have another 4 or 5 years for it to come out to the Chinese market. That is the real situation right now in China.

　　邵教授：在中国，目前的一线治疗选择不多，因为中国市场上只有两种抗HER-2药物，曲妥珠单抗和拉帕替尼。开始一线治疗时也只有两种选择，曲妥珠单抗联合不同化疗方案或拉帕替尼和卡培他滨。我们没有帕妥珠单抗或T-DM1，它们在中国的上市还需要等待4~5年。这是目前中国的现实。

　　Dr. Winer ： For second line， our standard at this time is T-DM 1 and T-DM 1 given as a single agent and if for an reason the patient does not receive T-DM 1 in the second line setting， for example we receive trastuzumab with another chemotherapy agent or trastuzumab and lapatinib which is a regimen we occasionally use then we have evidence to support giving T-DM 1 in third line setting. T-DM 1 is a drug we use， it is a drug that tends to have quite modest toxicity and can be quite effective and in the second line setting at least compared to capecitabine and lapatinib there is a survival advantage.

　　Winer教授：我们当前的标准二线治疗是T-DM1单药。如果患者在二线治疗时没有用过T-DM1，如使用了曲妥珠单抗联合其他化疗或曲妥珠单抗联合拉帕替尼——这种方案偶尔也会应用，有证据支持三线治疗使用T-DM1能够获益。T-DM1毒性轻微，在二线治疗应用时，至少和卡培他滨和拉帕替尼相比，有生存获益。

　　Oncology Frontier: As you mentioned， T-DM 1 has been launched in US and you have mentioned its application in HER 2 positive metastatic breast cancer in second line treatment and above. Can you elaborate on its clinical value and indicate its patient prospect. How about its safety profiles?

　　《肿瘤瞭望》：如您提到的，T-DM1已在美国上市，用于HER-2阳性转移性乳腺癌的二线及以上治疗。能否请您谈一谈它的临床价值和适用人群，它的安全性怎样？

　　Dr. Krop : Eric alluded to T-DM 1 as the standard now for most patients in the United States after progression on pertuzumab and trastuzumab. The reason is because of its efficacy which was superior to capecitabine and lapatinib and also superior to trastuzumab based regimens in later lines of therapy. One of the things that makes T-DM 1 particularly appealing is its favorable side effect profile. It does not have many of the usual chemotherapy toxicities， it does not cause hair loss， it does not cause much neutropenia or neuropathy and the side effects are that it can have this fatigue and some gastrointestinal side effects which are usually very mild compared to other drugs so from a patient’s standpoint it is very well tolerated. It does have some toxicities that need to be followed. It can cause thrombocytopenia in grade 3 or higher levels in about 10% of patients and it can cause elevations of transaminase in about 5 or 6% of patients at significant levels but those are usually transient. They are not usually symptomatic and they respond to dose reductions. From a patient’s perspective it is a very well tolerated drug and physicians need to be aware of the potential toxicities but for the most part， for most patients， these really are not clinical problems.

　　Krop教授：Winer博士刚刚谈到，在美国，T-DM1已成为帕妥珠单抗和曲妥珠单抗治疗后疾病进展的大部分患者的标准治疗。其原因是其有效性优于卡培他滨和拉帕替尼，而且在二三线的治疗中，也优于曲妥珠单抗方案。T-DM1的副作用问题较小，这使得该药格外具有吸引力。它没有化疗药物的很多常见毒性，不会引起脱发、不会导致严重的中性粒细胞减少或中性粒细胞缺乏，其副作用有乏力和一些胃肠道副作用，与其他药物相比，通常都很轻微。因此从患者角度上讲，它的耐受性很好。它也有一些毒性需要随访：可引起3级或以上的血小板减少，发生率约10%，可导致转氨酶升高，5%或6%的患者出现显著升高，但通常是一过性的。这些副作用一般没有症状，减少药物剂量可改善。从患者的角?壬辖玻馐且桓瞿芎芎媚褪艿囊┪铩Ａ俅惨缴枰私馄淇赡艿亩拘裕源蟛糠只颊叨裕⒉皇切枰俅补刈⒌奈侍狻?

　　Oncology Frontier  : In China， T-DM 1 is not available yet. Professor Shao， how do you consider its future clinical use prospect in China?

　　《肿瘤瞭望》：在中国，T-DM1还没有上市，邵教授，您如何看待它未来在中国的临床应用？

　　Professor Shao : That is a very hard question I have to answer. Right now the T-DM 1 trial， I think it is the registered trial， and it will start in the early next year but still it will require some time to submit data to the CFDA to get some time to approve it. I think it is for the trial right now， the HER 2 positive way. We have joined a lot of the international clinical trials， for example the APHINITY trial that you have mentioned and the ALTTO trial where we have contributed quite a lot of numbers， particularly in our site. From the data it looks like it is pretty promising so for me it is really hard to answer this question for the future. We just have to prove while doing our work to try to prove how to get the fastest improvement in the new drugs and bring them to China， for our HER 2 positive breast cancer patients.

　　邵教授：这个问题回答起来很难。T-DM1的注册试验将在明年年初开始，到向CFDA提交数据并批准还需要一定时间。在HER-2乳腺癌方面，我们参加了很多国际临床试验，例如刚刚提到的APHINITY试验和ALTTO试验，后者我们提供了大量病例，特别是我所在的中心。从数据上看，T-DM1的前景非常好。目前我很难回答将来会怎样，我们必须通过自己的工作来证实，将新药的最新发展引入到中国，用于我们的HER-2阳性乳腺癌患者。

　　Oncology Frontier  : Now let us move to the next topic. Real world research and evidence from clinical trials can complement each other and both are non-replaceable. Please give us a general description of the function and significance of real world data.

　　《肿瘤瞭望》：最后我们转换一下话题。真实世界研究和临床试验证据互为补充，二者都是不可替代的。请几位教授向我们讲解一下真实世界数据的作用和意义？

　　Dr. Winer: I think when you are talking about real world data you are talking about what is often called Big Data as well. This is looking at large databases that include patients who have been treated with different regimens so we are not talking about randomized clinical trials， we are not talking about non randomized clinical trials， we are talking about essentially experiencing clinical practice. It is a form of data that is just beginning to be explored. Something that is related but where we have less in the way of treatment detail are databases such as the SEER Medicare database in the United States where we have information generally speaking about treatment and about outcomes but where there is much less detail than you would ever really imagine in a clinical trial. Some of these new efforts include efforts from ASCO to develop something called Cancer Link. There are health insurance databases and there are other efforts to do this as well. I think that you have to keep in mind that this is not a substitute for clinical trials. There are biases that are introduced when you evaluate treatments in this kind of setting that you simply can not correct for. That said， with enough data you can begin to at least generate hypothesis that might then lead to smaller and more efficient clinical trials.

　　Winer教授：我想当我们在谈到真实数据时，我们也是在谈论大数据。它涉及了大型数据库，纳入了采用不同方案治疗的患者，因此我们讨论的不是随机临床试验，也不是非随机临床试验，我们实际上是在讨论经验性临床实践。对这类型数据的探索和开发才刚刚开始。有一些相关的数据库，但在治疗方面的细节不多，例如美国的SEER医疗数据库，那里有我们通常所说的治疗和结局相关的信息，但细节要比在临床试验中所想像的少得多。在这类新的工作中，ASCO也作出了努力，开发了Cancer Link。还有健康保险数据库和其他形式。我认为我们需要牢记的是，它不是临床试验的替代品。我们在解释这种情况下的治疗方案时，会引入偏倚，而且很难纠正。也就是说，在拥有足够数据的情况下，我们至少可以生成假设，并由此衍生出更小的但是更有效的临床试验。

　　Professor Shao: Just as Dr. Winer just mentioned， our future is where we try to do what we call precise medicine. Maybe that is the future that we hope but still as right now， we try to generate this program in looking for some links for the future to practice. Right now it is not practical.

　　邵教授：就像Winer教授说到的，我们的未来是尝试进行精准医疗的未来，或许会实现，但当前我们还只是在尝试建立相关项目，以寻找到将未来变成现实的方法。但现在还不现实。

　　Oncology Frontier : Currently， what kinds of challenges are we facing in the real world data related research?

　　《肿瘤瞭望》：开展真实世界数据相关研究目前存在哪些挑战？

　　Dr. Winer  : I think the latest challenge in this real world data research is the fact that one cannot control for all the potential biases that go into decision making about different treatments. I think where these data are most useful are in evaluating potentially late outcomes and looking at what percentage of patients have HER 2 positive breast cancer who are treated with trastuzumab and 10 years later have heart failure. Looking at the frequency of brain metastases in women with HER 2 positive metastatic breast cancer and there in fact if you capture everybody with HER 2 positive metastatic breast cancer you end up having a denominator and a numerator and you can have a fairly precise estimate. I think that with time we will be better at looking at some of these comparisons of one regimen versus another in the real world data but as I mentioned earlier there is still a large place for clinical trials and this is not a way to avoid doing clinical trials.

　　Winer教授：我想在真实世界数据研究方面最近的挑战是：在我们对不同治疗方案做出决策时，我们无法控制所有的潜在偏倚。我想这些数据最有用的是在评估可能的长期结局方面，例如看看接受了曲妥珠单抗治疗的HER-2阳性乳腺癌患者在10年后有多大比例发生了心衰；看看HER-2阳性转移性乳腺癌中脑转移的发生率如何——事实上，如果我们能捕捉到每一例HER-2阳性的转移性乳腺癌，最终我们就有了分子和分母，可以得到一个非常精确的估计。我想慢慢的，我们能在真实世界数据中更好地比较比较两种方案，但就像我前面说到的，临床试验还有很大空间，而真实世界数据并不是可以避免进行临床试验的办法。

　　Dr. Shao : Just as I said， it is still the future but right now we are doing some basic work. For example right now in our centers we are trying to do over 1000 cases for the different sub-types. We are trying to generate the sequencing for looking for the mutations， we are also looking for the proteomics for the different protein expressions. All these 1000 cases have different treatments also these cases have some survival which are very good， some are relapsed， so we have to generate these data just as Dr. Winer said we have to find the links. What we are trying to find is the analysis to look for links and which treatment is better or which is worse， and which markers are predictive， so that is what we are trying to do right now but still it is a basic work right now. It is maybe 4 or 5 years away. I am not sure but it gives some hope.

　　邵教授：我前面说到，这是未来，现在我们还在做一些基础工作。例如，当前在我们中心，我们在涵盖1000多例乳腺癌各种亚型患者中进行了研究，对其进行测序以寻找突变，并且进行蛋白组学研究以寻找不同的蛋白质表达。所有这1000例病例的治疗方案不同，他们的结局有的很好，但有的复发。我们得出了这些数据，然后就像Winer博士所说的那样，试图找到联系。我们希望能找到联系，了解不同治疗方案的优劣，了解哪些标志物有预测价值。但现在只是基础，可能还需要等待4~5年。我不敢确定，但我抱有希望。

　　Dr. Krop: I think there certainly is a role for real world data and big data in complementing what we have learned from clinical trials. I think it is important the populations that go on clinical trials are clearly different than in the real world unselected patients. It really is important to look at how drugs are used in the real world and what the outcomes are. As Dr. Winer also said， there are a number of confounders and potential biases in real world or big data. The quality of the data often is not as good as we would like. Right now that is a problem and a limitation in how we use real world data. I think as Dr. Shao said， their group is working very hard at getting very high quality data with molecular pathology data as well and that will be very helpful. I think as institutions across the world will move more towards electronic medical records and more sophisticated medical records， we will be able to get better data and as the analyses programs become more sophisticated we will be able to improve the quality of our real world data and again I think that can be nothing but beneficial in moving forward.

　　Krop教授：真实世界数据和大数据作为对临床试验的补充无疑是有价值的。参加临床试验的患者人群显然有别于真实世界中未经选择的患者，这一点很重要。了解在真实世界中药物是如何应用的，以及结局如何，非常重要。Winer也说道，真实世界数据或大数据中有很多干扰和潜在偏倚。数据的质量不如期望的那样。这是目前我们使用真实世界数据所存在的问题和限制。就像邵博士所言，他们的小组正在非常努力的工作，尝试获得高质量的分子病理方面的数据，这将非常有帮助。我想全球的研究所都会像电子医疗记录和更精细的医疗记录发展，我们将能够获得更好的数据?Ｍ保治龀绦蛞不岜涞酶痈呒叮颐蔷湍芴岣哒媸凳澜缡莸闹柿俊?前进只会带来获益。