ASCO乳腺癌热点之我见

　　Geyer教授：ASCO是一个非常令人期待的会议。我们团队，美国乳腺与肠道外科辅助治疗研究组（NSABP)）与美国肿瘤学研究组联合开展的一个重要研究系列在大会上报告，对此我们都非常高兴。我们尝试通过这些研究来真正了解蒽环类药物对于HER-2阴性乳腺癌的作用。事实上由于经费问题，我们做了3项研究来完成这一课题，希望能够摆脱蒽环类化疗药物。因为这种药物有心脏毒性以及白血病的风险，而有证据显示，在早期研究中观察到的该类药物的疗效可能主要见于HER-2阳性患者，而现在有了HER-2靶向疗法，因此问题就来了，HER-2阴性患者是否仍然需要蒽环类药物。根据我们的研究结果，结论是肯定的，用蒽环类药物治疗HER-2阴性患者有明显的疗效，尤其是那些有高风险的患者。

　　在HER-2阳性乳腺癌领域，ASCO上也有非常重要的研究公布。一个来自西班牙的研究组研究了帕妥珠单抗在二线治疗中的应用，该研究结果为阴性（统计学分析显示为阴性），我觉得这巩固了CLEOPATRA试验的发现，指出了HER-2双靶向治疗的重要性。我们还发现，当我们尝试对新辅助治疗方案降级，特别在应用T-DM1以及帕妥珠单抗时，与标准TCHP疗法相比，相关的支持数据不多。因此我认为我们需要研究如何在维持药效的同时降低毒性，将会面临一些挑战。

　　邵志敏教授：ASCO会议真正给了我们许多新的信息，特别是在乳腺癌的辅助治疗、新辅助治疗和转移方面。ASCO会议还给我们提供了关于外科手术治疗的信息，与过去相比有细微的变化。虽然在乳腺癌领域有著名的圣安东尼奥乳腺癌大会，但ASCO会议上也公布了非常多的信息。我们也投递了一些摘要，其中一项卡培他滨在三阴性乳腺癌中的应用，入选了Poster Discussion（壁报讨论）。我和芬兰的Henrik Lindman博士讨论过，他是FinXX研究的主要研究者。该研究的10年生存随访数据在会议上公布。其中，三阴性乳腺癌患者可以从加用卡培他滨的治疗中获益。我们报告的研究称作Cbcsg-10研究，探索三阴性乳腺癌患者能否从加用卡培他滨治疗中获益。目前随访时间较短（约30个月），但也看到在无癌生存率方面的改善是有统计学意义的。目前还未达到中位生存期，我们还需要等1年半的时间，在2018年我们会对数据进行更新。同时如Geyer教授所言，在HER-2阳性乳腺癌方面也有大量新数据在本届ASCO会议上报告。

　　KRISTINE/TRIO-021研究及NSABP B-41研究意义解读

　　Geyer教授：KRISTINE研究是一个降低化疗毒性的尝试。KRISTINE研究的对照组应用了标准的治疗方案——TCH+P方案（卡铂、多西他赛、曲妥珠单抗和帕妥珠单抗），这个方案来自TRIO研究，我们现在知道这是一个非常有效的方案。德国的研究组在一项随机II期研究（TRYPHAENA试验）中对其安全性进行了研究，该研究同时显示TCH+P方案可获得很高的病理完全缓解率（pCR），达到60%。这个方案在美国确实已经成为了最常应用的辅助治疗方案。

　　因此KRISTINE研究基本上是想看是否能将两个化疗药物及曲妥珠单抗换成T-DM1，因为T-DM1在转移性乳腺癌中有着非常高的活性，并且有很好的安全性。研究者寄希望于能继续保持T-DM1的疗效，甚至通过联合应用帕妥珠单抗来增强其疗效。研究显示T-DM1联合帕妥珠单抗确实非常有效，44%的患者达到pCR，但是不如TCH+P方案（56%）。不得不说，这个研究的结果是阴性的，TCH+P方案不能被替代。但不难想像，在患者不能很好地耐受TCH+P方案、或年龄较大、或有其他基础疾病时，应用TDM-1联合帕妥珠单抗也是合适的，它可以作为一个有效的替代方案。

　　的确在尝试降低化疗药物毒性方面仍存在挑战，但对此我抱有希望。因为对于HER-2阳性乳腺癌来说，双重靶向HER-2治疗会是主要且有效的治疗方案，我们应该可以找到办法来保证在撤除一定化疗药的同时维持疗效。我个人认为，HER-2阳性患者是一个非常有趣的群体，我开始考虑应用免疫检查点抑制剂的研究。因为很显然，双重靶向HER-2治疗的获益很大一部分来自组分及ADCC的激活，很有可能免疫检查点抑制剂能进一步放大这一效应，如果真是这样的话，我们真的可以降低化疗毒性，治愈大多数患者且无需承担TCH+P方案的副作用风险。因此我认为KRISTINE研究虽然是一个结果阴性的研究，但同样也是一个信息量非常大的研究。

　　NSABP B-41研究基本上想解决几个问题。其中一个问题在提出时，我们仍在考虑应用AC序贯每周紫杉醇联合曲妥珠单抗作为标准方案，当时这个问题是能否将曲妥珠单抗替换为拉帕替尼，来获得相同的或者更好的效果，或者能否在曲妥珠单抗基础上联合应用拉帕替尼，通过小分子药物与曲妥珠单抗的双重靶向HER-2治疗来提高pCR。我们之前对pCR已经做过报道。应用曲妥珠单抗的对照组效果确实要比预料中的好，比结果预期好10%。有趣的是，拉帕替尼也获得了与曲妥珠单抗同样的pCR，当将两个药联合使用时，pCR会更高一些，但差异没有统计学意义。

　　我们在ASCO会议上报道的是该研究的长期随访数据。当然，这个研究不够大，其长期效果的说服力不够，算是一个描述性的、类似于探索性的分析。但即便差异没有统计学意义，并且联合使用的效果并不比曲妥珠单抗好很多，但明显是联合使用的效果更好。我发现有趣的是拉帕替尼虽然与曲妥珠单抗的pCR相同，长期随访效果也相同。我们如何去解释这个结果呢。因为在这项临床试验中，手术后所有患者都应用曲妥珠单抗，这就像所有在HER-2试验里的患者在手术后应用曲妥珠单抗一样。但即便pCR相当，拉帕替尼替代曲妥珠单抗似乎会对患者的长期效果有一定的影响。我认为，我可以想到的唯一解释是，应用抗体和ADCC稳定成分并联合化疗或许对免疫系统起到一定的重要作用。这是我对数据的个人理解，统计学分析结果很明确，组间并没有显著差异。

　　邵志敏教授：我只想补充一下，我想目前在HER-2阳性的乳腺癌中，曲妥珠单抗是一个主要的药物。对于HER-2阳性乳腺癌患者来说，这个药非常有效。不管在原发初始治疗中还是一线治疗中，其他药物同曲妥珠单抗是不可比的。但是在临床治疗中，双重靶向HER-2仍然有效。比方说，当曲妥珠单抗治疗失败时，使用拉帕替尼仍是有效的。我们不能根据临床试验的结果就完全排除临床实践的应用。

　　新辅助治疗中pCR的意义再探

　　Geyer教授：在临床上，新辅助治疗对于帮助增加患者的手术治疗选择是非常重要的。患者因肿瘤太大而不能立即进行手术时，新辅助治疗可以将之降期，从而能够手术；还有需要接受乳房切除术的患者，通过新辅助治疗可以进行保乳手术；新辅助治疗还可以给患者更多的时间来考虑若切除了乳房，能否接受乳房重建……因此抛开能否达到pCR不谈，新辅助治疗就能带来很多获益。当然，当患者接受治疗后，乳房及淋巴结的肿瘤消失，达到病理学完全缓解，我们知道这些患者的反应很好，对此大家是乐见其成的。越来越明显的是，HER-2靶向治疗在帮助ER阴性、HER-2阳性乳腺癌患者获得pCR中非常重要，会带来截然不同的结局。

　　就像B-41试验数据显示的那样，pCR非常重要，不能达到pCR预示了高复发风险。我们对一些很有前景的新药，如T-DM1进行了研究。我们与德国乳腺组织以及其他组织合作开展了全球试验，针对接受了曲妥珠单抗单药或双靶向HER-2治疗、仍有残余病灶的HER-2阳性患者，对其随机分组，观察T-DM1治疗是否能改善这些高危患者的预后。有趣的是三阳性患者，即ER阳性、PR阳性、HER-2阳性的患者的pCR略高，但增加得并不多。因此我认为，即便在HER-2阳性的患者群体中，ER阴性患者与ER阳性患者也会有一些区别。我们在尝试继续改善治疗的时候，需要对这些不同的亚型采取不同的治疗方法。

　　邵志敏教授：pCR是新辅助治疗的一个非常重要的指标，NSABP-B18、NSABP-B27等研究都清晰地证实了这一点。当患者达到pCR时，可以获得更长的生存期。但就像刚才Geyer博士所说，在不同亚型中，pCR有着不同的价值。毫无疑问，在HER-2阳性乳腺癌患者中，达到pCR预示着生存预后很好，但在Luminal型乳腺癌中情况却不同。在临床试验中，我们不会用pCR来作为Luminal型乳腺癌的研究终点，因为它不能很好地预测总体生存率。因此要根据乳腺癌的不同亚型来具体情况具体分析。我想在未来的五到十年里，就像刚才Geyer博士所说，HER-2阳性患者中的三阳患者可能就会成为新的亚型，在三阴性乳腺癌或者Luminal型乳腺癌中可能也会有更细微的分型。所以我们要分情况去理解。在某些亚型中，pCR可以预测生存，而在另外一些亚型中，pCR是不能预测生存的。

访谈原文

　　Oncology Frontier: ASCO meeting always bring the most updated information about tumor therapy every year， which progress of breast cancer research are you interest in this year? Which progress can play a role to improve the current clinical diagnosis and treatment?

　　Prof. Geyer: ASCO is a very much anticipated meeting， and I know that for our group， the NSABP， we were very pleased that an important series of studies that we’ve been doing with the US Oncology Research group trying to really understand the role of anthracyclines and HER-2 negative patients was reported. We actually did a series of three studies that we had to do that way， because we had some challenges in funding so it’s always a challenge to have these important questions looked at. We had worked together on these three studies to see if we could get rid of the anthracyclin chemotherapy drugs， because we know that there are risks for cardiotoxicity， there were risks for leukemia， and there was evidence that it might be that the benefits that we saw in the early studies， happened in the HER-2 positive patients， and now that we had HER-2 directive therapies， the question was， well， do we still need the anthracyclines， in the HER-2 negatives， and the bottom line was that we looked at our results and the answer is yes， there are clearly benefits for anthracyclines in HER-2 negative patients， particularly those that have higher risk. So， we were pleased we had that bit of data.

　　I think that the HER-2 session had also a very important studies. There was a study from the Spanish group looking at the Pertuzumab， in a second-line setting， that while the study was negative (it could be considered negative based on the statistics)， it really reinforced， I think， what we saw in the Cleopatra trial， and it pointed to the importance of the dual HER-2 targeted in therapy. We also saw that when you attempt to deescalate neoadjuvant therapy， comparing the standard TCHP regiment with TDM1 in particular， and the Pertuzumab， we lost some advocacy there， so I think we are going to face some challenges in looking at that data on how we can maintain activity， while deescalating the toxicity.

　　Prof. Shao: As for me， the ASCO meetings really gave us a lot of new information， especially for the breast cancer， on the adjuvants， and the neoadjuvants， or metastasis. For the ASCOs gave us also even information about surgical treatment， which right now has a little change from the previous one. For breast cancer， we had San Antonio， but also we have very much information published which is presented in the ASCO meetings. I wrote abstracts and presented a post in post discussion session about the Xyloda (capecitabine) on triple-negative disesase. I talked to Dr. Henrik Lindman in Finland. He is the PI of FinXX trial. He published now for the 10 year survival follow-up， and it found for the subgroup of triple negative breast cancer， that additional capecitabine is beneficial， so we just presented Cbcsg-10 trial， which is especially in the subtype for the triple negative group we are looking for the additional capecitabine， which play a role or not. During the limit time of follow-up， only about 30 months， specific disease free survival is of p-value. Still， it is not an median survival， so we had to wait for another one and half  year， on 2018， so we’ll probably will give an update in the information， so that’s what we saw. But as Doctor Geyer said we also have a large new information for the HER-2 positive breast cancers.

　　Oncology Frontier: In this ASCO， there presented the results of KRISTINE/TRIO-021 which is the dual targeted neoadjuvant treatment in early breast cancer and another 5 years survival results of B-41 NSABP study. How do you interpret the results of the two studies? Is there any implication for clinical treatment?

　　Prof. Geyer: KRISTINE was a study that I looked at as an attempt to deescalate the toxicity of the chemotherapy. The controller in KRISTINE was the standard regiment developed by TRIO using carboplatin， taxotere， trastuzumab and pertuzumab， or TCHP， which we know now that it is a very active – The German group in the   TRYPHAENA study had done a randomized phase 2 trial to look at safety， but we know that they did show a very high PCR rate with a TCHP of 60%， and that actually in the United States has become really the most commonly neoadjuvant regiment.

　　And so KRISTINE basically wanted to see if you could replace the 2 chemotherapy drugs， and the trastuzumab with TDM-1， given the impressive activity in TDM-1 in metastatic disease it is a very favorable safety profile. There was a hope that we might be able to maintain the activity， maybe even make it higher using the TDM-1， with the Pertuzumab. And the study showed that indeed the TDM-1 and Pertuzumab was quite active， 44% of the patients had a pathology complete response， but that was not as high as what was seen with the TCHP regiment， which was 56%. So you have to build the study as negative， TCHP has not been replaced yet， but certainly you can imagine that if you have a patient that might not tolerate TCHP well， an older patient， a patient with other illnesses and things， but where you thought that therapy was appropriate， and certainly it’s an active alternative.

　　But I do think that we are going to have challenges deescalating the toxicity of the chemotherapy. I am still hopeful that we can， because it is clear that in HER-2 positive breast cancer the main therapy and efficacy， I think， is dual HER-2 targeting， and we ought to be able to figure out how to maintain that with a back-off of the chemotherapy we used. I find that the HER-2 positive patients population to be a very interesting group to start thinking about check points inhibitors studies， because it is evident that a major part of what we see in the benefits from dual HER-2 targeted therapy is probably due to the immune component and the ADCC activation， and so it is quite possible that the check points inhibitors might augment that further， and if that is the case， we could really then deescalate the chemotherapy toxicity and cure most women without the current side effects of TCHP. So I think KRISTINE was a negative study， but an informative one.

　　B-41 was a study that we did through the NSABP， that basically asked several questions， one - and at that time we were still considering sequential AC followed by weekly packed taxol with the trastuzumab as a standard， so we wanted to ask at that point， could we substitute the lapatinib for trastuzumab and get equivalent or better activity， and could we add the pattern to trastuzumab and increase pCR rate to go to dual HER-2 targeting with small molecules with the trastuzumab， and we had reported previously that when we looked at PCR rate， the thing that surprises was that patients in the control with the trastuzumab， surprisingly did better with the trastuzumab than our projections on how that group would do –and they did about 10% better than what we thought. The interesting thing was that our lapatinib did achieve the same PCR rate as with trastuzumab， but when you combine them， it was a bit higher， although not statistically significant， because the difference was not great enough， and so what we reported at ASCO was the long term follow up data， and it’s interesting there， we saw there that the， and again the study was not large enough， it wasn’t powered for these long term outcomes， so it is really a descriptive， kind of exploratory analysis that we were reporting， but when you look at the data， even though there are no statistically significant differences， it was evident that the best outcomes appeared to be with a combination， and although it wasn’t a lot better than what the trastuzumab did by itself， and lapatinib， even though the PCR rate was the same， the long term outcomes was the same， what I find very interesting， and how would you explain that， because in our trial， after surgery， everyone got trastuzumab， so all these patients received trastuzumab as was this was done in the HER-2 trial after surgery， and yet the substitution of lapatinib to the trastuzumab seemed to have an impact on long term outcomes even though the pCR rate were identical. Yet， I think， the only explanation I can come up with， suggests that having that antibody with the ADCC fixing component around， in combination with the chemotherapy may be doing something important for the immune system.

　　These are the personal observations about the data. I guess I have made clear statistically， we have to say that there were no statistically significant different between arms.

　　Prof. Shao I just want to add a comment. I think right now in HER-2 positive breast cancer， trastuzumab is  a major agent. It’s the drug for the HER-2 positive breast cancer， because it is most effective right now. If you are trying to compare the other one， in the primary setting or first line use， is never comparable with trastuzumab. But even the results in these two trials are negative， still in the clinical practice， dual therapy has effect. For example， if trastuzumab fails， you can still use lapatinib. You just cannot use the result of clinical trial to rule out all the clinical practice use.

　　Oncology Frontier:. With these new data of neoadjuvant targeted therapy research， some old questions come up again: Should improving of pCR be the main purpose of neoadjuvant therapy of early breast cancer? What kind of dual targeted therapy can improve pCR? Which populations of patients in which improved pCR were more likely to have benefits in long-term survival?

　　Prof. Geyer: Clearly， clinically， neoadjuvant therapy is important in helping improve operative options for patients. Patients who have cancers that are too big to have operation initially， can have it converted to operable cancers. Women might have mastectomy may have breast conservations. So there is a lot of benefit to neoadjuvant therapy， outside whether or not it achieves pCR， I think it also allows women to have a lot of time to think about if they are going to have mastectomy， whether their options are reconstructions， so there are a lot of value to neodjuvant therapy. They are outside the pCR. Clearly， when the patients’ cancers in the breast or in the lymphnodes disappear on the therapy， they have complete remission， we know those patients do quite well，so we were all very happy for those patients. It is becoming more and more evident that HER-2 positive therapy in ER negative HER-2 positive patients achieving pCR is very important and can make quite difference in outcome. So we showed that in B-41 data as well as another element in B-41 data show pCR is very very important. Because the failure to achieve pCR really predicts the high risk of recurrence， we have looked at positively introducing new therapy， such as T-DM1. We collaborate with German Breast Group and another center in global trial where patients with HER-2 positive cancers receive HER-2 targeted therapy， and it could be trastuzumab alone， could be dual HER-2 targeted therapy， yet they have residual disease， we did randomized study seeing TDM-1 might improve the outcome in those higher risk women. The interesting thing is the triple positive， ER positive， HER-2 positive patients， pCR proved a little bit better， not a whole lot better. So in that sort of is， I think， even in the case of HER-2 positive breast cancer， the ER negative and ER positive patients are probably a little bit different. As we try to continue to improve out therapy， we have looked at the difference approaches for those subsets as well.

　　Prof. Shao: pCR is a very important factor for neoadjuvant therapy as shown by NSABP-B18， B27. If you reach the pCR， you get prolonged survival. Still in the subtype， as Doctor Geyer said， in different subtype， it has different value. Definitely， in the HER-2 positive breast cancer， you got pCR， the survival is definitely good. But it’s not the case in the luminal type. The luminal type may not use the pCR as your endpoint for the clinical trial， because it’s not very well courage for the overall survival. So it really depends. The breast cancer is divided in different subgroup. I think in the futures， maybe five of ten years， even in the HER-2 positive just as you said， triple positive may have some difference subtype， even in the triple negative or luminal type. So it really depends on to understand. The pCR may predict overall survival in some subtypes， in other subtypes， it may not.