编者按：随着抗HER2抗体偶联药物（ADC）及精准治疗的不断发展，乳腺癌正步入一个全新的治疗时代。在2024年CSCO年会上，复旦大学附属肿瘤医院张剑教授与德国慕尼黑大学乳腺中心主任Nadia Harbeck教授就乳腺癌治疗领域的最新进展进行了深入交流。两位教授不仅分享了ADC药物在HR+晚期乳腺癌患者治疗中的显著疗效及安全性管理策略，还深入探讨了基因检测在指导患者个体化治疗中的重要作用。本次对话不仅揭示了全球乳腺癌治疗的前沿动态，更为未来的临床实践提供了宝贵的参考和启示，引领乳腺癌治疗迈向更加精准、个体化的新高度。

 

张剑教授：很荣幸能邀请到Nadia Harbeck教授参加此次访谈。首先为大家介绍一下Nadia Harbeck教授，她是德国慕尼黑大学乳腺中心主任，肿瘤治疗和临床试验部门负责人、妇产科肿瘤保守治疗学主任以及遗传性乳腺癌和卵巢癌中心主任。此外，她还是慕尼黑综合癌症中心指导委员会成员。Nadia Harbeck教授经验丰富，尤其是在乳腺癌治疗领域享有盛誉。我们有一些问题想请教您，2024年ESMO大会刚刚落幕，在HR+晚期乳腺癌患者治疗中，有哪些ADC的新发现或重要研究结果引起了您的注意？

 

It’s my honor to invite Professor Nadia for this interview.First，let me introduce her，although everyone knows Professor Nadia.Professor Nadia Harbeck is director of the Breast Center and holds the chair for Conservative Oncology at the Dept.of OB&GYN，LMU University Hospital，Munich，Germany.She also heads the Oncological Therapy&Clinical Trials Unit，Dept.OB&GYN and the Center for Hereditary Breast and Ovarian Cancer at LMU University Hospital，Munich.She is a Steering Committee Member of the Munich Comprehensive Cancer Center(CCCMunich LMU).I know that our professor has a lot of experience and is very well-known worldwide，particularly in breast cancer.We have some questions to ask.The 2024 ESMO Congress has just come to a close.What new findings or important research results of ADCs in the treatment of patients with HR+advanced breast cancer have caught your attention?

 

Nadia Harbeck教授：刚刚于两周前在西班牙巴塞罗那结束的ESMO大会上，我们看到了DESTINY Breast-06（DB-06）研究的更多更新结果。数据显示，尽管不同实验室之间的检测结果并不完美，但具有相当好的一致性。因此，建议对于肿瘤检测结果为HER2 0的患者，务必进行重新检测，因为可能存在微弱的表达差异，特别是HER2超低水平表达，即肿瘤细胞HER2低表达状态的检测染色率≤10%。在约60%的HER2（0）病例中，DESTINY Breast-06研究的中央实验室实际上又发现了HER2低表达。此外，我们还观察到一些值得关注的患者报告结果，这些结果表明在T-DXd组中，患者生活质量得以维持。因此，我认为在早期HR阳性/HER2低表达乳腺癌的治疗中使用该药物是安全的。

 

 

At the ESMO Congress，which just two weeks ago finished in Barcelona in Spain，we saw more updates on the DESTINY Breast-06 study.We saw data that there is quite good concordance，although not perfect，between different laboratories for the testing.So the recommendation is，if the patient has a HER2(0)finding in her tumor，that we always retest，because there may be a faint staining，either ultra-low，which is 10%or less tumor cell stains for HER2-low status.So in about 60%of the HER2(0)cases from local pathology，the central lab in the DESTINY Breast-06 study found actually HER2-low staining.And the other thing is that we saw some very interesting patient-reported outcomes showing that the quality of life is maintained in the T-DXd arm.So I think there is no worries now that we use this drug in earlier settings in HER2-low hormone receptor-positive early breast cancer.

 

张剑教授：是的，正如Nadia教授所说，DB-06研究非常重要。相关数据表明，该研究中患者生活质量（QOL）并没有恶化。2024年ESMO大会上，DB-06研究的两项数据分别以LBA的形式公布，其中胡夕春教授报道了DB-06研究中PRO的数据，您认为PRO数据的公布对于接受治疗的患者来说有何重要意义？

 

Yes.As Professor Nadia has said，DB-06 is very important.Studies have shown that the QOL is also not deteriorating in this study.At the 2024 ESMO Conference，the two data of the DB-06 study were announced respectively in the form of LBA，among which Professor Hu Xichun reported the PRO data of the DB-06 study.Do you think the publication of PRO data has any significance for patients receiving treatment?

 

Nadia Harbeck教授：确实如此，PRO数据对于患者很重要。特别是在使用新药治疗时，我们也会看到一些副作用，例如T-DXd可能引发血液系统方面的不良反应。如果医疗中心没有采取适当的预防措施，患者还可能出现胃肠道毒性。因此，询问患者的感受至关重要。从DESTINY系列研究的整体生活质量数据来看，T-DXd治疗的患者生活质量较为稳定。虽然患者会出现恶心和呕吐，但在临床实践中，我们会使用三联止吐方案，这是类似于化疗的方案，而有些中心可能会使用两种药物联合的止吐方案。随着时间的推移，对于没有出现不良反应的患者，我们可以考虑减量，从这个角度来看PRO对于患者来说是很重要的。此外，根据DESTINY Breast-04研究的数据，我们看出患者的疼痛实际上是有所缓解的，DB-06研究中也观察到了这一点。因此，ADC药物在减轻症状方面效果更好，这让我们可以很放心的使用该药物。

 

Yes，definitely.I think，in particular，with new drugs where we also see some side effects，like for trastuzumab deruxtecan，there is some hematological side effects.There is some GI toxicity if the centers didn’t take the proper precaution for the anti-emesis drugs.It’s always important to ask the patients，see how they feel about it.And what we know from the quality of life data from the DESTINY program overall is that the quality of life is maintained.Patients do complain about the nausea and emesis.So I think that is something that we really have to take care of in our clinical setting.We give a three-drug anti-emetic regimen，just like we do with chemotherapy.Other centers use two drugs.Maybe over time，we can de-escalate in patients who don’t have any problem.So I think the PRO data are very important.We also know from the DESTINY Breast-04 study that the pain actually is reduced.And that has been seen also in the DB-06.So I think the better drug，which is the ADC，is more effective in reducing symptoms.And I think that is very reassuring.

张剑教授：实际上我们在控制某些胃肠道毒性方面仍然面临一些挑战，即便是我们已经使用了三到四种抗呕吐药物。在您的临床实践中，您通常是如何治疗这些患者的？您会选择降低T-DXd的剂量，还是通过延长给药周期来控制这些副作用呢？

 

Yes.Actually，we still have some trouble with how to control some GI toxicities.So what’s your clinical practice to control some patients?Even we use some three or four anti-emetic drugs.So do you lower dose of the T-DXd or just expand the duration of this drug to control this?

 

Nadia Harbeck教授：我们一般是按照药品说明书的建议来处理。通常会先给患者使用三联抗呕吐方案，对于那些长期治疗耐受良好的患者，可能会尝试减少药物剂量，当然这需要与患者保持密切沟通。如果患者确实出现问题，那就可以考虑减量。我们对其他药物也是这样处理的。不过，这确实很难一概而论，因为在一些注册试验中，我们也遇到过没有使用任何抗呕吐药物的患者，他们的情况却非常稳定。因此，我认为这主要取决于患者的个体耐受情况，只有在尝试用药后，才能真正了解他们的治疗反应。

 

I mean，we do what’s in the package insert.We start with the three-drug regimen in patients who are fine over a longer period of time.One may try to reduce that，always talking back to the patient.If patients really have problems，then a dose reduction，I think，is the appropriate way to move forward.That’s what we do with all the other drugs.But I think that it’s hard to tell because we also treated some patients in the registration trials.They didn’t have any anti-emetic treatment.And they did absolutely fine.So I think it’s how patients individually tolerate.And there is just no telling unless we try the drug and see how patients react to it.

 

张剑教授：是的，在接受治疗之前，我们确实可以进行评估和判断。实际上，如果早期发现问题，我们可能一开始就会考虑降低剂量，我完全同意这一点。下一个问题是，当前对于一线CDK4/6抑制剂经治后出现进展的HR+晚期乳腺癌患者，您会选择跨线使用CDK4/6抑制剂治疗、ADC药物治疗还是其他靶向治疗（如PAM通路抑制剂）？

 

Yes，we can tell or we can distinguish before we receive this treatment.Actually，if we found that，we could lower dose at first，I think.Yes，I totally agree with that.And we still have the third question is，Would you currently choose to cross over to a CDK4/6 inhibitor，an ADC drug，or another targeted therapy（just lik PAM inhibitor）for patients with HR+advanced breast cancer who have progressed after first-line CDK4/6 inhibitor therapy?

 

Nadia Harbeck教授：在德国，我们可以使用在这种情况下可及的所有靶向药物。在为患者进行一线治疗时，我们通常会检测PIK3CA基因、ESR1突变、BRCA状态，最近我们还会检测AKT突变情况。当患者出现疾病进展时，这些信息可以帮助我们选择其他靶向治疗。不过，现有数据表明，如果患者在CDK4/6抑制剂治疗6个月内出现进展，采取其他基于内分泌的治疗意义不大。在这种情况下，我们可以尝试使用PIK3CA抑制剂或AKT抑制剂，以排除内分泌耐药导致的快速进展。除此之外，我更倾向于选择化疗。目前，ADC药物尚未用于一线治疗。我希望基于DB-06研究的结果，T-DXd能获批。否则，我们会先使用化疗作为一线治疗，ADC药物作为二线治疗的选择。

 

In Germany，we have access to all the targeted agents that are available in this setting.So what we do when we put patients on the first-line treatment is we do measure PIK3CA.We measure ESR1 mutation.We measure germline BRCA status and，quite recently，also AKT alterations.And then when the patient progresses，we have all of this available and could choose another targeted therapy.But I think the data is very strong that if the patient responds less than six months on the CDK4/6 inhibitor，it really doesn’t make sense to go for another endocrine-based step.You could try a PIK3CA inhibitor or an AKT inhibitor in that setting，just to make sure it’s not the endocrine resistance that’s causing the rapid progression.But other than that，I would go to chemotherapy.Right now，we don’t have an ADC for the first-line setting.But I hope，based on the DESTINY Breast-06study，that we’ll have email approval rather soon for T-DXd.Otherwise，we just go for first-line chemotherapy and then would choose the ADC for the second-line treatment.

张剑教授：在德国，所有基因检测费用都能用保险报销吗？

 

Does all the genetic testing are covered by insurance in Germany?

 

Nadia Harbeck教授：在德国，如果基因检测用于指导治疗决策，例如肿瘤生物学相关的检测，通常是在保险覆盖范围内。如果是针对遗传性乳腺癌的生殖系检测，也同样可以报销。因此，我们很幸运，能够获取所有必要的信息，并且相关药物的费用也可以报销，不过像阿培利司（alpelisib）这样的药物在德国尚未上市，我们需要单独申请这些药物。

 

Yes，if it’s needed for therapy decision-making，like the tumor biology，it’s covered.If it’s the germline testing for hereditary breast cancer，it’s also covered.So we’re in a quite fortunate situation that we can get all the information and then also have the drugs reimbursed although alpelisib for example is not marketed in Germany.We have to apply for it and on an individual basis.

 

张剑教授：实际上，这些指征表明我们应该使用组织样本。那你们会进行血液样本检测吗？如果我们在血液样本中发现了PI3CA突变，这可能并不意味着可以使用PI3K抑制剂。这种检测在德国也能得到保险覆盖吗？

 

Okay，actually the indications are that we should use the tissue samples.So do you use blood sample testing?When we found a PI3CA mutation in blood sample testing，it may not be an indication for using the PI3K inhibitors.Is this testing also covered by insurance in Germany?

 

Nadia Harbeck教授：我认为这取决于你想要寻找什么。ESR1突变通常是由于对抗芳香酶抑制剂的耐药性引起的，它是随着时间逐渐发展而形成的。因此，在患者已经接受了芳香酶抑制剂治疗后，进行液体活检来检测这一突变是合理的。相比之下，PIK3CA突变通常是肿瘤最初就存在的。在SOLAR-1研究中也使用了原发性肿瘤样本，因此，我们可以较早地进行这些检测以获取相关信息，并且这类检测通常可以获得保险覆盖。然而，我们无法进行多次NGS检测，需要尽量在提交的样本中获取所有必要的信息。除了ESR1突变外，我们可以多次进行检测，因为ESR1是随时间演变的变化的。

 

I think it depends on what you’re looking for.The ESR1 mutation is something that is sort of caused by Resistance to aromatase inhibitors，so it develops over time.So it makes sense to do this in a liquid biopsy，later on when the patient already had an aromatase inhibitor for the PIK3CA mutation that’s something that the tumor basically starts with and then the SOLAR-1 study.Also the primary tumor samples were used so we can do this rather early and just to have that information and that would be covered and What we cannot do is like to do NGS after NGS after NGS.So we sort of have to get everything with the sample that we send in except for the ESR1 mutation.Which we can redo，because it’s something that develops over time.

 

张剑教授：我们都知道，PI3CA/AKT/PTEN在治疗前后通常保持不变，特别是在内分泌治疗中。然而，ESR1突变往往是获得性变化的。关于NGS检测，进行检测的最佳时机是何时？是在一线治疗期间，还是在治疗后？如果进行血液样本检测，我们需要一些时间来获得结果，而一些患者对此十分担忧。这在你们的临床实践是怎样的？

 

Okay，I got it.I have another question:we all know that PI3CA/AKT/PTEN are mostly the same before and after treatment，especially for endocrine therapy.However，the ESR1 mutations are often acquired.Regarding NGS testing，what is the proper timing to have this test—during the first-line treatment or just after?If we are testing blood samples，we need some time to get the results，and some patients are very worried about that.What is your clinical practice?

Nadia Harbeck教授：在我们的临床实践中，我们的做法是在患者接受CDK4/6抑制剂治疗期间提交肿瘤组织样本。在患者开始治疗后，我们会评估除ESR1突变外的多种标记物。对于ESR1突变的检测，我们则在疾病进展时进行，以确保准确掌握肿瘤突变的最新状态，这项检测作为单独的液体活检是可以报销的。

 

What we do is we send in the tumor tissue during CDK4/6 inhibitor.So right after the patient is on treatment，we assess the markers except for ESR1.ESR1 we would do upon progression and to make absolutely sure that we cover the current status of the tumor mutations and that would be reimbursed as a separate liquid biopsy.

张剑教授：这也是一个重要的信号，可以为我们的临床实践提供参考。最后一个问题是，ADC药物在提高疗效的同时，其安全性也是临床关注的重点。在HR+晚期乳腺癌患者中，常见ADC药物的主要副作用有哪些？对于不良反应管理，您有哪些临床经验可以和我们进行分享？

 

That’s a good signal for also have some reference to our clinical practice.And last question is While the efficacy of ADC drugs is improved，its safety is also the focus of clinical attention.What are the major side effects of common ADC drugs in patients with HR+advanced breast cancer?What clinical experience can you share with us about the management of adverse reactions?

 

Nadia Harbeck教授：我们注意到，无论是T-DXd还是Sacituzumab Govitecan（SG）都会出现血液毒性，通常我们不会进行一级预防。如果患者在第八天给药前的状态不佳，我们会考虑给予二次预防。此外，胃肠道毒性也会出现，因此我认为从一开始就应根据当地的临床实践方案使用抗呕吐药物，具体是两种还是三种药物联合都可以。

 

对于T-DXd，我们需要密切监测间质性肺炎（ILD）。因此，我们必须提醒患者，如果出现咳嗽或呼吸急促等症状，即使是周五深夜也要及时就医，并立即进行肺部CT扫描。如果有疑虑但没有呼吸科医生可咨询，我们可以先让患者使用类固醇以确保安全，之后再安排与呼吸科的会诊。我认为迅速应对ILD的症状是非常重要的。此外，这些药物的疗效良好，尤其是T-DXd可以长期使用，但可能会导致疲劳。因此，我们需要与患者讨论其生活方式，以帮助他们应对疲劳，必要时也应考虑调整剂量。

 

I mean we see with both the T-DXd as well as with the Sacituzumab Govitecan（SG），we see hematological toxicity where we don’t usually give primary prophylaxis.But we would and I think the hematological toxicity in my experience is more pronounced with SG.We would give secondary prophylaxis if we feel the patient don’t make it to the day eight Administration then we see GI toxicity.So I think anti-emetic regimens right from the beginning with the infusion be two drug be three drug Whatever is local practice.

 

I think is recommended and for T-DXd.We do have to monitor for ILD，so we have to tell the patient if there’s any signs of coughing shortness of breath，please come in every time even if it’s Friday at midnight.Just come in and then we need to do an CT scan of the lungs and if in doubt and there is no Pneumonologist available，we could start the patients on steroids just to make absolutely sure and then consult with Pneumonology the day after or so，so I think rapid treatment for signs of ILD Important and other than that，I think these drugs work very well.What we see with long time，because T-DXd you can give for a very long time is also some fatigue，so we have to talk to patients about lifestyle，about how they can counteract that and the fatigue gets really bothersome.Maybe dose reduction would also be warranted.

 

张剑教授：今天下午我们还会讨论这个问题。在临床实践中，您是否会考虑对一些ILD为2或3级的患者进行再挑战？如果有，这些患者的结果如何？

 

I think this this afternoon We still have a talk about that.So，you know clinical practice Do you give any just any one or two patients with ILD to grade 2 or grade 3 to re-challenge?And what’s the results of these patients?

 

Nadia Harbeck教授：我们尚未进行此类患者治疗的再挑战。我的经验主要来自临床试验，当时明确规定仅在1级无症状ILD（仅在分期CT上发现）情况下，若患者在一个月内恢复，方可考虑对2级ILD患者再挑战。对于3级ILD，我会非常谨慎，不会进行再挑战。然而，我认为现在需要更多数据，例如在某些注册数据库中，关于那些快速恢复的2级ILD患者的信息，以评估是否可以进行再挑战。

 

在ESMO会议上，我们看到了来自法国团队的数据，他们的注册研究显示ILD发生较早，且既往ILD是主要风险因素。因此，这类患者再挑战应在非常受控的环境下进行。尽管如此，我们确实有患者在早期使用依维莫司（everolimus）时出现ILD，后来再尝试使用T-DXd，结果相对较好。但此类尝试应仅限于对治疗过程充分理解，并愿意在出现问题时及时就医的患者。

 

we haven’t done that yet.Our first experience obviously was the clinical trials，but that was absolutely forbidden you can only re-challenge in grade 1 which is Asymptomatic just discovered on a on a staging CT and if patients recovered within a month，you could re-challenge with grade 2.We’ve never done this grade 3 I would be really very cautious not to do this，but I think we now need data and like you asked me we need information maybe in some registries about patients with grade 2，who recover very quickly on the steroids whether we could re-challenge.

 

At ESMO actually we saw the data from the French group looking at their registry with over 600 patients where they saw that ILD actually occurs quite early，and the major risk factor is prior ILD.So，I think we need to do this in a very controlled setting.Although having said that we have some patients who had ILD on everolimus much earlier and then we tried them on T-DXd and in so far that worked quite well.But this has you can only do this with patients who are very compliant Understand what you’re talking about and you’re sure will come back if there’s any problems.

 

张剑教授：确实，对于高度选择性的患者，或许我们可以考虑再挑战，Nadia Harbeck教授的经验对我们非常有帮助。这就是我所有的问题。再次感谢Nadia Harbeck教授为我们提供的宝贵经验，这可能会对我们的临床实践产生重要影响。再次感谢您！

 

Yes，so in highly selective patients，Professor Nadia，maybe I have to re-challenge，and I think we can gain a lot of experience from her.Those are all my questions.I should also say thank you again to Professor Nadia for providing us with valuable experience that may impact our clinical practice.Thank you again.