编者按：HER2+（HER2阳性）乳腺癌是一类侵袭性较强，预后较差的乳腺癌亚型，随着更多新的靶向药物获批应用于临床，HER2+乳腺癌患者预后不断改善。既往无抗HER2靶点治疗的情况下，HER2+患者的复发风险较高；经过抗HER2治疗后，患者的复发风险大幅度下降。近年来，抗体偶联（ADC）药物的出现使HER2+乳腺癌患者的治疗走进了新时代，但仍存在一些未被解决的问题。在第七届晚期乳腺癌国际共识会议（ABC7）上，肿瘤瞭望特邀采访了西班牙巴塞罗那Vall d’Hebron肿瘤研究所的Javier Cortes教授，请他就HER2+晚期乳腺癌领域的变化进行总结与展望。

 

 

What do you think is the biggest change or the most important research progress in HER2+advanced breast cancer since ABC6?

 

Javier Cortes教授：相关研究数据显示，trastuzumab deruxtecan（T-DXd）在HER2阳性晚期二线、三线甚至更多线的治疗中都显示出了显著的生存获益，主要是无进展生存（PFS）和总生存（OS）的大幅改善。因此，目前已明确将该药作为HER2阳性乳腺癌二线标准治疗方案，这是毋庸置疑的。

 

I think that without any doubt，the data we have seen with trastuzumab deruxtecan（T-DXd）in both second line or third line and beyond，showing not only an improvement in progression free survival but also a very nice and dramatic improvement in overall survival has established this agent as the clear second line new standard of care.

 

 

HER2 expression has certain spatial and temporal heterogeneity.When and how do you perform HER2 testing and evaluation in clinical practice?

 

Javier Cortes教授：在我看来，我们必须区分好HER2低表达和过表达的肿瘤。尽管肿瘤存在明显的异质性，HER2过表达的肿瘤变化相对较小，基本保持在7%左右。另一方面，HER2低表达是一个非常动态的特征。尽管初步评估显示，大约有50%到55%的患者显示出HER2低表达，但后续活检显示，这一百分比最高可达85%甚至90%。因此，我认为识别HER2低表达患者，使患者有机会在未来接受T-DXd治疗是很重要的。

 

I think that in my opinion we have to differentiate between HER2 low and HER2 overexpressing tumors.So although it is true that there is a clear heterogeneity in tumors，HER2 overexpressing tumors do not change that much.It changed in the range of 7%across time.So I think that for the HER2 low expression，that’s absolutely something very，very dynamic.So it is true that when we looked at the HER2 low expression，it happens in the range of 50 to 55%of all patients.But when we look at the sequential biopsies，we can observe this as high as 85 or even 90%of patients.So I think it is important to look for the HER2 low expression to give the patients the opportunity to receive T-DXd in the future.

 

 

HER2 ADCs already have a new standard of second-line treatment and are making their way to the first-line.Looking ahead，what do you think will happen to the treatment of HER2+advanced breast cancer?

 

Javier Cortes教授：我认为在一线治疗中T-DXd很有可能优于CLEOPATRA研究方案，即曲妥珠单抗+帕妥珠单抗+紫杉（多西他赛）方案，这就意味着T-DXd或许能够成为HER2阳性乳腺癌一线治疗的标准方案。不过还仍有一些悬而未决的问题需要解决，例如，患者是否需要永久接受T-DXd治疗，或者是否可以将T-DXd作为诱导化疗，然后再使用曲妥珠单抗和帕妥珠单抗进行维持化疗？关于这一点，我们正在进行一项临床试验，该研究首先使用T-DXd进行治疗，维持化疗使用曲妥珠单抗和帕妥珠单抗。所以我认为虽然将T-DXd纳入一线治疗几乎是势在必行，但更好地了解该药物的最佳持续时间也十分重要。

 

I think it’s very likely that T-DXd will be superior to the CLEOPATRA based strategy，involving taxane-trastuzumab-pertuzumab in the first-line setting.So this will mean that maybe T-DXd will be the standard of care in the first line.So nevertheless，there are open questions that have to be addressed in the future.So for example，do we need T-DXd forever or would it be possible to go for T-DXd as induction therapy followed by maintenance with trastuzumab and pertuzumab?Of this regard，we are conducting a clinical trial looking at this point，starting with T-DXd followed by maintenance of trastuzumab and pertuzumab.So I think that T-DXd is very likely to be positioned in the first line setting，but we have to understand better which is the optimal duration of this excellent drug.