Giuseppe Curigliano教授：HR 乳腺癌治疗进展及待解决的问题

温医一院刘海光 2024-05-27 发布于浙江

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编者按：第14届欧洲乳腺癌大会（EBCC-14）于日前在意大利米兰召开，会议聚焦乳腺癌多学科管理中的临床和转化研究新数据。肿瘤瞭望特邀采访了本次大会举办国主席（National Chair）、意大利米兰大学医学院副教授Giuseppe Curigliano，就本次会议相关内容进行介绍。

肿瘤瞭望：您能分享一下EBCC-14上一些令人兴奋的数据或亮点内容吗？

Giuseppe Curigliano教授：我认为本次大会有两个摘要很重要，其中一篇是有关体育活动对转移性乳腺癌患者生活质量和结局的影响（PREFERABLE-EFFECT），另一篇是关于免疫检查点抑制剂在HR+/HER2-早期乳腺癌领域中的使用（KEYNOTE-756）。在辅助治疗期间进行体力活动是预防癌症复发和改善生活质量的最佳方法。

KEYNOTE-756研究最新数据表明，对局部晚期和高风险HR+/HER2-乳腺癌患者，在新辅助化疗时加入pembrolizumab。可改善患者的病理完全缓解（pCR）率，尤其对于CPS评分和TILs较高的患者效果更为明显。我认为这是一个有潜力的治疗策略，但需要进一步观察后续无事件生存（EFS）的数据。

Oncology Frontier：Could you share with us what are some of the most exciting changes or highlights of this year's EBCC-14?

Giuseppe Curigliano：I believe the most important two abstracts that will be presented are one related to the impact of physical activity on quality of life and outcome of patients with metastatic breast cancer and the second one is related to the use of immune checkpoint inhibitors in the area of HR positive HER2 negative early breast cancer. Doing physical activity is the best way to prevent cancer recurrence and to improve the quality of life while during treatment in the adjuvant setting.

The second abstract is related to the KEYNOTE-756. This is a neoadjuvant trial for locally advanced and high risk HR positive HER2 negative disease in which pembrolizumab has been incorporated in the neoadjuvant chemotherapy of patients with early breast cancer. Addition of pembrolizumab increased the rate of pathological complete response and this benefit is mostly concentrated in those patients with high CPS score and hight TILs. I believe this is a strategy that should be implemented in the future but what we need to know from this prospective randomized trial are the date of event-free survival that will be presented later in time.

肿瘤瞭望：您认为在HR+乳腺癌患者治疗中，CDK4/6抑制剂扮演着什么样的角色，您是否看好其未来的发展前景？

Giuseppe Curigliano教授：CDK4/6抑制剂，如ribociclib、abemaciclib和palbociclib等已经成为HR+/HER2-转移性乳腺癌患者一线治疗的标准药物。这些药物在一线治疗的相关研究都显示出其改善了HR+/HER2-转移性乳腺癌患者中位无进展生存（PFS），其中一些研究也显示出了总生存（OS）的获益。我们也了解到，abemaciclib和ribociclib已经在早期HR+/HER2-乳腺癌中进行了探索（monarchE研究、NATALEE研究）。目前，我们已经获得了abemaciclib在高危HR+/HER2-人群中辅助治疗随访五年的数据。monarchE研究最新数据显示，在高危HR+/HER2-患者中，abemaciclib改善了患者的5年无浸润性疾病生存（IDFS）率和无远处复发生存（DRFS）率。因此，abemaciclib实际上已经在欧洲和美国获得批准，被纳入高危HR+/HER2-乳腺癌患者的辅助治疗。

NATALEE研究的数据也已经发布，尽管随访时间较短，3年ribociclib治疗的数据也显示ribociclib似乎可以改善患者的IDFS和DRFS。但NATALEE研究入组的患者人群与monarchE研究略有不同，NATALEE研究还纳入了部分中风险患者。

Oncology Frontier：What role do you think CDK4/6 inhibitors play in the treatment of HR+ breast cancer patients, and are you optimistic about their future development prospects?

Giuseppe Curigliano：CDK4/6 inhibitors, ribociclib, abemaciclib and palbociclib are the standard of care in the first-line setting for patients with HR positive HER2 negative metastatic breast cancer. All of them demonstrated an improvement in median progression-free survival and some of them also benefit in overall survival. We know also that abemaciclib and ribociclib have been tested in early HR positive HER2 negative disease. We have now the data of abemaciclib in the adjuvant setting with a median follow-up of five years. abemaciclib in high-risk HR positive HER2 negative improved both invasive disease-free survival and distant relapse-free survival. So I believe abemaciclib actually approved in Europe and in the United States should be incorporated in the adjuvant treatment of high-risk HR positive HER2 negative disease.

The data of NATALEE have been presented also with a shorter follow-up and also ribociclib before three years seems to improve invasive disease-free survival and distant relapse-free survival. The patient population of the NATALEE is a little bit different, because it's also incorporating patients at intermediate risk.

肿瘤瞭望：在关于“HER2-low”的辩论中，您的观点为“Trastuzumab deruxtecan for all HER2-negative metastatic breast cancer patients”，请为我们介绍一下相关原因。

Giuseppe Curigliano教授：DESTINY-Breast 04研究的数据表明，在HER2 1+/2+但FISH未扩增（HER2-low）的患者中，trastuzumab deruxtecan（T-DXd）可以显著提高HR+患者的中位无PFS（10.1个月）和总生存（OS）。我们正在期待DESTINY-Breast 06研究的数据，（如果研究为阳性结果）该治疗策略也将应用于HER2（0）患者。我个人认为T-DXd应该列为所有HER2-low患者的首选治疗。当然，我们也在等待DESTINY-Breast 06研究的数据，如果在HER2（0）人群中显示出不同的临床获益率，我们将根据安全性决定优先选择T-DXd还是标准化疗。但我期待的是T-DXd治疗效果优于化疗。

Oncology Frontier：In the debate on 'HER2-low', your opinion is 'Trastuzumab deruxtecan for all HER2-negative metastatic breast cancer patients', please tell us the relevant reasons.

Giuseppe Curigliano：We have the data of the DESTINY-Breast 04 demonstrating clearly that the use of trastuzumab deruxtecan, in HER2(1+) and (2+) with FISH (Fluorescence In Situ Hybridization) non-amplified improved both the median progression-free survival with a median PFS of 10.1 months and overall survival. And we are awaiting the data of DESTINY-Breast 06, in which this strategy will be also implemented in patients with HER2(0). Personally, I believe that trastuzumab deruxtecan should be the mainstay in treatment for any HER2-low patient. For sure, we will see the data of DESTINY-Breast 06 and eventually, if a different clinical benefit rate in the HER2(0) population, we will decide based on safety profile if to prefer T-DXd to a standard chemotherapy. But what I expect is that T-DXd will be superior to chemotherapy.

肿瘤瞭望：靶向治疗的出现为HR+/HER2-晚期乳腺癌带来了较好的生存获益，如今正值ADC药物研发的热潮，您认为在HR+/HER2-晚期乳腺癌患者治疗领域，未来将有哪些靶向治疗药物出现（包括ADC）？

Giuseppe Curigliano教授：在HR+/HER2-晚期乳腺癌一线治疗中，内分泌治疗联合CDK4/6抑制剂是首选。在二线治疗中，我们采取根据生物标志物驱动的治疗策略。因此，如果患者伴随PI3K突变、AKT突变或PTEN突变，根据CAPItello-291的数据，可以使用fulvestrant联合capivasertib，中位无进展生存期可达7.3个月，且不受AKT变异的影响。SOLAR-1和BYLieve研究（在CDK4/6使用后的情况下）的结果提示我们也可以使用Alpelisib，中位无进展生存期为7个月。此外，如果患者有ESR1突变，我们还可以考虑用Elacestrant进行治疗，患者的中位PFS也接近9个月。对于那些在一线治疗中使用CDK4/6抑制剂时间较长且存在BRCA突变的患者，我们也可以考虑使用PARP抑制剂。

我们正在等待 DESTINY-Breast 06研究的数据，以了解是否可以将T-DXd纳入HER2低表达和HER2（0）人群的二线治疗。未来，我们将看到一线采用内分泌联合CDK4/6抑制剂进行治疗，二线将针对内分泌敏感人群根据生物标志物进行治疗选择。从三线开始，我们将使用ADC进行治疗。目前为止，T-DXd出现后，靶向Trop-2 ADC药物sacituzumab govitecan（SG；Trop-2靶向药物）也出现了。SG应是HER2 0的首选治疗方案。未来，我们将有更多的治疗选择，如datopotamab deruxtecan（dato-DXd）可用于HER2（0）和Trop-2阳性的患者。因此，未来的主要问题是如何更好地安排ADC的使用顺序。也许我们需要设计以中位PFS作为主要终点的临床试验解决这一问题。

Oncology Frontier：The emergence of targeted therapy has brought better survival benefits for HR+/HER2-advanced breast cancer. Currently, the development of ADC drugs is in the upsurge. What targeted therapy drugs (including ADC) do you think will appear in the treatment field of HR+/HER2-advanced breast cancer patients in the future?

Giuseppe Curigliano：In the first line, the mainstay in treatment is endocrine therapy plus CDK4/6 inhibitors. In the second line, we have a biomarker-driven approach. So, if you are PI3 kinase mutant or AKT mutant or PTEN mutant, we have today, of course, based on the CAPItello-291, the use of capivasertib in combination with fulvestrant with a median progression-free survival of 7.3 months independent of the AKT alteration. We may use Alpelisib based on BYLieve trial (in the post CDK 4-6 setting) with a median progression-free survival of 7 months. We may use also Elacestrant， If patients are ESR1 mutant receiving at least 1 year of CDK 4-6 inhibitors, with a median PFS close to 9 months. For those patients who have a longer exposure to first-line CDK4/6 inhibitors, we can use also PARP inhibitors if there is a germline BRCA mutation.

And we will wait for the data of DESTINY-Breast 06 to understand if you can incorporate in the second line also trastuzumab deruxtecan for HER2-low and HER2(0) population. In the future, what I will see is a first-line endocrine therapy plus CDK, a second-line biomarker-driven for endocrine-sensitive population, and finally from third-line and beyond, you will have a sequence of ADC. Up to now, trastuzumab deruxtecan followed by sacituzumab govitecan (anti TROP 2) in HER2 low. Sacituzumab govitecan should be the first option in HER2 0. In the future, we will have more options, datopotamab deruxtecan for HER2(0). And so, the main question for the future is how to better sequence ADC. And maybe we need to design clinical trials with median progression-free survival too as a primary endpoint.