Javier Cortés教授：早期HER2阳性乳腺癌治疗突破双刃——靶向新药

摘要：2025年3月12～15日，第19届圣加伦国际乳腺癌大会（SGBCC 2025）在音乐之都维也纳召开。来自全球的乳腺癌领域专家汇聚一堂，共同就乳腺癌诊疗领域的前沿进展和热点争议话题进行讨论。在会议现场，西班牙巴塞罗那国际乳腺癌中心（IBCC）主任Javier

编者按：2025年3月12～15日，第19届圣加伦国际乳腺癌大会（SGBCC 2025）在音乐之都维也纳召开。来自全球的乳腺癌领域专家汇聚一堂，共同就乳腺癌诊疗领域的前沿进展和热点争议话题进行讨论。在会议现场，西班牙巴塞罗那国际乳腺癌中心（IBCC）主任Javier Cortés教授带来了题为“New anti-HER2 approaches- moving up to the (neo)adjuvant setting?”的精彩演讲，肿瘤瞭望特邀Javier Cortés教授分享他对早期HER2阳性乳腺癌（新）辅助治疗的见解与展望。

《肿瘤瞭望》：请您分享一下参与2025 SGBCC的感受，此次盛会的举办具有怎样深远的意义？

Javier Cortés教授：感谢您的邀请。参加像SGBCC这样的大型国际学术会议，为我们提供了与同行交流并相互学习的宝贵机会。在本次会议上，我们不仅深入了解了早期乳腺癌治疗策略的最新进展，还从多学科角度探讨了乳腺癌的综合治疗模式。会议内容涵盖了肿瘤学的核心视角，并广泛涉及了与乳腺癌治疗相关的多个学科领域，包括放射治疗、病理学、外科手术以及影像学等。通过跨学科的交流与合作，我们致力于优化乳腺癌患者的治疗方案，并将这些研究成果以清晰、准确、高效的方式进行传播，以便更好地推动临床实践的发展和进步。

Oncology Frontier：Could you share your feelings about participating in the 2025 SGBCC and the far-reaching significance of hosting this grand event?

Dr. Javier Cortés：Thank you very much for inviting me to be here with you.When attending conferences like this, we interact with colleagues and learn from each other. At the SGBCC, we learn a lot about early breast cancer strategies. This is a meeting that does not only include medical oncology perspectives but also all the specialties, including radiation therapy, pathology, surgery, and radiology. We work together and try to optimize the way we treat our patients, and clearly disseminate these findings. We will be able to interact with each other much better .

《肿瘤瞭望》：本次SGBCC大会上，您分享了关于“New anti-HER2 approaches—— moving up to the (neo)adjuvant setting?”的讲题。请您介绍一下当前有哪些新型抗HER2治疗手段迈入或即将迈入（新）辅助治疗阶段？您认为其中最具前景的是哪一项？为什么？

Javier Cortés教授：随着研究的深入，我们逐渐认识到，晚期转移性乳腺癌的治疗策略并不能完全适用于早期乳腺癌的治疗。近年来，针对HER2阳性转移性乳腺癌的治疗取得了重要突破。帕妥珠单抗（Pertuzumab）、曲妥珠单抗（Trastuzumab）、抗体药物偶联物（ADC）以及德曲妥珠单抗（T-DXd）等药物在改善晚期转移性乳腺癌患者的长期预后、无进展生存期（PFS）和总生存期（OS）方面表现优异。然而，这些药物在早期乳腺癌中的应用效果仍存在不确定性。

因此，我们需要开发更优化的临床试验设计，以使这些药物达到预期。2025 年 1 月，NEJM刊登了随机、多中心、开放标签 III 期临床试验——KATHERINE研究的无浸润性疾病生存（iDFS）最终分析数据和总生存期（OS）第二次期中分析数据，充分证实了ADC药物恩美曲妥珠（T-DM1）单抗辅助治疗可显著延长 HER2 阳性早期乳腺癌患者（新辅助治疗后仍有残留浸润性病灶）的 OS，并持续改善 iDFS。

图1. 研究主要终点 iDFS

图2. 研究关键次要终点 OS

我们在新辅助治疗阶段也在不断探索新的药物组合和治疗策略。我认为，未来的发展方向应聚焦于预后最差的患者群体，以实现更显著的改善。此外，我认为我们需要改变临床试验的设计方式，更多地采用基于患者治疗反应的策略。例如，我们可以根据患者的早期反应来决定是否加入化疗。回顾40年前，为降低毒性，我们曾尝试降低治疗强度，而如今，随着液体活检和基因检测技术的进步，我们有望更精准地筛选出最可能从这些药物中获益的患者群体。

Oncology Frontier：At this SGBCC conference, you presented on the topic: "New anti-HER2 approaches – moving up to the (neo)adjuvant setting?" Could you elaborate on the novel anti-HER2 therapies that have entered or are poised to enter the (neo)adjuvant treatment stage? Which one do you consider the most promising and why?

Dr. Javier Cortés：In the last few years, we have learned that what happens in a metastatic setting does not always translate into the early breast cancer setting. Last year, we saw a great improvement in the outcomes of HER2-positive metastatic breast cancer. We have drugs such as pertuzumab, Trastuzumab、ADC,and T-DXd, which have shown improvements in long-term outcomes, progression-free survival, and overall survival. However, sometimes the way these drugs translate into improvements in the early-risk setting has not been so clear.

So in my opinion, we need to develop better clinical trial designs to optimize the improvements we expect. For example, we now have the example of the KATHERINE trial with T-DM1 in patients who have the worst prognosis—those who did not achieve pathological complete remission.

We are also exploring different drugs in the neoadjuvant setting. I think this is the way to move forward: to select the patient population with the worst outcomes to achieve better improvements. Last but not least, I think we need to change the way we design clinical trials and try to adopt more response-oriented strategies. For example, we might add or omit chemotherapy based on the response. Let's go back 40 years to the period when we used to cut back on treatments. Let's select those patients who we think will benefit most from these drugs.

《肿瘤瞭望》：创新药物的研发往往是从晚期应用走向早期应用。请您谈谈遵循这一研发路径的必要性，影响一个创新药物从晚期走向早期的关键因素是什么？

Javier Cortés教授：推动创新药物从晚期走向早期至关重要。以早期HER2阳性乳腺癌为例，尽管目前大多数患者可通过现有治疗手段获得治愈，但仍有部分患者无法达到理想的治疗效果。因此，进一步优化治疗策略并开发更多有效药物是改善患者预后的关键。令人欣慰的是，德曲妥珠单抗、恩美曲妥珠单抗等多款靶向药物已获得美国食品药品监督管理局（FDA）批准，用于早期HER2阳性乳腺癌患者的治疗。然而，临床需求仍未完全满足，仍需不断探索更多潜在的有效治疗药物。

在临床试验方面，优化并创新临床试验方案的设计也是推动创新药物走向早期应用的重要因素。首先，应根据复发风险选择合适的患者群体。高复发风险HER2阳性乳腺癌患者可能从新型疗法中获得更高的治疗获益。以2024年9月发表于JCO的APHINITY试验为例，该试验纳入了4800多例意向治疗（ITT）人群，随机分组后予以化疗联合曲妥珠单抗联合或不联合帕妥单抗辅助治疗。结果显示，与曲妥珠单抗单靶相比，曲妥珠单抗+帕妥珠单抗（HP）使高复发风险患者浸润性疾病复发风险降低23%，使淋巴结阳性亚组患者浸润性疾病复发风险降低28%，OS获益趋势更高。

然而，随机对照试验并非唯一选择，我们或许可以探索其他更具创新性和针对性的临床试验设计方法。我非常期待与各方共同探索这种可能性。

Oncology Frontier：The development of innovative drugs often progresses from advanced-stage to early-stage applications. Could you discuss the necessity of this R&D pathway and the critical factors influencing a drug’s transition from late-stage to early-stage use?

Dr. Javier Cortés：Certainly, we need more and better drugs in early breast cancer, and this also applies to HER2-positive disease. It is true that today, the majority of patients with HER2-positive early breast cancer will be cured, but not all of them. So if we are unable to cure all of our patients, we need to improve the outcomes for all of them. This is why we need more and better drugs, some of which have been evaluated and/or approved in the metastatic setting. Examples include T-DM1 and tucatinib. These drugs should also be explored in the early breast cancer setting.

There are different approaches to selecting the optimal clinical trial design. The first is to select the patient population based on the risk of relapse. If we have higher-risk patients, we might anticipate higher benefits. But there are other ways to improve clinical trial designs. For example, instead of randomizing some patients to A versus B arms, maybe we should go for more innovative designs. Let's go for a new strategy-based clinical trial. Remember, for example, the APHINITY trial with pertuzumab, which enrolled 4,000 patients in the early-risk setting in the adjuvant space. With these 4,000 patients, we all used pertuzumab. APHINITY was not for tiny tumors. So maybe we do not need to randomize thousands of patients. Maybe we have to design clinical trials in other ways. I'm really looking forward to exploring this possibility altogether.

《肿瘤瞭望》：您对于未来早期HER2阳性乳腺癌的（新）辅助治疗有怎样的期待？

Javier Cortés教授：尽管当前早期HER2阳性乳腺癌的治疗已取得进展，但未来治疗方向仍存在诸多挑战和机遇。基于上述提到的APHINITY研究结果，曲妥珠单抗联合帕妥珠单抗已成为早期HER2阳性乳腺癌患者新辅助治疗和辅助治疗的标准治疗方案。在此基础上，针对德曲妥珠单抗的临床试验也已启动，这预示着未来治疗策略的进一步优化。

我认为，未来早期HER2阳性乳腺癌的（新）辅助治疗将朝着“精准化”和“个体化”的方向发展。一方面，我们有望在降低治疗强度的同时维持甚至提升治疗效果，从而降低患者的治疗负担和不良反应。另一方面，我们也需要为部分高危患者升级治疗策略，以进一步改善预后。为此，我们需要在两方面取得突破：首先，通过更精准的生物标志物和临床评估工具，识别哪些患者需要更强化的治疗，以及哪些患者可以从减量化治疗中获益；其次，通过优化临床试验设计，推动更多药物从晚期走向早期。一些已在转移性乳腺癌中获批的药物，未来有望在早期乳腺癌中发挥重要作用，关键在于优化药物的价值。

Oncology Frontier：What are your expectations for the future of (neo)adjuvant treatment in early-stage HER2-positive breast cancer?

Dr. Javier Cortés：I think it's difficult to predict the future of new adjuvant approaches in the HER2-positive field because today we have very good outcomes. We have trastuzumab, pertuzumab, and chemotherapy as the standard of care for stage II and stage III. We have started to design DS-8201 clinical trials. I think that in the future, we will see very good outcomes with less treatment. But it's true that we also need to escalate the strategies for a group of patients. First, we have to identify much better who the patients are who need more. Second, we need to identify much better those who need less. And this can be done with a different type of trial. I think that some of the drugs which have been approved in a metastatic setting will also be approved in the early breast cancer setting. The point here is how to optimize the value of these drugs—again, through better patient selection and better clinical trial designs.