Giuseppe Curigliano教授：晚期乳腺癌患者治愈展望——创新疗法

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。肿瘤瞭望特邀采访了ESMO候任主席、意大利米兰大学医学院副教授Gius

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。肿瘤瞭望特邀采访了ESMO候任主席、意大利米兰大学医学院副教授Giuseppe Curigliano，就本次会议上其报告的讲题及晚期乳腺癌患者治愈等观点进行了分享。

肿瘤瞭望：本次SGBCC大会上，您分享了关于“Breakthroughs and innovation in advanced disease – arriving in the curable setting soon?”的讲题，首先请您谈谈您对治愈的理解？我们应该如何定义晚期乳腺癌的治愈？

Giuseppe Curigliano教授：在我的讲课中，我首先解释了一种药物在转移性乳腺癌中获批到它被应用于早期乳腺癌治疗之间的时间跨度。这一过程在上世纪90年代大约需要10年，而如今已时间跨度已经缩短至4年左右。例如，帕博利珠单抗（Pembrolizumab）从被批准治疗转移性乳腺癌到被批准治疗早期乳腺癌大约用了4年左右。我在讲课中提出的最重要的一点是，如何预测某种药物在早期乳腺癌治疗中对总生存期（OS）的影响。因为在我看来，一种药物是否真正具有突破性，取决于它能否提高治愈率，而治愈率的本质也就是OS的获益。然而，目前所有的临床试验主要以病理完全缓解率（pCR）、无浸润性疾病生存期（iDFS）或无事件生存期（EFS）作为主要研究终点。

正如我在演讲中所提到的，我们可以利用统计学方法，在患者层面和临床试验层面更准确地预测某种药物是否能够提高总生存期。其中决定系数（R²）是一种重要的方法。如果R²值大于0.7，通常意味着pCR与总生存期之间存在强相关性；如果在0.5到0.6之间，则通常不存在相关性。如果我们查看帕博利珠单抗的临床试验数据，会发现它正符合这一规律：pCR率的提高确实与总生存期的改善有关。因此，在未来的临床试验设计中，我们也需要采用这一方法。

So, thank you for your question, because I tried in my presentation first to explain which is the timeframe between the approval of a drug in the metastatic setting that will arrive in the early breast cancer setting. And there is a range that is between 10 years in the 90s to four years today. Just if you remember Pembrolizumab, it was approved in the metastatic setting at least four years before the data had been translated in the early breast cancer setting. But the most important point I raised is how to predict the benefit of a specific drug in the early breast cancer setting in terms of overall survival. Because in my opinion, a drug is really transformative if you increase the cure rate. And the cure rate, namely, is an overall survival benefit. All the clinical trials are designed and having as a primary endpoint or pCR or invasive disease-free survival or event-free survival.

As I said in my talk, we have statistical methods on the patient level and the trial level to better understand if a drug will be positive on overall survival or not. And one of the methodologies, the coefficient of determination, R-squared. If this is more than 0.7, usually there is a strong correlation between pCR and overall survival. If between 0.5 and 0.6, usually there is no correlation. And if you check the data in the clinical trials for Pembrolizumab, this was exactly the case because an increase in pCR was also related to an improvement in overall survival. So in future trial design, you need also to apply this specific methodology.

肿瘤瞭望：目前有哪些创新手段有机会使晚期乳腺癌实现治愈？您如何评价这些方式？

Giuseppe Curigliano教授：在晚期乳腺癌的治疗中，情况会有所不同。因为在这一阶段，OS并不是必须的衡量标准，OS在早期是重要关注点，在晚期则不然。我个人认为，在转移性乳腺癌的研究中，客观缓解率（ORR）和无进展生存期（PFS）依然是合理且有效的研究终点。需要明确的是，晚期乳腺癌目前仍无法治愈，其对总生存期的影响无法完全保证，这主要受疾病生物学特性的限制。因此，在晚期或转移性乳腺癌的治疗研究中，我依然认为PFS是一个可行的替代终点。

You know, in advanced breast cancer, of course, is another issue because in that case, you don't need, for sure, overall survival, sometimes you may have, some other times, no. Because personally, I believe also response rate and progression-free survival is a valid endpoint in the metastatic setting. So metastatic disease is not curable. The impact on overall survival cannot be guaranteed due to the biology of the disease. So in advanced breast cancer or metastatic breast cancer, I believe still PFS is a valid surrogate endpoint.

肿瘤瞭望：在您看来，当前我们距离实现晚期乳腺癌的治愈还有多远？如ESMO、CSCO、SGBCC等组织，以及临床医生可以通过哪些方面的努力推动乳腺癌走向治愈？

Giuseppe Curigliano教授：这是一个很好的问题。我认为，在某些类型的乳腺癌（例如HER2阳性乳腺癌）中，我们需要设计以治愈率为主要研究终点的临床试验。比如，如果患者是原发性转移性乳腺癌，且未出现致命的转移病灶，那么我们是否可以真正实现部分患者的治愈呢？现在，我们已经拥有非常有效的治疗手段，因此，这正是值得深入研究的方向。在推动晚期乳腺癌向可治愈目标迈进的过程中，CSCO、ASCO、ESMO等学术组织可以携手合作，推动针对特定人群的临床试验。这些患者在单个中心或单个国家中可能较为罕见，但如果从全球范围内展开合作，则能汇集足够的病例数，以填补晚期乳腺癌治疗中尚未满足的医学需求，真正向“治愈”这一目标迈进。因此，这应该是各学术组织共同努力的方向。

This is an excellent question. I believe in some disease, like HER2-positive, we need to design a clinical trial in which potentially cure rate can be really the primary endpoint. I mean, if you have a de novo metastatic disease with the no lethal metastatic presentation, don't you believe that we can achieve to cure some of these patients? Now we have a very effective treatment. So it's important that societies like CSCO, ASCO, ESMO may work together to promote clinical trial in very special populations that maybe are rare if you consider them in a single center or in a single country. But there are many if you collaborate on the global level to specifically meet medical need like cure in advanced disease. So these should be the effort of all scientific societies together.

肿瘤瞭望：在实现晚期乳腺癌治愈的道路上，您认为当前最大的挑战是什么？您对未来乳腺癌的治愈有怎样的期待？

Giuseppe Curigliano教授：目前，我们已经能够治愈许多乳腺癌患者，因为早期诊断的推广使得三阴性乳腺癌、激素受体阳性乳腺癌和HER2阳性乳腺癌的治愈率大幅提高。我认为，当前最大的挑战是如何优化治疗方案，以减少治疗相关的毒性。未来，我们需要开展创新型临床试验，不仅关注治愈率，还应充分考虑治疗带来的毒副作用。例如，对于低风险患者，如果采用5年的内分泌治疗可能影响其生活质量，那么我们是否可以设计一项非劣效性研究，验证一种毒性更低的替代方案，既能保持相同的治愈率，又能减少不良反应？在我看来，这样的研究方向对患者更有利。

We cure a lot of patients now because with the early diagnosis, the cure rate is very high for triple negative, HR positive and HER2 positive disease. So I believe what we need to improve now is optimized treatment in order to reduce toxicity. So we need innovative trial that beyond cure, they should consider also toxicity of specific agents because in my opinion, if you have to cure a patient that is a low risk with five years of endocrine therapy that may impact on the quality of life of those patients. If you have a trial that is a non-inferiority trial in which you demonstrate that an alternative regimen can achieve the same results in terms of cure rate but with less toxicity. So this is what we need may be in the interest of our patients.