编者按：在2024年SABCS大会上，香港大学李嘉诚医学院Janice Tsang教授在年度进展环节介绍了“早期乳腺癌领域的治疗更新”。会后，肿瘤瞭望特邀采访了Janice Tsang教授，请她就早期乳腺癌治疗领域的最新研究进展进行了分享。她不仅回顾了KEYNOTE-522等关键研究的探索性分析结果，还深入探讨了乳腺癌个体化治疗面临的挑战及解决方案，为乳腺癌领域的同行们提供了宝贵的经验。
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肿瘤瞭望：您在2024年SABCS会议年度回顾环节介绍了“Early Breast Cancer Updates”，请您回顾讲课内容，为我们介绍下本次大会上早期乳腺癌治疗领域令您印象深刻的研究进展。
You introduced "Early Breast Cancer Updates" in Year in Review session. Please review the lecture and tell us about the research progress in the field of early breast cancer that impressed you at this conference.
Janice Tsang教授：我是来自中国香港的肿瘤科医生Janice Tsang，同时也是香港乳腺肿瘤学组的创始人。非常荣幸能够在2024年SABCS大会上对早期乳腺癌领域的进展进行回顾。实际上，2024年对早期乳腺癌来说是一个激动人心的年份。首先，我认为我们已经对免疫肿瘤学的附加价值建立了足够的信心，特别是在KEYNOTE-522研究中使用帕博利珠单抗（pembrolizumab）取得的成果方面，我们已经获得了稳健且一致的数据，数据显示，当帕博利珠单抗与新辅助化疗联合使用时，它能给早期三阴性乳腺癌患者带来更多获益，这些获益体现在病理完全缓解（pCR）、无事件生存期（EFS）以及五年总生存期（OS）等多个方面。
不仅如此，我们还发现了一些相关的生物标志物，这些成果不久前由Joyce O'Shaughnessy在SABCS大会上发布。不过，我们仍然有很长的路要走。观察KEYNOTE-522研究中的OS数据能够发现，帕博利珠单抗组相较于对照组确实有约5%的绝对获益，准确来说是4.9%。这一获益对于患者的OS来说意义重大。毕竟，如果回顾乳腺癌辅助治疗的历史数据，4.5%的OS提升已位列前五了。
然而，这可能仅对部分乳腺癌患者有效，因为正如我们所见，即使在帕博利珠单抗问世之前，已有约81%的患者仅通过新辅助化疗就能在五年内实现总生存期的延长。而在使用帕博利珠单抗的治疗组中，尽管OS有5%的提升，但总体来看，约15%的早期三阴性乳腺癌患者仍面临着生存的挑战。因此，我们仍然没有明确的答案，仍需要加倍努力，探讨如何对这些未应答的患者进行治疗强化，或者是否可以对有反应的患者进行治疗减量，或者能否通过分层来筛选一些可能不需要提前使用帕博利珠单抗的患者。我认为这是迈向更精确医学的更进一步，因为帕博利珠单抗并非没有副作用，尤其是在亚洲和中国等地区，其不仅存在经济方面的“毒性”，还涉及合理用药与可忍受毒性相匹配之间的平衡，以及免疫治疗相关的毒性问题。
此外，我还想补充一点关于激素治疗的内容。除免疫治疗之外的其他疗法，我认为另外一个令人兴奋的进展是降阶梯治疗，或者说是去蒽环类药物的治疗。最近，Harold Burstein在《临床肿瘤学杂志》（JCO）上发表了一篇很精彩的综述文章。根据我们目前的了解，对于HER2阳性乳腺癌患者，我们可以相当有信心地豁免除蒽环类药物。而对于激素受体阳性HER2阴性（HR+/HER2-）乳腺癌患者和三阴性乳腺癌患者，可能在这一阶段我们仍然需要使用蒽环类药物。
然而，2024年公布的I-SPY 2.2的数据也同样引人注目，这项研究中有很多令人兴奋的发现。如您所见，那些通过MammaPrint评定为高风险的患者，比如Ⅱ-Ⅲ期接受了新辅助治疗的乳腺癌患者，其治疗方案包括多西他赛（Docetaxel）与Dato-DXd的联合使用，或根据情况加用度伐利尤单抗（Durvalumab）（免疫治疗）。基本上，在经过几轮治疗后，患者无需进行MRI监测，仅通过观察肿瘤体积的评估和反复进行活检，我们就能识别出那些已达到完全病理缓解（pCR）的患者，并可以直接进行根治性手术。这意味着，对于一些患者，我们或许可以避免使用化疗。因此，在去蒽环类药物的同时，我们或许有一天也可以告别化疗。
这一点得到了TRAIN-3研究的进一步证实和支持。TRAIN-3研究（摘要号：RF1-03）是一项Ⅱ期研究，由荷兰的同道在SABCS大会上快速口头报告环节中进行了展示。基本上与之前的研究类似，患者接受治疗时无需进行影像学引导的优化，而是采用了更有效的新辅助化疗。当患者通过影像学引导和重复穿刺活检证明能够达到早期病理完全缓解时，他们可以直接进行根治性手术。这项研究是针对HER2阳性乳腺癌患者的Ⅱ期研究，尽管TRAIN-3研究的数据需要通过Ⅲ期临床试验进一步验证，但根据我们目前的了解，未来或许某些患者群体能够免于化疗。这一策略不仅局限于三阴性乳腺癌患者，HER2阳性乳腺癌患者也有可能受益。
此外，对于HR+/HER2-晚期乳腺癌患者，随着新一代抗体药物偶联物（ADCs）的出现，我认为也将带来更多的附加治疗价值。在Mafalda Oliveira及其团队的Ⅱ期SOLTI VALENTINE试验中（摘要号：LB1-06），HER3-DXd联合或不联合来曲唑（letrozole）的数据也显示出了附加价值。实际上，在接受治疗的试验组患者不仅副作用较少，依从性更好，而且临床结果也更为理想。这也进一步证明了即将问世的ADC的附加价值，并展示了其在临床中的重要意义。
最后，回顾2024年的研究进展，我认为精准医学的发展与生物标志物的进步和ctDNA的应用相关，特别是monarchE研究中使用ctDNA取得的成果，展示了我们在这方面取得的进步。结合我之前提到的其他研究，这些成果表明，我们在逐渐更多地使用液体活检技术，并结合影像学指导，帮助我们更精准地对特定的临床亚型患者进行分层。
从这点来看，乳腺癌已不再仅是一种常见病，而是一种罕见异质性较大的疾病。这意味着，通过不同的ctDNA水平或不同的影像学反应，我们实际上能够对患者的治疗反应进行分层。然而，尽管通过避免化疗或蒽环类药物可以减轻患者的负担，但这也需要依赖影像学监测和穿刺活检来进行血清监测，从而带来一定的副作用。因此，在财务方面，这种做法并非没有副作用，而其实施的前提还依赖于医疗系统是否有足够的人力支持。我们了解得越多，就越能意识到自己认知的不足。特别是在中国，我们仍然面临许多挑战，也有很多关于临床管理的问题，如各省之间是否能公平提供足够的诊断和治疗策略，以及是否具备足够的生物标志物检测能力。
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I'm Dr. Janice Tsang, medical oncologist from Hong Kong, the founding convener of the Hong Kong Breast Oncology Group. I'm honoured and blessed to actually share the year in review on early breast cancer at the San Antonio meeting this year, 2024. Actually, this is actually an exciting year for early breast cancer. I think firstly, we have built enough confidence with regard to added value of immuno-oncology, particularly the use of pembrolizumab in the KEYNOTE-522 study, because now we have robust and consistent data with regard to benefits of pembrolizumab when combined with neoadjuvant chemotherapy in early-stage triple negative breast cancer women across complete pathological response rate, event-free survival, as well as the five-year oversurvival.
Now, not only that, we are also having some biomarkers. Actually, that has just been released by Joyce O'Shaughnessy at the San Antonio meeting. But there is still a long way to go, because if you look at the data from the oversurvival outcome for the KEYNOTE-522, yes, there is actually absolute about 5%, to be exact, 4.9% of added value in oversurvival in the pembrolizumab arm as compared to control arm. This is actually quite a big breakthrough with regard to an impactful result, because if you look at all the adjuvant data so far, 4.5% of oversurvival gain is actually top number five among all the adjuvant therapy in the breast cancer history.
However, this is only perhaps benefiting a subgroup of breast cancer women, because as you can see, even before the advent of pembrolizumab, there is already about 81% of women who do not need pembrolizumab by just being exposed to neoadjuvant chemotherapy alone. They would actually achieve oversurvival at five years. And with 86.6%, that is this 5% gain with the use of pembrolizumab, we are still having 15% roughly of breast cancer women in the early stage triple negative subtype actually having problem with the oversurvival. Therefore, we still have no answers, or we still work extra hard to actually see how to escalate in these non-responders, and whether we can actually de-escalate for the responders, or whether we can stratify some patients who might not really need the pembrolizumab up front. I think that's the next step to go for better precision medicine, because pembrolizumab is not without side effects, not just financial toxicities, the issue of matching science with affordability, particularly in Asia and China, and also the issue of immune-related toxicities.
And maybe I could also add a bit on the hormone therapy as well, a few. Switching from IO, I think the other great excitement is de-escalation, or perhaps saying goodbye firstly to anthracycline. There is a very nice review paper by Harold Burstein in JCO, just published not long ago in November. Probably at the moment, from what we've learned, for HER2-positive disease, we can take off anthracycline quite with confidence. At the moment, with hormone-positive HER2-negative disease and triple-negative breast cancer women, perhaps we still need anthracycline at this stage.
However, if we look at the I-SPY 2 data, which is also very exciting and presented this year, as you can see, patients who are actually deemed high-risk with mammaprint, who are, say, Ⅱ-Ⅲbreast cancer patients, and they are actually put on neoadjuvant, either Docetaxel and Dato-DXd with or without durvalumab, the IO. Basically, just within a few cycles, and with zero monitoring of MRI, looking at the functional total volume of the tumour, and also repeated core biopsies, we can actually identify those who actually achieve complete pathological response, and could go straight to definitive surgery. This might mean, for some patients, we could actually spare them from chemotherapy. And so, on top of saying long goodbye to anthracycline, we might also be saying goodbye to chemotherapy one day.
This is further consolidated and supported by the TRAIN-3 study, which is a phase two study presented by our Netherlands colleagues at one of the rapid fire session at San Antonio. Basically, very similar. So, patients are actually monitored with zero image-guided optimisation, with the use of better neoadjuvant chemotherapy. When patients could achieve early complete pathological response as evidenced by image guidance, and also repeated core biopsy, they could, again, go straight to upfront definitive surgery. This is actually focused on stage two, HER2 positive breast cancer women in the context of the TRAIN-3 . Of course, the data needs further consolidation with prospective clinical trials in the context of phase three trials. But from what we have learned, probably there is one day, or at least a subset of patients, who could actually be spared from chemotherapy. At least, not just to the negative breast cancer patients, but perhaps HER2-positive disease.
Furthermore, for HER2-negative hormone-positive disease, I think there is also added value of upcoming new ADCs, antibody drug conjugates. And one of the phase two data presented by Mafalda and her team from the SOLTI VALENTINE trial is also showing added value of HER3-DXd with or without letrozole. And actually, women who are actually put on the tested arm, they have less side effects and better compliance, and also better clinical outcome. This is also showing added value of upcoming ADCs, and with a plethora of the added value and clinical significance of ADCs.
And finally, for the year in review, I think the better precision medicine with regard to better biomarkers, and also the use of ctDNA, especially with the use of ctDNA from the monarchE study that's just presented, and also in other studies as I've just shared, I think we are actually using more and more of these liquid biopsy, or like image guidance, to help us further stratify, apparently, particular clinical subtype.
This is not a common disease anymore, but a rare heterogeneous disease, meaning by different ctDNA levels or by different response to image guidance, we are actually stratifying different response towards a particular treatment. Yet, while we are sparing patients, say, from chemotherapy or from anthracyclines, this is at the cost of serum monitoring with radiology and core biopsy, so that is not without side effects in terms of financial toxicities, and also provided there is enough manpower in the healthcare system. So the more we know, the more we know how much we do not know. Particularly back in China, there are a lot of issues with regard to clinical governance, and also with regard to whether we have enough manpower and the equity across province to actually have the equal diagnostics and therapeutic strategies, and also equity to biomarker testing.
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肿瘤瞭望：KEYNOTE-522的探索性分析（LB1-07）发现，无论是否添加帕博利珠单抗，TcellinfGEP都是预测pCR和EFS改善的指标。TMB仅在帕博利珠单抗+化疗组中显示与EFS改善相关，您如何看待此项探索性分析的结果？
The exploratory KEYNOTE-522 analysis (LB1-07) found that TcellinfGEP was predictive of improved pCR and EFS with or without the addition of pembrolizumab. TMB was associated with improved EFS only in the pembrolizumab+chemotherapy arm. What do you think of the results of this exploratory analysis?
Janice Tsang教授：实际上，自ESMO 2024会议以来，我们已经获得了KEYNOTE-522研究的五年总生存期数据，而在SABCS上，Joyce O'Shaughnessy进一步更新了与潜在生物标志物相关的研究进展。她指出，T细胞炎症基因表达谱在帕博利珠单抗治疗中对pCR和EFS的评估可能具有一定的预后价值，但对于预测帕博利珠单抗的疗效反应则未能提供有效的预测指标。此外，肿瘤突变负荷（TMB）与帕博利珠单抗的应用也存在一定关联。
我认为这些发现仍然处于探索阶段，距离最终的结论还有很长的路要走。正如我常说的，“我们了解得越多，就越能意识到自己认知的不足。” 基本上，我认为我们仍然有一些临床问题需要解答，或许还需要进一步探索潜在的生物标志物。首先，我们需要问的是，是否所有纳入KEYNOTE-522研究的患者都有绝对适应症接受辅助帕博利珠单抗治疗。其次，在临床中，我们有时会遇到一些患者，他们的治疗反应非常好，可能在手术前就已经达到了pCR和CR。此次大会上，Marlene Koch的研究提出了这样的病例——一位临床医生患者在接受帕博利珠单抗和紫杉醇、卡铂类药物的治疗后，达到了pCR，并进行了手术，而没有使用蒽环类药物。我们是否可以有机会避免让部分患者使用蒽环类药物，而不仅仅是豁免辅助免疫治疗呢？我认为这是我们需要填补的一个空白，包括是否存在其他附加的生物标志物，可以帮助我们更好地确定免疫治疗和化疗（特别是蒽环类药物）的使用。
更重要的是，我们是否能够将辅助免疫治疗的使用与临床病理特征结合起来，特别是将肿瘤浸润淋巴细胞（TILs）的情况纳入考虑，并观察那些TILs表达水平高的患者也能避免接受强度较高的标准治疗？我认为，我们需要更多的合作和进一步的前瞻性试验，并结合生物标志物的监测，来更好地识别不同亚组的患者，这些患者可能从标准的KEYNOTE-522方案中获益，或者能够缩短辅助免疫治疗的疗程，甚至有可能豁免辅助免疫治疗，或者豁免新辅助治疗中的蒽环类药物部分。
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So actually, since the ESMO-2024, we have the overall survival data at five years for the KEYNOTE-522, and at this San Antonio meeting, we have further updates with regard to potential biomarkers as presented by Joyce O'Shaughnessy, and actually, it was noted that T cell inflammatory gene expression profile seemed to have some prognostic value in terms of complete pathological response rate and event-free survival for pembrolizumab. Yet, there is not predictive with regard to response to pembrolizumab. What's more, there is also association of tumor mutation burden with regard to the use of pembrolizumab.
I think the findings are actually exploratory, there are still a long way to go, the more we know, the more we know how much we do not know, as I always say, so basically I think there are some clinical questions that we still need to answer and perhaps we need further exploration of potential biomarkers. Firstly, is whether there's any absolute indication for adjuvant pembrolizumab for all patients who are actually recruited to the KEYNOTE-522. Secondly, I think in a clinic, we sometimes will have patients who have very good response with complete clinical response and complete pathological response perhaps even before surgery and there's actually a very nice paper by Marlene Koch actually talking about there is such a patient who is actually a physician, so basically she got actually complete pathological response with upfront surgery after pembrolizumab with the taxol carboplatin arms and without having the anthracyclines. So is there any place that we can spare some of the patients from anthracyclines, not just sparing them from the adjuvant immunotherapy? I think this is actually one of the gaps that we need to fill and whether we can have other additional biomarkers to help us to define the use of better immunotherapy and also the use of chemotherapy, particularly anthracyclines.
What's more, whether we can incorporate the use of the adjuvant immunotherapy whether we can incorporate the clinical pathological features with TILs and to see those with actually high TILs actually could actually also be spared from very intense standard therapy. I think we need more collaboration and also further prospective trials and also in connection with the monitoring of the biomarkers to better identify different subset of patients who would benefit from standard KEYNOTE-522 regimen to shorter duration, perhaps shorter duration of adjuvant IO or even those who could be spared from the adjuvant IO or those could even spare from the new adjuvant anthracycline base part.
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肿瘤瞭望：您认为，在推进乳腺癌的个体化治疗进程、提升治疗效果以及优化患者生活质量方面，目前还存在哪些亟待攻克的关键问题？同时，您能否分享一些可行的策略或措施，以供乳腺癌研究与治疗领域的同行们参考与借鉴？
In your opinion, what are the key problems that need to be solved in promoting the process of individualized treatment of breast cancer, improving the treatment effect and optimizing the quality of life of patients? In the meantime, can you share some feasible strategies or measures that you would like to share with your colleagues in the field of breast cancer research and treatment?
Janice Tsang教授：尽管在2024年年底（特别是在SABCS上），我们看到了许多令人振奋的临床研究数据，但我认为，我们始终面临着一个持续的挑战——如何将科学与可负担性相匹配。同时，尽管我们掌握了大量显示临床效果增益的临床数据，但这些成果是否能够转化为患者报告结局，从而更好的改善患者生活质量，以及是否会导致更多的毒性、副作用或经济负担，仍然需要我们从更全面的角度进行评估。
此外，我认为，全球经济目前处于衰退期，尤其是后疫情时代，诊断和治疗策略的公平性仍然是一个突出问题。尽管我们已经证明了不同免疫治疗策略对特定乳腺癌亚型患者的附加价值，但我们是否能够在全球范围内为所有乳腺癌患者提供这些治疗，不论其文化背景、经济状况或地理位置，仍然是我们面临的重大挑战。因此，我们需要携手合作，不仅要倾听同行的声音，还要积极倾听患者的声音，因为更好的个性化治疗并不意味着实际没有副作用产生。
在避免某些治疗的同时（例如化疗），患者可能需要进一步的密切监测或重复穿刺活检，正如TRAIN-3研究、I-SPY2研究或其他类似设计的研究所提示的，无论对于患者或者照护者而言，我们都需要一个决策共享的过程，来与患者和家属进行公开讨论或双向讨论。在中国文化中，家庭是社会的一个基本单位，所以很多时候我们不仅和患者本人交谈，还会与核心家庭成员共同进行讨论，因为他们全家作为一个整体共同抗击癌症。
此外，患者的价值观、经济状况、生活理念、生活质量以及她们希望达到的生活目标，都是我们在治疗决策时必须充分考虑的因素。我们需要进行开放的讨论，并确保患者能够参与到多学科团队（MDT）的讨论中去，使患者的治疗方案和管理能够得到各领域专业人员的全面审议。
对于乳腺癌治疗的挑战，我强烈推荐大家阅读《柳叶刀》上发布的共56页的《柳叶刀乳腺癌委员会报告》。这篇报告详细讨论了如何平衡乳腺癌女性的临床治疗效果和减少疾病负担的问题。乳腺癌一直是全球女性中发病率最高的癌症，在各大洲和各个国家都存在，我们应当倾听患者的声音，尤其是在诊断时、病情不佳时，以及传递坏消息时，始终保持倾听的态度，关注患者的未满足需求，以便更好地与患者和家属共同制定个性化的护理计划。
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While we are actually having so much exciting data towards the end of the year from all the clinical trials especially at the San Antonio meeting, I think we always have the ongoing challenge of matching science with affordability and also while we have all the clinical data showing added value in clinical outcomes, whether that is also translated to patient reported outcomes, better qualities of life and also whether that is actually just translated to further toxicities, side effects or financial toxicities, I think we need a more holistic approach.
What's more, I think we have economy downturn at the moment globally post-COVID time and also there is issue of equity to better diagnostics and also therapeutic strategies. While we have proven added values of different neutral articles and also proven strategies for various subset of breast cancer women, whether we can provide these for all breast cancer women across continents, across culture, across economy background, I think that's our challenge and therefore we need to join hands not just only to listen to ourselves to have better communication with our colleagues but firstly to actively listen to our patients , because better personalized care doesn't mean that it's actually not without side effects.
With sparing patients from particularly treatment, say sparing from chemotherapy, patient might need further close monitoring or further repeated core biopsy as eluded by say the TRAIN-3 study or the I-SPY2 or other similar study designs. And whether this is what the patient or carer's goals, we need to have a decision-making shared process to have open discussion or a two-way discussion with the patient and the family members. In the Chinese culture the family unit is a basic unit of the society so a lot of time we are not just talking to the patient herself but also the family at least the nuclear family as a whole because they are fighting the cancer together as a family.
What's more is patients core values, their financial status, their philosophy of life and also their concerns of qualities of life and life goals and things that they want to do and not to compromise because of any kinds of treatment. We also need an open discussion. And also we need to ensure that patients have access to multi-disciplinary team discussion, i.e. each of the patient's program and also their management has been thoroughly discussed by all the different specialists in the MDT team. There is a very good paper 56-page Lancet Commissions on Breast Cancer which I would strongly encourage everyone to read. Basically it talks about the challenges and also the balance everything how we could ensure that we are actually having better overall clinical outcome of breast cancer women but also not having overburden of the disease because the number of breast cancer is increasing. It's been always number one cancer for female around the world and across all continents and countries. and we should also listen to our patients to see their views and also to be able to communicate at the time of diagnosis, at the time when the disease is not doing well, at the time of breaking various kinds of bad news that we are always there be listened and also listen to their unmet needs so that we can collaborate, co-create and co-construct better care for the patient, their families and also those around them.
Janice Tsang教授
香港大学李嘉诚医学院荣誉临床助理教授，肿瘤医学专家
香港乳腺肿瘤学组（HKBOG）创会主席
（来源：《肿瘤瞭望》编辑部）
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