Editor's Note: At the 2024 SABCS conference, Professor Janice Tsang from the Li Ka Shing Faculty of Medicine, The University of Hong Kong, presented on "Early Breast Cancer Updates" during the annual progress session. Following the conference, Oncology Frontier conducted a special interview with Professor Janice Tsang, inviting her to share the latest research advances in the treatment of early-stage breast cancer. She reviewed the exploratory analyses of key studies such as KEYNOTE-522 and also delved into the challenges and solutions for personalized treatment of breast cancer, providing valuable insights for colleagues in the field of breast cancer.Oncology Frontier：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.
Professor Janice Tsang: 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.
Oncology Frontier: 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?
Professor Janice Tsang：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.
Oncology Frontier: 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?
Professor Janice Tsang：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.
