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Kathy D. Miller, MD: Hi, I am Dr Kathy Miller. Welcome to the Medscape InDiscussion podcast series on breast cancer and HER2. Today, we’re going to think about predicting the future, predicting which patients will have a pathologic complete response (pCR) to therapy. That’s become an incredibly important landmark for us, both in the clinical care of patients and in research, as we think about new treatments or reducing the intensity of treatments. I am delighted to welcome Dr Lajos Pusztai as my guest today. This is completely in his wheelhouse and area of expertise.
Dr Pusztai is a professor of medicine at Yale University and co-director of the Cancer Center, Genomics, Genetics, and Epigenetics program. Dr Pusztai is also chair of the Breast Cancer Research Committee of the Southwest Oncology Group and has worked in this area for a number of years. Dr Pusztai, welcome to the Medscape InDiscussion Breast Cancer and HER2 Podcast.
Lajos Pusztai, MD, DPhil: Thank you, Dr Miller. It’s a real pleasure to be here, and I look forward to discussing this topic. There have been so many remarkable improvements in the neoadjuvant therapy of HER2-positive disease,
Miller: Before we think about predicting who’s more likely to have a pCR, can you remind our listeners why we care about pCR in the first place?
Pusztai: pCR is a pathologic complete response. And the definition is no residual invasive disease in the breast and lymph nodes. This outcome of the neoadjuvant therapy, probably regardless of the regimen that induces it, has been associated at a patient level with really excellent long-term metastasis-free survival. It’s not a perfect surrogate. There is still probably a 2%-5% risk of metastatic recurrence, even with a complete pathologic response. And we increasingly realized that many of these recurrences are happening in the central nervous system, in the brain.
pCR becomes a little bit controversial at the trial level as an early surrogate endpoint for efficacy, but by and large, I do believe that higher complete pathologic response identifies a more effective chemotherapy regimen that ought to be associated with better outcomes for patients who get into that outcome group.
Miller: We have so much to talk about today because we need to think separately about predictors for those patients who are HER2 positive, and then those patients who may have lower levels of HER2 expression. But first, you mentioned something that might be confusing and puzzling to many of our listeners: On an individual-patient basis, there’s very little question that patients who have a pCR do better. They have a lower risk of recurrence than those who don’t have a pCR. But when we’ve tried to look at that association at the clinical trial level, do trials that have an improvement in pCR always have an improvement in disease-free survival or overall survival (OS)? It is not a particularly good predictor at the trial level. Do we have any insights into that apparent disconnect?
Pusztai: There is no perfectly airtight or validated explanation for this, but I have a pretty reasonable potential explanation. The conundrum is that many traditional chemotherapy trials in the neoadjuvant space — for example, adding carboplatin or a platinum to a taxane-anthracycline regimen — improved the pCR rates, often by 15%-20%, yet the event-free survival (EFS) rates did not improve at all or just very non significantly. On the other hand, some of the immunotherapy trials showed a relatively small improvement or not even significant improvement in the pCR rate. Yet they showed an improvement in EFS. The prime example is the KEYNOTE-522 trial, where the final pCR difference with pembrolizumab was only about 6%, yet EFS and, now, OS also improved.
One reasonable explanation for this is that the different regimens induce a different sort of impact on not just the pCR rate, but the distribution of residual disease. So pCR is wonderful, but having a 0.5 cm invasive residual cancer is still better than having a 1 cm invasive cancer.
A 1 cm residual invasive cancer is better than having a 3 cm. So the pCR endpoint does not take into account the effect of the new adjuvant treatment on the distribution of the RCB among those who did not achieve a pCR. And in the I-SPY study, which had multiple different arms, each arm is relatively small, but each arm included different types of neoadjuvant regimens. We noticed that different kinds of treatments cause a different distribution in the residual cancer burden (RCB) distribution of the patients. Immunotherapy drugs and HER2-targeted therapy drugs actually shifted the RCB to lower categories across the entire population. So there were fewer RCB-3, fewer RCB-2, fewer RCB-1 patients. So in other words. Even the residual disease patients had a better outcome in terms of their response than the control group. Whereas some other regimens, like actually carboplatin, did not have this sort of overall shift towards smaller amounts of residual cancer. It just moved some of the minimal residual disease into pCR, and that’s probably a somewhat logical explanation why those types of neoadjuvant therapies may not improve the recurrence free or EFS, because they move an already good prognosis group, minimal residual disease, to a very good prognosis pCR group, whereas those regimens that move a lot of the extensive residual cancer to a small or medium amount of residual disease they can have a much more pronounced impact on survival. That’s my hypothesis, and we published a paper describing this.
Miller: It’s a fascinating hypothesis, and we only need to look at the impact of hormone therapy on pCR to realize that the importance of pCR is very much related to the mechanism of action of that therapy. Because pCR rates to hormone therapy are exceedingly low, yet they clearly reduce recurrence and improve OS. It’s good to hear you talk about the data and the ability to begin to parse what other therapies might be shifting all of the extent of residual disease classes, and what might just be tipping patients who were almost at a pCR into a pCR, but without really changing the outcome for those other patients.
Pusztai: Thank you for reminding me and bringing up this very important point that the post-surgical adjuvant therapy, of course, has a major impact on the outcome of patients with residual disease. So the endocrine therapies for the ER-positive patients, capecitabine for the triple-negative patients, and T-DM1 shortly, in HER2, also in the HER2-positive space. And if these adjuvant regimens are highly effective, then this really diminishes the importance of the initial complete response or the lack of it to the initial neoadjuvant therapy.
Miller: I wouldn’t say it diminishes it, perhaps, but it allows us to use pCR in a different way of selecting patients for more vs less therapy, rather than your future depends on achieving a pCR.
Pusztai: Exactly. And it also has implications for cost-effectiveness and toxicities. It’s a really, really fascinating area to think about the implications of intensifying new adjuvant therapy to maximize pCR rates vs minimizing and aiming for the regimen that accomplishes pCR, maybe not in the largest population, but in a subset, and try to intensify the treatment for those who have not achieved the pCR.
Miller: Let’s talk about the classically HER2-positive patients, because to be able to really begin to individualize therapy, it would be helpful to have a better sense of who is more or less likely to achieve a pCR. So what have we begun to learn about those predictive factors?
Pusztai: I think the single most important predictive factor is the estrogen receptor status, the ER status. All of the neo-adjuvant trials showed that those who are ER-positive and HER2-positive have a lesser chance to accomplish a complete response than those who are ER-negative. Probably the second most important component is the initial T and N (tumor and nodes) stage of the disease.
We increasingly see this in trials: The clinical stage matters for the probability of pCR and for long-term survival. Additional biomarkers emerge in this space, like the HER2DX assay that identifies the HER2 extremely high or highly amplified cases, which again, have a better chance of responding, homogeneous HER2 expression throughout the tumor increases the probability of pCR. Probably tumor-infiltrating lymphocytes (TIL) continue to carry a predictive function, although it’s less well studied in the HER2-positive context than in triple-negative disease. So I think there are multiple factors that contribute, and the single most important one is the ER status, the estrogen receptor status.
Miller: We saw that very powerfully in the recently reported Compass-pCR trial, which gave patients a pared-back chemotherapy regimen. Just 12 weeks of single-agent taxane with dual HER2 inhibition, just right off the bat, as you reminded us, those patients who were ER positive had only about half the likelihood of pCR. But if you added the HER2 DX score, you could identify a group of patients before they even started treatment who had a greater than 75% likelihood of achieving a pCR, compared to patients in whom that likelihood was only about 30% or a little less than 30%. You can already imagine how that might impact the treatment patients received in the neoadjuvant setting. Those are really big differences.
Pusztai: Absolutely. So the CompassHER2 trial. The overall pCR rate was about 44%, so that’s not particularly high compared to what more complex, more toxic, and more expensive regimens could do. But if you look at the population that was the HER2 DX High, they actually had a pCR rate, which is entirely in the same ballpark as the most sort of complex, expensive, and toxic regimens could do. For example, trastuzumab deruxtecan.
Miller: Let’s think a little bit about those that have lower levels of HER2 positivity, either the HER2 low or the zero. If they’re ER negative, we would call those triple negative and lump them together. That is another group of patients who are frequently treated with neoadjuvant therapy, in this case with a checkpoint inhibitor. Have we begun to have some insights into who’s more or less likely to achieve a pCR in that group?
Pusztai: Yes, so the HER2 low group is sort of a heterogeneous group. They include ER-positive patients and ER-negative patients. So the majority of the HER2 low cancer patients are also ER positive, so they would be currently considered as HER2 negative ER positive patients. And in that patient population, from a different sort of angle, we already identified the subset that is highly sensitive or more sensitive to chemotherapy, neoadjuvant chemotherapy, and probably even immunotherapy than the ER-positive population by and large. And that is the MammaPrint ultra high group. It probably also would apply, although less well studied, to the extreme high end of the recurrence score, like 31 or above.
So those ER-positive patients are most likely to accomplish a pCR, but their pCR rates are still not as high as what we see in triple-negative disease or in the traditional HER2-positive patient population.
Miller: In that ER-positive, HER2-negative patients, the pCR rates are not only lower, but it does not seem to have the same impact on long-term outcome. If we hone in on those that are ER-positive, HER2-negative, with the MammaPrint ultra high, does that predictive value of pCR reemerge?
Pusztai: Nobody knows the answer for that for sure, but of course it would make sense to assume, and that’s why we hope that that’s the population which has its high risk MammaPrint or recurrence score to high risk implies that they are to high risk despite taking the appropriate therapies, so they have a high residual risk.
And if there is a better therapy for these folks, then this is the population where the association between improving the pCR rate would have the strongest association with improving outcome, because their outcome otherwise is not that great. This is why they are called ultra-high risk. There is a clinical trial that tried to address this.
Miller: I do want to hear about the clinical trial, but of the ER-positive, HER2-negative patients, about what proportion are in that ultra-high-risk group?
Pusztai: It’s about 25%, 30%. But that’s among the MammaPrint high group. About a third of those 25%-30% are the ultra high. So if you take all comers, and that is all ER positive patients, this MammaPrint ultra-high population is probably 10%-15% at most. So it depends on the denominator.
Miller: I do want to give you a chance to tell us about the clinical trial because this is not a particularly common group, but 10%-15% of the ER-positive HER2-negative group is not a small number of patients.
Pusztai: Yes, so that’s about the same number as the triple negative population. It’s probably about 10% of all breast cancers.
Miller: Tell us about the current clinical trial for that group of patients.
Pusztai: The I-SPY Clinical Trial Group noticed a few years ago that the MammaPrint ultra-high, ER-positive, HER2-negative population had a doubling of their pCR rates when they received neoadjuvant Taxol. Concurrently, pembrolizumab followed by dose-dense AC (doxorubicin [Adriamycin] and cyclophosphamide). A couple of other arms of the I-SPY that also included immunotherapy drugs such as durvalumab or pembrolizumab combined with some experimental toll-like receptor antagonist drugs, all concurrent with weekly Taxol showed the same improvement in pathologic CR rate, A doubling of pathologic CR rates. So that initial observation in three separate arms of the I-SPY trial prompted the cooperative group study to validate this observation in a large sort of nationwide randomized two-to-one trial, which compares standard of care, neoadjuvant chemotherapy in this population that’s ER positive, HER2 negative, and MammaPrint ultra high vs the same standard of care, chemotherapy plus durvalumab.
We used durvalumab because that was the study that originally prompted this concept. The standard care arm in that trial is Taxol and dose-dense AC. The trial aims to accrue 900 patients, and we have accrued about 300 in the first two years. And, we look forward to completing the study. It’s important for this population because they’re high risk with the current therapies, and also that’s one of the few trials that was designed by the cooperative groups and does not include a maintenance immunotherapy component like the KEYNOTE-522 trial has, which of course has important implications for costs and potentially for toxicity as well.
So that’s a pure neoadjuvant trial that isolates out the impact of adding an immune checkpoint inhibitor durvalumab to neoadjuvant chemotherapy in this highly chemotherapy-sensitive, or the most chemotherapy-sensitive subset of the ER-positive population. And of course, after completion of their surgery, they all continue with their sort of residual disease-appropriate endocrine therapies.
Miller: In our last couple of minutes, I want to take you to the traditionally triple-negative population, which is also a group where neoadjuvant therapy is frequently recommended, where pCR at the individual level has a significant impact on prognosis. Other than anatomy and disease extent, what do we know about who’s more likely to achieve a pCR in that group?
Pusztai: In the triple negative population, the single most important variable or factor that could predict pCR is the extent of TILs. There are many ways to capture the presence of immune cells, but the most straightforward is probably just counting the TILs.
And the higher the TIL count, the greater the likelihood of benefit or pCR from the adjuvant chemotherapy. With an interesting caveat that TILs are also prognostic even in the absence of any therapy, so small triple negative disease with a very high TIL count, like 50% or 70%, actually has an excellent survival outcome even in the absence of chemotherapy.
So that’s a very bold proposition, but it’s supported by some really intriguing data from the Netherlands, where in the late 1990s and 2000s, it was standard care for the country not to do chemotherapy in small, triple negative patients. So they have a substantial population of triple negative patients who were not receiving any chemotherapy after their initial diagnosis.
And in that cohort, those who had a very high TIL count did really well.
Miller: So this feels like a really simple and powerful prognostic marker that we have not really exploited in the clinic. Most of our standard pathology reports don’t report TILs. With any new pathology assessment, there will be questions about reproducibility from pathologist to pathologist, and how reliable the assessment is. I can only imagine that the ASCO/CAP group is going to be tackling this sometime soon.
Pusztai: Yes. The challenge with TILs used to be the reproducibility, but I think the International TIL, TIL study group really came up with some fairly straightforward standardization process. I think the TIL counting is getting more and more sort of reproducible across pathologists than reliable, but the biggest challenge is that it’s a continuous variable and there’s no TIL-positive TIL-negative. All the thresholds that we would introduce are arbitrary, so unlike very well-defined values for the recurrence score assay or MammaPrint, that can define that if you are above this, we do that. If you are below that, then we do something else. This threshold doesn’t exist from prospective randomized trials for TILs, and I think that’s one of the important limitations of really acting on it in the clinic.
So we know that the higher there is, the better, but how high should it be to even consider, for example, not doing chemotherapy, or doing it? So the threshold, I think, is a major issue that limits its clinical implementation.
Miller: We will look forward to that in future studies. And I know, having seen several of those TIL correlative analyses, the thresholds that they have looked at as being high or low are all over the map. So that would be a challenge trying to employ that now, but you can see it coming in the future.
Pusztai: Yes.
Miller: Today. We’ve talked with Dr Pusztai about predictive factors for achieving a pCR. For those that are traditionally HER2 positive, the ER positivity was by far the most predictive, but some recent data suggest that the HER2DX assay is also important for the traditional triple negative patients. TILs remain prognostic and predictive of pathologic CR, even with chemotherapy alone, not just with checkpoint inhibitors. Some new information from I-SPY now being tested in a cooperative group trial, looking at the benefit of checkpoint inhibition in patients whose tumors are ER positive, but MammaPrint ultra high, A group that we might not have traditionally thought about neoadjuvant therapy, but for whom chemotherapy is certainly justified given their high risk. and a suggestion that. The checkpoint inhibition might be helpful for that group as well. And of course, across all of those different phenotypes, anatomy is still important. It’s harder for our systemic therapies to eradicate a really big tumor than it is to eradicate a really small tumor.
To our listeners, thank you for tuning in. Please take a moment to download the Medscape app to listen and subscribe to this podcast series on breast cancer and HER2. Dr Pusztai, thank you so much for joining us and sharing your expertise.
Pusztai: Thank you. It’s my pleasure.
Miller: This is Dr Kathy Miller for the Medscape InDiscussion podcast.
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Resources
Overall Survival With Pembrolizumab in Early-Stage Triple-Negative Breast Cancer
Oncotype DX Breast Recurrence Score®: A Review of Its Use in Early-Stage Breast Cancer
Toll-like Receptor-Based Strategies for Cancer Immunotherapy
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Cite this: Beyond pCR Rates in Breast Cancer and HER2: Understanding Response, Residual Disease, and Outcomes - Medscape - Mar 24, 2026.
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