Prof. Xu：Good afternoon professor Cortes. It is my honor to have today’s online communication with you. My name is Yingying xiu， I am a breast surgeon from the department of breast surgery at the First Hospital of China Medical University. At this year’s ASCO meeting your research for PHERGain trial has attracted wide attention. It provides a nice way to evaluate early response of neoadjuvant therapy and lets some patients who are sensitive to dual HER2-blockade could be chemo free. I think it is a very exciting result， but for this study I still have some questions to ask you if you don’t mind.

 

I remember previous literature showed the metabolic change in breast tumor could be detected as early as two weeks after beginning anti-HER2 therapy， and in TBCRC026 trial the PET evaluation was performed at 15 days after trastuzumab and pertuzumab. But in your study PET scan was given after two cycles of dual HER2-blockade， about 6 weeks. Why did you choose this time point? In your opinion， which is the best time point? Thank you. 

 

Prof. Cortes：First of all， thank you so much for the interest in this study and also for giving me the opportunity to discuss with you and to give my personal thoughts， my personal comments about this project. As you very nicely mentioned before， this is a study that tries to de-escalate chemotherapy for those patients with HER2-positive early breast cancer. The basic idea of this project is to try to develop an strategy based study， which means that for all patients with this disease we will try to start with anti-HER2 therapy only， without chemotherapy， and depending on the PET scan and depending on the pathological complete remission， the patients will receive or not chemotherapy. And if we are able to observe a similar invasive disease-free survival (iDFS) than expected then we will be able to de-escalate treatment. So， the question you raised before I think it is important， we have， and you are completely right， preliminary reports showing that PET scan or MRI after very early on time， two to three weeks， we can predict which patients will have a pathological complete remission， and this is right. So， why did we decided to go for two cycles， which is in general about 5 to 6 weeks? Well， it was a bit arbitrary， but it is true that we will need to try to have the maximum value of the PET scan， so imagine， and it is true， that after two weeks you did very good， but imagine there are some patients that maybe will respond after 4 or 5 weeks， we want to be sure that nobody who could have benefited from this strategy will not have it. That is why we decided it to go a little bit more and go for 5 to 6 weeks instead of two weeks. But it is true， that maybe in two weeks could be enough.  

 

Prof. Xu：Thank you. So， in your study， the treatment status was adjusted by PET response or not， so what is the definition of PET response? What is the optimal PET cut-off as you SUVmax for pCR?

 

Prof. Cortes：That is a lovely question. And the honest answer is we do not know which is the optimal cutoff. But it is true that there is some data in the literature saying that a response and reduction in the SUV of 40% or more is good enough to consider a response. Is this the optimal cutoff? This is something we are trying to also analyze in this study， if we can see a better cutoff but the literature says at 40% reduction is considered a good response. 

 

Prof. Xu：I think it is the second primary endpoint of your study， right?

 

Prof. Cortes：So， this is the first co-primary endpoint， we have two primary endpoints. One of them is patients who achieved pathological complete response between those patients who achieve a PET response. 

 

Prof. Xu：Thank you. So， definitely PET/CT is a more accurate assessment， whoever in our country， specially， in a lot of places in China due to economical， medical resource or other factors， ultrasound and MRI are the most commonly used to asses during the neoadjuvant therapy. So， do you think we could use these ways instead of PET/CT to guide treatment adjustment?

 

Prof. Cortes：Well， first of all I do not know if we can use PET scan to do that， we should remember that we need the second co-primary point which is the most important one， which is – long term outcomes to see if this strategy works. So， if this strategy works which means， once again， PET response， no chemo， pathological complete response， no chemo. So， if this strategy works， I think that in the future we have to discuss about further strategies with cheaper assessment such as ultrasound or MRI. The point with the PET scan is that with the data we have today it correlates very nicely with this pCR， moreover in our study we think it is something very， very remarkable， I would say. For those patients who achieve this PET response a significant number of patients will have pathological complete response 37.9， almost 38%， which is a very impressive number. So， can we achieve these numbers with MRI? With ultrasound? Well， it is not very well known. But with PET is clearly something of interest. In the future， again， if we demonstrate that this works， it is much cheaper to go for PET scan twice but decrease the chemotherapeutic agents in maybe one out of three patients. 

 

Prof. Xu：So， you will wait for the disease-free survival data， right? But， I think the primary endpoint is 3 years invasive-free survival， right? So， you will wait that data to see if the response cutoff is the best one， right? And we can use PET/CT to do the prediction， right? 

 

Prof. Cortes：That is totally right， exactly. So， we will wait to have these results and if we have the results， we might expect， then we will say–listen， let´s start with the PET scan response， pCR， and depending on that we will give or not chemotherapy. 

 

Prof. Xu：I think is a very smart design. It is very interesting. 

 

Prof. Cortes：Thank you so much my friend. I think it is provocative， I think it is quite innovative. But I think in the future if we want to de-escalate treatments these type of trials should be conducted， in my opinion. 

 

Prof. Xu：Yes. So， in your study I see you collected tissue and blood samples at the baseline， at two cycles of neoadjuvant therapy and surgery. Do you think we have other biomarkers that could be used to assess early response of neoadjuvant therapy? Maybe a combination of the imaging and the biomarkers to decide which one is sensitive and which one is not， such as for PER-ELISA trial after two weeks of Letrozole they do the opposite， the Ki67 was used to guide treatment next step， maybe we can make the combination of the imaging and the biomarker.

 

Prof. Cortes：Sure. Absolutely， definitely you are completely right. We will have blood sample but also tissue samples. So not only Ki67， but also tumor‐infiltrating lymphocytes maybe we will try to discuss how the PAM50 platform， so HER2 or non-HER2 we will try afterwards to build something to define which is the optimal group of patients who will not need chemotherapy. 

 

Prof. Xu：So， now do you have some interesting results with the tissue or blood samples? 

 

Prof. Cortes：We are doing that effort now and I hope to maybe have some data for San Antonio， but I do not know. But at this time， I want to be honest， we do not have anything yet. So， I do not have any data. 

 

Prof. Xu：I hope you will have soon data. And we know there are many factors related to the sensitivity of the anti-HER2 therapy， and your study shows that a PET response was higher in hormone receptive-negative， and HER2， IHC 3+ patients， on these patients condition with pCR population?

 

Prof. Cortes：Okay， we should not forget something， in general， who are the patients that might respond better to a PET scan? Maybe those ones who are more sensitive to anti-HER2 therapies which are patients with ER-positive， HER2-positive. So， maybe patients without hormone receptor positivity are the ones who are more likely to respond. However， because of that， many of these patients will receive chemotherapy afterwards. So， this is why maybe we can say – listen， in our arm B in those patients who receive no chemo treatment at the very beginning， ER-positive was not clearly correlated with response. But the answer is very clear， because more patients with hormone receptor positive tumors receive chemotherapy compared with patients with ER-negative tumors. Again， we have to build everything there to understand which is the optimal group of patients who will not need chemotherapy. Probably those ones with ER-negative， HER2， 3+， those patients are more likely to respond to anti-HER2 therapies， also helping with the addition of the PET. 

 

Prof. Xu：I remember in the PAMELA trial we find the intrinsic subtype is different with IHC to detect HER2， for the hormone receptor positive patients maybe about 40% is a real HER2-enriched patient. But in hormone receptor negative patients there are about 85% is the HER2-enriched patient and can be sensitive for dual anti-HER2 therapy. So， do you think we can use intrinsic subtype of PAM50 or the HER2 heterogeneity detection initially， in other words， begin before we do the neoadjuvant therapy? It will be helpful to develop treatment strategies.

 

Prof. Cortes：Sure. And this something we will definitely look at. Again， I think that the HER2-enriched respond better to anti-HER2 therapy， which is very clear. But also， we should not forget they also respond better to chemotherapy. The point here is， are we able to de-escalate treatment based on the intrinsic subtype? Not today， because we have not done any clinical trial based on this biomarker with an invasive disease-free survival endpoint. So， I agree with you that if we look all these things， we will be able to optimize which patients will not need chemotherapy in the future. 

 

Prof. Xu：Okay. I have a last question. In the KATHERINE trial adjuvant treatment was T-DM1 results in 50% lower risk of recurrence or trastuzumab alone among HER2-positive patients who have residue invasive disease after completion of neoadjuvant therapy. Now， the proportion of the dual HER2-blokcade in KATHERINE was less than 20%. So， we also know in APHINITY trial that trastuzumab and pertuzumab has a good survival data even in high risk lymph node positive patients. I see in your study arm A， for non-pCR of the dual blockade during the neoadjuvant therapy you will go on and give them pertuzumab and trastuzumab to do the adjuvant therapy. So， we still have no head-to-head comparations between PH and T-DM1 for non-pCR patients we know. But in your clinical practice which regime would you prefer for non-pCR patients with dual HER2-blockade neoadjuvant therapy?

 

Prof. Cortes：What a beautiful comment， what a beautiful question. So， in my clinical practice… So， in clinical studies again we have to see the results， although it is true that once KATHERINE became available some patients who did not achieve pCR after chemotherapy， herceptin and pertuzumab， we have a dilemma about， can we change into T-DM1. And there are some patients， not many， I don’t have the numbers， maybe 8 to 10 patients who received T-DM1. But in my clinical practice when I go for chemotherapy， herceptin and pertuzumab， and we do not achieve pCR， I switch to T-DM1. The question is out of there and it is a very good question: What is better? To change to T-DM1 or to continue with herceptin and pertuzumab? I do not know. But if I can switch， I do it. 

 

Prof. Xu：it is my opinion， I think these kinds of patients maybe there are in two situations: one is near pCR， so the residue disease is about maybe smaller than 1 cm. I think it demonstrates the sensitivity of the neoadjuvant treatment of HP and these patients maybe we will let them go on dual HER2-blockade adjuvant therapy， maybe it is fine. And the other is real non-pCR， the residual disease is much larger maybe because of drug resistance， maybe this kind of patients we can recommend T-DM1 for adjuvant therapy. That is my opinion. 

 

Prof. Cortes：Sure， that is again a very good point. If we look at KATHERINE patients who receive anti-HER2 therapy before surgery and they have a very good response but not complete， also benefited from the use T-DM1. But of course， it is not the same. And it will continue with herceptin and pertuzumab， I do not know. So， it is very reasonable to continue with herceptin and pertuzumab but if you are asking me， in my clinical practice， I would prefer to change. 

 

Prof. Xu：As the KATHERINE trial? 

 

Prof. Cortes：As the KATHERINE study， correct. 

 

Prof. Xu：Okay， thank you. Do you think the toxicity of T-DM1 is much higher than HP regimen? 

 

Prof. Cortes：Well， HP has diarrhea which is not an issue without chemotherapy but could be. T-DM1 is harder， it produces more asthenia， of course thrombocytopenia， transaminitis. I think it is worse compared than herceptin and pertuzumab. But also， the toxicity profile is very nice with either of these strategies. 

 

Prof. Xu：In your clinical practice， the T-DM1 toxicity it is fine， right?

 

Prof. Cortes：Yea， it is fine. I prefer herceptin and pertuzumab， but T-DM1 is also very good. 

 

Prof. Xu：Okay. Thanks again for solving many of my puzzles. Thank you so much. 

 

Prof. Cortes：Thank you so much. Thank you. 

 

Prof. Xu： And hope the epidemic will pass soon. And we can have the chance to talk face-to-face. 

 

Prof. Cortes：That would be great. Thank you so much my friends and thank you so much again for your interest in this study. Thank you.  

 

Prof. Xu：The last question is， as mentioned in the abstract follow up is ongoing for ideas and endpoint depending on the results of this second co-primary endpoint， this strategy could select a group of patients who would not need chemotherapy， how will the results of this study change clinical practice?

 

Prof. Cortes：The good news， I think this is an excellent comment， the good news is that at least in many countries herceptin and pertuzumab are approved in this setting. So， this will depend on clinicians if they feel comfortable and confident on this study and on these results， you can do it in the clinical practice because you do not need anything to be approved. The drugs are there， it is just to decrease the use of chemotherapy. It is not to add anything， just to decrease chemotherapy. So， it will depend physician by physician the confidence in the study. Let’s see the results and we will be more than happy to discuss with you again the data.