Martine J. Piccart-Gebhart, MD, PhD, on Personalizing Treatments in HR-Positive/HER2-Negative Breast Cancer

If we start with this important trial, it is the 4th very large trial asking the question whether when we use multi acid signature and it indicates a good biology, not a very aggressive tumor. If we can omit chemotherapy in luminal breast cancer and just give these patients optimal endocrine therapy, Now OPTIMA is probably the, of the four trials that have tried to address this question, TAILORx, MINDACT, RxPONDER and OPTIMA, I think it's the one that has been best designed. The reasons for that are that the the choice of the endpoints is better than the in the other trials, the endocrine therapy that had to be given to young women was a variant function suppression based, which was very important because that was not the case of the other trials. So at the end, we saw chemotherapy effect in the young women in these other trials. But there was this long debate, was this direct chemotherapy effect or just an indirect effect of chemotherapy on the variant function? Also, it's the only trial with the recruitment of women with more than 3 positive notes. Now I recognize that this particular cohort of 511 patients is not a very large 1, so there will remain some uncertainty. But when you look at the curve you, you have the impression that indeed biology beats anatomy, meaning that if you have more than 3 positive notes but a favorable genomic predictor, you are going to do well without chemo. The the benefit of chemo is going to be really very, very modest. So I believe that this will change the way oncologist view the question should I give chemo yes or no. I think up to now most of us would not offer the test to young women because of all the uncertainty and certainly not do it in women with four to 9 positive notes based on OPTIMA. This is going to change. I still think that we have to be very honest and transparent with our patients. When we discuss, we have to explain that this trial has a follow up that is still a little short for years and that the courts of patients of greatest interest of the young women and the four to 9 positive notes are relatively small. So we have some uncertainty remaining and then it's a question of share decision making with the patient. So I can imagine that a young patient, 44 year old with two kids, 4 positive notes might decide still to get chemo because of the uncertainty. While a 69 year old patient when she will be told that the chemo benefit is likely very, very small will probably decide not to take chemotherapy. So it's a very well designed study and it has an impact on clinical practice. I think then another important trial I discussed was the NATALEE trial, the first translational research results. And what is very disappointing is that in all these large adjuvant trials, we do conduct this translational research analysis. I think we are very naive in thinking that we are ever going to identify clinically useful biomarkers. So a biomarker telling us this is the patient that will indeed benefit from the escalator therapy with the new drug and while these other patients will not. We have tried to do that for the last 10 years in all these trials. And honestly we have found some prognostic biomarkers, but not a single predictive biomarker. And my point is that cancer is such a complex disease, we need to understand that translational research has to be more comprehensive. So we should leave look at lots of factors, so not only the genetic basis of the tumor, but we need to examine how the pathology slides look like. We have to incorporate all these modalities which is something that is happening now with artificial intelligence. And so I can see that we are going to transit move to a very exciting period where our capacity to identify these predictive biomarkers will be enhanced significantly. I have just one worry. The worry is that artificial intelligence needs a lot of data. And then if you think you have discovered your multimodal biomarker, you know, you will still have to independently confirm that it works on another data set. And I'm worried because we see today that the large trials are fully controlled by pharma and sometimes they are not willing to give access to the data. So that's a problem that we will need to try to solve in the future. And then the easiest presentation to discuss was the results of the phase III lidERA according to menopausal status. So this is a very exciting new drug that will undoubtedly play a role in the adjuvant treatment of early luminal breast cancer. We just don't know today to which women we are going to give the drug. It's not yet FDA approved, I believe, but this drug is most likely one of the most important endocrine therapies we have ever seen up to now. And it was reassuring to see that the benefits in comparison with standard endocrine treatment is seen regardless of menopausal stages, that adherence is better, less patients stop treatment for toxicity or switch to another endocrine therapy. So this was very reassuring and I'm not very anxious to see further trials with this drug in particular. My preference, but I don't think the trial exists, would have been to look at what this drug can do after five years because, you know, in in this disease we still have a huge problem of late relapses with no effective therapy there. And I could imagine that a drug like that, which is very effective also against ESR1 mutations, could be playing their very important role.