Endocrine Therapy: 70-Gene MammaPrint Test Predicts Benefit in Early-Stage Breast Cancer Laura Van ’t Veer PhD

Endocrine Therapy: 70-Gene MammaPrint Test Predicts Benefit in Early-Stage Breast Cancer Laura Van ’t Veer

Laura Van 't Veer, PhD By Laura Van 't Veer, MSC, PhD

Breast cancer patients who are diagnosed with breast cancer that is endocrine sensitive. So those tumors that are estrogen receptor positive, their standard of treatment is 5 years of endocrine treatment, Tamoxifen or tyrosine kinase inhibitor. So recent trials have shown that an extension of that 5 years to 10 years benefits patients that which there's some benefit in survival. But the question has been for some time, who benefits because it's only a modest benefit and the extension of the therapy, like the 5 year initial one, comes with side effects, patients often don't like. So you would wanna give it only to those patients that really will have a benefit. So what we did, we looked at the IDEAL trial, which is a trial that looked at 5 year extension versus 2 and a half years. Extension by giving patients additional Letrozole, which is an aromatase inhibitor treatment. So the total treatment was either 10 years of a endocrine treatment or 7 and a half. And so what we did in this particular study that we looked at the original tumor blocks of the first diagnosis of these patients, which we can use to understand. Particular patient is of a low risk of recurrence or high risk of recurrence by using a test called MammaPrint. So MammaPrint is a 70 gene test that can divide patients in high risk or low risk for recurrence, which initially was used to define who needs chemotherapy. So those with a high risk of recurrence are recommended chemotherapy. So now what we did was in this IDEAL study where, extended endocrine therapy was given for 5 years or 2 and a half years. Who are the ones who benefit from this 5 years extended endocrine treatment. And what we found was that those patients that have a low risk for late recurrence are the ones who benefit from the 5 year extension with an aromatase inhibitor. So not the ones who have a high risk for an early recurrence because their recurrence is early, so they do not have any late risks so an extension of therapy doesn't benefit them, and also not patients who have an ultra low risk of recurrence because they don't have any or much risk for recurrence to begin with. So the group in the middle, which is about 40% of patients with endocrine sensitive therapy are the ones that could benefit from extended endocrine therapy. So what is presented here at San Antonio this year? Is this finding in the IDEAL trial, this same actually finding was reported at ESCO in 2021 on the NSABP B-42 trial. So that was also a trial where extended endocrine therapy was tested. In that case, it was 10 years of extent of total endocrine therapy versus the standard of 5 years. So also in that particular trial, we went back to the original tumor blocks of those patients when they were diagnosed, and we identified at patients who are MammaPrint low risk for late recurrence. Are the ones who benefit from extended endocrine therapy. So this means that we have now found in 2 clinical trials that were randomized for this particular question, the same thing. The extension of endocrine therapy is particularly beneficial for those patients who are at risk, low risk, but at low risk for a late recurrence. And finding that in 2 independent trial is really strong evidence that this is something that could be of clinical utility for patients who have this and for whom the physician and the patients have this question today.


What is the standard of care in this disease state and why choose to pursue the ideal trial? 

For patients diagnosed with estrogen receptor positive breast cancer, endocrine therapy sensitive standard of care is 5 years of an aromatase inhibitor or tamoxifen. And so the question has been or data has been there that extension of that 5 year gives a modest be extra benefit, but it's only modest and all of this therapy always comes with side effects. So you don't want to give it to everybody, so the we turn to the IDEAL trial, which is presented here at San Antonio.  and earlier to the NSABP B-42 trial, which was presented at ESCO last year, which both are trials studying extended endocrine therapy to see who benefits. And in both of those studies, we show that patients whose initial tumor is MammaPrint low risk for late recurrence. So their recurrence risk is after 5 years benefit from an extension of the endocrine therapy up to 10 years.


Can you please tell us about the trial design and why it was set up this way?  

So for patients with endocrine sensitive breast cancer, the standard is 5 years of endocrine treatment, and the question is, for whom would an extension benefit? And is then actually a 2 and a half year extension, so total of 7 and a half years, or a 5 year of extension, even better, that's a total of 10 years and so this IDEAL trial addressed the question where an extension of endocrine therapy with 5 years would do more than 2 and a half years. So when they evaluated the total trial, it actually didn't really matter the 2 and a half or the 5 years extension. But now that we looked into the biology of the disease that patients had a diagnosis, we show that the 5 year extension is specifically beneficial for those patients that have a MammaPrint low risk for late recurrence biology.


Can you give us significant data from the ideal trial?  

So what we show in this presentation at San Antonio is that the extension of endocrine treatment to 5 years gives a 10% survival benefit as compared to a 2 and a half year extension. For specifically for patients whose tumor biology is MammaPrint low risk for late recurrence. So that means that they're, they really have a 10% benefit, which actually relates to a 60% relative benefit as to just giving only 2 and a half years. And that's true for 40% of the patients that were treated in that trial, which is more or less, 40% of all patients were diagnosed with endocrine sensitive tumors.


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What are the most common questions you get from your colleagues about this study?  

The questions that people may have is, how do we recognize this group that benefits from extended endocrine therapy? And so you have to go back to the original tumor diagnosis and the tumor block that you can use to do a molecular test called MammaPrint to understand the risk of recurrence for that particular patient. So the MammaPrint test is able to identify patients at ultra low risk for recurrence, low risk for late recurrence, or high risk for early recurrence. The high risk for early recurrence are patients who benefit from chemotherapy, we now show that patients who are diagnosed with low risk for late recurrence benefit from extended endocrine therapy, and we know that those patients diagnosed with ultra-low risk tumors don't have much risk for recurrence anyway, so they're, their treatments can be more limited in time and they don't need any chemotherapy.


What are the primary end points of the ideal trial and where they met?  

So the endpoints to evaluate extended endocrine therapy were distant recurrence, recurrence free interval and the endpoint. So in the original trial, the difference between 5 year extension and 2 and a half years extension of endocrine therapy, we didn't make a difference for those endpoints. But now that we did this translational study by looking at the biological subgroups by MammaPrint in this patient population, we identified that those that have MammaPrint low late recurrence risk for those, the endpoints are met. So there is a significant difference in survival for those patients for the endpoints distant recurrence and recurrence-free interval.


What are the key takeaways from this research and data?  

Final takeaways To understand which patients benefit from extended endocrine therapy in 2 trials, we have shown that MammaPrint, low late recurrence patients are the ones that benefit from extended therapy. So if there is a question for a patient who has had and completed 5 years of the standards endocrine therapy, who needs. To have the extension, you can just look at the tumor biology. Do a test with MammaPrint and you would know which ones will benefit and which other ones actually will not benefit, so they don't have to suffer the side effects unnecessarily.

How does MammaPrint help with the use of endocrine therapy in Breast Cancer?

MammaPrint is a genetic test that measures the risk of breast cancer recurrence by analyzing the activity of 70 genes in a patient's tumor tissue. This information can assist physicians in making more educated judgments on the use of endocrine therapy in the treatment of breast cancer.

Endocrine therapy may not be indicated for individuals with early-stage breast cancer who have a low chance of recurrence according to the MammaPrint test, as the advantages of treatment may not outweigh the potential side effects. On the other hand, endocrine therapy is frequently suggested for individuals with a high risk of recurrence to lower the probability of the cancer returning.

In addition, the MammaPrint test can assist in determining which individuals are most likely to benefit from prolonged endocrine therapy. For instance, if MammaPrint indicates that a patient has a low chance of recurrence, he or she may not need to continue endocrine medication beyond the typical five-year timeframe. However, if a patient has a significant risk of recurrence, hormone therapy beyond five years may be beneficial.

Overall, the MammaPrint test can assist doctors personalize treatment strategies for breast cancer patients, including the use of endocrine medication, by providing valuable information. By personalizing a patient's treatment to his or her specific risk of recurrence, physicians can enhance outcomes and reduce the danger of unneeded treatment.


Laura Van ’t Veer, MSc, PhD - About The Author, Credentials, and Affiliations

Dr. Laura Van t' Veer is a world-renowned Molecular Biologist who serves as the HDFCCC's Breast Oncology Program Leader and Associate Director Applied Genomics. She is the founder of MammaPrint and the former Head of Diagnostic Oncology at the Netherlands Cancer Institute. Her study focuses on personalized medicine, with the goal of improving patient management by understanding the genetic makeup of the tumor as well as the patient's genetic makeup. Her UCSF laboratory has a strong research line that investigates human kinases and how kinase inhibitors generate response and resistance. She is the cancer convener for the UCSF Precision Medicine Platform. She chairs the I-SPY 2 trial's Biomolecular Committee, which ensures CLIA-compliant companion diagnostics. She is the Principal Investigator of the Athena Breast Health Network at UCSF, a 150,000-woman cohort study evaluating new paradigms to improve breast health in which she leads the targeted genome testing for 65,000 women for nine breast cancer susceptibility genes and a selection of 100 known susceptibility SNPs (SNPs). She is one of the principal investigators at the NIH Big Data to Knowledge Center on Genomics, which promotes global standardization of sharing annotated genomics data. Her involvement as chair of the AACR Diagnostic Policy Committee and chair of the National Biomarker Development Alliance's Scientific Advisory Committee highlights my leadership in this area.

Endocrine Therapy: 70-Gene MammaPrint Test Predicts Benefit in Early-Stage Breast Cancer Laura Van ’t Veer PhD

Dr. Laura Van 't Veer discusses Endocrine Therapy: 70-Gene MammaPrint Test Predicts Benefit in Early-Stage Breast Cancer