MammaPrint: Breast Cancer Dr. Nasrazadani SABCS 2022 70-gene 10 Year Follow Up
What has this 10 year follow up on this clinical data shown in patients with early-stage breast cancer? So this is in a real world retrospective study utilizing the 70-gene MammaPrint assay in a cohort of patients at UPMC of patients that were diagnosed with early stage breast cancer between 2005 to 2008, specifically looking at the ability to prognosticate, with regard to distant metastasis free interval, in patients that have an either low risk or high risk MammaPrint (test or genetic testing) index with the low risk profile being further stratified into ultra low, which is defined as an a MammaPrint index of 0.355 to 1 or low, not ultra low, and of course the high risk, which are previously been defined.
And we are addition, we’re looking at (early stage) breast cancer specific survival rate, and which we were successfully able to validate that indeed. There we, we find that there’s a statistically significant and clinically meaningful difference in patients that have low versus high and within low, ultra low versus ultra low, low, not ultra low specific cohorts.
What is the MammaPrint test?
A laboratory test used to predict if breast cancer may spread to other organs or return. The test examines the activation of 70 distinct genes in breast cancer tissue from women with early-stage invasive breast cancer that has not progressed to lymph nodes or has expanded to three lymph nodes or less. If the test reveals a high likelihood that the cancer may spread or return, anticancer medication may be required. Also termed 70-gene signature (or MammaPrint test).
What is the standard of care in early stage breast cancer?
So in early stage breast cancer, sometimes it’s very clear as far as the role for adjuvant chemotherapy, and sometimes it’s not so clear based on clinical pathologic parameters. And that’s why we utilize assays, like MammaPrint assays or similar assays, that help us determine, on a genomic risk level (Eg. low genomic risk), how to proceed with regards to giving the appropriate recommendations for these patients.
With the idea that if we can spare someone a chemotherapy, which may not have an, a significantly clinically meaningful benefits to be more thoughtful in our recommendations a particular interest that would’ve been really what setting MammaPrint (test)apart is the fact that now defining this ultra-low risk cohort allows us to not only make recommendations perhaps about chemotherapy, but endocrine directed therapies.
So it follows that, as we are seeing with the ultra-low cohort, that certainly they have the associated with clinical parameters that are more low-risk, for which you probably would not be as a medical oncologist (experts in clinical oncology), and we would not be leaning towards adjuvant chemotherapy. However, as we know with endocrine-directed therapy, there are certainly issues, especially with patients that have a lot of comorbidities, or we know there are issues with compliance and intolerance, and in our elderly population with osteoporosis.
This and other kinds of side effects make it a little bit difficult to really stick to their standard of care, durations of that are recommended for endocrine-directed therapy. So if we are able to identify patients within this ultra-low cohort, perhaps we can consider a shorter duration of endocrine-directed therapy, on which now considering these types of data, which is further validating publications that have been done by the Agenda group, that will perhaps, based on these, that we have trials that are being designed to look at shorter duration to appropriate deescalation of endocrine-directed therapy.
Rather than the 5-year mark, would it be appropriate to do 2 years? And then have more confidence in our recommendations to shorten the duration in the appropriate cohort where the risk would not be at the expense of prognosis. And I think specifically we are seeing not only in this study, but also in previous publications again, this validating in the larger agenda cohorts showing that in this specific patients who do have, harbor, the tumors that have ultra low, MammaPrint index that indeed their prognosis is so excellent that really it follows that it hypothetically maybe the end directed therapy does not necessarily have to be at that 5 year mark.
And perhaps we can do something shorter while they are getting a magnitude of benefit. But again, we can perhaps spare them from toxicities or be more comfortable knowing that compliance is going to be an issue.
So the trial design actually follows previous studies, with MINDACT studies specifically looking to validate the 70-gene panel (or MammaPrint test) and its ability to prognosticate high versus low risk and whether or not chemotherapy decisions regarding chemotherapy can change outcomes, modeled based on previous studies and validating those findings.
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What is the 70-gene expression signature?
A laboratory test used to predict if breast cancer may spread to other organs or return. The test examines the activation of 70 distinct genes or gene expression in breast cancer tissue from women with early-stage invasive breast cancer that has not progressed to lymph nodes or has expanded to three lymph nodes or less. If the test reveals a high likelihood that the cancer may spread or return, anticancer medication may be required. Also known as MammaPrint (test).
What significant data can you share with us?
I think there are two bits of information that are specifically important to touch upon. One as we’ve kind of went over already, where the findings regarding the ultra low risk group. However, do you think it is very important to you, again, emphasize the importance of this cohort and perhaps using these molecular assays to find these patient cohorts again in, for thoughtful deescalation in the right patient panel. However, on conversely, we did see when we stratified these findings by age, looking at patients that were either over 50 or less than or equal to 50 years of age.
While we did see similar trends as far as excellent prognosis in the ultra low risk group, and then slightly less favorable and the also still excellent. The low, non ultra low risk groups with a significantly less favorable outcomes in the high risk group.
The trends followed in both sets. However, in the cohort of patients that were less than or equal to 50, we did see that when we were looking at the occurrence of distant metastases, metastases events that the events that occurred in the specifically the low not ultra low group, that these events were occurring after 5 years. So this is a group that would be classified within the low risk group.
However, after 5 years, if we’re seeing events occurring, that is presumably the time when we were making decisions or having discussions about discontinuation of endocrin directed therapies and whether then we should be looking more closely or at least warrants more of a discussion of extending perhaps beyond the 5 years. So in conversely to what we’re talking about, the ultra low risk group, and I think it’s going to be really exciting to hear the results of the IDEAL study that was going to be discussed later today. And I think that’s going to give us guidance on how to proceed specifically in this cohort.
So specifically within our data set, of course, it’s a a smaller cohort of validating much larger data sets. But things that were of interest, interesting in this study is that although the, these types of assays (Eg. MammaPrint test) are for hormone receptor positive HER2-negative patients specifically.
This study did enroll a small proportion of patients who actually harbored HER2-positive disease, and interestingly, when we looked at the BluePrint subtype analysis, we found that while there certainly was a significant portion of these (early stage) breast cancer patients that had HER2 or HER2 enriched, of course with the largely every most of these patients being within the luminal subtypes and as well as a smaller population of basal subtypes still, there were certainly a portion of the HER2-positive.
The patient’s harboring HER2-positive disease that were luminal subtype. And so it’s interesting because it tells us more about what are the driving pathways within the subset that you would anticipate would be her to risk perhaps. And another particularly unique aspect of our data that we obtained from the UPMC cohort was that when we broke it down by therapies that received, so one important point to make a disclaimer about this data is that the MammaPrint assay was obtained independently.
It was not used for clinical decision making in a clinical practice, and it was used as for research (translational research) purposes after the fact. So therapies given were based on physician discretion at that time. But when we look back to see that, when they were broken down by therapies received, interestingly within our cohorts of the low sorry, within the ultra low risk, everyone received endocrine direct therapy primarily or no therapy.
And so the prognosis, excellent was expected and really it makes sense that chemotherapy, adjuvant chemotherapy was not advised for these other groups. However, in the high risk groups or the low, not ultra low groups when at the physician’s discretion when chemotherapy was given, we didn’t see actually that results were not as favorable or superior rather than patients that only received endocrine therapy.
Which is counterintuitive because the whole point is that the idea is that we want to be able to identify breast cancer patients that would benefit from adjuvant chemotherapy to make their prognosis better. And going back and looking at some of the clinical pathologic parameters we saw that they were not as well balanced or looking at stratifying, who got endocrine directed therapy and who also got chemotherapy within those specific cohorts.
And that they were just harbored higher, the breast cancers were just higher risk to begin with, even within the subpanel, so that is the point that we acknowledge and that they were not well-balanced.
But again, this is a smaller city, but overall the trends still follow and the main conclusion still appropriately allow us to say that yes we were able to, of course, validate the ability of the MammaPrint assay to prognosticate with regard to high versus low. And of course the kind of the unique things that we talked about as far as the ultra lower group and then the less than or equal to 50 year old group and their specific (high) risk by nature of their group.
What were the primary endpoints?
The primary endpoints were looking at distant metastasis free interval and breast cancer survival specific. And yes, absolutely they were met. And again, they did show that concordant looking at the low risks versus the high risk absolutely did follow that there was a clinically meaningful and statistically significant difference in those parameters.
What are your closing thoughts?
At the expense of being redundant, essentially, really the two points of utilizing the MammaPrint assay perhaps in a lower risk population that we generally in practice perhaps would not be looking to obtain this test for, but the idea that perhaps we can identify patients that we think may actually be within that ultra lower risk group.
For which we may have a higher level of confidence if we know we’re going to run into issues with tolerating endocrine directed therapy or perhaps compliance issues. At least giving us a better idea of what we think the natural course history of that disease is going to be. And again, if we think that maybe they will not, for whatever reason going to be able to undergo the 5 years of standard of care directed endocrine directive therapy recommendation.
Would this be a patient profile that we would be more okay with in identifying these patients? And again, looking at the specific specifically looking at patients that are equal or less than to 50, acknowledging that even though there is a within that the low, not ultra low patient profile, even though they’re low risk with regard to their MammaPrint (test).
That certainly we see that these patients compared to our older population do have distant metastasis events popping up after 5 year mark, which again, is that point of when we are stopping endocrine direct therapy. So I think it warrants more of a a discussion about and who is the right person to continue that and whether we should be considering extending, considering the data.
Azadeh Nasrazadani, MD, PhD – About The Author, Credentials, and Affiliations
Dr. Nasrazadani is an Assistant Professor in the Department of Breast Medical Oncology, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center in Houston, Texas. She is involved in many studies and clinical trials, during this clinical trial, she was at UPMC.
Reference
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NIH – National Cancer Institute – MammaPrint. NIH – National Cancer Institute, 2022
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NIH – National Cancer Institute – 70-gene signature. NIH – National Cancer Institute, 2022