Posted on Dec 08, 2023
Thanks for speaking to us Ralph. Firstly, could you summarise the results of the study presented at San Antonio Breast Cancer Symposium (SABCS)?
Initially we started with looking at Oncotype DX itself, the Recurrence Score and the output it gives for oestrogen receptor alpha (ESR1), progesterone (PGR), Ki67, and HER2 (ERBB2). We wanted to compare how they relate to the results from MammaTyper®. And we found a very high concordance in two independent cohorts, particularly from Cologne.
Next, we were interested in how the Recurrence Score itself is related to the markers. Surprisingly, we found that progesterone receptor is highly negatively associated to the Recurrence Score. So, about 70% of the patients have very high progesterone receptor expression and very rarely have a Recurrence Score above 25. We then looked at independent cohorts from Heidelberg, where we found the very same result.
We worked with Rob Stein from the OPTIMA prelim study, where we did MammaTyper® measurement within a preliminary study where Oncotype, but also other systems like the ProSigna and MammaPrint, had been tested. And so, we checked whether, in this even larger cohort consisting of 407 patients, the progesterone receptor, either determined by Oncotype itself or by MammaTyper®, also distinguishes between high and low Recurrence Score. And we found that this is indeed the truth.
We have proven we have a very high sensitivity and specificity to be able to detect the patients who are below a Recurrence Score of 25 by local testing, which is clinically relevant. The Positive Predictive Value of MammaTyper® turned out to be 93.2%, with false positive cases being close to the predefined cut-off.
What surprised you the most about these results?
It’s very surprising from my point of view that only one gene (PGR) is so strongly associated and crucial for this 21-gene algorithm (Oncotype DX). This was surprising to me, but practically, this is also very helpful, because we can now discuss whether precision testing and true quantification of progesterone receptor is sufficient to spare further, costly testing and to spare chemotherapy.
It’s also very interesting from a clinical point of view to see that the progesterone receptor plays such an important role. Unfortunately, progesterone receptor testing is not always done in all countries worldwide. For example, in Great Britain, one does not test for progesterone receptor anymore, because clinicians question why this should be of importance, as they say it is not necessary as it is not a drug target.
However, progesterone receptor expression is highly predictive for survival, and moreover it’s even a true target, because you can give progesterone, which, in the case of high-risk node positive patients, gives them a survival benefit of about 7%, which was published some time ago. And so, the role of progesterone has been underestimated for diagnostic purposes, and still in the works in prospective trials as a druggable candidate.
What do you think of the correlation between PGR testing of MammaTyper® and Oncotype DX in this study?
I think this shows the accuracy of molecular testing by fully quantitative PCR. MammaTyper® is completely different to Oncotype in some technical aspects. You do not need to do macro-dissection like Oncotype. You do not need five housekeeping genes, it’s just two housekeeping genes for MammaTyper®, and it uses completely different kinds of primer probe set sequences.
But still, if you compare the Oncotype versus MammaTyper® progesterone PCR test, it’s almost identical and exchangeable. Even if you perform the Oncotype progesterone receptor assessment twice, you would not find a higher accuracy or correlation coefficient. It’s within the range of noise between two independent Oncotype measurements.
What are the next steps for this work?
The next step will be to look at survival. The OPTIMA prelim study now has more than five years of follow up. We are now in the position to look at whether the MammaTyper® progesterone assessment is highly prognostic, whether you can safely say “you don't need chemotherapy, you have a very, very good chance of survival”.
This is I think something which we should look at next: by comparing MammaTyper® and Oncotype DX progesterone receptor PCR results with overall survival and distant metastasis-free survival, and comparing the multigene expression profiling test of the first and second generation. We are currently discussing with our team and colleagues from the OPTIMA prelim trial, once we have all data available.
I think this will be the next very important step, and I’m quite optimistic that we can realise a good prediction of good outcome.
How should oncologists and pathologists use these results?
I think at the moment, some clinicians will say, well, this is level of evidence 1B, as it’s a technical comparison, retrospective with several independent cohorts, which came to the same conclusion. These are strong data, with clear cut tumour biological output.
Now the question is how to implement this IVD test into routine clinical practice, to accelerate decision making by local testing without the need to ship samples across the Atlantic to get an answer.
We have shown in multiple publications that MammaTyper® is very accurate across all continents and at each site, irrespective of whether it is in Canada, USA, China, Italy, Switzerland, Germany, France, or wherever. MammaTyper® has been approved as an IVD in Europe, and now it is available all over the world.
We have to discuss with the societies how to best implement it, to put it into the guidelines as the results are technically identical to the Oncotype DX testing, which has prospectively being shown to safely spare chemotherapy for breast cancer patients with oestrogen receptor positive, HER2 negative tumours – but most importantly, as we now know, being high for progesterone receptor mRNA.
For the ones which have low progesterone receptor and have a potential risk, I would say these tumours, which account for 30% of all patients, should still be sent to Oncotype as they have a 50% risk of having a Recurrence Score above 25. But for the rest, you can spare 70% of testing, you can spare time, you can make all the diagnostic discussions with the patient faster and less costly.
This is something which we have to discuss with the authorities, including the National Institute for Health and Care Excellence in Great Britain – I'm looking forward to discussing it with them. And I hope this helps for a timely introduction of MammaTyper® into general assessment to prevent chemotherapy.
We’re looking for clinicians to run studies with MammaTyper® to answer some of the remaining questions around the test. If you’d like to be a part of this, please contact us at info@cercabiotech.com.