I’m presenting data from a recently completed prospective phase II window of opportunity clinical trial.
What were you focussed on?
Tamoxifen, which is a widely used drug in breast cancer, how it impacts gene expression when this drug is given to patients who have never been treated, who did not see any therapy, who never had a previous cancer or anything like that. This has not been done from this angle so this will be the first study to look at that gene expression. What we have done is we give tamoxifen, randomly distribute patients into two groups, one group will go through usually the standard of care which means they wouldn’t usually get any medicine until they go through surgery one month later. The other group we give tamoxifen therapy for four weeks and then after four weeks the tumour is resected as usual and then from that tumour we do our various analyses including a very sophisticated high resolution gene expression analysis called RNA-Seq. That’s the data which I’m going to present.
How many patients were recruited?
We recruited a total of 59 patients between Roswell Park and my collaborators’ institute, the University of Chicago Medicine. Of the 59, 52 patients completed the study and those are the samples we analysed.
What were your findings?
The conventional role of tamoxifen has been that it will bind to the oestrogen receptor and prevent oestrogen from binding because oestrogen is the hormone which activates this receptor downstream activating a whole bunch of genes whereas tamoxifen will compete it so it’s called a competitive inhibitor and bind to the oestrogen receptor thereby inactivating it. That’s known for years from various research groups.
What we found was that in addition to targeting the conventional targets oestrogen receptor can also target genes regulated tumour suppressor protein p53. p53 is one of the most important tumour suppressor proteins which is inactivated one way or the other in most cancers and breast cancer is one of those. In this particular cancer, the subtype of breast cancer we looked at is called luminal breast cancer, there p53 is genetically normal – in scientific terms it is called wildtype. However, it is basically dysfunctional so that’s where the oestrogen receptor comes. Oestrogen receptor comes and binds to the p53 protein and inactivates it. This we knew, several years ago we published this, a few years ago, both in the cell models and in animal models and also in a prospective clinical trial in collaboration with a group in Germany and Baylor College of Medicine. That was consistent, all the data, but it still did not prove that this interaction indeed occurs in patients and when you give tamoxifen this interaction is disrupted. So that’s what we showed here. As a result of that disruption a whole bunch of hundreds of genes, more than 400 plus genes, are differentially up or down regulated in tamoxifen treated patients compared to the untreated patients.
What are the implications?
The implications are big in the sense that right now, even though p53 has been known to be a major tumour suppressor, especially in breast cancer p53 is not factored into decision making of therapy for various reasons because directly targeting p53 has been tough and some of the past data on p53, because of the reagents issue, has been equivocal. But now we have far better resolution techniques so our data would imply that depending on the p53 status the tumours can respond or not respond to tamoxifen. So that’s the big thing. Because even though theoretically all ER positive breast cancers are supposed to respond to tamoxifen because the drug is against a receptor and the receptor is there but in real life one of the main problems in the clinic is that many such patients don’t respond to tamoxifen to begin with, even if they respond after a while they develop resistance. So our findings say that just one of the important mechanisms behind that is that p53 status is different. If p53 is so-called normal p53 it will work, the patients with such tumours will be responsible, but if the patients’ tumours have a mutant p53 then even if tamoxifen disrupts the p53 interaction the resulting p53 is genetically dysfunctional to begin with so therapy will not be working. That’s the implication.
So to put it another way, our data will enable… we are to go through a larger clinical trial, of course, enable to make a decision which patients will be receptive or which patients will be benefitted by tamoxifen therapy and which patients will not be. Right now any woman who walks into the clinic at the breast cancer, the first thing clinicians do is to check for oestrogen receptor. As far as they are oestrogen receptor positive invariably they get tamoxifen therapy but many of them it won’t be of benefit. So we will be able to stratify the patients based on p53 status and that will have a major implication in conventional therapy.
Another thing which we did not address in this trial because the trial is always limited because, unlike other animals or cells, it’s hugely time-consuming and hugely expensive so you can only focus on one small thing in a clinical trial, but in combination with this from other studies what we see is that even in a subcategory of breast cancer called triple negative where the receptor is not there we see that tamoxifen can be beneficial if we stratify those patients in terms of p53 status. So that’s something new. But that is yet to go through a clinical trial but this is what we already know in patients. So it is very gratifying to see whatever we saw in the cells and animals now we can see in real patients. So that’s the big strength of the clinical trial.
