Dr Francis has told us that if there’s oestrogen still there in your pre-menopausal woman when she’s had chemotherapy or because she’s very young, it could be a big gain, apparently, from using ovarian function suppression. Can you tell me first of all what was your reading of what we heard today?
The SOFT trial, which is the trial that addressed this in the pre-menopausal group, compared Tamoxifen versus ovarian suppression plus Tamoxifen versus ovarian suppression plus an aromatase inhibitor, exemestane. If you looked overall the best of the three was ovarian function suppression plus exemestane; the next was ovarian function suppression plus Tamoxifen and the least effective was Tamoxifen. But then when you started to look at various subsets you found that Tamoxifen was just as good as the other three because all three groups had a very excellent prognosis whereas ovarian function suppression plus exemestane or Tamoxifen might be indicated for other sub-groups. Particularly striking was the 35 year old or under patient where they have very well-functioning ovaries, they have oestrogen levels that go sky high on Tamoxifen and in that group in particular it looked like adding in ovarian function suppression plus exemestane was significantly better than the others.
This was quite a big study so do you think we can now make recommendations about using ovarian function suppression?
Yes, I think so. I think that particularly in the less than 35 year old they deserve consideration for ovarian function suppression and an aromatase inhibitor but also for groups that have a high risk of recurrence regardless, so those with multiple positive lymph nodes and so forth. People who have a much higher risk of recurrence on Tamoxifen, a little bit of additional benefit that they might gain from having ovarian function suppression plus an aromatase inhibitor becomes a large benefit in them. So patients who have a high risk of recurrence and those patients less than 35 years of age would be the ones that would be focussed for ovarian function suppression in addition.
Of course it’s quite a drastic thing, would there be an impact on lifestyle, any toxicities that might concern women?
Yes there are. There’s no question that ovarian function suppression adds toxicity, absolutely true, and not every woman would be able to tolerate it, unfortunately. So you have to consider that, you have to consider the risk of breast cancer recurrence and death in a woman. Alternatively you could try somebody on the therapy and if they don’t tolerate it very well you could always go back to Tamoxifen. All three of those treatments are very good and it’s just that ovarian function suppression was a little bit better, particularly in the younger age group, and if they tolerate that well then that would be the best therapy for them.
So you’re cautious brief recommendations to doctors around the world, busy cancer doctors with patients, perhaps young ones, coming in, what would your recommendations be?
I’d recommend that they go on ovarian function suppression plus an aromatase inhibitor like exemestane, at least as a trial, and if they tolerate it well continue that for five years.
Thank you very much.
Of course, what we don’t know is whether Tamoxifen for ten years might be almost as good as the ovarian function suppression and exemestane for five, that wasn’t tested. It was Tamoxifen for five so whether longer duration of Tamoxifen would provide the same degree of benefit is unknown.
You’ve noticed some interesting things on oestrogen receptor mutations. What came up?
First of all, there’s an interesting history here. When people have looked for oestrogen receptor mutations in the past they haven’t been able to find them very often. It seemed remarkable to us that an important a protein as oestrogen receptor that is the cause of many breast cancers and when you target the oestrogen receptor it’s an excellent treatment, it’s hard to imagine why a tumour wouldn’t have mutated that receptor to make it even more active. Most of the studies looking for mutations were in the primary tumour originally; there was one exception. Dr Suzanne Fuqua, who happened to be in my group at the time, about fifteen years ago found a mutation in the oestrogen receptor, a couple of them as a matter of fact. Those were in patients with metastatic breast cancer and that turned out to be the key. If you look in samples of tumours from metastatic cancer after the patient has already become resistant to, say, an aromatase inhibitor or even Tamoxifen in some cases, that’s when you find these mutations. The reason is that the mutation existed in maybe a very small percentage of cells originally in the primary breast tumour but you couldn’t measure it because it was so rare. But with time and treatment you get rid of, with the treatment, the cells that don’t have the mutation and you bring out and enrich for the cells that do. So now you can detect it in a metastatic resistant tumour. It turns out that these mutations make you more resistant to endocrine therapy. They’re constituently active receptors; they don’t care about oestrogen any more, they’re just turning on and driving the tumour. Now, if we could invent new drugs or new ways of inhibiting those mutant receptors, that would be a new endocrine therapy.
Now, in practical terms how might you be able to exploit that knowledge to clinical benefit?
First of all we frequently re-measure oestrogen receptor in a metastatic tumour when a patient has recurred and failed their initial therapy. We biopsy that to see if it’s still oestrogen receptor positive. It usually is, not always, and then if it is we give another endocrine therapy. What one might imagine now would be that in addition to determining whether the receptor is positive or there, you could also measure to see if these mutations are there. If the mutations are there then further endocrine therapy is likely to be ineffective or less effective and you would go on to some other form of treatment. If the mutation is not there then the patient would be more likely to respond to another endocrine therapy and you would give that. So introducing the ability to measure for these oestrogen receptor mutations in patient specimens is something that we’ll have to think hard about going forward.
Is that something that doctors could easily incorporate into their routine?
Yes, there are platforms or companies or institutions that are measuring these things now and it wouldn’t be long before panels of these mutant oestrogen receptors would be available to measure on a routine basis. Right now it’s a little difficult unless you have exposure to a research laboratory but there are laboratories and commercial laboratories that are setting up for these assays.
And then you could switch therapy and personalise medicine sooner, quicker, with better results?