New therapies to treat advanced endometrial cancer
Professor Gini Fleming – University of Chicago Medical Center, Illinois, USA
Dr Fleming, you’re not a long way from home here in Vancouver from Chicago and you’re working on new therapies to treat gynaecological oncology, specifically advanced endometrial cancer, I think, you’ve been addressing here at the meeting. There’s a lot happening, isn’t there, could you survey this for me please? Briefly, what came out of your talks?
We were talking about how to move forward from the current standard which is carboplatinum paclitaxel for women with advanced or metastatic endometrial cancer. The interest has been in these so-called newer targeted agents and there have been two groups that have been particularly of interest. One are those that attack blood vessels, the anti-angiogenics and there have been many tested and all seem to have some level of activity.
And there is a big study on the Gynaecological Oncology Group at the moment, isn’t there?
Well there is a study that has already finished accrual and we’re hoping to have results by December. That was a randomised phase II study where one group of women got carbo-paclitaxel plus bevacizumab and the other got carboplatin paclitaxel plus temsirolimus, which is a different newer targeted agent that affects a different pathway.
Now what then is happening in endometrial cancer and how much grounds for hope with these two approaches might there be? The anti-angiogenic or targeting the PI3 kinase, the mTOR inhibitors?
Unfortunately, when used by themselves these newer so-called targeted agents have not proved to be overwhelmingly active. They all produce response rates in the range of 5-20%, depending on the study, and they haven’t been blockbusters. But I think the hope is that when used in combination with chemotherapy they may significantly improve outcomes but that remains a hope, we don’t know yet. I think it’s clear that genetically, and again there was another very exciting talk, unrelated to mine, by Dr Levine that the Cancer Genome Atlas has now finished their analysis of endometrial cancers and come up with entirely new classifications for endometrial cancers which we hope will provide new targets and new ways that we can improve cure rates for this disease. But in the meanwhile we know that lesions in the so-called PI3 kinase AKT mTOR pathway are pretty much universal in endometrial cancer so attacking them seems a very reasonable approach.
And I should ask you about metformin because that’s been talked about too.
It has and metformin is the favourite child of new agents right now because it’s very well tolerated, it’s widely used for diabetes and it’s very inexpensive and there has been data in a lot of different cancer types that among diabetics, those who use metformin are both less likely to get cancers, including endometrial cancer, and have better outcomes once they get those cancers. So those information are now being taken forward into trials and there’s an on-going randomised study in breast cancer, conducted by the NCI Canada actually, of standard therapy with or without the addition of five years of metformin. That should be very interesting. And the GOG, the Gynaecologic Oncology Group in the US, has proposed a trial of adding metformin to carboplatin paclitaxel therapy for endometrial cancer. That has not yet been approved by the NCI so we’ll see where that goes but it’s a very interesting and very non-toxic option.
Yes indeed, but what might be happening to cause these benefits?
I think there are two things that metformin does. One is metformin lowers insulin levels, that’s how it works to treat diabetes and there’s considerable evidence that insulin might both cause cancers and cause cancers to grow. There’s a whole pathway called the insulin-like growth factor receptor pathway and companies are busy making drugs which block that pathway, so-called IGFR inhibitors, both monoclonal antibodies and small molecules, but another way is simply to lower insulin levels. The second thing is that metformin is in fact an mTOR inhibitor so it acts through that other pathway that I was just discussing with you.
It is perhaps not as potent as some of the other mTOR inhibitors that are being developed specifically for that purpose so nobody really knows why but those are the two lead hypotheses as to why it might be of interest.
Now looking, though, at this GOG study with the temsirolimus and bevacizumab, what is actually happening in those two arms? What might be happening to cause them to diverge?
At this point we simply don’t have results. One possible thing that we might find is that because there is unfortunately, or fortunately, no control arm that we won’t be able to tell you whether it’s better than carboplatin paclitaxel alone but the hope is that one or the other arm will look much better and that possibly we’ll find some genetically targeted subset that we can say, ‘Oh yes, this is the group that temsirolimus really helps for.’ Thus far that has eluded us and I discussed that, it’s been very disappointing but we’re still trying.
Are there differences with respect to side effects between these two agents?
Very much so. Well metformin, obviously, there’s very few side effects, a little bit of weight loss which is a good thing for most women with endometrial cancer and a little bit of diarrhoea perhaps. Now bevacizumab, as is well known, causes high blood pressure and related side effects to that as well as risks of a bowel perforation and fistula. The temsirolimus causes a variety of side effects including mucositis, mouth sores, tiredness, high blood sugar levels, high triglyceride levels, so it’s not a benign agent.
Bevacizumab isn’t the only anti-angiogenic, are other ones in the running?
There are many other anti-angiogenics and in fact one of them, brivanib, is going to have its trial reported out later today in endometrial cancer, that will be interesting to see as it also targets a whole other mutation called the FGFR or fibroblast growth factor receptor which seems to be a so-called driver mutation in some endometrial cancers; that will be interesting. There are many others that are in the running. The tyrosine kinase inhibitors or the small molecule pills have in general been a little bit harder to combine with chemotherapy and thus far none of them have looked better than bevacizumab but many are still being tested.
OK, so you’ve been looking at new directions in advanced endometrial cancer, could you sum up what you think doctors can take away from this meeting here in Vancouver?
I think that the most promising of the new agents that we have at the moment are probably metformin, anti-angiogenics and bevacizumab, however, they are not yet proven. The current standard of care unfortunately remains surgery and carboplatin paclitaxel chemotherapy.
So how much improvement could we hope to get with this disease in the foreseeable future?
In the immediately foreseeable future I think realistically we’re not going to achieve cures of advanced disease with these new agents. Realistically if we could extend survival by six months we would be considering that we’re doing very well. So we’re not yet at the level of the home run that we’re looking for.
And the lessons for busy cancer doctors right now?
Wait for more trial results before changing your standard of care. However, I think that adopting carboplatin paclitaxel versus the Adriamycin containing regimen is probably reasonable for everyone in private practice as a standard of care.
Gini, thank you for joining us on ecancer.tv.
Thank you very much, it’s my pleasure.