IMPAKT Breast Cancer Conference 2013

The future of PI3K/AKT/mTOR inhibitors in breast cancer

Dr Sara Hurvitz - UCLA Santa Monica Hematology Oncology, USA

I’m very pleased to have the chance to talk with an expert on the PI3 kinase/AKT/mTOR pathways and other biomarkers that seem to be emerging as very important in breast cancer. Can I start off with the PI3 kinase because you’ve been working in a number of studies, the BOLERO-1 study. Can you, tell me first of all, why these biomarkers are important and what it is that you are contributing to the whole investigation to get agents that take action on these markers?

Well the PI3 kinase/AKT/mTOR pathway has been shown to be an activating pathway that contributes to resistance to targeted therapy. So when this pathway is activated it allows therapies that block the oestrogen receptor to not work any longer; it allows cells to continue to grow in the absence of oestrogen, for example, in ER positive breast cancers and may also contribute to resistance to trastuzumab which blocks HER2.

So it can defeat your best efforts, then?

Exactly and so a number of inhibitors of this pathway have been developed, really dozens of inhibitors of components of these pathways, PI3 kinase, AKT or mTOR or inhibitors that hit more than one of these components of the pathway. In our laboratory we have over fifty breast cancer cell lines and we’re able to evaluate new molecules pre-clinically against the cell lines and look at the activation of the pathway and how it relates to sensitivity to new agents that block this pathway.

Of course it’s quite a complicated science at the moment because there are many potential pathways. What is happening, what has emerged that looks promising at the moment?

Well everolimus is the furthest along. Everolimus blocks mTOR which is one of the later stages of that pathway, one of the proteins at the bottom of that pathway. That has now been validated in a phase III clinical trial and has been shown that in patients whose disease is resistant to an aromatase inhibitor, metastatic breast cancer that’s oestrogen receptor positive, that disease, if you give another aromatase inhibitor and combine it with everolimus, you improve the patient’s progression free survival and chance of responding to therapy. So this was approved by regulatory agencies last year.

Now what is it that you’re able to contribute with your cell lines and also, I gather, you do xenografts, for instance, that tie in exactly with your clinical work, because you are a clinician?

Absolutely. We’re able to analyse these molecules in different subtypes of breast cancer. Our work and others showed that everolimus or targeting mTOR may also be important in HER2 positive breast cancers or HER2 driven cancers. So this led to phase I testing of the molecule in combination with trastuzumab and chemotherapy that showed good responses and clinical benefit in very highly treatment refractory disease. That ultimately led to the BOLERO-1 study and BOLERO-3 study. BOLERO-1 is patients who have not had treatment yet for metastatic breast cancer; they all have HER2 positive disease and a third receive trastuzumab with paclitaxel, two-thirds receive everolimus plus trastuzumab-paclitaxel. So the study is looking at whether inhibiting mTOR will help prevent or prolong the time to resistance to trastuzumab. BOLERO-3 is asking a similar question but in patients whose disease has already demonstrated resistance to trastuzumab.

But you’re not asking these questions at random, you’ve got the precise science to tell you which questions to ask.

That’s the beauty of doing pre-clinical work to guide your clinical trial design.

You’re also quite interested in oestrogen receptor and you’ve got some interesting news there, for instance on cyclin D kinase inhibitors. Tell me all about that, what is that?

Well a few years ago my colleague, Richard Finn, looked at a new molecule that blocks cyclin D kinase 4 and 6 which is a very important protein that allows the cell to go through the cell cycle, to progress through the cell cycle. And he evaluated in the breast cancer cell lines and showed that the luminal types of breast cancer were most sensitive to inhibition with this molecule, that means ER positive or HER2 positive breast cancers. So this led to a phase I study that was very promising in hormonally driven metastatic breast cancer in combination with an aromatase inhibitor, which led to a phase II randomised study in which patients who had not yet been treated for metastatic breast cancer that was ER positive were randomly assigned to letrozole, an aromatase inhibitor, or letrozole plus the cyclin D kinase 4/6 inhibitor. The patients who received letrozole, their progression free survival was only around 7-8 months but the patients who received the cyclin D kinase 4/6 inhibitor, their progression free survival was 26 months. The difference between the two arms was highly significant and incredibly exciting but it was a phase II study. So the phase III study to confirm these findings has just opened, it’s an international randomised study looking at the combination versus single agent AI in this setting.

So it is beginning to look as if you’re getting on top of resistance in a number of areas of molecular medicine.

It’s certainly an exciting time, yes, because we are unfolding or unveiling a lot of clues to the molecular pathways activated that allow resistance to occur.

And PARP inhibition is another category, isn’t it?

It certainly is. PARP inhibition was a great hope for triple negative breast cancer and BRCA-mutated breast cancer.

Can you explain why?

In BRCA mutation, in cancers that have a BRCA mutation, there is a problem with DNA repair mechanisms. A back-up pathway is PARP, it’s an enzyme that comes in and takes care of DNA replication problems but it’s a faulty back-up mechanism. So if you have a cancer that can’t repair DNA well because there’s no BRCA expression and you have this limping enzyme that’s trying to get the cancer through, the cancer is able to divide and grow. But if you block that back-up pathway the cell dies. So it makes a lot of sense to look at these molecules in BRCA mutated cancers. What everyone tried to do was to extrapolate and also look at them in triple negative breast cancers because what has been shown is that triple negative breast cancers, even though they don’t carry a BRCA mutation, they have down expression of BRCA protein in a number of cases. So there was a trail that looked at this, a phase II trial that had very exciting data, but when the phase III data was shown it was negative. The problem is that the molecule that was being looked at truly didn’t inhibit PARP to an appreciable extent, it was a promiscuous inhibitor of many targets but didn’t inhibit PARP strongly. So there are other drugs that are being developed now that inhibit PARP rather exquisitely and the hope is that not only will they be effective in BRCA2 mutated cancers but that perhaps looking at them in triple negative cancers would also be useful.

But you’re painting a very confident picture about the future of understanding the molecular basis of some of these breast cancers, a lot more of these breast cancers than ever has been possible in the past. Will this translate, though, to practical progress in treating the disease?

One would hope and I think that’s what this is all about is hope.

How much?

Exactly. I think that we are building our positive attitude on the successes of the recent past. If you look at trastuzumab it has completely altered the natural course of HER2 driven cancers. We all hope that that will not be the last molecule that changes the course of disease. Everolimus, an mTOR inhibitor, has also really given hope to a very treatment-resistant type of breast cancer that’s the most common breast cancer that women get. So I think there’s good reason to have a sense of hope as we move forward and uncover these mechanisms and look at molecules that target them.

Could breast cancer become the new diabetes?

I think in many ways it has. I have patients who have stage 4 incurable breast cancer that have been living more than five years with control of their disease. So I think we’re seeing it more and more like a diabetes, a chronic condition that must be continually treated but that doesn’t kill a patient quickly. Hopefully we’ll get better at that because still there are subsets of breast cancer and patients who have breast cancer who do succumb to the disease very quickly and in those situations, the triple negative subset, the highly resistant HER2 type of breast cancer, it’s less hopeful. So we still have work to be done.

So in your view what should busy cancer doctors be thinking about all of these wonderful and exciting developments?

Again we should, all of us, as much as possible participate or encourage our patients to participate in clinical trials because that’s the only way to validate pre-clinical findings. We may detect a new molecular abnormality in breast cancer and develop a targeted therapy to that abnormality but until we test it clinically we won’t know whether or not it’s safe or effective. Sometimes inhibiting a molecular abnormality actually doesn’t have any benefit in the cancer.

And you’re not going to be defeated by the multiple pathways that cancer does sometimes seem to develop for overcoming…?

It’s a very good point and that’s why we’re seeing more therapies that target multiple pathways and combinations of therapies to try and block those back-up pathways.