The BOLERO-2 study confirms everolimus and exemestane in ER/PR+ advanced breast cancer improves PFS

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Published: 26 Sep 2011
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Prof José Baselga – Massachusetts General Hospital Cancer Center, USA

Results from a phase III clinical trial have shown that combining two existing cancer drugs to treat post-menopausal women with advanced breast cancer resistant to hormonal therapy significantly improves outcome. Researchers told the 2011 European Multidisciplinary Cancer Congress that women treated with a combination of everolimus and exemestane had an improved progression-free survival of nearly seven months compared to women who were treated only with exemestane.

European Multidisciplinary Cancer Congress (EMCC) 2011, 23-27 September, Stockholm

The BOLERO-2 study confirms everolimus and exemestane in ER/PR+ advanced breast cancer improves PFS

Dr José Baselga – Massachusetts General Hospital Cancer Center, USA


José Baselga, Mass. General, Harvard University, Barcelona still?

Yes, absolutely.

Welcome. You’ve just dropped a little bombshell in this meeting at ECCO with your BOLERO trial. I like the Spanish name, of course, it’s very important, it keeps the European base. Tell us about it.

The BOLERO trial is a trial, as you know, of an mTOR inhibitor, everolimus, in combination with exemestane versus exemestane in patients with metastatic HER2 ER+ breast cancer. What we have observed is a striking improvement in progression free survival, so the patients that received exemestane alone, the progression free survival time, the median, was four months; in the mTOR arm it was eleven months, so this is probably the most positive ever trial in metastatic ER+ disease. So the benefit is quite remarkable.

And they’d all had aromatase inhibitors?


They’d either had one or two or… they hadn’t had exemestane before?

They had to have prior either letrozole or anastrozole.


One or the other.

So these are tough patients to treat?

Correct. So these are patients that are tough to treat, so all got prior AI, the majority had also prior chemotherapy. About 50% had disease prior tamoxifen, so in overall more than 50% had received three or more lines of therapy for breast cancer. So this is a heavily pre-treated patient population.

And this is a first ever, isn’t it? Aromatase plus an mTOR.

Yes. It’s the first.

And you’re going to move this up front?

The first thing we have to do is to digest all the data and see where we go from there. The biology underneath this is huge. We knew for a long time that it was a cross talk between mTOR and ER but this basically proves it. We had to realise that mTOR inhibitors by themselves are not very active so ER is important and I think we can learn a lot from what’s happening there.

What’s your gut feeling about what the mechanism is of the interaction?

I think it’s very clear. mTOR blocks ligand independent ER transcription and in that setting oestrogen dependent ER signalling becomes extremely important. So this is a feedback loop, clearly. So unless you block ligand dependent and ligand independent ER transcription, you will not see an effect. This is something that in preclinical models it has been well established, work by many labs has shown that for a number of years now. But we were never able to prove that in the clinic and now this is proved. So if you put together this data from the BOLERO-2 together with our neoadjuvant study, that was the basis for BOLERO-2 that was also very positive, I think that it’s telling us something very powerful.

And BOLERO-2, because it’s in a pre-treated group, very pre-treated group, could well give you overall survival data?

It’s still early to say but I would not be surprised because the benefits of the progression free survival, as you say, in a person that has been so pre-treated, usually if one had to guess, I would not be surprised if we see a survival improvement.

And there’s no other treatment for them, these women?


There’s no rescue, so I would think that this will be a big impact. Where else are you going to put everolimus in the scheme of things? Because clearly we’ve been using it wrongly.

Right, so everolimus, there is also very exciting data with Herceptin in the HER2 positives. There is another study that has finalised accrual and we’re hoping to see the results soon and that is Herceptin plus everolimus in Herceptin refractory patients. So that’s going to be an important study.

So same idea, same model, resistant patients, see if you can get round the resistance with an mTOR inhibitor.

Same principle, yes. And then, of course, as you suggested, it would be very interesting to start thinking on how to bring mTOR inhibitors in the early adjuvant setting. We know that ER tumours are not very sensitive to chemotherapy so anything that enhances ER inhibition in this population could be very important. So this is a moment just to digest the data, as I said, but it would seem to me that mTOR inhibition will play a major role in all this disease status of ER positive breast cancer.

José, thank you very much indeed for dropping in to ECCO at Stockholm and good luck with the developments in Boston, this all sounds very exciting.

Thank you so much.