ECC 2013

Biomarkers in the BOLERO3 trial

Prof Guy Jerusalem - Centre Hospitalier Universitaire du Sart-Tilman, Liège, Belgium

Now the distinguished BOLERO study, you’re looking at part of BOLERO3, you’re looking at biomarkers. Now, give me the back story on this, BOLERO was trying to find out what?

Initially we looked at patients heavily pre-treated, HER2 positive disease, they all received previously a taxane therapy, they all were resistant to trastuzumab and so they either received vinoralbine, trastuzumab and everolimus or vinoralbine, trastuzumab and a placebo. And it has been shown at the ASCO meeting that when we add everolimus we gain five weeks. This is statistically significant but the question is, of course, is this clinically meaningful.

OK, so you’re talking about looking at the biomarkers in this case but BOLERO itself found that there was a benefit for breast cancer, patients with breast cancer, in progression free survival. You have specifically looked at which biomarkers?

So the hypothesis is that the patients that had an activation of the PI3K/AKT/mTOR pathway are resistant to trastuzumab and they benefit more if we add everolimus than the average patient. So we looked to three biomarkers, candidate biomarkers, in the preliminary analysis because we will do also other analyses later. These are biomarkers that reflect an activation of this pathway, in particular the peak with the mutation status, the high phosphorylated S6 and the low PTEN, that was the three candidates and the hypothesis that patients that had a mutation of these biomarkers that they benefit more.

So you’re giving everybody vinoralbine, also trastuzumab but in addition you’re giving everolimus and you’ve found that the ones who have the markers that tell you they should be sensitive to everolimus, lo and behold, they get a better survival.

Yes, absolutely. So we have found that in patients with high phosphorylated S6 we have a gain of three months, patients with low PTEN four months.

Is this progression free or overall?

Always progression free survival.

Progression free survival.

The overall survival data will come next year and of course then we can also correlate with overall survival.

There is talk at this meeting that progression free survival in some diseases is a good surrogate for overall survival. Do you think this is going to translate to an overall survival advantage in these patients with breast cancer?

We will see. Of course five weeks is a short interval so we will see. But Cliff Hudis in the discussion speculated we will not see a major overall survival benefit.

What is your very refined study telling us about the use of biomarkers and similar tools to individualise cancer therapy.

I think this is the main point. Probably we will not see a major overall survival benefit but what we’re seeing is that some individual patients will really have a major benefit from these drugs and we have to identify who are the individuals who really benefit from this kind of approach.

Can you spell out for me which patients specifically then need or could, on the basis of these early results, need everolimus, the mTOR inhibitor.

Yes, definitely these are preliminary data so it should be validated. We cannot today state these patients need it but it is a rationale…

But if they have the biomarker?

It is a rationale that if they have the biomarker they benefit from it but it should be validated. These are data from one study and next year we’ll see the data from BOLERO1 and I think it would be a very good idea also to look to these patients and to see if the same thing arises, that patients with these biomarkers will also benefit more from everolimus.

So coming out of the conference here in Amsterdam, the European Cancer Conference, what’s the bottom line message for cancer doctors treating patients with this refractory stage of breast cancer?

Not everyone needs the same treatment. We will see probably in the near future that patients who receive a double blockade at the receptor level will benefit more than if you give just trastuzumab but there are still patients that need other approaches and probably this is one of the ways to further individualise and to identify the patients where there is still a need also in HER2 positive disease.

Because a double blockade sounds great but there could be toxicities.

There are toxicities, in general they are rather well tolerated but today we have also seen the data from Professor Baselga in the neoadjuvant setting and again patients with PI3K mutations, they have less PCR rate. So we do not expect that these patients will really benefit from the dual blockade but it makes sense to think that these patients may benefit from a blockade in the PI3K/AKT/mTOR pathway.

So what’s the brief practical message for doctors right now?

We still need to do research in this field.

But individualising the therapy seems to have something going for it?

Absolutely.