ASCO 2011 Annual Meeting, 3—7 June 2011, Chicago

PTEN expression does not diminish trastuzumab effectiveness

Professor Edith Perez – Mayo Clinic, Florida, USA

One of the highlights related to radiation therapy actually. I think there was a very good presentation by the group from NCI Canada demonstrating that local regional radiation was superior to local breast irradiation to optimise survival in the setting of early stage breast cancer. This could be important for practice.

That’s going to rock a boat or two.

That is right, yes. You know, in the area of systemic therapy we didn’t have any breakthroughs in terms of new drugs showing efficacy, but I think the presentation that we’re giving relating to biomarkers could be really very important for people to understand breast cancer a bit better.

Tell me about it, go on.

We, and many others, are interested in the issue of how can we select patients who best benefit from one therapy versus another. And this is especially important in the setting of HER2 positive disease. There are several mechanisms of resistance that have been promoted as potentially being important, and one of them is PTEN. PTEN is a tumour suppressor gene and it’s important for the PI3-kinase-Akt cascade.

So what we set to do was test for PTEN protein in a large group of patients, 1802 patients who participated in the N9831 adjuvant trastuzumab or Herceptin trial. Because we wanted to ask the question, really, does PTEN loss correlate with lack of sensitivity to Herceptin or trastuzumab. So we did a very thorough analysis, and this is what we found. Actually both patients with PTEN positive or patients with PTEN negative breast cancer derived the same benefit to adjuvant trastuzumab. This is really important because many people thought PTEN loss, the patients would not be responsive to trastuzumab. And now we have definite data to state this point.

How come? Bypass pathway?

I think it’s totally associated with bypass pathways, well stated.

You’re the expert! So has PTEN got any relevance anymore?

Not in the setting of HER2 positive breast cancer, certainly the adjuvant setting. We will be looking at some metastatic cases just to solidify the findings in the adjuvant setting. But in the adjuvant setting I think we have a definite study, and resources should be utilised for looking at other markers. So we are doing this kind of work, and we’re very interested in multi-gene profiles, and we expect to have data very shortly, related to that type of research.

How are you doing the multi-gene profiles? What’s the technology?

We’re utilising DASL at this moment, but we plan to validate the results of DASL looking at RT-PCR technology, and ultimately we want to do next generation gene sequencing but first we’ll get the data from DASL and we expect those data to be available just in a few weeks.

That’s fantastic. So, the gene sequencing issue, are you waiting for the next technology to come along? I think it’s called next-next technology, or are you thinking, I’m going to wait until the price comes down, or what?

Well right now, the price is not too bad actually, compared to what it used to be just about two years ago. And more than that, we are working with various companies including Ilumina Corporation, so we are actually testing the latest technology. But it’s more than technology, we have an excellent team of basic scientists and bioinformatics because it’s more than just getting the sequence data from the machines, it’s being able to analyse those data. And it’s great to have this kind of expertise at our place at Mayo.

Have you got a lot of bioinformatics?

Yes, we do.

People who don’t understand biology but they’re very good at mathematics.

They’re amazing, actually. To look at the tremendous numbers of data points that we’re getting from next generation gene sequencing studies, or DASL for that matter.

Proteomics? Epigenomics? I mean, could the PTEN study be explained by an epigenetic phenomenon, or what?

When we were actually doing this next generation gene sequencing experiment we were looking at epigenetics, specifically methylation studies, so we’re going to look at this issue. But for PTEN the protein was felt to be what was important and that’s exactly what we decided to look at in our study. However, we will be looking at the genes as part of these other technologies that we have already started to evaluate.

Next year, what’s going to be mature for the ASCO 2012?

Well, in terms of our work, we’ll have our DASL data completed because we need to correlate that with disease-free survival. So it’s very good that in our trial we have now seven year median follow-up time. And this is the correct timing to look at this correlation.

That’s terrific.

Yes.

New drugs on the horizon?

Many.

Many?

Many. That is right, yes.

Have you got any money on any pathways? Not on the drugs but the pathways?

No, I cannot invest in any of these types of work because of my research but I know other people do. There is some very interesting pathways with targeted drugs, that I think look very promising for breast cancer.

No word on triple negative breast cancer this year, is that because nothing’s happened?

I tell you, a lot is happening, but really that relates to the fact that we now think that triple negative is not one disease, triple negative may be eight different sub-types of breast cancer and we need to really understand the genetic make up a bit better, and then test specific drugs for those specific subtypes of breast cancer. You know the field of proteomics has become even more complex than it used to be, and one of the challenges of that field is that what may be important is phosphorylation of proteins and it’s right now very difficult to test for phosphorylations with specimens currently available. So although theoretically it’s very appealing to really be able to test for those phospho proteins, it’s not that simple.

True. And there’s only a million proteins to worry about.

You got it.

Edith, thank you so much.