AACR 102nd Annual Meeting, 2—6 April 2011, Orlando, Florida

Biomarker target for lung cancer chemoprevention

Professor Paul Bunn – University of Colorado, Denver, USA

Dr Paul Bunn, you’ve been talking about lung cancer and particularly, and very interestingly, about lung cancer prevention. What specifically have you been doing?

Lung cancer is the leading cause of cancer death in the world and about 80% in developed countries are caused by cigarette smoking so to prevent lung cancer, the best thing to do is to get people to stop. But unfortunately when you stop smoking you’re still at risk for lung cancer and throughout your lifetime you remain at increased risk compared to a never-smoker. So what can we do for former smokers to reduce the risk of lung cancer?

And you’ve been conducting a trial, haven’t you?

We’ve been conducting a trial, it’s called the Chemoprevention Trial, and the agent in this case is an agent called iloprost and iloprost is a prostacyclin. The drug is approved as a vasodilator for primary pulmonary hypertension, so it has been on the market for a long time so we know it’s a pretty safe drug; for chemoprevention, an agent that somebody is going to take for some years, it has to be safe.

So you’ve been looking at a surrogate marker for improvements in that risk, haven’t you?

Correct, and the question is what is the best surrogate marker? We believe that it’s bronchial histology. There’s a WHO classification of the bronchial pathology going from normal all the way to carcinoma in situ and there are seven grades. So the purpose of the study was to see if you could make the histology better, lower the grade. The worse the grade, the higher the risk of lung cancer; if you can lower the grade you would reduce the risk of lung cancer, presumably.

Now would you walk me through the study, very briefly, please?

So patients were eligible who had 30 pack years of smoking and had abnormal cells in their sputum. So these are people who didn’t have cancer but were at risk from their smoking history and their sputum. They had a bronchoscopy and then they were randomised to placebo pill or iloprost. There were 150 subjects and half of them randomised to iloprost, half of them randomised to placebo.

What were the differences?

There was a statistically significant improvement in the bronchial histology in the former smokers who got iloprost and the people who were current smokers, all of whom continued to smoke, there was no improvement in their bronchial histology. So what that shows, people say, well you have to be careful about chemoprevention because maybe people will use it as an excuse to keep smoking. Well there was no benefit in the current smokers that continued to smoke but the benefit was in the former smokers.

So you get a reduction of the dysplasia?

Correct.

How significant might that be ultimately in preventing lung cancer then?

At base line we could look at the histology in the former smokers versus the current smokers. Not surprisingly the histology was worse in the current smokers so there was a difference. So we know that if you stop smoking risk goes down, so the assumption is that the histology would matter. From the former smokers that stopped, the improvement in histology was greater than the difference in their baseline histology between the current and formers. So the magnitude of the difference was pretty big, so we would predict that that would be big enough to reduce lung cancer risk but, of course, we need a big randomised trial to prove that now.

It is a prediction, as you say; it would be great to do this in a full scale study. But this is an indicator, what do you guess might be the implications coming from this for preventing cancer?

The question is if I had thirty pack years of smoking, since iloprost is commercially available would I take it? And I would think long and hard about doing that but, of course, we need another trial. But the other good thing is with this magnitude of difference, you can do intermediate marker trials in a hundred subjects. Part of the problem has been without an intermediate marker, how many people do you need and how do you do a trial. So there are a lot of promising agents. This study shows that you can do a study with a reasonable sample size in a reasonable period of time in this manner.

You’ve got a big difference with iloprost, what about other agents? What candidate agents might there be, do you think?

Certainly there are many, certainly COX-2 inhibitors are still out there, certainly things like EGFR inhibitors. Now obviously EGFR inhibitors work best in EGFR mutants and oftentimes the bronchial epithelium, you don’t have a mutation yet, but the EGFR receptor is markedly over-expressed in dysplastic epithelium.

So what’s the bottom line message coming out of this very hopeful study?

Support cancer research and have more trials like this and get the randomised trial done.

Dr Paul Bunn, it’s been great talking with you here on ecancer.tv.

Thank you very much.

AACR 102nd Annual Meeting, 2—6 April 2011, Orlando, Florida