Advances in the treatment of colorectal cancer

Dr Patrick Johnston – Queens University, Belfast, UK

Professor Patrick Johnston, you’re on the programme of NCRI and you are of course a world expert in the treatment of a variety of malignancies but I suspect you’re more interested in what’s happening in colorectal cancer here at this meeting. Where are the headlines and what’s happening and what can patients expect to hear from us experts?

Thanks Gordon, I’m actually chairing the programme this year so it’s a real honour and privilege in some respects. Colorectal cancer has actually come to an important inflection point in its treatment and how we actually approach the disease. We’ve really reached an impasse in terms of how we’re going to move ahead. Over the last decade we’ve had many new targeted therapies introduced, some successfully, such as EGFR inhibitors and Avastin targeting VEGF but we’re now at that point where we’re not seeing the huge benefits any more of additional targeted agents coming through. We’ve had ras molecular phenotyping, looking for ras mutations, being able to define who should and should not get EGFR inhibitors but really now we’re into this era of personalised medicine, how do we do it both in late stage disease, metastatic disease, and also then of course in adjuvant early stage disease? One of the challenges within that is the way these treatment regimens have been developed is empirical, it comes from an infectious disease methodology nearly.

But don’t tell the patients that it’s empirical.

But it is to some degree.

I think the patients assume that we know better than just to try a few things in a cocktail.

Well, empirical in the sense that they were done the right way; they were based on principles of pharmacology and combination drugs. But now we’re actually having biology drive trials and that sematic definition of disease while very relevant, whether it’s colon cancer, breast cancer or lung cancer, actually more importantly now it’s the sub-setting and the stratification. So is it type A, B, C, D or E based on that molecular stratification? That’s really going to be one of the big debates in colorectal cancer at the conference.

Starting at the beginning, of course, because there’s now a notion that aspirin might be a preventive agent in particular people with a particular genotype.

Yes, that’s right. So particularly with ABC mutations and with the HNPCC family, so that data John Burn has published in The Lancet is really, really important. We’ve all known and suspected for some time that aspirin is very important as a chemoprevention strategy, if you like, particularly in colorectal cancer. But now, having the ability to target high risk groups and either delay onset or, indeed, prevent the onset of cancer, of colorectal cancer, is really important.

So what’s new then at NCRI in terms of coning down on the colorectal genome?

In terms of what’s new in general it’s really now down to developing tools for stratification. So there are some presentations on the COIN trials that are actually looking at going beyond ras mutations, trying to look at other proteins such as epiregulin and amphiregulin that may highlight important components or patient groups within colorectal cancer that may benefit from EGFR inhibitors. Looking at BRAF mutations, is there something new to be done there? There’s now targeting c-Met, is that an avenue that needs to be explored particularly in KRAS mutant patients? So those are some of the themes that are being explored.

And these are all druggable targets?

These are all druggable.

These are all targets for which there are drugs in the pipeline?

That is correct. Absolutely.

What role is imaging playing in this whole business of sorting out, of stratifying, groups of patients who should get one treatment versus another?

The role of imaging, as you know, is one that is becoming much bigger. We are now seeing the spectrum of functional imaging allowing us to in the patient see whether we’ve actually hit the target for the first time. So with certain types of probes you can actually begin to see, yes, you’ve been able to target EGFR, you’ve been able to target c-Met, you’ve been able to target mTOR, you’ve been able to target MEK.

And without a second biopsy?

And without a second biopsy. And that information, how we process and use that information going forward, I think, is going to be part of the challenge. We’ve now moved to a point where we know that we’re going to have to look at the evolution of what’s happening around a given receptor or signalling pathway as we knock it out. Why? Because cancer cells are adaptive and they can use other mechanisms to circumvent targets that we knock out. So trying to learn what those signalling pathways are, what regulates them, what’s the importance of a given mutational background, those are some of the key questions that will dominate. And functional imaging will be part of how we actually begin to address that.

So it’s pretty optimistic? Congratulations on putting a great programme together, Paddy, and thanks very much for talking with us.

Not at all, it’s a real pleasure. Thank you.