AACR 2015

New data shows that generic drivers are found in benign conditions

Prof Razelle Kurzrock - University of California, San Diego, USA

This is a prevention session. The idea is to look for genetic drivers before the cancer is fully developed and use some of our targeted therapies in that stage to prevent the development of cancer. So that was the idea of the whole session. I was asked to speak because I’ve recently been involved with some data showing that these genetic drivers can also appear in benign disease and in benign conditions that is not even a disease. So that throws a wrench in the prevention process because how do we know when we should target those genetic drivers if they can be meaningless, if they can be in people that are perfectly healthy and never progress to cancer?

Could those genetic drivers have a normal role which you could inhibit and therefore do a lot of harm?

That is the potential. We don’t understand yet why we’re finding these genetic drivers in normal conditions. So the question is, if we’re going to give drugs that have potential side effects to people that are perfectly normal, that in itself is probably not a good idea and could it even be harmful? Many people are not yet aware that some of these genetic drivers that we’ve associated with cancer can actually occur in many people who will never develop cancer. That’s the whole point that I was trying to make, that the prevention strategy, while very important, is not that simple. There are a few great examples and I’m going to give you one that is actually a puzzle to me but I think is of extreme interest. Melanomas, which are a very lethal cancer, the main genetic driver that is found in about 50% of patients with melanoma is a mutation in a gene called BRAF. There are several breakthrough drugs that have been developed and approved recently that target that mutation. What most people don’t realise, however, is that in benign moles, which everybody has, about 80% of them have BRAF mutations and they’re the identical mutations that are found in melanomas. So if you were to start treating as a prevention strategy benign nevi that have this supposedly cancerous driver, you would be just treating everybody. So that really throws a wrench in the prevention strategy. We have to ask the question why is this mutation that is so strongly associated with cancer also found in 80% of moles that will never turn cancerous.

Of course chemoprevention is coming up in a number of branches of cancer now and it must always, therefore, be difficult to know whether you could possibly be doing more harm than good.

And that’s absolutely the point. It will be very important to know and to differentiate which drivers are truly found in cancer and not in normal tissue that does not turn cancerous and which drivers have crossover for reasons that we really don’t understand. This BRAF mutation is a complete puzzle; we absolutely know it’s a driver for melanoma, we know that when we target it in melanoma patients the melanoma tumours regress. But then the chemoprevention strategy doesn’t really work if it’s found also in 80% of moles that will never turn cancerous. So we just have to be aware of these issues before we embark on a chemoprevention strategy.

What should the cancer doctor be doing about all this then?

I think that chemoprevention, as we’re beginning to develop it, is not yet in the routine realm. This is in the realm of clinical trials so the regular cancer doctor, I don’t think the data is there for him or her to be doing a chemoprevention strategy. On the other hand, there may be patients at high risk that will want to be participating in some of these big trials that will try to figure out what are the good chemoprevention strategies, the helpful strategies, and what are the strategies that may not work as well.

Is there anything else that you think needs to be borne in mind in this whole field of endeavour because it’s going somewhere, but we don’t seem to know where at the moment?

One of the sweet spots that has not been hit well in cancer is in newly diagnosed patients. So we have been using genomically driven therapies and immunotherapy in people with very advanced disease, with patients with metastatic disease that have failed multiple therapy. That’s a very difficult situation. Now we’re talking about very early disease prevention but the sweet spot may be in patients with newly diagnosed disease where we know they definitely have a cancer but the cancer has not yet evolved and metastasised. To me, that’s the next strategy that needs to be approached.