Future Horizons in Lung Cancer
Future of imaging in lung cancer
Prof Tony Ng - King's College London, London, UK
The meeting is about the future of imaging in lung cancer in general so if you think about the failure of a lot of the medical oncology drugs that are molecularly targeted agents they really call for the need to develop newer imaging agents that are matched to the drugs. The second point that’s really important is to come up with a solution that’s health economically viable. We cannot image patients with PET every month when we see cancer patients in clinic, that’s just not going to work. So what I talked about, if I want to sum it up, is the future thought, the thought about the future where we take blood from patients, assess the mechanisms of resistance when they are starting on whatever molecularly targeted agent that they have, whether that is against tumour cells or immune checkpoint, then follow them up monthly or two-monthly. Whenever you see a patient you don’t just do a physical exam but you actually do a blood test on them that’s specifically designed to look for secondary resistance mechanisms.
Now, for those patients who are then deemed high risk then you then take them to the hospital and perform a more specialised imaging test which might be a PET-CT, it might be MRI, but again that test will be matched to the drug that you are giving to the patient or matched to the resistance mechanism that we understand might arise. The example I gave was epidermal growth factor receptor targeting which is really one of the most important targets in non-small cell lung cancer, particularly in the Far East, in Europe, we’re talking about 20% of the population. But we do need to know which patients are going to develop the resistance mechanism in time as we follow up the patient. So that, for me, calls for a non-invasive way of monitoring patients or monitoring tumour evolution and the state of the art technologies known to us are a blood test and an imaging test. When you combine the two of them, that’s where you will get the maximum sensitivity and specificity. If you do it that way it becomes also health economically viable and you can detect which patients get the resistance and exactly when they get the resistance. Early detection of resistance is probably the key to solving the problem.
Why aren’t these blood tests currently being carried out?
The particular tests that I describe are based on small vesicles in the blood called exosomes but they contain bits of nucleic acid, the microRNA. So the Mayo study which was an early detection trial using low dose CT, there was a JCO paper in 2014, that combined the sensitivity and specificity of both the circulating microRNA and the low dose CT in detecting cancer by again this principle of enhancing sensitivity and specificity. What I’m describing now is actually taking it from the early diagnosis or early detection space into the detection of resistance mechanism space. There what I’m proposing is actually looking to exosomes which not only contain the nucleic acid but the protein based resistance mechanism. So it’s a much more holistic way of looking at a cancer cell and the exosomes are really the ideal vehicle for you to spy on cancer cells that you can’t see. So let’s face it, if you have less than a thousand cells in the body you won’t be able to see it with PET-CT but you might be able to detect early signs of those tumour cells recurring or becoming resistant by looking at the blood test and if we set the negative predictive value relatively high for the blood test, then we take those patients to imaging and we get rid of the false positives. So that’s the idea of combining blood tests and imaging. So an early form of that has already been used in early detection but what we need to do now is to take that into the resistance realm and try to solve the problem.
I used to be an HIV doctor so it’s almost a little bit like taking blood from patients who are on anti-retroviral, every time you see them in the clinic looking at viral load, do RTPCR on the viruses and then the minute the virus comes up on drug you know, you detect it early and you know what the drug might be that you need to counteract that resistance. It’s the same principle for cancer except for cancer it’s a lot harder for the reason that cancer cells used to be normal human cells so a lot of the drugs that we put on cancer cells will be toxic to the normal cell. So unlike HIV where we can do quadruple combination, we cannot do in cancer. Some of the time we combine two drugs, that’s already too toxic. So you need to think about a biomarker that can predict the resistance and sequentially act, a little bit like playing chess in a way – if you know what the next move is you prompt the enemy, or your opponent, to make that move, you already know what move to look for and you’ve got a counter move. So that’s the idea of borrowing from what we’ve learned in HIV but doing it in a more sophisticated way using imaging and blood biomarkers.
Are imaging agents also improving?
There are imaging agents that are based on radionuclide imaging. Of course they are more molecularly targeted so they are not going to be good for all the patients because tumours can be expressed in all sorts of receptors – EGFR, cMET, those are the examples I gave. So it’s not going to be one, two for all patients. So that’s exactly where the advantage of the blood test is – if you do the blood test you can have a panel blood test and then you can select the patient for the right imaging agent. That’s another reason for putting the blood tests first, because your imaging agent might be good only for 10% of the patients that amplify cMET in the lung cancer setting. So those PET agents will be specific, they can be coupled with MRI, there are all sorts of MRI techniques that can be used to detect pharmacodynamic response but generally they are not specific at the molecular level because they are more generic, looking at the structure, perfusion, so on and so forth. But again in this country we have quite a few combined PET-MR machines. In the UK and worldwide there are lots of PET-MR machines so there’s a lot of development we can undertake and put these tools into the clinic and work with oncologists and try to overcome secondary resistance. That is the future.
