WIN 2016

Liquid biopsies to track clonal evolution and resistance in mCRC

Dr Alberto Bardelli - Candiolo Cancer Institute, Turin, Italy

My lab has been studying CRCs, colorectal cancer, for about ten years. Ten years ago there was virtually no genetic determinants of response or resistance to any therapy and we now just have help in  trying to stratify genetics on clinical responses. I presented a few cases today, therapies with HER2 inhibitors, TRK inhibitors, ALK inhibitors, and the overall message that I was trying to convey is that we can measure responses and especially we can now use blood to quickly understand why patients relapse. I’m considered a pessimist in the field of targeted therapies; most of the therapies, even when they are directed against the right oncogene, only last for a short bit and then the patient relapses. What we have used in the past few years is clonal evolution tracking in cfDNA and that’s what I spoke about today.

How has this developed?

Two years ago we discovered that the most commonly used targeted therapy in colorectal cancer, which is EGFR blockade, a relapse to this therapy was associated with the development of RAS mutations and we used plasma to discover that. Later than that things have picked up speed and what we can now do is instead of waiting to complete the study on one hundred patients to understand why most of them will relapse we follow them live essentially. So every two weeks we do a liquid biopsy and we understand pretty adequately what happens in their blood and how resistance eventually develops.

You mentioned before dinosaurs, if you don’t mind I’d like to get back to that. I realise this is a scientific clinical meeting but I was pretty shocked by how poor we had previously made parallels between the evolution on cells that have been living on this planet for billions of years and tumours. We should not be surprised by that but we are in a way and we sort of rediscovered one of the old principles of biology. So it’s possibly not surprising that there are bacteria that can live in the deepest of an ocean or at the top of Mount Everest and there are cells that evolve resistance to any treatment that you want to throw at them. So I think that’s a profound lesson.

So my lab has stopped, in a way, to study targeted therapies and shifted to study evolution. I didn’t have a chance to talk about this today but most of my people now have started projects that are related to understanding evolution in cancer cells and finding a way that we can stop them.

Has the process of surveying every two weeks had an effect on the patient’s quality of life?

We’re talking about blood draws, they are very often done when the patient is coming to the hospital for treatment or for other reasons, CT scans etc. But on occasion we would ask patients to do this on purpose, they are typically very compliant with that especially because the alternative would be a tissue biopsy which is a very invasive procedure.

The other thing which I didn’t have time to mention today is that we are trying to shift, it will take time but I think it may be possible, to shift from blood to urine. There is evidence that tumours will release DNA in the blood and this DNA is then processed by the kidneys and eventually will end up in urine. If that happens then we may be able to use urine as a source of information, it’s really non-invasive and the patient can ship samples collected at home without the need to go and have a blood draw.

Where do you see this leading the field in the coming years?

There is a subtype of targeted therapy which is immunotherapy that in a subtype of colorectal tumour delivers an incredible benefit which is very durable. That is checkpoint blockade on MSI colorectal cancer. I didn’t have time to talk about this but we have followed these patients now using liquid biopsy and we think we start to understand why they don’t relapse. So in the future it will be very exciting to not only measure clonal evolution but measure what we call mutational burden, number of new antigens, evolution of new targets for immuno-oncology.