14th International Medical Education Workshop on Molecular Targeted Therapy of Cancer (MTTC)

Blood biopsies for tumour cell detection

Dr Alberto Bardelli - University of Torino Medical School, Turin, Italy

It’s essentially a non-invasive new approach to detect cancer genetics in the blood of patients. It’s based on the principle that every tumour will release at some point its DNA into circulation. Of course patients that have advanced disease will have a major burden and so the detection can be facilitated but in principle this can work in every patient. What we reported, for example last year in Nature, and what we are about to report in Cancer Discovery is that this helps us and the clinicians to track molecular evolution in individual patients. So, for example, in my field we are very interested in understanding why patients that receive a targeted agent, say for example a CRC patient that receives EGFR blockade, cetuximab or panitumumab, after a few months will relapse. So what is the cause of this relapse? Because obtaining surgical biopsies or needle biopsies are difficult and potentially challenging we have switched to this new approach.

Is this DNA from the blood?

This is DNA from blood that we isolate, in fact, from plasma. What we have developed is a technology to pick up individual mutations in the blood. What we reported last year is that if we follow the patients over each therapy and we monitor the response by CT scan and eventually the relapse, what we can see much earlier in the blood of the patients is the emergence of the clones that became resistant to the targeted agent. In fact we do see these recurrences months before the CT scan detects eventually the relapse. We think this is an important opportunity to intervene early by knowing exactly which is the clone that is emerging and intercepting this clone with another therapy. That’s why we are very excited about liquid biopsies.

Is it technically challenging?

Yes, it is. It has been the most difficult part and in fact we spent many years on this. We have started this in 2008, in fact, and we have built a facility in the Institute dedicated to this. It’s an isolated facility with positive pressure in which we handle material very carefully and the technicians have to wear special protection because we have a sensitive technology to detect these mutations. Imagine that we have really to detect one little mutant allele in ten thousand wildtype alleles so this is very difficult and potentially at high risk of contamination. So what we have developed and perfected is a technology that is very sensitive and allows us to detect the exact amount of these alleles in the blood of patients.

Does this also demonstrate how heterogenic tumours are during their development?

Yes, in fact what we see, and what I presented today, is our vision of how resistance develops in these patients. We have a founder mutation that we can track throughout the entire disease. This is an event, for example, happening in the adenoma, for example an APC mutation which we have successfully used to track the disease. This is a mutation that in principle should not be responsible to the therapy and therefore should stay and measure the tumour burden. Then we have clones that emerge upon selection with a specific therapy and these clones have different alterations and in fact we can track multiple clones in the blood. We find this very exciting and we believe this will recapitulate the heterogeneity of the tumour, especially in patients that have multiple lesions. For example you can imagine CRC patients that have lesions in the liver and possibly in the lung and by doing this approach we can recapitulate the entire disease burden.

Do you see this type of biopsy becoming widespread?

At AACR this year I was chairing a session dedicated to this; I’ll be speaking at ASCO soon about this and there are many groups that are working very actively. I think this will be translatable into the clinic and I think this will be… I know this is about … but it will be practice-changing.

Will this be available in most large hospitals?

Eventually it will become available in most centres but the problem of contamination is a major issue and the sensitivity is a major issue. So our technology has still to be improved. The approach that we use is home-made so we have developed machines to do this but in the future they will be systematic approaches, I’m sure, because there is such a high interest.