Early Detection of Cancer: Myth or Reality?

Kaitlyn Waters:

Hi everyone. Welcome to this podcast from Cambridge Health Tech Institute for Molecular Medicine Tri-Conference, which will take place February 19 to the 24th, 2017, in San Francisco, CA. I'm Kaitlyn Waters, associate conference producer at CHI. We have with us here today, one of our speakers from the Circulating Cell-Free DNA Symposium, Dr. Abhijit Patel, M.D., Ph.D., Assistant Professor in the Therapeutic Radiology Department at Yale University. Dr. Patel, thank you for joining us.

Abhijit Patel:

Thank you for inviting me, Kaitlyn.

Kaitlyn Waters:

Liquid biopsy has become a hugely popular term in the past couple of years. Especially since technologies are enabling more sensitive detection. The technology is there but this is still not a technique that is standard of care. Why do you think that is?

Abhijit Patel:

You exactly described the situation very accurately in that we've known about circulating tumor derived DNA fragments being present in the blood of cancer patients for several decades now, but it's really only recently that technology such as digital PCR and next generation sequencing have allowed us to extract clinically useful information from these circulating DNA fragments. I think it’s really these technologies that have enabled us to envision using circulating tumor DNA for clinical purposes but there's still a bit of reluctance among oncologists to actually adopt some of these technologies for clinical practice. I think that's just true for any new technology. I think as additional clinical evidence becomes available and as oncologic societies such as ASCO or NCCN start to incorporate some of these methods in their guidelines, then I think this will get used in a more mainstream way.

I think there's also some practical issues such as reimbursement levels that still need to be figured out, at least here in the United States, that's the case. Then there's issues surrounding the practicality of performing the testing, so some of the next generation sequencing work flows are complex and it requires central reference laboratories, generally, to perform the testing. I think as some of these things get ironed out and some of the assay methods become easier and cheaper, I think it will also become more available within smaller laboratories.

Kaitlyn Waters:

There seems to be a lot of debate around the viability of liquid biopsy for early detection. What is your take on this and how does your current research tie in?

Abhijit Patel:

Early detection is probably the most impactful application of circulating tumor DNA or liquid biopsy, but I think it's also the most challenging because you're looking for these rare mutant DNA copies from a small early stage tumor and it's really most useful if you're able to detect it from a small early stage tumor. If you're able to detect sort of an occult malignancy that's already advanced, well that's somewhat useful but you're unlikely to cure the patient at that point. I think finding the early stage diseases is the key but I think the problem is, in early stage disease, there are so few copies of the mutant circulating DNA release into the blood that the technologies to detect that DNA have to be extremely robust.

I think the challenge is further compounded by the fact that you don't know which mutation you're looking for because you don't even know if the patient has cancer and so you're forces to look very broadly across broad variety of cancer related genes. You're looking for mutations that you don't know whether they're actually there in the tumor or not, so the assay has to be designed to be very broad and across that broad area has to suppress any errors that occur in that broad area. Even if very low level errors occur in your assay, this could be mistaken for true mutations when you're looking for such low levels or such small copy numbers. My laboratory is very interested in this as are many others and I think also now there're commercial entities that are pursuing this goal as well, which I think is very exciting.

I think one of the solutions to this will be to develop the technology to a point where you've kind of reached almost a theoretical maximum sensitivity, where you have capture the vast majority of the possibly mutated DNA molecules in your blood sample and then you make the mutation calls with very high confidence. I think once we have a technology like that, they I think it's going to be the biology that, really, we'll need to understand and to see whether this is truly a practically implementable screening approach for cancer. Some of the concerns there that I think large clinical trials as are being conducted by some companies now, will help to shed light on this. Specifically, are there low levels of mutant DNA in the blood of patients or individuals without cancer?

We know that there're precancerous lesions or precancerous changes that can happen that have some of the same mutations that are present in the blood of patients with cancer and it remains to be seen whether some of these mutations are actually being spilled into the blood in sufficient quantities to make it difficult to identify true positive cases. I think there's a lot to be learned about the biology still but I think we also need to improve the technology so that we can really get to the biological questions.

Kaitlyn Waters:

Where else do you see the future of liquid biopsy going?

Abhijit Patel:

I think the most immediate application for liquid biopsy will be for noninvasive mutation detection. I think that's sort of the goal. There's the application for which we have the most clinical data already and basically to identify mutations such EGFR, KRAS, to guide therapeutic management decisions. I think that's something that's already happening clinically and I think will happen more broadly or will be accepted more widely in the near future. I think other applications, such as monitoring response to therapy by following changes in levels of circulating tumor DNA over time, I think, are very promising and will require more clinical data but I think that is also an area that I think is very exciting. Especially for diseases where we don't already have good protein biomarkers to follow.

I think circulating tumor DNA also has a very different kinetic response profile than most protein biomarkers and I think that can be used in a clinically advantageous manner. Finally, early detection, I think, is the Holy Grail of the field and it'd be really exciting to see that become a reality but that's going to really require large clinical trials to really demonstrate it's efficacy. Also as I mentioned the technologies need to be really refined to enable that, but I think there's certainly promise in that area. Finally, I think it's great to see such an explosion of interest in this field over the past few years. Now there're hundreds of academic laboratories and more than I think 30 companies working in this area.

We're seeing very obvious clinical applications to this and I think it's really just a matter of now, when rather than if circulating tumor DNA gets more widely accepted as a clinically useful modality.

Kaitlyn Waters:

Thank you for your time Dr. Patel.

Abhijit Patel:

Great. It's been a pleasure. Thanks so much.

Kaitlyn Waters:

That was Dr. Abhijit Patel, M.D., Ph.D., Assistant Professor in the Therapeutic Radiology Department at Yale University. He'll be speaking at the Circulating Cell-Free DNA Symposium at Molecular Medicine Tri-Conference, taking place February 19 to 24, 2017. If you would like to hear him in person, go to www.triconference.com for registration information, and enter the key code podcast. I'm Kaitlyn Waters, thank you for listening.

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