Colorectal Cancer: Challenges in Next-Generation Sequencing

Transcript:Daniel G. Haller, MD: We have a great, great promise ahead of us and great challenges. And one of the great challenges is with the new next-generation sequencing. One can unearth many, many mutations in patients, and there are both scientific and ethical issues that arise when one does that. Because not every mutation is actionable. Meaning the mutation may have no role in that patient’s particular tumor, and you may be finding things that you don’t know actually what to do with. There are trials underway, for example, the ASSIGN trial in ECOG-ACRIN. Peter O’Dwyer is the chair of that and he’s been working very hard on it, where patients’ tumors will be sequenced, look for mutations, and then find drugs that would seem to be most likely actionable or active in those mutations. It’s extraordinarily hard to do. There’s the MATCH trial through the NCI which is doing the same thing in a broad number of tumors. ASSIGN is for colorectal cancer.

So first you have to get the tumor. Do you get the archival tumor or do you get a fresh biopsy? In the ASSIGN Study it’s a fresh biopsy. Although KRAS is a fairly stable mutation, so one can use archival tissue. For many mutations you don’t want to test the tumor that the patient had, you want to test the tumor the patient now has. So in the ASSIGN Trial many discussions took place about getting new biopsies — it’s going to be done, it’s going to be paid for so that we know what we’re treating.

The second thing is you have to find a drug that’s available and provided in almost all cases by pharmaceutical firms who are willing to donate their drug, if you will, to a study with 5 or 6 possible other drugs contained within it. And then you have to find mutations that actually have an action that you can use. And. in colon cancer. those likely will be things like BRAF, for example, and we can talk more about that. MET is another one. We have MET inhibitors, we have BRAF inhibitors, but we have to find the very small subsets of patients who not only have a mutation. but where the drug actually has activity.

This is an exciting new area. In fact, there are a lot of studies ongoing now to see whether so-called liquid biopsies, which would be real-time biopsies that can be done multiple times during treatments. Because it likely is true, it is known to be true, especially in lung cancer, that mutations can be changed by whatever treatment you just got. So, you can’t just do the archival tissue, and you can’t just do one biopsy. You may need to do them sequentially before each new biologic intervention. So, liquid biopsies would be a delightful answer to that problem of not having to stick needles into people. What one does need is validation to show that the liquid biopsy actually does reflect what a standard histologic specimen would show. And that is ongoing. And the larger number of studies are available in non—small cell lung cancer than in colon, but work is being done in colon cancer as well.

Transcript Edited for Clarity