The Hunt for Predictive Markers in Metastatic Colorectal Cancer - Episode 11

Precision Medicine Further Explored in Metastatic CRC


John L. Marshall, MD: We are now doing molecular profiling routinely in colon cancer, but, remember, that’s a small subset. Like in lung cancer, there have been new discoveries of fairly rare mutations. They are also being seen in colorectal cancer. And so, as we do more profiling, as we do more broad testing, we are uncovering some unexpected needles in the haystack. I’m a strong advocate for this. We have to realize that most of the time, using our current assays, we’re not going to find some amazing lock for which we have the perfect key. Every now and then you do. So I would say keep fishing.

We’re moving forward to develop better biomarkers not just to find new medicines but to improve our performance with our current medicines. We try medicines, cross our fingers, give them for a few months, and see if they have worked. That’s a huge amount of waste and toxicity if we could figure out, beforehand, that the patient isn’t going to respond to the treatment—whether it’s oxaliplatin or irinotecan or EGFR therapy or even bevacizumab/immuno-oncology. If we could figure out who’s responding and who’s not, it would be incredibly valuable to us and our patients. And so, those new biomarkers are being developed and are being brought forward to make us better doctors, not just to add to our list of drugs but to try to improve our performance.

Richard Kim, MD: Mutational status in colorectal cancer does change. One that has been studied extensively is RAS status. We know that patients who are RAS wild type who get an EGFR drug, over time, as they develop resistance to the drug, will develop a RAS mutation. This was studied in a series with liquid biopsies. In terms of other mutations, does that change over time? I think more research needs to be done in that area.

In colon cancer, a serial biopsy may have some benefits. By doing the serial biopsy on patients, you could possibly monitor response to treatment or pick up some of the resistance mechanisms. However, there are certain disadvantages to doing a serial biopsy. You are not capturing the whole tumor heterogeneity. By doing a biopsy of 1 area, you are not capturing the whole real-life evolution of certain mutations. Secondly, it’s just not practical to do a tissue biopsy on patients every time they progress. Currently, other than on the basis of a trial, a serial biopsy is not recommended.

In colon cancer, the liquid biopsy is not ready for prime time. The gold standard is still to get a tissue biopsy and assess molecular abnormalities from the tissue. However, there are potential advantages to using a liquid biopsy. You could actually capture the resistance mechanism or possibly monitor response to treatment in real time. There are other potential applications for a liquid biopsy as well. It could possibly be a prognostic biomarker. There’s data that demonstrate that checking a liquid biopsy with circulating tumor DNA [deoxyribonucleic acid] can predict, can be prognostic, in terms of the response rate and progression-free survival and overall survival. A trial in China that was presented this year stated that doing a liquid biopsy early on could actually detect early colon cancer as well. Therefore, there are a couple of advantages to doing a liquid biopsy. In the future, as more data come out on liquid biopsies and the technique improves, hopefully a liquid biopsy will replace a tissue biopsy.

Alan Venook, MD: So MATCH is a basket trial. The idea with MATCH is that you can do a large screening of molecular features. You find a molecular feature that, theoretically, might be actionable, and then take a drug off the shelf and treat the patient. In general, I don’t think it’s a particularly efficient way to find drugs that work for colorectal cancer patients.

If we luck out, that would be wonderful. So far, there has not been much headway. In colorectal cancer you need an actionable mutation. Fifty-five percent or 60% of patients have RAS mutations that, at least right now, we can’t overcome. So I’m not convinced that doing a basket trial like MATCH is very helpful. I’ll be convinced otherwise as soon as we find a drug that actually works. But so far, it has not helped us very much.

COLOMATE is a study that’s looking at cell-free DNA. I think they’re looking for mutations in the blood. And so, liquid biopsies are very popular. They are very cool but need to be in the range of research right now. The same limitation that applied to MATCH applies to COLOMATE. When you find a mutation, you have to have a solution. There is a paucity of drugs right now to treat what we guess are driver mutations in colorectal cancer.

I think COLOMATE gets to where we have to be, which is not to be doing biopsies of tumors all the time. If we can find the tumor mutation in the blood, that would be great. It also gives us a chance to do what’s equally as important in patients with resistance or who are progressing: to resample the tumor—in this case, the blood—to look to see if there are changes in the circulating tumor DNA, which might tell us the mechanism of resistance and help us to determine how we might treat the patient differently.

Transcript Edited for Clarity