How Tumor Sidedness Now Influences Colorectal Cancer

Michael Cusnir, MD:In colorectal cancer, tumor sidedness, meaning where the tumor originates—in the right side or left side of the colon—is something we have been looking at for many years. Even with very old data, when we had only fluorouracil [5-FU] as our sole chemotherapy option, we already knew that tumor sidedness mattered, in terms of the survival of patients and how we should treat them. So this emerging data stems off what has been known for many, many decades.

The interesting thing about tumor sidedness, regarding a patient’s prognosis, is that overall, patients who have tumors that originate on the right side of the colon have a worse prognosis than patients who have tumors that originate on the left side of the colon. That is usually mediated by different embryologic origins. We know that the right side of the colon originates in what we call the midgut, on the embryonic apparatus. The left side originates from the hindgut. That may partly answer why we see a difference in prognosis between tumors that originate on one side versus tumors that originate on the other.

Tumor sidedness is not only prognostic, which we are always discussing. We do not want to confuse the 2 main issues in oncology: prognosis and prediction.Prognosismeans what the patients are facing the moment that they are diagnosed.Predictivemeans I can change it with any of my therapies that I can offer my patient.

We know, from historical data on 5-FU to the most modern of studies, that sidedness is prognostic. What it’s starting to show is that there’s a predictive factor. I can change the behavior of some of those tumors based on how I treat them.

What accounts for the difference in outcome, as I said, is that it could be the embryologic origin. Over the past few years, from a retrospective review of the data of 2 of the main studies that we have looked at in a subgroup analysis—the FIRE-3 and CALGB/SWOG 80405 studies—they actually found that there’s a difference in what we call the consensus molecular subgroups of the patients who had right-sided versus left-sided tumors. The reason I say that this is only part of the answer is because a lot of those subgroup analyses were only of patients who wereKRASwild type. We still need to analyze more of the data from clinical trials that have not already selected forKRASwild type and may have taken both sides of the coin—of wild type and mutant tumors. Based on what we know, it’s embryologic and consensus molecular group migration, and there is a difference between the 2 sides of the colon.

There are some other differences that could be seen in tumor sidedness.KRAStumors seem to be predominant in the right side. The same goes for microsatellite instability, which tends to be seen more in the right side. If that is the case, a lot of the immunologic tumors would have a higher incidence of benefit with immunomodulatory drugs like PD-1 [programmed cell death protein 1] inhibitors and things like that, which nowadays provide a better prognosis with minimal toxicity.KRAS-mutant patients tend to have a worse prognosis. The interesting thing, when you look at this, is that in the studies we have analyzed, in subgroup analyses the worse prognosis was not mediated by theKRASmutation. As I said earlier, in those studies, there were noKRASpatients. They were allKRASwild type, and they still face a worse prognosis.

Transcript edited for clarity.