Marshall Addresses Sidedness Issue in Colorectal Cancer

John L. Marshall, MD

Following the findings of the CALGB 80405 trial, which showed inferior results for patients with right-sided colorectal cancer (CRC) versus those with left-sided CRC—researchers decided to examine molecular variations between left-sided colon tumors and rectal tumors.

OncLive: Can you discuss the rationale behind your research?

In an interview with OncLive at the 2017 Gastrointestinal Cancers Symposium, John L. Marshall, MD, chief, Division of Hematology and Oncology, Medstar Georgetown University Hospital, discussed the results of this analysis and other ongoing efforts to determine the underlying molecular basis for the sidedness issue in colorectal cancer.Marshall: For about 15 years, we have had literature that's said right-sided colon cancer behaves worse than left-sided colon cancer. Many ignored that literature until last year when data from a study called CALGB 80405 was presented, which demonstrated a lower survival rate for the right-side, even though both sides received the same treatment.

Now, we're thinking differently about colon cancer. We all believe that there is something fundamentally different about the molecular characteristics of the 2 sides. It's not about the location of left versus right, but those sides make different cancers. However, we don't know what makes that fundamental difference yet. Our study that we presented was focused on determining those differences because we treat rectal cancers differently than other colon cancers.

In our study, we looked at rectal cancers, compared them to other left-sided colon cancers and tried to determine if they're the same or different. One important paper that we presented looked at the molecular profiling of rectal cancers compared to left-sided cancers and showed that there are some subtle differences in the molecular characteristics.

What were the main differences between the left-sided and right-sided colorectal cancers?

More importantly, another study showed that there was no difference in clinical outcomes between right versus left. The reason this is important is because doctors are now thinking clinically about if it is a right-sided or left-sided tumor. We should bundle rectal cancer in with left-sided colon cancer for the moment. These two studies determined that we don't need to additionally stratify for rectal cancers. Right now, it's right versus left and we'll continue to figure out what the molecular characteristics are. The most important clinical findings around are the actionable mutations. The one that we're excited about is microsatellite instability, which is more common on the right-side then on the left-side which is true for rectal as well. Additionally, BRAF mutations are more common on the right-side than the left-side.

What are the next steps following this research?

What we need to do since this has clinical implications is find the molecular characteristics that are driving these differences. It will help us enormously.A next step includes continuing to conduct prospective studies looking at the molecular characterization of the right-side versus left-side. That's going to help us in terms of figuring out how to act in a metastatic setting. It's not clear to me that even with next-generation sequencing that we're going to find the secret gene.

In my opinion, the most exciting abstract that was presented does not have to do with molecular profiling, it has to do with the microbiomes that live in our colon. We're only just beginning to understand the biology of why these bacteria are causing our colon cancer.

If more studies are done in that area and confirm that bacteria can be the cause of these cancers, what kind of impact can that have on the treatments?

Are there any other ongoing areas of investigation in CRC that you are excited about?

A question I hope this research answers is, why are we seeing so many young people with this disease? There was a beneficial lecture and presentation on being able to predict who's going to get colon cancer or not, and it begins to answer the question of why these certain people get colon cancer. This may also help determine right-sided versus left-sided since we think there are different bacteria that live on different sides of our colon and have different functions. It may all come together as we begin to understand those bacterial colonies that we all carry around inside of us. Right now, for example, if you were to get some sort of colonoscopy or test determined that you have a certain negative colony of bacteria, we might be able to figure out how to fix that. The more we understand, the more we can modify behavior, which is more important for prevention and identification but it will also help us to understand the best treatment options for an individual patient.A big area in every cancer is immunotherapy. Guidelines have already listed checkpoint inhibitors as appropriate therapy for refractory MSI-high colon cancer. One message for doctors is it is important to measure MSI in everybody. It doesn't matter what age or stage the patient is, every single patient with colon cancer should be screened because in the metastatic setting you have therapies that are positively driving this disease.

However, that leaves about 85% of patients who don't have MSI. An exciting line of research is trying to make tumors receive the immune system’s attention, whether it's vaccines or other kinds of therapies to confine the checkpoint inhibitors to the tumor. That's an incredibly exciting avenue.

Marshall J, Lenz HJ, Xiu J, et al. Molecular variances between rectal and left-sided colon cancers. J Clin Oncol. 2017;35(suppl 4S; abstr: 522).