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Tumor Sidedness in CRC: Distinguishing Factors

Panelists: Alan Venook, MD, University of California San Francisco; John L. Marshall, MD, Georgetown University; Mark Kozloff, MD, Ingalls Cancer Care; Richard Kim, MD,
Published: Tuesday, Nov 20, 2018



Alan Venook, MD:
Tumor sidedness is a very interesting concept, and it’s one that we understand the ramifications of—for right-sided versus left-sided tumors. The biology is still a bit illusive. The possible explanation, of course, is that they are just different biologically. If you think back to embryology, the right colon comes from the midgut and the left colon comes from the hind gut. So they’re different tissues to begin with. That could be an explanation.

There’s a difference in the microbiome in the right side versus the left side. Different bacterium are more common or less common, and that may also be a factor. It’s hard to exclude either of those as factors. This is obviously a pretty complex question.

In CALGB/SWOG 80405, despite a lot of molecular testing, we could not show that any particular gene mutations explained sidedness. But as we’ll present soon at the ESMO [European Society for Medical Oncology] Congress, we believe that we now have a handle on this.
We went through what’s called a machine learning platform, or artificial intelligence, where you sort of put the data together and test different hypotheses without any bias. You just put one element next to the next, to the next. It’s obviously something I can’t explain to you, but it’s sufficed to say that by the statistical artificial intelligence, you can come up with a hierarchy of events. We believe that will explain the sidedness based on the molecular features of the cancer that are seen much more on the right side than on the left side. That’s our hypothesis. I think all of us assumed it would be something like that. Whether that’s correct or not remains to be seen, but we think we’ll have a handle on it pretty soon.

There are some simple, different genetics. Again, we know that mutational events are not randomly distributed throughout the colon. Predisposed right-sided mutations would be ones such as the BRAF mutations and the hyper-methylation on the right side. That’s not enough to explain sidedness though. There are just not enough of those events. MSI [microsatellite instability]-high cancers tend to be on the right side as well, but each of these can also be seen on the left side. So it’s not quite that simple.

I realized that I should look more deeply into the whole sidedness question when we began to understand BRAF mutations and expected them to be on the right side. Five or 6 years ago we saw a handful of young people with right-sided cancers who did very poorly. I assumed those patients had BRAF-mutant tumors. They didn’t. Some of them didn’t, and that made us aware of the fact that something else is going on in the right side other than the incidence of BRAF mutations. To see that there’s such a big difference in sidedness was really stunning. This was something that wasn’t apparent to us. So again, these mutations are good targets but they don’t explain everything.

Patients with BRAF mutations, in my opinion, should almost never get first-line standard therapy. Or, if they get standard therapy, they should immediately move to some sort of BRAF inhibitor strategy, which is now in the NCCN [National Comprehensive Cancer Network] guidelines and is being studied actively. Hopefully we’ll continue to make progress there.

Richard Kim, MD: Based on the clinical trial data that’s out there—based on the PEAK study, the FIRE-3 study, and the CALGB/SWOG 80405 study—left-sided RAS wild-type tumors benefit from the use of anti-EGFR therapy over anti-VEGF therapy. If you look at the ESMO guideline, it clearly states that patients with left-sided RAS wild-type tumors should get EGFR therapy. If you look at the NCCN guidelines, they still give you the choice of using an anti-VEGF drug and anti-EGFR drug. In my practice, when I see a patient with left-sided RAS wild-type tumor, I have a discussion with the patient about the details of the studies. I explain that there is an overall survival benefit for the anti-EGFR drug in a left-sided tumor. Now, that accounts for about 20% to 25% of the patients.

However, the main limitation of using EGFR therapy in the first-line setting is due to the toxicity. If you are on the drug for a very long time, you get the rash. You get the paronychia. So that’s a discussion that I will have with the patient, and, at the end, we will make a final decision. But definitely, for left-sided RAS wild-type tumors, using an anti-EGFR drug is definitely an option. It’s definitely reasonable to use in certain cases.

Transcript Edited for Clarity
 
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Alan Venook, MD:
Tumor sidedness is a very interesting concept, and it’s one that we understand the ramifications of—for right-sided versus left-sided tumors. The biology is still a bit illusive. The possible explanation, of course, is that they are just different biologically. If you think back to embryology, the right colon comes from the midgut and the left colon comes from the hind gut. So they’re different tissues to begin with. That could be an explanation.

There’s a difference in the microbiome in the right side versus the left side. Different bacterium are more common or less common, and that may also be a factor. It’s hard to exclude either of those as factors. This is obviously a pretty complex question.

In CALGB/SWOG 80405, despite a lot of molecular testing, we could not show that any particular gene mutations explained sidedness. But as we’ll present soon at the ESMO [European Society for Medical Oncology] Congress, we believe that we now have a handle on this.
We went through what’s called a machine learning platform, or artificial intelligence, where you sort of put the data together and test different hypotheses without any bias. You just put one element next to the next, to the next. It’s obviously something I can’t explain to you, but it’s sufficed to say that by the statistical artificial intelligence, you can come up with a hierarchy of events. We believe that will explain the sidedness based on the molecular features of the cancer that are seen much more on the right side than on the left side. That’s our hypothesis. I think all of us assumed it would be something like that. Whether that’s correct or not remains to be seen, but we think we’ll have a handle on it pretty soon.

There are some simple, different genetics. Again, we know that mutational events are not randomly distributed throughout the colon. Predisposed right-sided mutations would be ones such as the BRAF mutations and the hyper-methylation on the right side. That’s not enough to explain sidedness though. There are just not enough of those events. MSI [microsatellite instability]-high cancers tend to be on the right side as well, but each of these can also be seen on the left side. So it’s not quite that simple.

I realized that I should look more deeply into the whole sidedness question when we began to understand BRAF mutations and expected them to be on the right side. Five or 6 years ago we saw a handful of young people with right-sided cancers who did very poorly. I assumed those patients had BRAF-mutant tumors. They didn’t. Some of them didn’t, and that made us aware of the fact that something else is going on in the right side other than the incidence of BRAF mutations. To see that there’s such a big difference in sidedness was really stunning. This was something that wasn’t apparent to us. So again, these mutations are good targets but they don’t explain everything.

Patients with BRAF mutations, in my opinion, should almost never get first-line standard therapy. Or, if they get standard therapy, they should immediately move to some sort of BRAF inhibitor strategy, which is now in the NCCN [National Comprehensive Cancer Network] guidelines and is being studied actively. Hopefully we’ll continue to make progress there.

Richard Kim, MD: Based on the clinical trial data that’s out there—based on the PEAK study, the FIRE-3 study, and the CALGB/SWOG 80405 study—left-sided RAS wild-type tumors benefit from the use of anti-EGFR therapy over anti-VEGF therapy. If you look at the ESMO guideline, it clearly states that patients with left-sided RAS wild-type tumors should get EGFR therapy. If you look at the NCCN guidelines, they still give you the choice of using an anti-VEGF drug and anti-EGFR drug. In my practice, when I see a patient with left-sided RAS wild-type tumor, I have a discussion with the patient about the details of the studies. I explain that there is an overall survival benefit for the anti-EGFR drug in a left-sided tumor. Now, that accounts for about 20% to 25% of the patients.

However, the main limitation of using EGFR therapy in the first-line setting is due to the toxicity. If you are on the drug for a very long time, you get the rash. You get the paronychia. So that’s a discussion that I will have with the patient, and, at the end, we will make a final decision. But definitely, for left-sided RAS wild-type tumors, using an anti-EGFR drug is definitely an option. It’s definitely reasonable to use in certain cases.

Transcript Edited for Clarity
 
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