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Left- Versus Right-Sided Tumors in CRC

Panelists: Johanna C. Bendell, MD, Sarah Cannon Research Institute; Cathy Eng, MD, FACP, The University of Texas MD Anderson Cancer Center; John L. Marshall, MD, The Ruesch Center for the Cure of GI Cancers ; Michael A. Morse, MD, Duke Cancer Institute; Dale R. Shepard, MD, PhD, FACP, Taussig Cancer Institute, Cleveland Clinic
Published: Friday, Apr 06, 2018



Transcript: 

John L. Marshall, MD: Let’s shift gears a little bit from molecular to anatomic. It seems that right and left are different cancers. Dale, why don’t you kind of summarize what those findings were? We’ll talk a little about how they apply to us, clinically.

Dale R. Shepard, MD, PhD, FACP: Clinically, we know that they’re of different biology. That’s become really clear with the subset analysis of 8045. Patients respond differently to EGFR therapies. We know that there are differences, in terms of likelihood of peritoneal metastasis or liver metastasis. Left-sided tumor patients live longer.

John L. Marshall, MD: Are you telling a patient, “You’ve got right-sided cancer. Get your affairs in order?”

Dale R. Shepard, MD, PhD, FACP: In all fairness, we don’t. Globally, we sort of know that there are differences. But I still don’t think we’re at the level where we understand it enough to make those decisions and comment on that.

Cathy Eng, MD, FACP: I think it’s important to keep in mind that the trial was specifically in the treatment-naïve metastatic patient population. The data are on treatment-naïve patients.

Dale R. Shepard, MD, PhD, FACP: Correct. That’s exactly right.

John L. Marshall, MD: There are some subsequent studies.

Cathy Eng, MD, FACP: There are other smaller studies.

Dale R. Shepard, MD, PhD, FACP: But most of what we know, you’re exactly right, is with that first therapy. A lot of the differences, in terms of what we do, depend on the algorithm you use to decide what to treat that patient with, initially, as first-line therapy. I tend to give VEGF therapy as first-line treatment. And so, it doesn’t matter, as much, about the lower response rates to right-sided colon cancer with EGFR agents. That’s where I think it depends more, from a practical standpoint, in terms of changes in biology.

John L. Marshall, MD: We’ll get to therapy in a minute. Michael, is there any clue as to what’s going on here? Why would “anatomically right” be different from “anatomically left?” We know more about the CMS (consensus molecular subtype) panels and the like, and RAS and BRAF and MSI. Is there any clue as to what’s going on? Do you know?

Michael A. Morse, MD: Yes. But to be fair, many of these things don’t always pan out when one looks further. We obviously know that, embryologically, they’re different. So, there is reason to believe that the biology can be different. There have been some limited analyses done, even on normal colon, to look at gene expression as you move along the colon. It does vary, from the left side to the right side of the colon. So, the normal tissues have some differences. One of the more interesting observations has been that in right-sided tumors, there tends to be lower expression of the ligands for EGFR, regulin, and epiregulin, because of methylation patterns. In that situation, you can certainly imagine that if there aren’t adequate ligands, it’s not a driver for the pathway. So, of course, an anti-EGFR therapy might not work. Of course, again, that’s really based on 1 analysis.

John L. Marshall, MD: Johanna, where does the right end and where does the left begin?

Johanna C. Bendell, MD: Embryologically, you divide at the splenic flexure. So, usually, the transverse in these analyses have gone along with the right side.

John L. Marshall, MD: But I've even heard people say, “Well, if it's a little bit over here, it's a little bit over there.” I joke that, because I'm the division chief, I have to make sure that everybody puts in the correct ICD-10 code. But you need to put in the correct ICD-10 code. I could imagine a day when payers would say, “Well, you can’t do that drug because it’s right-sided,” right?

Transcript Edited for Clarity 

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Transcript: 

John L. Marshall, MD: Let’s shift gears a little bit from molecular to anatomic. It seems that right and left are different cancers. Dale, why don’t you kind of summarize what those findings were? We’ll talk a little about how they apply to us, clinically.

Dale R. Shepard, MD, PhD, FACP: Clinically, we know that they’re of different biology. That’s become really clear with the subset analysis of 8045. Patients respond differently to EGFR therapies. We know that there are differences, in terms of likelihood of peritoneal metastasis or liver metastasis. Left-sided tumor patients live longer.

John L. Marshall, MD: Are you telling a patient, “You’ve got right-sided cancer. Get your affairs in order?”

Dale R. Shepard, MD, PhD, FACP: In all fairness, we don’t. Globally, we sort of know that there are differences. But I still don’t think we’re at the level where we understand it enough to make those decisions and comment on that.

Cathy Eng, MD, FACP: I think it’s important to keep in mind that the trial was specifically in the treatment-naïve metastatic patient population. The data are on treatment-naïve patients.

Dale R. Shepard, MD, PhD, FACP: Correct. That’s exactly right.

John L. Marshall, MD: There are some subsequent studies.

Cathy Eng, MD, FACP: There are other smaller studies.

Dale R. Shepard, MD, PhD, FACP: But most of what we know, you’re exactly right, is with that first therapy. A lot of the differences, in terms of what we do, depend on the algorithm you use to decide what to treat that patient with, initially, as first-line therapy. I tend to give VEGF therapy as first-line treatment. And so, it doesn’t matter, as much, about the lower response rates to right-sided colon cancer with EGFR agents. That’s where I think it depends more, from a practical standpoint, in terms of changes in biology.

John L. Marshall, MD: We’ll get to therapy in a minute. Michael, is there any clue as to what’s going on here? Why would “anatomically right” be different from “anatomically left?” We know more about the CMS (consensus molecular subtype) panels and the like, and RAS and BRAF and MSI. Is there any clue as to what’s going on? Do you know?

Michael A. Morse, MD: Yes. But to be fair, many of these things don’t always pan out when one looks further. We obviously know that, embryologically, they’re different. So, there is reason to believe that the biology can be different. There have been some limited analyses done, even on normal colon, to look at gene expression as you move along the colon. It does vary, from the left side to the right side of the colon. So, the normal tissues have some differences. One of the more interesting observations has been that in right-sided tumors, there tends to be lower expression of the ligands for EGFR, regulin, and epiregulin, because of methylation patterns. In that situation, you can certainly imagine that if there aren’t adequate ligands, it’s not a driver for the pathway. So, of course, an anti-EGFR therapy might not work. Of course, again, that’s really based on 1 analysis.

John L. Marshall, MD: Johanna, where does the right end and where does the left begin?

Johanna C. Bendell, MD: Embryologically, you divide at the splenic flexure. So, usually, the transverse in these analyses have gone along with the right side.

John L. Marshall, MD: But I've even heard people say, “Well, if it's a little bit over here, it's a little bit over there.” I joke that, because I'm the division chief, I have to make sure that everybody puts in the correct ICD-10 code. But you need to put in the correct ICD-10 code. I could imagine a day when payers would say, “Well, you can’t do that drug because it’s right-sided,” right?

Transcript Edited for Clarity 
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