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Potential Biomarkers in Metastatic Colorectal Cancer

Insights From: Charles S. Fuchs, MD, Harvard Medical School; Daniel G. Haller, MD, FACP, FRCP, Perelman School of Medicine; Richard Kim, MD, University of South Florida College of Medicine
Published: Monday, Apr 11, 2016


Transcript:

Richard Kim, MD:
PTEN is a tumor suppressor gene, and EGFR also activates the PI3K PTEN pathways. We know the loss of PTEN actually upregulates the PI3K pathway. So PTEN could be a potential biomarker in EGFR drugs. And the current data out there may suggest that loss of PTEN or PTEN mutation actually may confer resistance to EGFR drugs. However, there are two problems with PTEN as a biomarker. Number one is that there’s no standardized test to test for PTEN, so there’s a lot of variance between which tests you use. The second thing is that there’s a very high discordance between the primary site and the metastatic site. So, therefore, based on those two limitations, we cannot recommend that a patient get tested for PTEN up front.

Charles S. Fuchs, MD: As the landscape of the genomics of colon cancer evolves, we know certainly that RAS and RAF, and microsatellite instability need to be assessed and can inform clinical care. But where are we going beyond that? Well, HER2 is certainly relevant for breast cancer, relevant for gastric cancer, and may be relevant for colorectal cancer. The HERACLES study was a European effort to say can we identify patients whose colorectal cancers over expressed HER2? They found those patients. They then treated them with trastuzumab and lapatinib and actually found significant responses that were relatively durable. It’s one small study. It needs to be confirmed, but I know that many oncologists are now calling up their buddy in pathology saying, “Hey, can you do me a favor, can you do that HER2 test on my patient with colon cancer?” I don’t blame them for doing it, though we clearly need more data. It’s interesting. It’s compelling, and it may evolve that that’s going to be a standard recommendation.

There are a variety of other genes that are clearly targetable in colon cancer that are mutated. The problem is, we just don’t know the right drug yet, but we will get there, namely with PI3K. We haven’t found the drug yet, but I’m sure we will. With p53, which is frequently mutated in colon cancer, maybe that gene by itself is not targetable, but some of the downstream events happening after a p53 mutation may be targetable. The Wnt signaling pathway is really important in colon cancer. It’s been a Holy Grail. How do we target it? It’s so obvious. It’s so common in colon cancer, but it’s been tough to target. We have one paper where we at least found one subset of patients who have activation of the Wnt signaling pathway, where we did find a target, but it was only a small fraction of patients with metastatic disease. We need to unravel that pathway, among the others, so we can come up with better drugs.

Transcript Edited for Clarity
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Transcript:

Richard Kim, MD:
PTEN is a tumor suppressor gene, and EGFR also activates the PI3K PTEN pathways. We know the loss of PTEN actually upregulates the PI3K pathway. So PTEN could be a potential biomarker in EGFR drugs. And the current data out there may suggest that loss of PTEN or PTEN mutation actually may confer resistance to EGFR drugs. However, there are two problems with PTEN as a biomarker. Number one is that there’s no standardized test to test for PTEN, so there’s a lot of variance between which tests you use. The second thing is that there’s a very high discordance between the primary site and the metastatic site. So, therefore, based on those two limitations, we cannot recommend that a patient get tested for PTEN up front.

Charles S. Fuchs, MD: As the landscape of the genomics of colon cancer evolves, we know certainly that RAS and RAF, and microsatellite instability need to be assessed and can inform clinical care. But where are we going beyond that? Well, HER2 is certainly relevant for breast cancer, relevant for gastric cancer, and may be relevant for colorectal cancer. The HERACLES study was a European effort to say can we identify patients whose colorectal cancers over expressed HER2? They found those patients. They then treated them with trastuzumab and lapatinib and actually found significant responses that were relatively durable. It’s one small study. It needs to be confirmed, but I know that many oncologists are now calling up their buddy in pathology saying, “Hey, can you do me a favor, can you do that HER2 test on my patient with colon cancer?” I don’t blame them for doing it, though we clearly need more data. It’s interesting. It’s compelling, and it may evolve that that’s going to be a standard recommendation.

There are a variety of other genes that are clearly targetable in colon cancer that are mutated. The problem is, we just don’t know the right drug yet, but we will get there, namely with PI3K. We haven’t found the drug yet, but I’m sure we will. With p53, which is frequently mutated in colon cancer, maybe that gene by itself is not targetable, but some of the downstream events happening after a p53 mutation may be targetable. The Wnt signaling pathway is really important in colon cancer. It’s been a Holy Grail. How do we target it? It’s so obvious. It’s so common in colon cancer, but it’s been tough to target. We have one paper where we at least found one subset of patients who have activation of the Wnt signaling pathway, where we did find a target, but it was only a small fraction of patients with metastatic disease. We need to unravel that pathway, among the others, so we can come up with better drugs.

Transcript Edited for Clarity
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