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Predictive Markers for mCRC

Insights From: Richard Kim, MD, Moffitt Cancer Center; Scott Kopetz, MD, PhD, MD Anderson Cancer Center
Published: Monday, Feb 24, 2020



Transcript: 

Scott Kopetz, MD, PhD: For patients with newly diagnosed metastatic colorectal cancer, one of the first things that we do is obtain a molecular profile. And this at a minimum includes a KRAS/NRAS, and we’ll use the term “RAS” to lump them together; BRAF, HER2, looking for amplifications; and an MSI [microsatellite instability] status. And there are a number of ways that that can be done, including immunohistochemistry, PCR [polymerase chain reaction], or next-generation sequencing.

This information is important to help us understand the best treatment options for the patients, and I think that increasingly there are data suggesting this is important to have at the very earliest time possible in the course of a patient’s metastatic disease treatment continuum.

NTRK fusions are also seen in metastatic colorectal cancer. We do see that they are present more commonly in patients who have MSI-high tumors, but still are present, albeit it under 1% frequency, in other populations as well. So that’s something that is performed typically as part of the initial biomarker assessment. Although this commonly is done with different assays in some settings, it’s something that we would encourage if there’s tissue available. And certainly prioritize the NRAS, KRAS, BRAF, HER2 amplification, and MSI assessment above a fusion testing.

Richard Kim, MD: There are certain biomarkers that we already know that are actionable such as KRAS, NRAS, BRAF, and the NTRK fusion. However, there are other predictive biomarkers that are slowly emerging. The problem with these biomarkers is that these are very rare. So, for example, there is a ROS1 fusion, there is a RET fusion, and there’s an ALK fusion. Now, usually patients with a ROS1 fusion are patients with poor prognosis. Now, these are all less than 1%, to say the least. However, studies have shown that if you do have this fusion, there are drugs able to target those, especially the RET fusion. We know there is the BLU-667 compound and there’s a LOXO-292 compound that’s currently out there being used for thyroid and lung cancer. And the incidence of RET fusions in colon cancers is less than 1%. However, if you find that in your molecular profiling, you’ll be able to possibly get a drug on a trial off-label, and the response rate seems to be very, very high.

Other predictive markers that we are looking at in this moment are polysomatic mutations. These are patients who are microsatellite stable but tend to have high tumor burden. And this somatic mutation occurs mostly in young patients. And that’s one of the biomarkers that’s evolving for possible response to checkpoint inhibitors. So that’s something that’s in the future that’s ongoing right now. And the other thing is BRCA mutations. Usually, a BRCA mutation in colon cancer is associated with BRCA1. But now we have PARP [poly (ADP-ribose) polymerase] inhibitors that are currently now approved. It’s a maintenance therapy in pancreatic cancer. So, if you have a patient with a BRCA1 mutation in colon cancer, a PARP inhibitor is something that we could use as well. These are some of the predictive markers that are emerging. Once again, the incidence is very low but if you don’t check it, we’ll never find them. So I think that’s why for me it’s important to test the whole panel at the beginning.

Transcript Edited for Clarity
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Transcript: 

Scott Kopetz, MD, PhD: For patients with newly diagnosed metastatic colorectal cancer, one of the first things that we do is obtain a molecular profile. And this at a minimum includes a KRAS/NRAS, and we’ll use the term “RAS” to lump them together; BRAF, HER2, looking for amplifications; and an MSI [microsatellite instability] status. And there are a number of ways that that can be done, including immunohistochemistry, PCR [polymerase chain reaction], or next-generation sequencing.

This information is important to help us understand the best treatment options for the patients, and I think that increasingly there are data suggesting this is important to have at the very earliest time possible in the course of a patient’s metastatic disease treatment continuum.

NTRK fusions are also seen in metastatic colorectal cancer. We do see that they are present more commonly in patients who have MSI-high tumors, but still are present, albeit it under 1% frequency, in other populations as well. So that’s something that is performed typically as part of the initial biomarker assessment. Although this commonly is done with different assays in some settings, it’s something that we would encourage if there’s tissue available. And certainly prioritize the NRAS, KRAS, BRAF, HER2 amplification, and MSI assessment above a fusion testing.

Richard Kim, MD: There are certain biomarkers that we already know that are actionable such as KRAS, NRAS, BRAF, and the NTRK fusion. However, there are other predictive biomarkers that are slowly emerging. The problem with these biomarkers is that these are very rare. So, for example, there is a ROS1 fusion, there is a RET fusion, and there’s an ALK fusion. Now, usually patients with a ROS1 fusion are patients with poor prognosis. Now, these are all less than 1%, to say the least. However, studies have shown that if you do have this fusion, there are drugs able to target those, especially the RET fusion. We know there is the BLU-667 compound and there’s a LOXO-292 compound that’s currently out there being used for thyroid and lung cancer. And the incidence of RET fusions in colon cancers is less than 1%. However, if you find that in your molecular profiling, you’ll be able to possibly get a drug on a trial off-label, and the response rate seems to be very, very high.

Other predictive markers that we are looking at in this moment are polysomatic mutations. These are patients who are microsatellite stable but tend to have high tumor burden. And this somatic mutation occurs mostly in young patients. And that’s one of the biomarkers that’s evolving for possible response to checkpoint inhibitors. So that’s something that’s in the future that’s ongoing right now. And the other thing is BRCA mutations. Usually, a BRCA mutation in colon cancer is associated with BRCA1. But now we have PARP [poly (ADP-ribose) polymerase] inhibitors that are currently now approved. It’s a maintenance therapy in pancreatic cancer. So, if you have a patient with a BRCA1 mutation in colon cancer, a PARP inhibitor is something that we could use as well. These are some of the predictive markers that are emerging. Once again, the incidence is very low but if you don’t check it, we’ll never find them. So I think that’s why for me it’s important to test the whole panel at the beginning.

Transcript Edited for Clarity
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