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Practical Considerations in Molecular Testing in CRC

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, Feb 29, 2016


Transcript:

Daniel G. Haller, MD:
There are very clear guidelines now for mutational testing of patients with colorectal cancer with metastatic disease. And, these have been recently published in the JCO. In fact, there was a provisional clinical opinion, or a so-called PCO, where an expert group, led by Carmen Allegra, looked at all of the literature that currently exists in regard to the so-called extended RAS testing.

It’s been some years since we recognized that if one does KRAS testing, typically, it was on exon, codons 12 and 13. But, quite a number of studies were published that show that there were additional mutations that occurred both in KRAS and NRAS. So the new testing includes 5 more exons and 10 more codons to truly extend by about 15% the number of patients who are going to be resistant to EGFR agents. So, this is extremely important. Not only do these patients not benefit from therapy, but many of these studies actually show that patients with these mutations actually do worse if they’re exposed to EGFR agents. So, you save them not doing better, you save them toxicity, and you save cost. So, now instead of 60% of patients being eligible for EGFR agents, it’s down to about 45% or 40%, depending on the study that one looks at.

Standard care RAS testing has been in use for 5 or 6 years, and I think almost everyone in practice knows this. This is part of standard treatment when one is considering an EGFR inhibitor. The extended RAS testing is less well known, in part, because much of it has been embedded in studies from Europe. Much of it, the American physicians have not looked at as often as the Europeans have. Also, people have not understood how to order the test. In many instances, when I’ve spoken to physicians, they don’t know it’s available, they don’t know how to order it, and they’re not sure how it’s going to be reimbursed. So, I think this new PCO by ASCO is going to go far in supporting physicians in their knowledge of the extended RAS testing, how they order it and how they get paid to do it.

Charles S. Fuchs, MD, MPH: Widespread genetic testing is a challenge in this disease because it requires new technology, and it also requires you to do that technology in a time frame that’s relevant to clinical care. So, obviously, we have to get all-RAS testing and not every center has it. And, moreover, some centers have it, but the pathologist tells you, I can get that back in six weeks. Well, we can’t wait six weeks to get those data.

So, we really need to have our own centers or the vendors we go to get us all-RAS, and get it to us in real-time, because patients are not willing to wait more than two weeks, maybe even less, before they know what their treatment options are. So these are the challenges that I face at Dana Farber, and I’m sure it happens at other centers. Beyond that, we really want to know the other genes and we want to know it in real-time. So, getting real-time testing on a variety of things—MSI, BRAF, KRAS, all-RAS—that’s what we need. Not every vendor and not every pathology lab is able to do that so rapidly, but it needs to happen.

At our center, the Dana Farber Cancer Institute, we use next-generation sequencing of about 300 or 350 genes where we’ll get all the clinically relevant genes for colorectal cancer. That’s a technology, admittedly, that’s not going to be available in every center or, for that matter, at every community hospital. Other centers are using RAS-specific tests. Sometimes the technology is called, pyrosequencing, where you’re just focused on a limited number of genes, or maybe even a limited area of selected genes. As long as you’re covering all-RAS, that’s fine, if you can get that in a CLIA-certified laboratory. They can do it in a time frame that informs clinical care.

Admittedly, I would prefer that people not stop at RAS. We want them to continue to do BRAF and MSI. But, in terms of the technologies, I think that they’re all beneficial. There’s no question, in terms of the future of colon cancer, multi-gene, 300-gene panels of sequencing is the ideal, but it’s not practical for every community center. So, as long as they’re getting the clinically relevant targets that we know of, and can do it in real-time using any technology, pyrosequencing, PCR, it doesn’t matter, because they all get you reasonable sensitivity. It’s a matter of getting them and getting them rapidly.
                                                                                                                                                                                                                                                                                                                
Transcript Edited for Clarity
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Transcript:

Daniel G. Haller, MD:
There are very clear guidelines now for mutational testing of patients with colorectal cancer with metastatic disease. And, these have been recently published in the JCO. In fact, there was a provisional clinical opinion, or a so-called PCO, where an expert group, led by Carmen Allegra, looked at all of the literature that currently exists in regard to the so-called extended RAS testing.

It’s been some years since we recognized that if one does KRAS testing, typically, it was on exon, codons 12 and 13. But, quite a number of studies were published that show that there were additional mutations that occurred both in KRAS and NRAS. So the new testing includes 5 more exons and 10 more codons to truly extend by about 15% the number of patients who are going to be resistant to EGFR agents. So, this is extremely important. Not only do these patients not benefit from therapy, but many of these studies actually show that patients with these mutations actually do worse if they’re exposed to EGFR agents. So, you save them not doing better, you save them toxicity, and you save cost. So, now instead of 60% of patients being eligible for EGFR agents, it’s down to about 45% or 40%, depending on the study that one looks at.

Standard care RAS testing has been in use for 5 or 6 years, and I think almost everyone in practice knows this. This is part of standard treatment when one is considering an EGFR inhibitor. The extended RAS testing is less well known, in part, because much of it has been embedded in studies from Europe. Much of it, the American physicians have not looked at as often as the Europeans have. Also, people have not understood how to order the test. In many instances, when I’ve spoken to physicians, they don’t know it’s available, they don’t know how to order it, and they’re not sure how it’s going to be reimbursed. So, I think this new PCO by ASCO is going to go far in supporting physicians in their knowledge of the extended RAS testing, how they order it and how they get paid to do it.

Charles S. Fuchs, MD, MPH: Widespread genetic testing is a challenge in this disease because it requires new technology, and it also requires you to do that technology in a time frame that’s relevant to clinical care. So, obviously, we have to get all-RAS testing and not every center has it. And, moreover, some centers have it, but the pathologist tells you, I can get that back in six weeks. Well, we can’t wait six weeks to get those data.

So, we really need to have our own centers or the vendors we go to get us all-RAS, and get it to us in real-time, because patients are not willing to wait more than two weeks, maybe even less, before they know what their treatment options are. So these are the challenges that I face at Dana Farber, and I’m sure it happens at other centers. Beyond that, we really want to know the other genes and we want to know it in real-time. So, getting real-time testing on a variety of things—MSI, BRAF, KRAS, all-RAS—that’s what we need. Not every vendor and not every pathology lab is able to do that so rapidly, but it needs to happen.

At our center, the Dana Farber Cancer Institute, we use next-generation sequencing of about 300 or 350 genes where we’ll get all the clinically relevant genes for colorectal cancer. That’s a technology, admittedly, that’s not going to be available in every center or, for that matter, at every community hospital. Other centers are using RAS-specific tests. Sometimes the technology is called, pyrosequencing, where you’re just focused on a limited number of genes, or maybe even a limited area of selected genes. As long as you’re covering all-RAS, that’s fine, if you can get that in a CLIA-certified laboratory. They can do it in a time frame that informs clinical care.

Admittedly, I would prefer that people not stop at RAS. We want them to continue to do BRAF and MSI. But, in terms of the technologies, I think that they’re all beneficial. There’s no question, in terms of the future of colon cancer, multi-gene, 300-gene panels of sequencing is the ideal, but it’s not practical for every community center. So, as long as they’re getting the clinically relevant targets that we know of, and can do it in real-time using any technology, pyrosequencing, PCR, it doesn’t matter, because they all get you reasonable sensitivity. It’s a matter of getting them and getting them rapidly.
                                                                                                                                                                                                                                                                                                                
Transcript Edited for Clarity
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