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Practical Advice on Molecular Testing in Lung Cancer

Panelists:Benjamin Levy, MD, Mount Sinai Health Systems, ; John W. Longshore, PhD, Carolinas Pathology Group; Gregory J. Riely, MD, PhD, Weill Cornell Medical College; Mark A. Socinski, MD, University of Pittsburgh; Thomas E. Stinchcombe, MD, University of North Carolina at Chapel Hill; Jared Weiss, MD, University of North Carolina School of Medicine
Published: Wednesday, Mar 23, 2016


Transcript:

Mark A. Socinski, MD:
John, let me turn to you. I’ve always said for years that we should be providing our pathologists with adequate tissue samples, that the heavy lifting, so to speak, from the pathologist’s point of view is done by viewing the morphology in making that decision. But a lot special stains are used. Could you comment on the use of IHC special stains: how many, not too many, those sorts of issues?

John W. Longshore, PhD: Sure, absolutely, I’ll be happy to do that. The testing landscape has really changed over the past 10 years. Histological diagnosis is very important. Tissue stewardship is something we’re hearing a lot about now, making sure we have sufficient tissue for all the necessary biomarker testing. Now, this is particularly an issue for lung cancer because we have the highest number of biomarkers we need to assay and usually the smallest biopsies, either the core needle biopsy or fine needle aspirate. So tissue stewardship is very important.

In cases where we are really favoring a primary lung cancer, an adenocarcinoma usually, we can limit ourselves only using two markers. We will use TTF1 as a marker for adenocarcinoma and either p63 or p40 as a squamous cell carcinoma marker. And if there is no evidence of differentiation and we’re thinking primary lung, that’s usually what we do before we will proceed to biomarker-based testing. So tissue stewardship is something, really, that you hear a lot about in pathology circles these days.

Mark A. Socinski, MD: The whole purpose is really to prioritize tissue once you make a diagnosis and you have a firm diagnosis for the multiple molecular tests. One of the most common questions that I get asked by community oncologists is, “How much do you need to do all of this testing?” Obviously, there’s a lot of variables there. So what’s your answer to that question?

John W. Longshore, PhD: If you choose appropriate biomarker tests, you really do not have to have a dramatic amount of tissue. We’re used to, in pathology, working with small tissue samples in lung cases, and we like to try to reserve those with very high tumor content for the biomarker test. Because it’s not really the quantity of tissue that’s important, but it’s the quantity of tumor that is important. So making sure we get a good biopsy that has sufficient tumor content really is what drives the biomarker testing landscape.

Mark A. Socinski, MD: It goes without saying, all of us who are in tertiary care centers understand the importance of the clinicians communicating well with the pathologists, to give them a tentative diagnosis. I find a lot of these pathologists may be doing excessive IHC stains because they don’t know the clinical history. They might be concerned that this is a pancreatic primary or colon primary, and they’re doing these other stains to rule these things out. But it uses up tissue in this particular area.

John W. Longshore, PhD: It absolutely does, and particularly in the community setting, communication is the key. We are all blessed to be at institutions that have a lot of multidisciplinary tumor boards, and communicating between oncology—either your radiologists or pulmonologists who are doing your biopsy work—and pathology, and the molecular group who is doing your testing, is very important. So, in this day and age of being able to Skype, WebEx, have teleconferences, really there’s no excuse for not being able to have multidisciplinary tumor conferences even in the community setting.

Mark A. Socinski, MD: I want to get back to Greg and ask him once he goes to tier 2, so to speak: how wide should you cast that net? Is it the foundation medicine approach where we get a lot of things we don’t know what to do with? Should you be more focused? What are the various platforms out there? How should doctors think about this?

Gregory J. Riely, MD, PhD: When you look at that second tier, when you’re going beyond the standard FDA-approved test, you’re looking for things that are going to make patients eligible for trials. And you’re looking for things that may help you use drugs with other indications that might be helpful for you. Now, that’s maybe, if you’re being optimistic, another 10 or 12 genes. But there are platforms out there that can look for 400 gene mutations, 400 gene amplifications, rearrangements, and beyond. When we’re sitting here thinking about doing a test, and we just heard the challenges of tissue acquisition, the challenges of tissue stewardship, it’s incumbent upon us to be as efficient as possible when we do these tests. And so when we look at what the next level includes, it’s hard not to do 400 genes if it’s the same amount of DNA as you’d require to look at 10 genes.

Mark A. Socinski, MD: As long as it costs the same.

Gregory J. Riely, MD, PhD: As long as it costs the same. So, the broader the better in that regard. But one key next step is not to over-interpret those results. One of the challenges when you’ve done 400 gene mutation tests is what you get back: there are 16 mutations, 14 genes you’ve never heard of, and then 2 genes you’ve heard of but that don’t really have any relevance at all in the lung cancer world. You don’t know what to do with that. And I have to say that I’ve seen some mutation testing platforms where they over-interpret those results, and their routine recommendation is to use everolimus. That seems to be a kind of knee-jerk reaction, and you should try everolimus in this patient. And we know that everolimus has been tested in this patient population and has a response rate of 3% or less. It’s not the right approach. So that’s the caveat really: the broader the better, but don’t over-interpret those results.

Mark A. Socinski, MD: And John, I wanted to get back to you: the other thing about tissue stewardship. I will tell you that one of the issues that takes up a lot of my nurses’ and our program administrators’ time is getting tissue from outside institutions, from one place to the other. You would think you were trying to rob Fort Knox half the time. What are the issues there? Any suggestions in how to make this easier for doctors?

John W. Longshore, PhD: We are all very guarded with our tissue samples from our patients. Things have gotten much better in pathology in the last five years about sharing slides and sharing blocks with outside institutions, because we realize in the local setting, particularly in the community, we may not have access to the sophisticated levels of testing that are needed to characterize these patients. So, work with the lab who is doing your testing or who is doing your consultation and see if you are uncomfortable with sending a block to them. What’s the minimum number of unstained slides that they will accept for the test? And if you don’t want to let the block leave your institution, and some institutional policies do prevent blocks leaving, then perhaps you can send unstained slides, or if you do have a molecular pathology lab, even isolated tumor DNA from previous biomarker testing should be acceptable.

Transcript Edited for Clarity
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Transcript:

Mark A. Socinski, MD:
John, let me turn to you. I’ve always said for years that we should be providing our pathologists with adequate tissue samples, that the heavy lifting, so to speak, from the pathologist’s point of view is done by viewing the morphology in making that decision. But a lot special stains are used. Could you comment on the use of IHC special stains: how many, not too many, those sorts of issues?

John W. Longshore, PhD: Sure, absolutely, I’ll be happy to do that. The testing landscape has really changed over the past 10 years. Histological diagnosis is very important. Tissue stewardship is something we’re hearing a lot about now, making sure we have sufficient tissue for all the necessary biomarker testing. Now, this is particularly an issue for lung cancer because we have the highest number of biomarkers we need to assay and usually the smallest biopsies, either the core needle biopsy or fine needle aspirate. So tissue stewardship is very important.

In cases where we are really favoring a primary lung cancer, an adenocarcinoma usually, we can limit ourselves only using two markers. We will use TTF1 as a marker for adenocarcinoma and either p63 or p40 as a squamous cell carcinoma marker. And if there is no evidence of differentiation and we’re thinking primary lung, that’s usually what we do before we will proceed to biomarker-based testing. So tissue stewardship is something, really, that you hear a lot about in pathology circles these days.

Mark A. Socinski, MD: The whole purpose is really to prioritize tissue once you make a diagnosis and you have a firm diagnosis for the multiple molecular tests. One of the most common questions that I get asked by community oncologists is, “How much do you need to do all of this testing?” Obviously, there’s a lot of variables there. So what’s your answer to that question?

John W. Longshore, PhD: If you choose appropriate biomarker tests, you really do not have to have a dramatic amount of tissue. We’re used to, in pathology, working with small tissue samples in lung cases, and we like to try to reserve those with very high tumor content for the biomarker test. Because it’s not really the quantity of tissue that’s important, but it’s the quantity of tumor that is important. So making sure we get a good biopsy that has sufficient tumor content really is what drives the biomarker testing landscape.

Mark A. Socinski, MD: It goes without saying, all of us who are in tertiary care centers understand the importance of the clinicians communicating well with the pathologists, to give them a tentative diagnosis. I find a lot of these pathologists may be doing excessive IHC stains because they don’t know the clinical history. They might be concerned that this is a pancreatic primary or colon primary, and they’re doing these other stains to rule these things out. But it uses up tissue in this particular area.

John W. Longshore, PhD: It absolutely does, and particularly in the community setting, communication is the key. We are all blessed to be at institutions that have a lot of multidisciplinary tumor boards, and communicating between oncology—either your radiologists or pulmonologists who are doing your biopsy work—and pathology, and the molecular group who is doing your testing, is very important. So, in this day and age of being able to Skype, WebEx, have teleconferences, really there’s no excuse for not being able to have multidisciplinary tumor conferences even in the community setting.

Mark A. Socinski, MD: I want to get back to Greg and ask him once he goes to tier 2, so to speak: how wide should you cast that net? Is it the foundation medicine approach where we get a lot of things we don’t know what to do with? Should you be more focused? What are the various platforms out there? How should doctors think about this?

Gregory J. Riely, MD, PhD: When you look at that second tier, when you’re going beyond the standard FDA-approved test, you’re looking for things that are going to make patients eligible for trials. And you’re looking for things that may help you use drugs with other indications that might be helpful for you. Now, that’s maybe, if you’re being optimistic, another 10 or 12 genes. But there are platforms out there that can look for 400 gene mutations, 400 gene amplifications, rearrangements, and beyond. When we’re sitting here thinking about doing a test, and we just heard the challenges of tissue acquisition, the challenges of tissue stewardship, it’s incumbent upon us to be as efficient as possible when we do these tests. And so when we look at what the next level includes, it’s hard not to do 400 genes if it’s the same amount of DNA as you’d require to look at 10 genes.

Mark A. Socinski, MD: As long as it costs the same.

Gregory J. Riely, MD, PhD: As long as it costs the same. So, the broader the better in that regard. But one key next step is not to over-interpret those results. One of the challenges when you’ve done 400 gene mutation tests is what you get back: there are 16 mutations, 14 genes you’ve never heard of, and then 2 genes you’ve heard of but that don’t really have any relevance at all in the lung cancer world. You don’t know what to do with that. And I have to say that I’ve seen some mutation testing platforms where they over-interpret those results, and their routine recommendation is to use everolimus. That seems to be a kind of knee-jerk reaction, and you should try everolimus in this patient. And we know that everolimus has been tested in this patient population and has a response rate of 3% or less. It’s not the right approach. So that’s the caveat really: the broader the better, but don’t over-interpret those results.

Mark A. Socinski, MD: And John, I wanted to get back to you: the other thing about tissue stewardship. I will tell you that one of the issues that takes up a lot of my nurses’ and our program administrators’ time is getting tissue from outside institutions, from one place to the other. You would think you were trying to rob Fort Knox half the time. What are the issues there? Any suggestions in how to make this easier for doctors?

John W. Longshore, PhD: We are all very guarded with our tissue samples from our patients. Things have gotten much better in pathology in the last five years about sharing slides and sharing blocks with outside institutions, because we realize in the local setting, particularly in the community, we may not have access to the sophisticated levels of testing that are needed to characterize these patients. So, work with the lab who is doing your testing or who is doing your consultation and see if you are uncomfortable with sending a block to them. What’s the minimum number of unstained slides that they will accept for the test? And if you don’t want to let the block leave your institution, and some institutional policies do prevent blocks leaving, then perhaps you can send unstained slides, or if you do have a molecular pathology lab, even isolated tumor DNA from previous biomarker testing should be acceptable.

Transcript Edited for Clarity
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