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Molecular Testing in Thyroid Cancer

Panelists:Marcia S. Brose, MD, PhD, University of Pennsylvania; Naifa Busaidy, MD, FACP, FACE, University of Texas MD Anderson Cancer Center; Eric J. Sherman, MD, Memorial Sloan Kettering Cancer Center; R. Michael tuttle, MD, Memorial Sloan Kettering Cancer Center; Francis Paul Worden, MD, University of Michigan Comprehensive Cancer Center
Published: Monday, Apr 11, 2016


Transcript:

R. Michael Tuttle, MD:
Eric, this whole modern field of molecular biology and molecular pathogenesis. What do we know about what causes thyroid cancer, and what are those molecular triggers, or drivers, or whatever you guys call that stuff?

Eric J. Sherman, MD: So there are certain mutations that we’re seeing that are most common in thyroid cancer. Abnormalities in the MAPK pathway end up being a problem for over 7% of patients with papillary thyroid cancer. In some ways, you can almost split the cancers into two groups: those that are BRAF-like and those that are RAS-like. And those that are RAS-like have that molecular signature. Those are the ones that seem to respond better to radioactive iodine; they seem to do better overall. But then there’s this BRAF subset, which will sometimes still do well; but those are also the ones that are more likely going to be refractory to radioactive iodine. And those are the ones that are going to run into even more problems. Then there’s also this issue of this whole thing, Telomerase Reverse Transcriptase (TERT) and how to target TERT. I don’t think we really have a great idea, but these are tumors that now are becoming even more worrisome, especially if they’re not just a TERT mutation, but a TERT BRAF mutation. Those things can be a lot more aggressive, and those are tumors that we might have to worry about in the long-term on how they’re going to do.

R. Michael Tuttle, MD: So, Marcia, I see you’re shaking your head on that. You agree that this BRAF plus TERT is a bad thing?

Marcia S. Brose, MD, PhD: Well, I think that it’s interesting. I always look at the molecular testing in two different pots. There’s the molecular testing up front and then there’s molecular testing later. I think we’re starting to get markers of who is going to do badly. But we have to remember that as far as testing people molecularly, it’s very, very controversial whether you’re really adding value. Because remembering that 90% to 95% of these patients will be cured with surgery and radioactive iodine alone, the testing won’t necessarily change your plan. So, while, yes, it might give you a clue that this one is more likely to be in that 5%, you’re not actually going to change what you would do. It’s controversial about whether it’s really value added to do that testing at that point.

That’s very different, however, from the patients at the end in that 5% who are going to do poorly, because now we’re going to be using molecular testing to try to find novel targets. In addition to the things that we’ll talk about today that now work, there are additional therapies that are coming online that are specifically guided to specific mutations. So once a patient is already starting to run out of their options, you really want to get molecular testing. And then the other benefit of getting it at that point is that, say they’ve had recurrences over the course of the disease, which we all know could take 5 or 10 years, you want to do the testing on the most recent tissue because these can evolve. The molecular testing signature you get on the original surgery could be very different by the time they actually need to have additional therapies. And now the characteristics of that tumor may have evolved and they may have acquired additional mutations. So, you can’t necessarily be relieved when the person doesn’t have the things up front because even if they don’t, they may actually develop them later on.

Naifa Busaidy, MD, FACP, FACE: I just want to add to reiterate what Marcia was saying in terms of molecular testing: it has become cheaper, it’s easier to do. And most of these patients are still going to do well. But there’s a lot of people out there just ordering this testing as soon as the patient is diagnosed with thyroid cancer. And I think we can cause harm because now we have the 19 year-old girl who has a 1-cm papillary thyroid cancer, who had surgery, and somebody tested it for BRAF, and now she’s read the articles about what can happen if you have a BRAF mutation, and she’s freaked out the rest of her life.

Frank Worden, MD: Yes. I would add to that. The degree of anxiety that it can be creating does not warrant the testing. I saw a lady just the other day, same thing. She was young, she had a tumor contained to her thyroid, and she had one lymph node involved. With BRAF testing, she was demanding that she be seen by nuclear medicine right away for radioactive iodine therapy. It’s something we need to be cautious about. So, although I agree with Marcia, maybe down the road this can help dictate treatments. But up front, I think we have to take a step back before we just do it.

R. Michael Tuttle, MD: That anxiety really drives more treatments. It drives even more central surgery, more extensive surgery, central neck dissection. It’s really hard because I find patients, they equate, “If I have a risk factor, then if I do more, it must be better.” But I think you guys in oncology have had several examples where just because you can find a risk factor and you know somebody is going to recur, more well-meaning adjuvant therapy or treatments may not necessarily help. Naifa, take me back one step because we’ve been talking primarily about genetics in the tumor and guiding treatments and prognosis. But there’s also a role of the genetic testing in the evaluation of nodules. That seems to be traction more so than for prognosis. Talk a little bit about that.

Naifa Busaidy, MD, FACP, FACE: When a patient is initially diagnosed with a nodule, sometimes we can tell that the nodule is malignant by its features initially, or we can tell that it’s benign initially with fairly good accuracy. But there are these nodules in between either nondiagnostic or indeterminate, which also has subcategories. So sometimes cytopathology alone cannot tell us if that nodule is malignant or not. Even as good as our science is today, there’s no good predictors of being able to tell what those are. For those subgroups of nodules that are indeterminate or nondiagnostic, people have looked at how can we try to define better what’s malignant before going in for surgery or decrease the number of unnecessary surgeries that a patient needs. And then there’s other tests that are fairly good at having a high positive predictive value in terms of predicting whether that nodule is going to be malignant or not. So, it depends on what you’re looking for.

There are molecular markers that can be done on the simple biopsy and looking at whether you have mutations, or a gene classifier, or what have you to try and predict malignant versus nonmalignant. There isn’t an easier answer on whether everybody should be doing it or not. I think one has to step back and look at how good their cytopathologists are at predicting and what the true risk of malignancy is once those nodules are out. So, for some, it’s the right thing to do, and for others, it’s not. If you have good cytopathology, even with those markers, you can’t always tell if it’s malignant or not. I think it’s not the whole answer, but it is good to know there are tests out there and a right time to do it.

R. Michael Tuttle, MD: It’s helping us in that risk stratification. It’s not the be-all-end-all, but it’s there. But, Frank, what’s going to happen is now that we can do all these molecular testing on these nodules, you’re actually going to know when that nodule comes out whether it’s BRAF or whether it’s TERT or whether it’s RAS. So, we’re going to be put in that situation where you didn’t want that information, but, as part of the nodule, every 19 year-old is going to know if they were BRAF mutated. How do we deal with that?

Frank Worden, MD: I think that’s a very difficult thing to do. I really personally think a lot of it comes back to education. It’s up to us, as the providers who are taking care of the patients, to reassure the patients that this is prognostic information that may be of value. But it’s not going to dictate your treatment. So, I think that would be the place to start with that.

Transcript Edited for Clarity
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Transcript:

R. Michael Tuttle, MD:
Eric, this whole modern field of molecular biology and molecular pathogenesis. What do we know about what causes thyroid cancer, and what are those molecular triggers, or drivers, or whatever you guys call that stuff?

Eric J. Sherman, MD: So there are certain mutations that we’re seeing that are most common in thyroid cancer. Abnormalities in the MAPK pathway end up being a problem for over 7% of patients with papillary thyroid cancer. In some ways, you can almost split the cancers into two groups: those that are BRAF-like and those that are RAS-like. And those that are RAS-like have that molecular signature. Those are the ones that seem to respond better to radioactive iodine; they seem to do better overall. But then there’s this BRAF subset, which will sometimes still do well; but those are also the ones that are more likely going to be refractory to radioactive iodine. And those are the ones that are going to run into even more problems. Then there’s also this issue of this whole thing, Telomerase Reverse Transcriptase (TERT) and how to target TERT. I don’t think we really have a great idea, but these are tumors that now are becoming even more worrisome, especially if they’re not just a TERT mutation, but a TERT BRAF mutation. Those things can be a lot more aggressive, and those are tumors that we might have to worry about in the long-term on how they’re going to do.

R. Michael Tuttle, MD: So, Marcia, I see you’re shaking your head on that. You agree that this BRAF plus TERT is a bad thing?

Marcia S. Brose, MD, PhD: Well, I think that it’s interesting. I always look at the molecular testing in two different pots. There’s the molecular testing up front and then there’s molecular testing later. I think we’re starting to get markers of who is going to do badly. But we have to remember that as far as testing people molecularly, it’s very, very controversial whether you’re really adding value. Because remembering that 90% to 95% of these patients will be cured with surgery and radioactive iodine alone, the testing won’t necessarily change your plan. So, while, yes, it might give you a clue that this one is more likely to be in that 5%, you’re not actually going to change what you would do. It’s controversial about whether it’s really value added to do that testing at that point.

That’s very different, however, from the patients at the end in that 5% who are going to do poorly, because now we’re going to be using molecular testing to try to find novel targets. In addition to the things that we’ll talk about today that now work, there are additional therapies that are coming online that are specifically guided to specific mutations. So once a patient is already starting to run out of their options, you really want to get molecular testing. And then the other benefit of getting it at that point is that, say they’ve had recurrences over the course of the disease, which we all know could take 5 or 10 years, you want to do the testing on the most recent tissue because these can evolve. The molecular testing signature you get on the original surgery could be very different by the time they actually need to have additional therapies. And now the characteristics of that tumor may have evolved and they may have acquired additional mutations. So, you can’t necessarily be relieved when the person doesn’t have the things up front because even if they don’t, they may actually develop them later on.

Naifa Busaidy, MD, FACP, FACE: I just want to add to reiterate what Marcia was saying in terms of molecular testing: it has become cheaper, it’s easier to do. And most of these patients are still going to do well. But there’s a lot of people out there just ordering this testing as soon as the patient is diagnosed with thyroid cancer. And I think we can cause harm because now we have the 19 year-old girl who has a 1-cm papillary thyroid cancer, who had surgery, and somebody tested it for BRAF, and now she’s read the articles about what can happen if you have a BRAF mutation, and she’s freaked out the rest of her life.

Frank Worden, MD: Yes. I would add to that. The degree of anxiety that it can be creating does not warrant the testing. I saw a lady just the other day, same thing. She was young, she had a tumor contained to her thyroid, and she had one lymph node involved. With BRAF testing, she was demanding that she be seen by nuclear medicine right away for radioactive iodine therapy. It’s something we need to be cautious about. So, although I agree with Marcia, maybe down the road this can help dictate treatments. But up front, I think we have to take a step back before we just do it.

R. Michael Tuttle, MD: That anxiety really drives more treatments. It drives even more central surgery, more extensive surgery, central neck dissection. It’s really hard because I find patients, they equate, “If I have a risk factor, then if I do more, it must be better.” But I think you guys in oncology have had several examples where just because you can find a risk factor and you know somebody is going to recur, more well-meaning adjuvant therapy or treatments may not necessarily help. Naifa, take me back one step because we’ve been talking primarily about genetics in the tumor and guiding treatments and prognosis. But there’s also a role of the genetic testing in the evaluation of nodules. That seems to be traction more so than for prognosis. Talk a little bit about that.

Naifa Busaidy, MD, FACP, FACE: When a patient is initially diagnosed with a nodule, sometimes we can tell that the nodule is malignant by its features initially, or we can tell that it’s benign initially with fairly good accuracy. But there are these nodules in between either nondiagnostic or indeterminate, which also has subcategories. So sometimes cytopathology alone cannot tell us if that nodule is malignant or not. Even as good as our science is today, there’s no good predictors of being able to tell what those are. For those subgroups of nodules that are indeterminate or nondiagnostic, people have looked at how can we try to define better what’s malignant before going in for surgery or decrease the number of unnecessary surgeries that a patient needs. And then there’s other tests that are fairly good at having a high positive predictive value in terms of predicting whether that nodule is going to be malignant or not. So, it depends on what you’re looking for.

There are molecular markers that can be done on the simple biopsy and looking at whether you have mutations, or a gene classifier, or what have you to try and predict malignant versus nonmalignant. There isn’t an easier answer on whether everybody should be doing it or not. I think one has to step back and look at how good their cytopathologists are at predicting and what the true risk of malignancy is once those nodules are out. So, for some, it’s the right thing to do, and for others, it’s not. If you have good cytopathology, even with those markers, you can’t always tell if it’s malignant or not. I think it’s not the whole answer, but it is good to know there are tests out there and a right time to do it.

R. Michael Tuttle, MD: It’s helping us in that risk stratification. It’s not the be-all-end-all, but it’s there. But, Frank, what’s going to happen is now that we can do all these molecular testing on these nodules, you’re actually going to know when that nodule comes out whether it’s BRAF or whether it’s TERT or whether it’s RAS. So, we’re going to be put in that situation where you didn’t want that information, but, as part of the nodule, every 19 year-old is going to know if they were BRAF mutated. How do we deal with that?

Frank Worden, MD: I think that’s a very difficult thing to do. I really personally think a lot of it comes back to education. It’s up to us, as the providers who are taking care of the patients, to reassure the patients that this is prognostic information that may be of value. But it’s not going to dictate your treatment. So, I think that would be the place to start with that.

Transcript Edited for Clarity
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