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RET Testing in Papillary and Medullary Thyroid Cancer

Insights From: Jacob Sands, MD, Dana-Farber Cancer Institute; Benjamin Besse, MD, PhD, Institut d'Oncologie Thoracique; Alexander Drilon, MD, Memorial Sloan Kettering Center; Marcia Brose, MD, PhD, Perelman School of Medicine
Published: Wednesday, Nov 20, 2019



Transcript: 

Benjamin Besse, MD, PhD:
NGS [next-generation sequencing] testing with a short turnaround time is key, because most of the drugs we have access to can be given up front. In most of the cases, we have the results up front, but in one-third of patients with lung cancer, we know that we will not have sufficient tumor tissue to have the whole profile. In these cases, I highly recommend a new biopsy, in particular, in patients who are light smokers for less than 15 years or never-smokers.

In some cases, you cannot wait. The disease evolves too rapidly, and you have to start the treatment. Then you have to start the platinum-based chemotherapy, and this is not a mistake. What you should do in these cases is run parallel NGS testing, and if you have no sufficient tissue, schedule a new biopsy while the patients start this platinum-based chemotherapy.

Most of these drugs work. What if other patients are not on a platinum-based chemotherapy? The few data that we have suggest that in platinum-naïve patients, it could be a bit more active.

Marcia Brose, MD, PhD: In the past I wouldn’t have necessarily said that everybody should have widespread NGS infusion testing up front. Because in the case of differentiated thyroid cancer, both of the agents that we use, we use regardless of whether or not there’s a mutation.

The same is true in medullary thyroid cancer, where both vandetanib and cabozantinib work in patients both with and without RET mutations. I often would start patients on ones of these first-line agents and then go ahead and get the testing at a later point. However, now fusion testing, particularly in differentiated thyroid cancer, can identify both RET fusion and TRK fusion genes. And those are ones that we now have new agents for that can target these genes specifically, and with very little toxicity, because they’re so specific for the RET, or TRK genes by themselves that the overlapping toxicities and their pathways is minimal.

That can be such an improvement in people’s quality of life, it can be a game changer. So if the patient happens to have 1 of those with differentiated thyroid cancer—it’s not always that common, but if they do, it would possibly make me think about starting a patient on a RET inhibitor or a TRK inhibitor prior to being on the agents that we would recommend, for toxicity reasons.

The same is actually true in medullary thyroid cancer. Now that we have RET-specific targeted agents with the RET mutation, with the RET inhibitors, we would think about trying that first before the cabozantinib and vandetanib, because the adverse-effect profile is so much more improved when you target RET alone instead of targeting RET along with other targets that cause toxicity.

A lot of patients who have come to me have already had testing for germline mutations in RET, and that’s because with medullary thyroid cancer having such a high likelihood, up to 28%, 25% chance of having a familial RET mutation. However, there are some patients who come to me who have not had the hereditary testing. So I will test for this, usually the somatic tests first. The reason for that is that it will give me both the hereditary and the nonhereditary ones. It will answer the question I need to know for that patient, which is, do they have a RET mutation? If the answer is yes, which it is 65% of the time, in those patients I will then reflectively go back and do the hereditary testing. So it doesn’t necessarily mean that you have to do 1 order or the other. If they’ve had hereditary testing, though, you absolutely need to check for sporadic mutations, because you can have another 25% of patients who have that mutation. So it’s really important, especially in medullary thyroid cancer, that patients get checked for both.


Transcript Edited for Clarity
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Transcript: 

Benjamin Besse, MD, PhD:
NGS [next-generation sequencing] testing with a short turnaround time is key, because most of the drugs we have access to can be given up front. In most of the cases, we have the results up front, but in one-third of patients with lung cancer, we know that we will not have sufficient tumor tissue to have the whole profile. In these cases, I highly recommend a new biopsy, in particular, in patients who are light smokers for less than 15 years or never-smokers.

In some cases, you cannot wait. The disease evolves too rapidly, and you have to start the treatment. Then you have to start the platinum-based chemotherapy, and this is not a mistake. What you should do in these cases is run parallel NGS testing, and if you have no sufficient tissue, schedule a new biopsy while the patients start this platinum-based chemotherapy.

Most of these drugs work. What if other patients are not on a platinum-based chemotherapy? The few data that we have suggest that in platinum-naïve patients, it could be a bit more active.

Marcia Brose, MD, PhD: In the past I wouldn’t have necessarily said that everybody should have widespread NGS infusion testing up front. Because in the case of differentiated thyroid cancer, both of the agents that we use, we use regardless of whether or not there’s a mutation.

The same is true in medullary thyroid cancer, where both vandetanib and cabozantinib work in patients both with and without RET mutations. I often would start patients on ones of these first-line agents and then go ahead and get the testing at a later point. However, now fusion testing, particularly in differentiated thyroid cancer, can identify both RET fusion and TRK fusion genes. And those are ones that we now have new agents for that can target these genes specifically, and with very little toxicity, because they’re so specific for the RET, or TRK genes by themselves that the overlapping toxicities and their pathways is minimal.

That can be such an improvement in people’s quality of life, it can be a game changer. So if the patient happens to have 1 of those with differentiated thyroid cancer—it’s not always that common, but if they do, it would possibly make me think about starting a patient on a RET inhibitor or a TRK inhibitor prior to being on the agents that we would recommend, for toxicity reasons.

The same is actually true in medullary thyroid cancer. Now that we have RET-specific targeted agents with the RET mutation, with the RET inhibitors, we would think about trying that first before the cabozantinib and vandetanib, because the adverse-effect profile is so much more improved when you target RET alone instead of targeting RET along with other targets that cause toxicity.

A lot of patients who have come to me have already had testing for germline mutations in RET, and that’s because with medullary thyroid cancer having such a high likelihood, up to 28%, 25% chance of having a familial RET mutation. However, there are some patients who come to me who have not had the hereditary testing. So I will test for this, usually the somatic tests first. The reason for that is that it will give me both the hereditary and the nonhereditary ones. It will answer the question I need to know for that patient, which is, do they have a RET mutation? If the answer is yes, which it is 65% of the time, in those patients I will then reflectively go back and do the hereditary testing. So it doesn’t necessarily mean that you have to do 1 order or the other. If they’ve had hereditary testing, though, you absolutely need to check for sporadic mutations, because you can have another 25% of patients who have that mutation. So it’s really important, especially in medullary thyroid cancer, that patients get checked for both.


Transcript Edited for Clarity
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