Understanding Mutations and Targeted Treatments in Thyroid Cancer

3D illustration of thyroid gland: © Anatomy Insider - stock.adobe.com

While BRAF mutations are the most common genetic alterations in thyroid cancer, other mutations can be present and introduce challenges for thyroid cancer treatment. Though they are less frequent, RET, NTRK, and RAS mutations can occur in differentiated, medullary, follicular, and anaplastic thyroid cancers.

DNA- and RNA-based next-generation sequencing is the most crucial aspect in determining the right treatment option when assessing patients with thyroid cancer, according to Lova Sun, MD, MCSE.

“It is important in patients who are metastatic, are beginning to be, or are refractory to radioactive iodine, such that it is not a treatment option for them anymore to make an effort to perform next-generation sequencing, either on the initial thyroidectomy specimen or a biopsy of a metastatic site, and then perform a broad DNA- and RNA-based next-generation sequencing panel to identify these alterations, especially fusions, which can be missed by DNA-only based panels. It is important to incorporate RNA-based methods to make sure that we capture these alterations,” Sun, assistant professor of medicine at the Hospital of the University of Pennsylvania, said in an interview with Targeted Oncology^TM.

In the interview, Sun discussed the importance of identifying mutations in thyroid cancer and the targeted therapies that are available to patients.

Targeted Oncology: What are some of the common mutations seen in thyroid cancer?

Sun: When we think of thyroid cancer, we break it up into different histologic types. Most commonly, we are talking about differentiated thyroid cancer as well as anaplastic and medullary thyroid cancer as buckets. The most common alteration we see is BRAF, which is present in about half of those cases. About 10% to 20% of differentiated thyroid cancers harbor RET, which is in distinction to mutations in RET that we see in medullary thyroid cancer, so it is important to keep those distinctions in mind.

NTRK fusions are found, uncommonly, in about 2% to 4% of differentiated thyroid cancers. In terms of other types of alterations, mutations in RAS, including NRAS, can be found in papillary thyroid cancers as well as other types of differentiated thyroid cancer like follicular and Hurthle cell carcinoma, and then finally, anaplastic thyroid cancer can also harbor BRAF and rarely other mutations. A lot of heterogeneity, as you can see, in the different types of alterations that we see in thyroid cancer, which highlights the importance of using next-generation sequencing to identify these actionable alterations.

Are there specific challenges when treating thyroid cancers with NTRK and RET mutations?

I would say the first challenge that we are presented with as clinicians is the important mission of identifying these alterations. Thyroid cancer patients undergo a range of different treatments, including surgery, radioactive iodine, and sometimes even radiation therapy, especially when they are getting to that phase of being radioactive iodine refractory, and here, we are talking about the differentiated thyroid cancer patients. It is important to find these alterations, ideally using a broad-based DNA- and RNA-based next-generation sequencing panel.

I would say that's challenge number 1. Once we do identify these alterations, we are fortunate to have effective targeted therapies for both of these alterations that have high response rates are relatively tolerable. The bigger challenge to us is making sure that we are looking to identify these alterations so that we can treat our patients with the most effective therapy.

What targeted therapies are available for those mutations?

For NTRK fusions, which again are present in single digits, 2% to 4% of differentiated thyroid cancers, there are 2 FDA-approved agents and these are sort of disease-agnostic approvals. [For any] NTRK fusion-positive solid tumor, we have entrectinib [Rozlytrek] and Larotrectinib [Vitrakvi], 2 specific inhibitors for NTRK fusions, both with high response rates associated. [They are] generally tolerable with mostly central nervous system [adverse] effects, including mood changes.

In terms of RET, we used to have 2 approved agents: selpercatinib [Retevmo] and pralsetinib [Gavreto]. Unfortunately, pralsetinib was recently withdrawn. At this point, we have selpercatinib for thyroid cancer as our only approved agent for RET fusions, and keep in mind, selpercatinib and the RET inhibitors work for either RET fusions that are seen in papillary thyroid cancer or RET mutations that characterize medullary thyroid cancers. In fact, a recent phase 3 trial, LIBRETTO-531 [NCT04211337], just confirmed superiority of selpercatinib over frontline vandetanib [Caprelsa] or cabozantinib [Cabometyx, Cometriq]. This is for medullary thyroid cancer. Again, all these agents, whether we are talking about the NTRK or RET, have response rates upwards of 70%. [They are] effective drugs, relatively specific to the target they are inhibiting and well tolerated, especially compared with our otherwise frontline standard of care multitargeted tyrosine kinase inhibitors, such as lenvatinib [Lenvima] and cabozantinib.

In terms of selpercatinib, the [adverse] effects we watch out for are blood pressure elevation, sometimes liver function abnormalities, and some [gastrointestinal (GI) adverse] effects, and edema, but again, generally well-tolerated. The safety and efficacy profile of RET and NTRK inhibitors are certainly favorable, especially compared with our generic mutation-agnostic kinase inhibitors.

What other emerging research are there on these mutations or in thyroid cancer as a whole?

It is important to keep in mind that even though these drugs that I just talked about work well, they are not curative, and they do not work forever. Generally, we have responses that last for many months or even years on these agents, but eventually, patients do progress, and we are learning more about the mechanisms of resistance. When these patients do start not to respond to these agents, those are things like solvent front and gatekeeper mutations that prevent the drug from binding in the way they used to, as well as off-target resistance that we can see in genes such as MET, KRAS, and even BRAF that can sometimes be targeted with other drugs that are approved. It highlights the importance of looking for resistance mechanisms. At the time of progression on these agents, there are trials of next-generation agents such as repotrectinib [Augtyro] and selitrectinib that have some efficacy, even after progression on the approved agents that. We will await data from [these agents] and [see if they] are worth looking into if they are available for our patients. [Also,] biopsy, seeing a site of progression, can sometimes, though not always, lend an additional therapeutic option.

What would be your takeaways for clinicians treating thyroid cancers, specifically with targetable mutations?

It is important in patients who are metastatic, [are] beginning to be, or are refractory to radioactive iodine such that it is not a treatment option for them anymore to make an effort to perform next-generation sequencing, either on the initial thyroidectomy specimen or a biopsy of a metastatic site, and then perform a broad DNA- and RNA-based next-generation sequencing panel to identify these alterations, especially fusions, which can be missed by DNA-only based panels. It is important to incorporate RNA-based methods to make sure that we capture these alterations. If you are lucky enough to find an alteration in NTRK or RET and really confirmed that this is a disease-associated variant, not something like a synonymous alteration or uncertain significance alteration, I think that the recommendation is to opt for the corresponding targeted therapy, which as I have mentioned, have excellent efficacy as well as tolerability over a mutation-agnostic, multitargeted [tyrosine kinase inhibitors (TKIs)].

These are relatively uncommon alterations compared to BRAF, for instance, in thyroid cancer. These are not drugs that we are using all that commonly. I think it is important to, if possible, recruit assistance and collaboration with pharmacy colleagues who can make sure that we are monitoring patients appropriately. For the [adverse] effects that are a little idiosyncratic sometimes, not necessarily things that we always check on our toxicity labs, for instance, to make sure that we're administering these drugs safely. Certainly, the most important thing is to find these alterations, and then as quickly as we can, start patients who have progression on the corresponding targeted agent that has been shown to be efficacious in that setting.