Medical professionals discuss the recently published real-world evidence presented at the American Thyroid Association 2023 Conference.

Exploring Real-World Evidence Presented at ATA 2023

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Hyunseok Kang, MD, discusses the importance of balancing toxicities and other factors when initiating first-line treatments for patients with refractory DTC.

Determining Which DTC Patients May Benefit from Systemic Therapy

Hyunseok Kang, MD, discusses the importance of balancing toxicities and other factors when initiating first-line treatments for patients with refractory differentiated thyroid cancer (DTC), while emphasizing the need to set clear goals and communicate potential adverse reactions before allowing patients to make informed decisions.

Dr Worden, how about if I hand it over to you to talk a little bit about the clinical presentation of thyroid cancer?

: Great. Thank you, Lori. Typically, as medical oncologists, we don’t see these patients until, as Dr Wirth alluded to, when they become really incurable, which represents about 4% to 5% of these patients. So typically they’ll present with an incidental mass in their thyroid or perhaps in their neck. Sometimes these thyroid cancers are actually found on imaging studies of people coming for car accidents and get a CT [scan] of the neck. For example, they may find an incidence of nodules and then are eventually worked up. The paradigm for the treatment of these people really is surgery and neck dissection…followed by radioactive iodine therapy. And then the patients are followed with markers, thyroglobulin, and ultrasounds. And if there’s a locally advanced disease, they will go on to receive treatment, perhaps with another surgery or more RAI [radioactive iodine], until they become refractory. And that’s then when these patients are referred to us. In terms of the histologic subtypes of differentiated thyroid cancers, about 85% represent the papillary variance and others are follicular, which are rare. And we differentiate those by looking at the histology or having our pathologists help us to understand perhaps what kind of papillary thyroid cancer we’re dealing with. There are several variants and based on those variants, they can be aggressive. We also look at the genotyping of these tumors. For example, in follicular cancers, we can see PAX8-PPAR fusions, which represent a large genetic phenotype in that group. Also in papillary thyroid cancers, about 70% or so will have BRAF expression, which will become important as we talk about targeted therapies. So in general these mutations, when present with other promoters such as the TERT [telomerase] promoter mutations, lead to more aggressiveness. And as those genetic variants exist, they essentially become more RAI refractory.

Marcia, it would be great if you could talk a little bit more about the molecular phenotypes of thyroid cancer, particularly in relation to molecular testing. Very quickly, I think perhaps touching upon molecular testing in the diagnostic workup of thyroid nodules, but more importantly, I think in terms of molecular diagnostics in advanced thyroid cancer.

: Sure. I would say that we really do divide it into those 2 areas. So there can be some molecular testing used at the time of diagnosis when we’re doing the fine-needle aspirates, especially if a needle aspirate comes back with some sort of indeterminate histology. We’re not really quite sure how it’s behaving. The Afirma test can sometimes be sent off, and if [it shows] 

 fusion, I think we can assume it’s more likely associated with cancer. And that might actually guide some of the surgeons as far as whether they’re going to do a treatment, whether they’re going to do a thyroidectomy, maybe a partial thyroidectomy vs a full, and how far they’re going to go. It can also help in places where there is not necessarily an expert in thyroid cancer reading the histology because many very seasoned thyroid pathologists will be able to tell these things just by sight. But if people don’t look at them as often, sometimes molecular testing can really help them in knowing how to interpret some of the results they’re seeing. But where the 4 of us really get involved with molecular testing has to do with the ones who are RAI refractory. So they may have responded for a while, but we know that in 50% of people with metastatic disease, RAI will stop working at some point, and we have to do something about that. So these are patients with advanced cancer who no longer take up radioactive iodine and now they are candidates for systemic therapy. And there really is a role now in testing those patients with molecular testing, and I’d say RNA-based NGS [next-generation sequencing] up front. And the reason for that is that we have multikinase inhibitors [in the] first line [and] second line. We have 2 in the first line that are approved, which are sorafenib and lenvatinib, and in the second line, we have cabozantinib, which doesn’t depend on the genotype of the patient. However, if [it is a patient with] papillary thyroid cancer and they have a known 

 fusion, these patients now have other treatment options other than the multikinase inhibitors. And we’ll talk about them a little bit more in this program, but really, the bottom line is that they have more options. And because they have more options, some of those other options, the highly targeted NTRK inhibitors, and RET inhibitors have a very good adverse effect profile improved over what we would say the multikinase inhibitors have and they’re more effective. So now we really have a rationale for moving those highly targeted agents up front.

There is one exception in my opinion, which is BRAF, because the BRAF inhibitors aren’t quite as good as the multikinase inhibitors as far as efficacy. They might be about the same, maybe slightly better as far as tolerability, but they really are inferior as far as overall response rate. So I still hold off on treating [with] the BRAF inhibitors, using BRAF inhibitors after I might have used lenvatinib in the first-line setting, but for the most part, knowing about those 

 fusions up front is important. So now I do RNA-based NGS prior. There is a rationale, and this does come up a lot, especially in countries and places where money is limited. We don’t want to be doing RNA-based NGS on all patients because 85% of the time we actually won’t need that information. And so if we’re going to cure the patient, it doesn’t matter what their genotype is if we know that they’re going to get cured with surgery and radioactive iodine alone. So in addition to those patients, if you take them, the people who do have advanced cancer, we know that over 50% of them will have the 

 mutation. These tend to be mutually exclusive. So if you do 2 steps of testing where you first [look for] the 

 mutation, then you can do an inexpensive test and remove…half of the population and then only do the expensive test, which is the RNA-based NGS, on half of them. There is a rationale for doing 2-step testing. The downside, you use up more tissue and it takes longer. So depending on where you are and whether or not you can get the RNA-based NGS, I often try to do that first if it’s possible, but there is a rationale for splitting it for money-saving purposes.

 Marcia, let me ask you something.Can you tell us a little bit about what you do when you have a patient, say, who had a thyroidectomy maybe 3 years ago, there’s plenty of tissue in the pathology archives, and they develop new metastatic disease? Do you have to do a biopsy of the new sites of metastatic disease for accurate NGS testing or can you go to tissue that’s sitting in the archives?

: There are 2 answers to that. The first point you’re bringing up is the fact that most of these mutations, especially these translocations I’m talking about, were present probably at the time that thyroid cancer first came. So you could go back and find them potentially in those original cases and those original blocks. The problem is that the good test that is going to pick up the translocations has to be RNA-based, and RNA tends to degrade, and for the most part, paraffin blocks that are older than 2 years will have insufficient material. Sometimes I try anyway to see if there is RNA, but very often in cases where it’s 2 years or over 2 years, I’m going to be stuck having to look for a site of disease where I can get a fresh biopsy. Not because the genetics will have changed, but more because the RNA will have degraded and I’m going to actually need a fresh sample to obtain the RNA for the analysis.

Shared insight on best practices in diagnosing patients with differentiated thyroid cancer with a focus on histologic and molecular subtypes. 

Diagnosing DTC: Clinical Workup and Molecular Testing

titled “Treatment Approaches and Sequencing Strategies in Differentiated Thyroid Cancer.” I am Dr Lori Wirth, associate professor of medicine at Harvard Medical School [in Boston, Massachusetts] and medical director of the Center for Head-Neck Cancers. I am joined today by a panel of good friends and experts in thyroid cancers. I would like to welcome my esteemed fellow panelists to introduce themselves. Frank, why don’t we start with you?

: Hi, my name is Frank Worden. I am a clinical professor of medicine at the Rogel Cancer Center at the University of Michigan [in Ann Arbor, Michigan]. I specialize in head-neck cancers and endocrine cancers including thyroid, neuroendocrine tumors, and renal cancers.

: Thanks, Lori. I’m Ezra Cohen from the University of California, San Diego [in San Diego, California]. I’m a professor of medicine and my interest is head, neck and thyroid cancers as well.

: Hi, I’m Marcia Brose. I am a professor at the Sidney Kimmel Cancer Center in Philadelphia, [Pennsylvania,]and the Thomas Jefferson University Medical School, and my specialty is thyroid cancer and also personalized therapy.

Welcome, everyone. Thank you for joining us for today’s program. We’re going to be discussing a number of recent updates in the treatment of differentiated thyroid cancer, [which] we might call DTC during the program, presented at key conferences in 2022. We’ll discuss the data in the context of guidelines, the treatment landscape, and the impact on clinical practice. So let’s get started with our first topic. First,…a brief overview of the epidemiology of thyroid cancer. Overall what we’ve been experiencing in the last 10 years is kind of interesting because the incidence of thyroid cancers was rapidly increasing in our population until we recognized that we were overdiagnosing cases of low-grade cancers that were never going to cause any illness. That epidemic of overdiagnosis has been addressed recently, and now we’re seeing a decrease in the numbers of thyroid cancers being diagnosed. So in this past year, we expect that approximately 43,800 cancers will be diagnosed in the US [United States]. There’s an interesting female-to-male ratio where we see 3 times as many women being diagnosed with thyroid cancer than men. I don’t know that anybody really understands quite why that is.

In terms of deaths, we see a relatively low number of deaths; only approximately 3,300 deaths will be seen in the US due to thyroid cancer this year. Thyroid cancer in women is the 7th most common cancer. It’s less common in men, of course. In terms of the different histologic diagnoses, the vast majority of thyroid cancers are differentiated thyroid cancer, and approximately 97% of cases are differentiated thyroid cancer. That’s the focus of our program today. Now the 5-year overall survival rate of DTC is 98%. Two-thirds of patients will be diagnosed with local regionally advanced disease only. Those patients in general do very well, but when patients do develop distant metastatic disease, their median overall survival is only about 5 years. Those are the patients who ultimately may die of their thyroid cancer, and that’s really what we’re going to be focusing on today.

Opening discussion on the advent of differentiated thyroid cancer (DTC) and management, moderator Lori J. Wirth, MD, provides and overview of prevalence, subtypes, and prognosis. 

Francis Worden, MD

Articles

Exploring Real-World Evidence Presented at ATA 2023

Determining Which DTC Patients May Benefit from Systemic Therapy

Diagnosing DTC: Clinical Workup and Molecular Testing

Overview on Differentiated Thyroid Cancer (DTC)