New Developments in Thyroid Cancer

Kate O'Rourke

January 11, 2021

In a widely publicized story from 2020, a Florida news reporter discovered she had thyroid cancer after a viewer sent her a concerned email about a lump on her neck. Although such anecdotes are surely not scientific evidence, they do speak to the growing awareness of thyroid cancer among the public, no doubt due in part to the steady, worldwide increase in its incidence observed in recent decades.

To find out more about what may be behind the growing number of cases of thyroid cancer, and the latest treatments we have to combat it, Medscape reached out to two experts at the University of Michigan in Ann Arbor: Megan Haymart, MD, an endocrinology research professor of thyroid cancer and professor in the Division of Metabolism, Endocrinology and Diabetes, and Frank Worden, MD, professor of medicine and a medical oncologist. This interview has been edited for length and clarity.

Medscape: How much of an increase in the incidence of thyroid cancer has there been in recent years? And has that generally been a worldwide observation?

Dr Megan Haymart

Dr Haymart: There has been a marked rise in low-risk thyroid cancer over the past few decades. The most notable change was in South Korea, where incidence increased from 12.2 cases per 100,000 from 1993-1997 to 59.9 cases per 100,000 from 2003-2007. However, other countries, such as the United States, Italy, France, and Australia, also saw a rise in thyroid cancer incidence during the same time period. 

Do we know what is causing that increase? 

Haymart: The etiology of the rise in thyroid cancer incidence is debated. Most data suggest that overdiagnosis secondary to the greater use of imaging studies, especially neck ultrasound, is part of the story. Whether or not there is also a new risk factor that contributes to the change in incidence remains controversial. It may be multifactorial, with overdiagnosis as the predominant driver.

There is also some debate about whether many of these slow-growing tumors actually warrant treatment. What is your opinion on this?

Haymart: Yes, some thyroid cancers are relatively indolent, and more detection can lead to patient harm secondary to downstream treatments. Other thyroid cancers can behave aggressively. Therefore, it is very important to differentiate which thyroid nodules need evaluation and management and which thyroid nodules can be safely followed.

What are the most recent drug approvals for thyroid cancer, and where do they fit in the treatment paradigm for this disease?

Dr Frank Worden

Dr Worden: The most recent drug approved is selpercatinib (Retevmo). This drug is approved for RET-altered thyroid cancers, namely RET-mutated medullary thyroid cancers and RET fusions in radioactive iodine (RAI)-refractory differentiated thyroid cancers (ie, papillary and Hurthle cell) and anaplastic thyroid cancers.

A New Drug Application (NDA)  was submitted to the US Food and Drug Administration for pralsetinib (Gavreto) for patients with advanced or metastatic RET-mutant medullary thyroid cancer (MTC) and RET fusion-positive thyroid cancers. Where might this drug fit in the treatment paradigm? 

Worden: Pralsetinib and selpercatinib will revolutionize the treatment of RET-fusion RAI-refractory differentiated thyroid cancers and more importantly in MTC RET-mutated thyroid cancers. The activity and tolerability of these agents will allow patients to likely remain on treatment and improve progression-free survival and hopefully overall survival.

What do we know about the toxicity profile of pralsetinib?

Worden: In general, the side-effect profile for pralsetinib is much better tolerated than pan-kinase inhibitors such as sorafenib (Nexavar) and lenvatinib (Lenvima). Some patients experience fatigue, constipation, muscle aches, high blood pressure, and fluid retention.

Can you explain the current role of targeted therapies in thyroid cancer? 

Worden: Most oncologists are embracing the use of next-generation sequencing to look for potentially actionable mutations. Although the majority of these mutations are rare in number, the therapies that act on these targets often are more tolerable than tyrosine kinase inhibitors that target primarily the vascular endothelial growth factor receptor and are likely to produce more durable responses. This provides patients with more treatment options and perhaps improved quality of life.

Which tyrosine kinase inhibitors are showing the most promise right now? 

Worden: Entrectinib (Rozlytrek) and larotrectinib (Vitrakvi) target neurotrophic tyrosine receptor kinase fusions, and pralsetinib and selpercatinib target RET mutations in MTC and RET fusions in RAI-refractory differentiated thyroid cancers and anaplastic thyroid cancers. Dabrafenib (Tafinlar) and vemurafenib (Zelboraf) show promise too in RAI-refractory papillary thyroid cancers. The combination of dabrafenib and trametinib (Mekinist) has been FDA approved.

What is the toxicity profile of these new drugs? 

Worden: As mentioned, fatigue, hypertension, and fluid retention are common for a lot of these agents. In addition, mild hepatic dysfunction is seen with selpercatinib. Fever and cardiac dysfunction can occur with the BRAF and MEK inhibitors.

Is there any subset of patients who do not derive benefit from the available therapies? 

Worden: Follicular thyroid cancers are associated with RAS mutations. Currently, there are no agents that meaningfully act on these biomarkers.

What is important for community oncologists to know about treating these patients? 

Worden: Next-generation sequencing should be done on all thyroid cancers to look for potentially actionable mutations. Although we do not have sequencing data, most would consider treating a driver mutation first and saving a pan-kinase inhibitor for patients who progress on such targeted therapies.

What relevant changes in the surgical management of thyroid cancer have occurred in recent years?

Haymart: In the past, almost all patients with differentiated thyroid cancer underwent total thyroidectomy. Lobectomy — removal of half of the thyroid instead of the full thyroid — is associated with less surgical risks than total thyroidectomy. Some studies have found that there has been an increase in the use of thyroid lobectomy in recent years.

This change in surgical management was noted after the publication of the American Thyroid Association's thyroid cancer guidelines in 2015. These guidelines encouraged less-intensive management in specific situations. However, despite the guideline recommendations and findings in recent studies, it isn't clear if there has been a uniform shift to lobectomy in select low-risk patients. That is, we don’t know if all patients who should be candidates for lobectomy are being offered this treatment option.

Haymart had has disclosed no relevant financial relationships. Worden disclosed funding from Bayer, Eisai  Merck, Bristol-Myers Squibb, and Lilly.

Kate O'Rourke is a freelance writer in Portland, Maine. She has covered the field of oncology for over 10 years.

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