RAI Treatment: Impact of Mutation Status


Experts in the management of thyroid cancer discuss radioactive iodine therapy and the clinical implications of mutational status in RAI- refractory DTC.

Lori Wirth, MD: The patient had NGS [next-generation sequencing] testing, and we know that she had the BRAF V600E and TERT promoter mutations. The BRAF V600E mutation upregulates the MAP kinase pathway; that’s one of the mechanisms by which thyroid cancers lose the ability to concentrate iodine. Do treating clinicians who give patients radioactive iodine [RAI] in the US, mostly endocrinologists or nuclear medicine specialists, use that molecular information to determine who should or shouldn’t get radioactive iodine? If she has a BRAF V600E mutation with a TERT promoter mutation, is it futile to even try? Or do you give these patients radioactive iodine treatment anyway?

Andrew Gianoukakis, MD: The short answer is no, we don’t use this information. Most patients with papillary thyroid cancer [PTC], 40% to 70%, will harbor a BRAF mutation. From the TCGA [The Cancer Genome Atlas] data we know that even the TERT promoter mutation is present in about 9% to 10% of well-appearing, low-risk, well-differentiated PTC. Both the BRAF V600E mutation and the TERT mutation can occur in what appears to be clinically, at the outset, very indolent and well-behaving disease. Most patients with PTC respond to the radioactive iodine, so there’s a lot more to be learned. There are investigations ongoing to try to scientifically, molecularly characterize and be able to identify patients that will and will not respond to radioactive iodine. It’s not just BRAF and TERT; hopefully one day we will be able to use a molecular signature in the classification of RAI-refractory disease.

Lori Wirth, MD: Andrew, another quick question for you. The thyroglobulin rise in this patient makes me think about the idea of a thyroglobulin doubling time. You talked earlier a little bit about dynamic risk stratification, where you look after initial treatment and if you see rising thyroglobulin, that might change your approach to following a patient versus if the thyroglobulin is remaining low. Do you calculate thyroglobulin doubling times in your patients you’re following on active surveillance? Is there a utility in doing that?

Andrew Gianoukakis, MD: In this case, the initial treatment thyroglobulin was 24 [ng/mL]; it was significantly elevated. It suggests either local recurrence of disease or distant disease. We don’t routinely check thyroglobulin levels at the time of initial surgery, mainly because there will be great overlap due to the normal thyroid tissue’s production of thyroglobulin. It’s not routinely done. Going forward, we would be able to look at this thyroglobulin of 24 [ng/mL], and have a repeat thyroglobulin 3 months, 6 months later, and gauge thyroglobulin doubling. There have been a couple of very good papers that have offered a prognostic significance to thyroglobulin doubling times. For one paper it was a doubling time of less than a year, for another paper it was a doubling time of less than 3 months. In both cases, the rapid thyroglobulin doubling time significantly portended progression and mortality. We do take into consideration the rapid doubling time when we see it, but we need to be careful; even a patient with a stable thyroglobulin may have rapidly progressive or progressive disease. As the tumor dedifferentiates, just like it no longer takes up radioactive iodine, it no longer efficiently makes thyroglobulin. This is why we use the thyroglobulin and anatomic studies, such as a neck ultrasound, CT scans, PET [positron emission tomography] scans, where we identify and track anatomic progression of disease with your radiologic scans, as well as use the thyroglobulin as a serologic biomarker of disease progression. However, both are used in a complementary way.

This transcript has been edited for clarity.

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