Case Studies in Thyroid Cancer - Episode 15

Case 2: RET Mutations and Disease Management

The panel of experts discuss the importance of molecular testing and RET mutations in thyroid cancer disease management.

Lori Wirth, MD: I think we all agree that this patient needs systemic therapy, there’s no argument there. Now let’s get back to molecular testing, with the patient’s germline RET wild-type, Andrew?

Andrew Gianokakis, MD: We kind of already covered this; we will look at somatic mutations and try to identify a RET mutation or a RET rearrangement, which can also occur. Then that aside, as Marcia mentioned, there may be a RAS mutation, but there’s very little else that we’re looking for that exists or that we can act on.

Lori Wirth, MD: This is new, right? We’ve been doing somatic testing in these patients for clinical trial enrollment over the last few years, but it’s brand new, right? There are now FDA-approved agents that can be used when a somatic RET mutation is found in the tumor; this is a new standard of care.

Andrew Gianoukakis, MD: Correct. If I’m remembering correctly, about 50% of that 75% will be RET somatic mutation positive.

Lori Wirth, MD: Exactly, yes, so it’s not a rare finding. You’re going to have a hit in at least half the patients you test, so you don’t want to not do this.

Marcia Brose, MD: Yes.

Lori Wirth, MD: Our patient did have the molecular testing done, revealing a RET M918T mutation. That mutation is interesting because that mutation when seen in the germline setting causes MEN2B [multiple endocrine neoplasia type 2B], which has a very aggressive phenotype of disease. MEN2B is rarer than MEN2A, I think in part because it’s such an aggressive phenotype. However, in sporadic cases, the RET M918T mutation is the most common RET mutation that we see. It’s not a surprise at all that this patient has this mutation. Briefly, in terms of RET oncogenic signaling, the normal RET protein is a tyrosine kinase that sits on the cell surface and signals through multiple pathways. It’s activated in thyroid cancer in 2 distinct mechanisms, either by point mutations or by fusions. We see the point mutations mostly in medullary thyroid cancer, and we see the RET fusions primarily in differentiated or follicular-derived thyroid cancers. Those 2 different mechanisms of RET activation both lead to oncogenesis and signaling through the RAS/RAF/MAP kinase pathway, PI3 kinase pathway, and other pathways as well. We do see RET mutations primarily driving medullary thyroid cancer. We don’t really see activating RET mutations in other solid tumors; I think that’s probably because we don’t really see RET expressed in many other tissues. We’ve talked a lot about the germline RET mutations and the most common ones, but I think the chart shows that there are a number of different germline RET mutations. We want to be looking for not just the 2 most common ones but use an assay that can detect all of the germline RET mutations; there are send-out labs that do this.

RET fusions are interesting; there are multiple RET fusion partners, 5 prime fusion partners with RET. In differentiated thyroid cancer, the 2 most common ones are CCDC6 and NCOA4, but more than 25 prime RET fusion partners have been described in follicular-derived thyroid cancers. We also see RET fusions in a small percentage of non–small cell lung cancers. However, you can see RET fusions very rarely in multiple other solid tumors as well, including pancreatic cancer. In terms of the NCCN [National Comprehensive Cancer Network] guidelines for medullary thyroid cancer, when patients have progressive disease, whether it’s symptomatic or asymptomatic, we do now have 4 drugs that are FDA approved. Vandetanib was the first drug, and cabozantinib is also FDA approved; both of those 2 drugs are VEGFR multikinase inhibitors. We now have both selpercatinib and pralsetinib that are FDA approved for medullary thyroid cancer that’s progressive, when patients harbor RET mutations, whether they’re germline or somatic mutations.

This transcript has been edited for clarity.