Moving Toward Personalized Medicine in Advanced DTC

Transcript:R. Michael Tuttle, MD: If I can come back to Marcia and Eric to round out this session. I hear you guys talk all the time about doing all this fancy molecular testing, and we test for 400 genes and most of the time it doesn’t help me. Is it really helping in the setting you’re talking about, in these distant metastases where you’re having to pick which treatment to use? I’ll spot you a BRAF, maybe use a BRAF inhibitor. But out of all the molecular personalized testing, is it really making a difference in what you’re doing in clinic? Marcia?

Marcia S. Brose, MD, PhD: I think we should almost come back to this question at the end of the discussion because it doesn’t matter for most of the steps, all the way up until I’ve run out of all of the FDA -approved agents. But we will get into a discussion about people that I have a feeling are going to do poorly. And for those people, I’m going to be already planning what I am going to be able to do next. Because they won’t necessarily get as good a benefit. And I always, with my patients, I like to have my plan B. So, I would say that for us, we really do wait. There is an exception to that though, and I think actually Eric can probably speak to this even better because a lot of the research is happening at Memorial Sloan Kettering Hospital, where we’re starting to look at how molecular markers also could help us with maybe improving outcomes. Do you want to talk a little bit about the ASTRA trial and how that might start to change the paradigm, if we know more about it? That’s not really a molecular test, but it’s starting to look at earlier steps of therapy.

Eric J. Sherman, MD: We do look at patients who we might not be thinking about systemic therapy for, but we would still be considering radioactive iodine as an option if the iodine worked. By looking at what kind of mutations are driving their disease, we have found that using a specific inhibitor—so for us, a MEK inhibitor with tumors with a RAS mutation, a BRAF inhibitor in tumors with a BRAF mutation, maybe in some patients who do not have either a RAS or a BRAF—that some of these drugs still might work. Or at least a MEK inhibitor might still work. And using that can actually make these tumors that did not upregulate the sodium iodine supporter, all of a sudden upregulated.

In some cases, tumors that did not pick up iodine at all, we can now see pick up about 100 times the amount that they did before, and they were able to be treated with reactive iodine again. The question that always exists is that if you’re able to do that in a patient with macroscopic RAI-refractory disease, are you leading toward benefit where you could have better control of the disease for the longer term, or not? We don’t know the answer to it, but it’s still a possibility. The other question that exists by doing these studies in later disease is, if we bring this up front and make radioactive iodine more potent in the adjuvant setting or in patients who have RAI-sensitive disease, can you actually then lead to a better benefit and maybe even potential leading to a better cure for some of these patients?

So, there is a randomized study, ASTRA, where patients were randomized to receive a MEK inhibitor versus placebo. This was not sub-grouped to only patients with RAS mutations or BRAF mutations, although it was set up for just papillary thyroid carcinomas where most of the mutations will be along this pathway. And what this study is going to try to see is, by doing that, are we going to do better in disease-free survival. That study just completed, so we’ll probably have the answer in about a year-and-a-half to 2 years from now. There’s also going to be a study that’s about to start in patients with RAI-sensitive metastatic disease, where they’re going to be randomized to receive a MEK inhibitor versus not a MEK inhibitor, and trying to see by using that in this setting, do we lead to a better outcome or not.

R. Michael Tuttle, MD: So, it sounds like we’re really right in that transition period where there’s clearly some defining roles of the molecular testing that are definitely helping us. It’s probably not for most of our patients because most of our patients are low- or intermediate-risk and the treatments work very well. And what we’re struggling with is asking, what’s the exact right place in the sequence to use the molecular testing?

Marcia S. Brose, MD, PhD: I’ll just sort of sum it up that we really have some interesting data, but they’re research questions. As far as standard of care, it has not actually been significantly changed, with the exception of the indeterminate nodules maybe helping decide who’s going to get a surgery. But with a really good cytopathologist, even that doesn’t warn it. So, really up front, the therapy hasn’t changed. You do surgery, you do your radioactive iodine according to the guidelines and when that’s appropriate, and that hasn’t changed.

R. Michael Tuttle, MD: Clearly driving our research, driving our clinical trials, trying to figure out where that issue is. Naifa?

Naifa Busaidy, MD, FACP, FACE: I 100% agree. There is one other thing. While it’s exciting to get 134-gene panel, 200-gene panel, 400-gene panel, we may know what to do with the BRAFs—maybe that’s all we know what to do with—but then you can get other mutations, like neurofibromatosis type 1(NF1). And how much have we consented the patient that maybe you have a germline, a secondary problem, that there’s ethics discussions that need to come as our gene panels expand? We’re finding diseases, we’re finding mutations we have no idea what to do with, and the patient is worried because now they have three or four mutations and/or we’ll find something that may have implications for a disease that now has a germline. This happens in all cancers. It’s just something we need to always think about when we’re ordering these tests.

R. Michael Tuttle, MD: Eric?

Eric J. Sherman, MD: I guess two things. At Memorial Sloan Kettering Hospital, we do consent them for knowing that we might find a germline. So, we let the patients know ahead of time we may find this, and we even ask the patients ahead of time, do you want to know this or do you not want to know this? Because that was a gigantic ethical question that was brought up through the whole university when we started to do these tests. The other thing I just want to bring up is, even though all this mutational testing has nothing to do with standard of treatment, we do have to remember that the standard treatment is not curative. And even though we’re decades or light years ahead of where we were just a decade ago, we still have a long way to go. And a lot of these molecular testing, these clinical stages, are extremely important to really move the thyroid cancer field forward. We’re not anywhere near where we really want to be.

Transcript Edited for Clarity