Transcript: Marcia S. Brose, MD, PhD: We actually know quite a bit about what happens at the time that iodine is no longer taken up by the cells. Genetically, we know that these cells shift and stop expressing the symporter that is required for iodine to be absorbed by the cell. We also know that there are other molecular changes that inhibit the trapping of the iodine inside the cell. So we know that there is a molecular shift that happens in the cell and a phenotypic difference that leads to this. That’s why iodine is no longer working. Interestingly, it may not happen in all the cells at the same time.

You might actually go through a phase in which some of the cells are still taking up iodine while others aren’t. If patients predominantly have iodine-avid disease, even if they have a couple of cells that aren’t taking it up, they still might get clinical benefit from that last dose. But the other side is the opposite. If they predominantly have cells that are not taking up iodine, their overall survival and their therapies are going to be directed at those cells that are growing anyway. If the iodine scan shows some uptake in a few cells, I’d say that’s sort of a remnant of an earlier phase of the disease. Those patients will need the additional systemic therapies, and iodine would no longer be indicated.

We know that if iodine is no longer working to cure the patients, their overall survival changes right away. There are a couple of papers on this. There was the Durante et al. paper with the group in France. It showed that when radioactive iodine is no longer working, the overall survival is clearly impeded. They actually divided up patients into 3 groups. They divided up the patients into those who didn’t take up iodine at all from the start, those who took up iodine but had persistent disease, and those who picked up iodine and had no evidence of disease. This sharply changed the overall survival, with the best being the patients who took up radioactive iodine and didn’t have any evidence of future disease. Those with the worst prognosis were the people who didn’t take up iodine from the start. And so, if it doesn’t work, it shows that you have a more aggressive phenotype.

That said, that overall survival data predated us having these other systemic therapies available. Now I’m wondering, if we were to go back and do that data again in the era of kinase inhibitor therapies, if that difference will be as dramatic. I do think that people might be living longer because we have these other therapies available. So now the question is: What do you do with those patients at the time that they don’t take up iodine? You need to do other things as well. And we know that from that paper, as well as the Tuttle et al. paper, which showed that when iodine stops working they become PET positive, that PET-positive patients have the same poor prognosis. Before we had systemic therapy, we knew that their overall survival was shortened to somewhere between 2.5 and 3.5 years. That’s actually a fairly short time, and that’s why the systemic therapies were so necessary for the treatment of these patients.

Transcript Edited for Clarity