<p>SSTR expression in gastroenteropancreatic neuroendocrine tumors (GEP-NETs) guides the selection of treatment based on the potential efficacy of PRRT in patients whose tumors have high, homogeneous SSTR expression. However, many tumors have low, heterogeneous SSTR expression. Researchers at the <strong>2025 Society of Nuclear Medicine & Molecular Imaging (SNMMI) Annual Meeting</strong> discussed important clinical questions regarding SSTR expression and treatment considerations in GEP-NETs.</p> <p><br></p> <p><em>Following these presentations, featured expert Daniel M. Halperin, MD, was interviewed by </em>Conference Reporter<em> Editor-in-Chief Tom Iarocci, MD. Clinical perspectives from Dr Halperin on these findings are presented here.</em></p>

One of the things that the Moffitt group has shown, which I think has been circling as a notion for quite some time, is that the vast majority of well-differentiated GEP-NETs have solid SSTR expression, particularly in the era of more sensitive positron emission tomography (PET) scanning. We did see in the data from Moffitt a modest difference between SSTR expression in the pancreas and small bowel, but we would expect the majority of well-differentiated GEP-NETs below the diaphragm to have pretty solid SSTR expression. I think that where things get a little bit murkier are in the areas above the diaphragm. We frequently see fairly modest SSTR expression in the lungs. Typically, we think of the lungs as being positive for SSTR expression around half the time, and, even then, the SSTR expression is usually not as high as it is in the small bowel. So, PET imaging is often used as a selective biomarker to help us decide if we can give PRRT. At many centers, it is also used to determine whether we can give “cold” SSA therapy.

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On occasion, we can see non–dotatate-avid disease grow out after therapy. I do not know what to make of the notion that the maximum standardized uptake value (SUVmax) may decrease after PRRT, which was also observed in a study presented at the 2025 SNMMI Annual Meeting by Moein Moradpour, MD, largely because I do not think that we have a good understanding of what changes in SUVmax really mean (abstract 251731). This was also discussed by Lisa Bodei, MD, PhD, during her session at this year’s SNMMI meeting. However, this issue may, to some degree, be separate from the question of retreatment. I think that, in the overwhelming majority of cases, we see preserved SSTR expression, and this enables repeat or second-line PRRT. A thought-provoking question is: If the SSTR expression is lower but still there, does this mean that you should have hit the tumor harder with something more potent? However, the presence of SSTRs alone does not mean that PRRT is necessarily going to be an effective therapy; there is more disease biology at play than that.

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Work on modulating SSTR expression has gone on for a long time, and it has been observed that we can make expression go from low to high, but less so from having no expression to having expression. The notion is to take tumors that might not have quite enough SSTR expression to be appropriate for PRRT and boost that to a range where we could get a sufficient therapeutic dose. I cannot think of a single clinical trial that has succeeded in getting far enough to tell us that we could do it and drive responses, but it is an interesting idea.

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I think that having a reasonable amount of non–dotatate-avid disease usually causes people to not offer PRRT in tumors that are otherwise large enough to be targeted, so not below the limit of sensitivity of the PET scan. Typically, we want the tumors to be avid. There have been different criteria in different trials over the years, but these days we are converging on giving PRRT when measurable disease is dotatate avid because of concerns regarding the potential for escape variants.

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I think that the most important thing is probably to put all these theranostic data in biologic context. People often describe SSTR expression in absolute terms, and they assume that 100% of well-differentiated GEP-NETs are avid on PET, while 0% of poorly differentiated neuroendocrine carcinomas have SSTRs. It is important to remember that plenty of poorly differentiated neuroendocrine carcinomas and nonneuroendocrine cancers have SSTR expression, but that often gets glossed over. It is both the target expression and the disease biology that determine the appropriateness of the therapy.