Contemporary guidelines recommend that genomic testing be considered for all patients with neuroendocrine tumors (NETs). However, it is currently unclear whether genomic alterations can be truly predictive of therapeutic response and toxicity risk. Researchers at the North American Neuroendocrine Tumor Society (NANETS) 2024 Multidisciplinary NET Medical Symposium presented data on these topics.

Following these presentations, featured expert Diane Reidy-Lagunes, MD, was interviewed by Conference Reporter Editor-in-Chief Tom Iarocci, MD. Clinical perspectives from Dr Reidy-Lagunes are presented here.

Although the possibility of finding a therapeutic alteration may be low, our group at Memorial Sloan Kettering Cancer Center and others have found that there are some prognostic mutations that may be helpful. At the NANETS 2024 Multidisciplinary NET Medical Symposium, there was a very exciting discussion on the role of MEN1 and DAXX alterations in pancreatic NETs (pNETs) by Rushabh Gujarathi, MBBS, and colleagues (abstract 28544). Patients who had these alterations experienced improved progression-free survival (PFS) when treated with PRRT compared with patients who did not have these alterations, which, again, is pretty exciting. Interestingly, our group had previously found that people with DAXX alterations had a shorter hepatic PFS following transarterial bland embolization than patients with wild-type DAXX. Now, these studies have small cohorts and are retrospective, but the findings indicate that one could envision starting to see an opportunity to look at next-generation sequencing for prognostic features to help guide therapies.

Another study by Samuel Antwi, PhD, et al presented at this year’s NANETS symposium used a case-control design with 842 pathologically confirmed pNET cases from the Mayo Clinic Biospecimen Resource for Pancreas Research to determine if germline variants are associated with a higher risk of pNETs (abstract 28299). Researchers reported that variants in MEN1, TSC2, ATM, and MSH2 were linked to a higher risk of this type of NET. We want to know about these types of germline mutations not only to ensure that other family members are tested appropriately but also because these mutations may result in some therapeutic manipulation.

One of our biggest concerns when using therapies such as PRRT or alkylating agents to help control disease is a patient developing a life-threatening toxicity such as myelodysplastic syndromes or leukemia. Age and prior treatments may contribute to the potential risk, but we do not have great data to prove that. As discussed at the NANETS 2024 Multidisciplinary NET Medical Symposium, Abhay Singh, MD, MPH, and his group are interested in whether CHIP mutations, such as the standard-risk mutation TET2 and the high-risk mutations JAK2 and TP53, should perhaps make us consider precluding treatment options that impact hematopoiesis (abstract 28694). The problem is that we still do not know yet if there is a correlation between these mutations and life-threatening toxicities. There is still more to come on understanding the risk-benefit ratio and the best biomarkers to identify who may be at risk.

A study by the University of California, San Francisco group looking at patients with early-onset pancreatic and gastrointestinal neuroendocrine neoplasms (NENs) that was presented at NANETS 2024 by Lizeth Estrada found that 37.3% of its patients with pancreatic NENs were positive with germline testing, and BRCA1 was one of the most commonly mutated genes (abstract 28495). This is much higher than we would have expected, so more research is needed to better understand risk factors in this young population. BRCA mutations are very sensitive to platinum-based agents and perhaps to PARP inhibitors as well, extrapolating from pancreatic adenocarcinomas.

There was another interesting phase 1/2 study from the National Institutes of Health (NIH) by Jaydira del Rivero, MD, and colleagues presented at the NANETS 2024 Multidisciplinary NET Medical Symposium by Frank Lin, MD, in which PRRT was combined with a PARP inhibitor to see if the PARP inhibitor can increase radiosensitivity and, hopefully, improve the efficacy (abstract 28530). In this study, 1 patient with a BRCA2 alteration had an exceptional response after only 1 cycle of therapy, which is very exciting. After the second cycle, this patient had a scintigraphic complete response in the liver. Whether that response was from the PARP inhibitor because of the patient’s BRCA2 mutation or because of the combination of the PRRT with the PARP inhibitor is not clear. Importantly, we still have work to do to make sure that the combination of PARP inhibitor therapy and PRRT does not increase bone marrow toxicity. We have also learned that combination therapies are not necessarily better than sequencing the therapies.

I will say that most neuroendocrine research has, ironically, come from N-of-1 clinical cases that we then take back to the laboratory to better understand. That is, in part, because we lack appropriate cell lines to conduct experiments in the laboratory. Neuroendocrine cancers grow slower than other cancers, and it is incredibly challenging to capitulate that model in the laboratory. When you try to manipulate the cells to get them to grow, they begin to behave in a way that is not typical of NETs. So, the development of really good preclinical models is one of the biggest challenges left for us to tackle in conducting research on this disease.