Genetic testing gets a lot of attention in other areas of cancer, but, unfortunately, it is currently rarely therapeutically useful for patients with lower-grade NETs. Contemporary guidelines recommend that any patient with a gastrinoma should be tested. Beyond that, the next most appropriate patients to test are those with high-grade neuroendocrine carcinomas, because these individuals are more likely to have abnormalities that might be amenable to targeted therapy, such as BRAF or NTRK inhibitors. Although these are very uncommon findings, there are agents that are available to treat these patients when they do occur. We hate to miss treatment opportunities, especially for patients with NETs for whom we have very limited treatment options. 

Younger patients (eg, those <40 years of age) with NETs should undergo genetic testing. Unfortunately, we are not going to find anything actionable in most patients with low-grade, small-bowel NETs, but we may find a mutation in those with pancreatic NETs. Familial syndromes are also an important consideration for young patients with NETs. For example, pancreatic NETs are one of the tumor types that may develop in patients with von Hippel-Lindau syndrome, and these individuals may present at a younger age and with a family history of disease. The identification of a heterozygous germline VHL gene pathogenic variant establishes the diagnosis of the syndrome if clinical features are inconclusive. Any patient who presents with hypercalcemia and a pancreatic NET should be tested for a mutation in the MEN1 gene, especially young patients with a family history of pancreatic neuroendocrine carcinoma or MEN1. 

For grade 1 and 2 NETs, especially for primary gastrointestinal NETs, we just have not generally found targetable mutations, and these tumors do not have a high tumor mutational burden. Generally, I do not test these patients, except in special circumstances. I may order testing for older patients who are running out of treatment options, but I cannot recall ever finding anything targetable in these instances. 

For pancreatic tumors, the situation is similar: we may be able to identify mutations, but we rarely find anything targetable. A lot of patients with pancreatic NETs have mutations in either DAXX, ATRX, or the MEN1 gene, but we have not learned the whole story behind how DAXX and ATRX might contribute to this disease or whether or not these mutations might make the pancreatic tumors more or less sensitive to certain treatments. 

At this point, we know that, for pancreatic NETs, there may be DAXX, ATRX, or MEN1 mutations, and sometimes abnormalities in the mTOR pathway, but we do not yet know how to utilize this information therapeutically to treat the NETs. There is no solid rationale for saying, “If you have this abnormality, you should be treated with this targeted drug.” We really do not understand enough about the biology of NETs to know how these mutations might be targeted. Again, in contrast, the high-grade neuroendocrine carcinomas are more likely to have an abnormality that might be amenable to a targeted therapy such as a BRAF inhibitor or that might be MSI-H such that immunotherapy may be appropriate.