Neuroendocrine Tumors: Targeted Therapies - Episode 2

Neuroendocrine Tumor Pathogenesis and Molecular Testing

Expert insight on the pathogenesis of neuroendocrine tumors and the best use of molecular testing to inform treatment decisions.

Diane Reidy-Lagunes, MD: The role of molecular testing in neuroendocrine cancers continues to evolve.Unlike other solid tumor malignancies, where the molecular genetics become critically important in terms of treatment, neuroendocrine cancers have not panned out in helping potentially, for example, to find a mutation that can help us drive treatment. The molecular alterations can help us in prognosis. We know that there are certain genes that can portend a poorer or more aggressive course, but we haven’t yet translated that piece into the clinic to say that all patients with neuroendocrine cancers should be molecularly tested. We do know that there are definitely some germline mutations that are familial genetic predispositions, such as VHL [Von Hippel-Lindau syndrome], or MEN1 [multiple endocrine neoplasia type 1], or tuberous sclerosis. All of those genetic predispositions should definitely be screened, particularly for our younger patient populations. There we’re looking for a strong family history, other characteristics based on physical examinations. We want to make sure we’re always ruling out the familial predispositions that our patient may potentially have. But the so-called somatic mutations have not yet panned out to help us drive treatment for neuroendocrine cancers in 2021.

There are guidelines certainly for germline mutations, based on family history, based on physical exam. Genetic counselors should most certainly be involved in a patient where there is a concern for familial predisposition, and genetic counseling and testing should certainly be considered in that patient population. For somatic mutations, we are looking in patients who have higher grade tumors, if there’s any question that maybe they could have high mutational burden or MSI [microsatellite instability] as per NCCN [National Comprehensive Cancer Network] guidelines and as per FDA-approved indications. If there is MSI, patients should be considered for immunotherapy. The reality is that most of our patients do not have MSI-high tumors, and most neuroendocrine cancers actually have what we call low mutational burden. That may be why our cancers tend to be a little bit more indolent or slower growing compared to other cancers because they don’t have high mutational burden and don’t have a lot of these alterations. In general, patients with germline mutations or suspicion for germline mutations should be sent to genetic counseling, but the role of somatic mutations outside of a potential MSI patient is very limited, unfortunately.

The tumor microenvironment of neuroendocrine cancers, we’ve actually known for a very long time it really is driven in part by VEGF and blood vessels. These neuroendocrine cancers really require that blood vessel nourishment for them to grow and propagate. We’ve actually for a couple of decades used the role of liver-directed embolization to block off those blood vessels and prevent it or allow a change in the microenvironment to not allow the cancers to grow. More recently in the last decade or so there’s been a big push to go even more to a micro level to use VEGF inhibitors to again impair that angiogenesis and prevent the cancers from growing and spreading. There are lots of opportunities with different types of VEGF inhibitors to inhibit the cancer through antiproliferative effects, focusing on that microenvironment with angiogenesis playing an important role.

Transcript Edited for Clarity