Mutations in Gastrointestinal Stromal Tumors

Shreyaskumar Patel, MD: One of the defining characteristics that actually has made gastrointestinal stromal tumor [GIST] a poster child of targeted therapy, at least in the solid tumor arena, is the identification of activating mutations that seem to be driving oncogenesis. Andy, could you walk us through what mutations have been identified, which are the common ones, and the specific nuances of the individual mutational subsets?

Andrew Wagner, MD: Sure. There are really 4 major mutations, the most commonly found mutations, in gastrointestinal stromal tumor. There are a few that are extremely rare, but it also can be present. By far the most common mutations are seen in KIT, which is a receptor tyrosine kinase. Of the mutations in KIT, the most commonly mutated area is in exon 11, which is the juxtamembrane domain. This leads to constitutive activation of the receptor. This mutation is commonly seen in GIST of all locations.

From the stomach, which as you just mentioned Shreyas, is the most common location for tumors to arise, but also from the small bowel and other locations. The next most common mutation is seen in exon 9 of KIT, which is part of the dimerization motif. This mutation is more commonly seen in tumors arising from the small bowel than from other locations. Although even in the small bowel, exon 11 mutations still predominate.

Another common mutation seen in patients with primary tumors or mutations in a related tyrosine kinase called platelet-derived growth factor receptor alpha, or PDGFR alpha. These mutations almost universally occur in tumors arising from the stomach. Of these mutations, two-thirds are in a particular amino acid, in aspartate 842, and it changed to a valine residue instead. There are other mutations as well, and we’ll come back to the significance of this a little later.

What’s interesting is that these mutations are found more commonly in registries of patients with tumors than in patients who develop metastases. It’s suggesting that this mutation is seen in tumors, more commonly at diagnosis, but may be at a lower risk of developing metastatic disease. The fourth most common site of mutation is in 1 of 4 genes encoding different subunits of succinate dehydrogenase, which is a Krebs cycle enzyme: SDHA, SDHB, SDHC, and SDHD.. Mutations here cause inactivation of the succinate dehydrogenase complex.

Probably through a variety of mechanisms, including upregulation of vascular endothelial growth factor production, as well as alterations in DNA methylation and changes in gene expression, leads to development of the tumor. The importance behind this class of mutations is several-fold. One is they tend to be more indolent than other KIT-mutant gastrointestinal stromal tumors. Two is they almost universally occur in the stomach as well. Three is that these are typically refractory to imatinib, which we’ll discuss again in a few minutes.

Perhaps the fourth point, which is also critically important, is that these are commonly inherited mutations. They may occur in the germline. Although not everyone who carries this mutation will be affected with this disease, it is something that can be a form of familial gastrointestinal stromal tumor or other disorders such as paraganglioma and pheochromocytoma.

Shreyaskumar Patel, MD: That’s a very good start. Just a couple of points; 1 question, 1 comment. It is important for us to reiterate that these are driver mutations and that they are nonoverlapping. In the sense that theoretically there shouldn’t be or cannot be a patient with a gastrointestinal stromal tumor who has both KIT and VEGFRA already as the driver mutations. Having said that, our clinical experience suggests that there is always the rare exception to the general rule.

But in that given patient who’s clearly a zebra and not a horse, one would think there are multiple primaries but not necessarily the same GIST with the 2 different mutations.

Transcript edited for clarity.

Andrew Wagner, MD, reports the following disclosures: Consulting with Deciphera, Daiichi-Sankyo, NanoCarrier. He also reports research funding to his institution with Daiichi-Sankyo, Eli Lilly, Karyopharm, Plexxikon, Aadi Biosciences.