clinical topic updates

Gastrointestinal Stromal Tumors That Lack KIT and PDGFRA Mutations

by Richard F. Riedel, MD


Wild-type gastrointestinal stromal tumors (GIST) lack KIT and PDGFRA mutations, but they may harbor other potentially targetable alterations. Our featured expert provides an update on the ongoing work to improve outcomes in this difficult-to-treat population.

Expert Commentary

Richard F. Riedel, MD

Associate Professor of Medicine With Tenure
Division of Medical Oncology
Duke University Medical Center
Associate Director of Clinical Research
Duke Sarcoma Center
Duke Cancer Institute
Durham, NC

“The treatment of wild-type GIST has fallen behind that of KIT mutant– and PDGFRA mutant–positive GIST, which I believe underscores the importance of emerging preclinical models. We need to better understand the underlying biology and test potential new treatments in order to improve outcomes for patients.”

Richard F. Riedel, MD

Within the sarcoma community, it is a strongly held belief that molecular testing should be performed on any patient for whom systemic therapy is being considered. This allows for the selection of appropriate therapy for an individual patient and, perhaps more importantly, the potential avoidance of treatments that would not be beneficial. 

“Wild-type” GIST, historically, has accounted for approximately 10% of all GIST tumors. We had previously used the term wild type to define GIST tumors that do not harbor KIT or PDGFRA mutations. However, this term is no longer very useful in that we have been able to further classify many non–KIT-mutant and non–PDGFRA-mutant GIST into specific molecular subtypes. For example, we now know that wild-type GIST actually include tumors with identifiable BRAF mutations, NF1-associated mutations, NTRK fusions, and succinate dehydrogenase (SDH) deficiency, the latter of which is perhaps the largest category of wild-type GIST. In my opinion, we should probably avoid the term wild type whenever possible and instead refer to the molecular subtype (eg, BRAF mutant–positive GIST and NTRK fusion–associated GIST), since many of these molecular alterations are potentially actionable. 

Patients with GIST lacking KIT or PDGFRA mutations are a particularly challenging group to treat given that these tumors do not typically respond to the therapies that are currently approved by the US Food and Drug Administration, such as imatinib. Historically, it has been challenging to find a clinical trial specifically for SDH-deficient GIST, NTRK fusion–associated GIST, or NF1-associated GIST. Some of the recently performed studies exploring novel tyrosine kinase inhibitors have allowed such patients to enroll. Generally speaking, however, data guiding the treatment of wild-type GIST are not robust, but molecular testing may help to guide treatment for individual patients. For example, it may be rational to use a commercially available BRAF inhibitor in a patient with BRAF mutant–positive GIST or an NTRK inhibitor in an individual with NTRK fusion–associated GIST. 

SDH-deficient GIST remain particularly challenging to treat. There are some anecdotal reports of responses to targeted therapies with anti-VEGFR activity, but these data are very limited. Immune checkpoint inhibitors, which have demonstrated promising activity in a number of malignancies, may have a role in select molecular subsets of advanced GIST, but, again, we await more robust data. 

The treatment of wild-type GIST has fallen behind that of KIT mutant– and PDGFRA mutant–positive GIST, which I believe underscores the importance of emerging preclinical models. We need to better understand the underlying biology and test potential new treatments in order to improve outcomes for patients. Dr Jason Sicklick and colleagues, for example, have recently developed a mouse model of SDH-deficient GIST that seems to recapitulate human disease. This model will allow for the future testing of novel compounds that will hopefully translate into human clinical trials. As an early proof of principle, these investigators found that temozolomide has preclinical activity in SDH-deficient GIST, and preliminary data in 5 patients with SDH-deficient GIST suggest that the drug has promising activity. 


Boikos SA, Pappo AS, Killian JK, et al. Molecular subtypes of KIT/PDGFRA wild-type gastrointestinal stromal tumors: a report from the National Institutes of Health Gastrointestinal Stromal Tumor Clinic. JAMA Oncol. 2016;2(7):922-928. doi:10.1001/jamaoncol.2016.0256

Brčić I, Argyropoulos A, Liegl-Atzwanger B. Update on molecular genetics of gastrointestinal stromal tumors. Diagnostics (Basel). 2021;11(2):194. doi:10.3390/diagnostics11020194

Kayes JK, Sohn JD, Kim BJ, Goze K, Koniaris L. Approach to wild-type gastrointestinal stromal tumors. Transl Gastroenterol Hepatol. 2018;3:92. doi:10.21037/tgh.2018.10.13

Kelly CM, Gutierrez Sainz L, Chi P. The management of metastatic GIST: current standard and investigational therapeutics. J Hematol Oncol. 2021;14(1):2. doi:10.1186/s13045-020-01026-6

Nannini M, Rizzo A, Indio V, Schipani A, Astolfi A, Pantaleo MA. Targeted therapy in SDH-deficient GIST. Ther Adv Med Oncol. 2021;13:17588359211023278. doi:10.1177/17588359211023278

Vallilas C, Sarantis P, Kyriazoglou A, et al. Gastrointestinal stromal tumors (GISTs): novel therapeutic strategies with immunotherapy and small molecules. Int J Mol Sci. 2021;22(2):493. doi:10.3390/ijms22020493

Yebra M, Bhargava S, Kumar A, et al. Establishment of patient-derived succinate dehydrogenase-deficient gastrointestinal stromal tumor models for predicting therapeutic response. Clin Cancer Res. 2022;28(1):187-200. doi:10.1158/1078-0432.CCR-21-2092

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