expert roundtables

Advances in the Diagnosis and Treatment of Gastrointestinal Stromal Tumors

by Michael C. Heinrich, MD; Arun Singh, MD; and Jonathan C. Trent, MD, PhD


Patients with gastrointestinal stromal tumors (GIST) now have several options for targeted therapy, and novel therapies are being developed to overcome resistance and to target additional molecular subsets. As such, advancements in GIST include those related to molecular profiling.


Have there been any recent advances to aid in the evaluation and treatment of patients with GIST? 

Arun Singh, MD

Associate Professor
David Geffen School of Medicine
UCLA Medical Center
Santa Monica, CA

“We now do genetic sequencing of the tumor in almost all of our patients with GIST.”

Arun Singh, MD

We have learned a number of things about the proper pathologic classification of GIST over the years and about the importance of appropriate immunohistochemical staining and of counting mitoses, which aid in risk stratification. We now do genetic sequencing of the tumor in almost all of our patients with GIST. Through this process, we hope to categorize a patient’s tumor into whether they have KIT or PDGFRA mutations and to determine whether there are primary or secondary mutations present. We also do immunohistochemistry to ascertain whether the tumor has loss of succinate dehydrogenase (SDH) subunits, and we sometimes do full next-generation sequencing (NGS) to identify other potential drivers, such as BRAF or NF1 mutations, or, in very rare cases, to see if we can identify an NTRK fusion, which would only be identified using NGS.

Information gained through sequencing is practically important, as it can impact treatment decisions. The choice of treatment is partially based on the specific subtype of GIST and the mutational profile. Over the past year, we have had 2 US Food and Drug Administration approvals (ie, avapritinib and ripretinib), which reflects the importance of targeting the PDGFRA- and KIT-mutant tyrosine kinases, respectively. Avapritinib is the first approved medicine that specifically targets the mutant PDGFRA tyrosine kinase, and ripretinib is the first drug approved in the fourth line for advanced GIST.

Circulating tumor DNA (ctDNA) assays have also recently been gaining interest. We are still exploring this technology, and it has the potential advantage of yielding a much better picture of the mutational spectrum of a GIST than you can get with an individual biopsy. When we biopsy our patients, we take only a single spot, but the ctDNA can potentially provide information about multiple spots if a patient presents with GIST in multiple locations. This is still in its early stages, and we have much more to learn about the utility of this technology in managing advanced GIST.

Jonathan C. Trent, MD, PhD

Professor of Medicine
Associate Director for Clinical Research
Sylvester Comprehensive Cancer Center
University of Miami Miller School of Medicine
Miami, FL

“In our practice, the measurement of ctDNA is standard for any patient who has progressed on first-line therapy in order for us to choose second-line therapy.”

Jonathan C. Trent, MD, PhD

There continue to be advances in molecular profiling. In a patient with a gastric GIST, it may be appropriate to do SDH staining first. If the tumor has lost the SDH protein by immunohistochemistry, it is considered an SDH-deficient GIST, and you might not need to perform NGS. In our practice, the measurement of ctDNA is standard for any patient who has progressed on first-line therapy in order for us to choose second-line therapy. For instance, if there are high levels of exon 13 resistance mutations, that would steer us to use sunitinib in certain settings. If there are high levels of exon 17 resistance mutations, we would not use sunitinib in that situation; we would use other tyrosine kinase inhibitors.

Another development is that, over the last year and a half, we have been using water contrast instead of barium, which is much better tolerated by patients. We have not analyzed the data retrospectively, but this approach seems to work for GIST. We do not use positron emission tomography (PET) scans routinely in our practice. We use them in select situations, but we generally discourage PET scans unless there is renal insufficiency or some other reason to order a PET scan. Some GIST (eg, those with lower mitotic rates) might not be distinguishable from background on PET. There is also the risk of false positives with PET, so you might have a lymph node or something in the pharynx or colon light up that is just inflammation, and it may lead to unnecessary biopsies. We use standard contrast-enhanced computed tomography for monitoring patients for recurrence or response to therapy.

Michael C. Heinrich, MD

Professor of Medicine
Professor of Cell and Developmental Biology
OHSU Knight Cancer Institute
Oregon Health & Science University School of Medicine
Portland, OR

“I would point to structure-based drug design as a therapeutic advancement. With therapies now available for molecular subclasses, I would strongly advocate mutation testing for any patient for whom we are considering a medical therapy.”

Michael C. Heinrich, MD

We, too, have made some changes that I believe are resulting in an improved patient experience. The worst thing about having a scan for many patients is the anxiety about what the scan might show. But the second worst thing is the barium (ie, taking the barium prior to the scan and the potential for abdominal cramping and explosive diarrhea). For a number of years now, we have been using water contrast instead of barium in patients with GIST. Water contrast is much better tolerated. The radiologists may have to get reacclimated just a bit because instead of a positive contrast, water provides a negative contrast; however, water still provides good contrast.

Regarding therapeutic advancements, I would point to structure-based drug design and the recent introduction of agents such as avapritinib and ripretinib. With therapies now available for molecular subclasses, I would strongly advocate mutation testing for any patient for whom we are considering a medical therapy; whether it is a postoperative therapy or a treatment for advanced disease, we really need to know the molecular driver of the disease. We have drugs that are highly effective in patients with GIST, but only in those with certain molecular subclasses.

I would also add that testing still has a role even when we have high confidence that there will be no recurrence after surgery. For instance, if you are determining that the tumor is SDH deficient and that the patient has a germline mutation, this means that siblings, parents, children, and other family members may be affected. If you branch out in the family tree, up to the parents, over to the aunts and uncles, and then down to the cousins and second cousins, sometimes you identify a large number of people who require lifelong screening. We have seen several families in whom we have tested family members for SDH deficiency because we wanted to screen for GIST or for paraganglioma. Sometimes you are able to identify patients with previously unrecognized GIST on a screening endoscopy. This can lead to successful surgery and highlights the potential benefits of lifelong surveillance for paraganglioma or secondary GIST.


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