GIST – Gastrointestinal Stromal Tumors: Overview

Gastrointestinal stromal tumors (GIST) are a relatively rare form of soft‑tissue sarcoma that can range from low‑risk to very aggressive, depending on tumor size, location, mitotic rate, and molecular features. These cancers usually start in the stomach or small intestine and arise from the interstitial cells of Cajal, specialized “pacemaker” cells in the digestive tract that help coordinate the muscular contractions moving food and waste through the GI tract; in the United States, recent estimates suggest roughly 4,000–6,000 new GIST cases are diagnosed each year, most often in older adults.

GISTs are defined by specific genetic changes that activate growth‑promoting signaling pathways, most commonly mutations in the KIT or PDGFRA genes that lead to overactive tyrosine kinase proteins driving tumor growth and survival. The discovery of these alterations led to the development of tyrosine kinase inhibitors (TKIs)—precision cancer medicines that block these signals and have transformed outcomes, turning GIST from a largely chemotherapy‑resistant disease with a median survival of around 18 months into one where many patients now live for a decade or longer on targeted therapy. Modern DNA and RNA sequencing allow doctors to identify the exact mutation in a patient’s tumor and select the TKI and dose most likely to work, or avoid drugs unlikely to help.

Symptoms and signs

Many people with GIST have no specific symptoms, especially when tumors are small, and the cancer is often found incidentally during imaging or endoscopy for other reasons. When symptoms occur, they can be vague and may include abdominal pain or discomfort, a palpable abdominal mass, bowel obstruction, nausea or vomiting, vomiting blood, black or bloody stools, or fatigue caused by anemia from slow bleeding in the GI tract.

Causes and risk factors

Most GISTs occur sporadically, meaning there is no known external cause and no clear way to prevent them. Risk increases with age (most patients are over 50), and the disease is slightly more common in men than women; rare hereditary syndromes such as neurofibromatosis type 1 (NF1) and Carney‑Stratakis dyad increase risk, but having a family member with a GIST usually does not. Because there are no established environmental or lifestyle risk factors, prevention strategies focus on early recognition and appropriate evaluation of symptoms rather than screening.

Diagnosis and testing

Diagnosis and staging of GIST typically involve a combination of endoscopy, imaging, biopsy, and molecular testing. Common tests include:

• Endoscopy and endoscopic ultrasound to visualize tumors in the stomach or small bowel and guide biopsy.

• CT and MRI scans to assess tumor size, location, and spread to the liver, peritoneum, or other sites.

• PET scans in selected cases to evaluate metabolic activity and early response or resistance to therapy.

• Biopsy for histology and immunohistochemistry (CD117/KIT, DOG1) plus genomic testing to identify mutations in KIT, PDGFRA, SDH, NTRK, and other genes that guide prognosis and treatment choice.

Genomic or biomarker testing is now a standard part of GIST care and underpins precision medicine. About 80–85% of GISTs carry oncogenic mutations in KIT or PDGFRA, and “wild‑type” tumors lacking these mutations (including SDH‑deficient and other rare subtypes) account for roughly 10–15% of cases and may require different strategies.

Treatment and management

Optimal GIST management involves a multidisciplinary team including surgeons, medical oncologists, pathologists, and radiologists. For localized tumors, complete surgical removal with negative margins remains the cornerstone of treatment, often followed by adjuvant TKI therapy with imatinib for higher‑risk disease to lower recurrence risk. Laparoscopic approaches are used in selected gastric GISTs, and neoadjuvant (pre‑operative) imatinib can shrink large or anatomically challenging tumors to make surgery safer and organ‑preserving.

For unresectable, recurrent, or metastatic GIST, TKIs are the mainstay of therapy, while conventional chemotherapy and standard radiation have limited roles. Key TKIs and sequence include:

• Imatinib (Gleevec): Standard first‑line therapy for most KIT‑ or PDGFRA‑mutant GIST, often continued long term; higher doses (800 mg) may be used in selected KIT exon 9–mutant tumors.

• Sunitinib (Sutent): Second‑line option for imatinib‑resistant or intolerant disease, improving progression‑free survival compared with placebo.

• Regorafenib (Stivarga): Third‑line multi‑kinase inhibitor that further delays progression after failure of imatinib and sunitinib.

• Ripretinib (Qinlock): Broad‑spectrum KIT/PDGFRA switch‑control inhibitor now established as preferred fourth‑line therapy and active across many resistance mutations.

• Avapritinib (Ayvakit): Precision TKI specifically approved for unresectable or metastatic GIST with PDGFRA exon 18 mutations, particularly D842V, which are poorly responsive to imatinib.

Radiation therapy is used selectively, for example to palliate pain or control bleeding, rather than as a primary treatment. With recurrence or progression, repeat molecular testing (tissue or increasingly ctDNA) is important to characterize new resistance mutations and guide subsequent therapy or clinical trial options.

Precision oncology and newer strategies

The overall goal of precision oncology in GIST is to match treatment to the tumor’s molecular profile and adapt as it evolves. Liquid biopsy approaches using circulating tumor DNA (ctDNA) can identify multiple KIT mutations and track changes over time, and early studies suggest ctDNA may help choose between TKIs (for example, ripretinib versus sunitinib in specific mutation patterns) and detect emerging resistance earlier than imaging.

Several newer agents and strategies are being explored:

• Ripretinib has shown durable disease control and survival benefit in heavily pretreated GIST and is also being studied in earlier lines and in specific mutation subsets.

• Avapritinib provides high response rates in PDGFRA D842V‑mutant GIST and is part of routine care for this genotype.

• Pimitespib, an oral HSP90 inhibitor approved in Japan, has demonstrated activity in patients refractory to imatinib, sunitinib, and regorafenib, with median progression‑free survival around 4–5 months in phase 3 data.

• Additional next‑generation KIT inhibitors (such as IDRX‑42/GSK6042981 and bezuclastinib) and rational combinations (for example, pairing TKIs with each other or with other targeted agents) are in clinical trials aimed at overcoming complex resistance.

Immunotherapy has not yet become standard in GIST, but ongoing research is evaluating immune‑checkpoint inhibitors and combination regimens in selected biologic subtypes and microenvironment‑focused strategies. For many patients, participation in clinical trials offers access to these novel therapies and contributes to further progress.

People living with GIST are encouraged to discuss with their oncology team: tumor mutation testing (including KIT, PDGFRA, SDH, NTRK and others), the optimal TKI sequence, whether surgery combined with targeted therapy is appropriate, and whether ctDNA‑based monitoring or clinical trials are available at their treatment center.

References

1. Demetri GD: Gastrointestinal stromal tumor. In: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2011, pp 1060-73.
2. Judson I, Demetri G: Advances in the treatment of gastrointestinal stromal tumours. Ann Oncol 18 (Suppl 10): x20-4, 2007.
3. Demetri GD, Benjamin RS, Blanke CD, et al.: NCCN Task Force report: management of patients with gastrointestinal stromal tumor (GIST)–update of the NCCN clinical practice guidelines. J Natl Compr Canc Netw 5 (Suppl 2): S1-29; quiz S30, 2007.
4. Bonvalot S, Eldweny H, Péchoux CL, et al.: Impact of surgery on advanced gastrointestinal stromal tumors (GIST) in the imatinib era. Ann Surg Oncol 13 (12): 1596-603, 2006.
5. Huguet KL, Rush RM Jr, Tessier DJ, et al.: Laparoscopic gastric gastrointestinal stromal tumor resection: the mayo clinic experience. Arch Surg 143 (6): 587-90; discussion 591, 2008.
6. Otani Y, Furukawa T, Yoshida M, et al.: Operative indications for relatively small (2-5 cm) gastrointestinal stromal tumor of the stomach based on analysis of 60 operated cases. Surgery 139 (4): 484-92, 2006.
7. Novitsky YW, Kercher KW, Sing RF, et al.: Long-term outcomes of laparoscopic resection of gastric gastrointestinal stromal tumors. Ann Surg 243 (6): 738-45; discussion 745-7, 2006.
8. Heinrich M, Shoemaker J, Corless C, et al. Correlation of target kinase genotype with clinical activity in imatinib mesylate (IM) in patients with metastatic GI stromal tumors (GISTs) expressing KIT. Proceedings from the 2005 annual meeting of the American Society of Clinical Oncology. Presented May 16, 2005 at a plenary session. Abstract #7.
9. Demetri GD, van Oosterom AT, Garrett CR, et al.: Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet 368 (9544): 1329-38, 2006.
10. www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-ripretinib-advanced-gastrointestinal-stromal-tumor. Accessed May 15, 2020.
11. FDA approves avapritinib for gastrointestinal stromal tumor with a rare mutation
12. Garcia-Carbonero R, Carnero A, Paz-Ares L. Inhibition of HSP90 molecular chaperones: moving into the clinic. Lancet Oncol. 2013;14(9):e358-369. doi:10.1016/S1470-2045(13)70169-4
13. Doi T, Kurokawa Y, Sawaki A, et al. Efficacy and safety of TAS-116, an oral inhibitor of heat shock protein 90, in patients with metastatic or unresectable gastrointestinal stromal tumour refractory to imatinib, sunitinib and regorafenib: a phase II, single-arm trial.Eur J Cancer. 2019;121:29-39. doi:10.1016/j.ejca.2019.08.009