Medically reviewed by C.H. Weaver M.D. Medical Editor 7/2021
Gastrointestinal stromal tumors (GIST) are a relatively rare but aggressive type of soft-tissue sarcoma. These cancers are most commonly found in the stomach or small intestine where they originate in the cells of Cajal, which are specialized cells lining the digestive tract responsible for initiating the rhythmic movement that propels food and solid waste through the GI tract. It is estimated that there are between 3,300 and 6,000 individuals diagnosed with GIST every year in the United States, most often in older adults.
GISTs are characterized by specific genetic abnormalities that cause overactivity of a specific gene, called the c-kit proto oncogene that results in the overproduction of certain tyrosine kinase proteins. Tyrosine kinases are responsible for helping the cancer cells survive and grow and their discovery led to the development of one of the first precision cancer medicines designed to target a specific genetic cancer causing abnormality. Tyrosine kinase inhibitors (TKI) are precision cancer medicines that blocks tyrosine kinase activity slowing the growth of the cancer. TKI’s are currently the main medical treatment for GIST.
Prior to the development of the first TKI-Gleevec patients with advanced GISTs faced a life expectancy of 18 months, now many of the initial Gleevec treated patients remain alive over 10 years from initiation of therapy. As a result of current DNA sequencing techniques, doctors increasingly also understand which class of patients benefit the most from Gleevec and other TKI’s.
Symptoms & Signs of GIST
People with a gastrointestinal stromal tumor (GIST) often do not experience any specific symptoms or signs. When symptoms do occur, they may be vague. Signs and symptoms that may occur with a GIST include the following:
- Pain or discomfort in the abdomen
- A mass in the abdomen that you can feel with your hand
- Bowel obstruction
- Nausea and vomiting
- Vomiting blood
- Blood in the stool
- Fatigue due to anemia is often caused by bleeding in the GI tract
Sometimes a GIST is discovered by chance when a person has an imaging test for an unrelated concern or condition.1,2
Cause of GIST's
The majority of GISTs develop sporadically, which means for no known reason.
Risk Factors for GIST
Doctors are rarely able to find a specific risk factor for patients diagnosed with a GIST, other than the hereditary syndromes mentioned below. However, the following factors may raise a person’s risk for developing a GIST.1,2
- Age: A GIST most often occurs in people older than 50.
- Gender: GIST occurs slightly more in men than in women.
- Family history: Having a family member with a GIST usually does not increase your risk of developing the disease.
- Hereditary syndromes that can increase the risk of a GIST include neurofibromatosis type 1 (NF1) and Carney-Stratakis dyad.
Because no non-hereditary, preventable risk factors have been found, there is no good way to prevent a GIST from occurring.
Diagnosis & Tests for GIST
Doctors use many tests to find, or diagnose cancer. In addition to a physical examination, the following tests may be used to diagnose a GIST and then determine the stage or extent of spread of the cancer in order to determine the best treatment. Not all tests listed will be used for every person.1,2
- Barium swallow: The patient swallows a liquid containing barium and then a series of x-rays are taken. Barium coats the surface of the esophagus and upper GI tract, making cancer or other unusual changes easier to see on the x-ray. If there is an abnormal looking area, an upper endoscopy and biopsy to find out if it is cancerous is typically performed. A barium enema may also be used to evaluate the lining of the colon and rectum on an x-ray after the barium has been given through the anus.
- Endoscopy: Endoscopy allows the doctor to see the inside of the esophagus, stomach or intestines. During an “upper” endoscopy, the doctor inserts a thin, lighted tube called an endoscope through the mouth, down the esophagus, and into the stomach and small bowel. With “lower” endoscopy, the scope is inserted through the anus. If abnormal areas are found, the doctor can remove a sample of tissue and check it for evidence of cancer by performing a biopsy.
- Computed Tomography (CT) Scan: A CT scan is a technique for imaging body tissues and organs, during which X-ray transmissions are converted to detailed images, using a computer to synthesize X-ray data. A CT scan is conducted with a large machine positioned outside the body that can rotate to capture detailed images of the organs and tissues inside the body.
- Magnetic Resonance Imaging (MRI): MRI uses a magnetic field rather than X-rays, and can often distinguish more accurately between healthy and diseased tissue than a CT. An MRI gives a better picture of cancer located near bone than does CT, does not use radiation, and provides pictures from various angles that enable doctors to construct a three-dimensional image of the cancer.
- Positron emission tomography (PET): Positron emission tomography scanning is an advanced technique for imaging body tissues and organs. One characteristic of living tissue is the metabolism of sugar. Prior to a PET scan, a substance containing a type of sugar attached to a radioactive isotope (a molecule that emits radiation) is injected into the patient’s vein. The cancer cells “take up” the sugar and attached isotope, which emits positively charged, low energy radiation (positrons) that create the production of gamma rays that can be detected by the PET machine to produce a picture. If no gamma rays are detected in the scanned area, it is unlikely that the mass in question contains living cancer cells. PET may be helpful in detecting resistance to treatment and for the very early assessment of response to therapy.
- Endoscopic ultrasound: This test is similar to an endoscopy, but the scope has a small ultrasound probe on the end. The probe uses sound waves to create an image of the stomach or rectum and nearby organs. The ultrasound image helps doctors determine if or how far the cancer has spread into nearby tissues.
- Biopsy: Your doctor may recommend a biopsy if a mass suspected of being a GIST or other cancer is found. A biopsy is the removal of a small amount of tissue for examination under a microscope. The type of biopsy performed will depend on the location of the suspected cancer. Other tests can suggest that cancer is present, but only a biopsy can determine a definite diagnosis.
Genomic or Biomarker Testing-Precision Cancer MedicinePrecision cancer medicine uses targeted drugs and immunotherapies engineered to directly attack the cancer cells with specific abnormalities, leaving normal cells largely unharmed. Treatment for a GIST can start before this testing is completed. Test results however may change the treatment plan.
Testing of GIST helps determine which precision cancer medicine is best to target the specific mutation causing the tumor to grow. Studies have also shown that depending on the tumor’s specific gene mutations, some patients may need higher doses of a drug called Gleevec (imatinib) to best control the tumor. Otherwise, they might not benefit from taking this drug at all.
A GIST may have one of several different mutations, some of which are more harmful than others. Different mutations have different prognoses and treatment. Approximately 85% of GIST contain oncogenic mutations in one of two receptor tyrosine kinases: KIT or PDGFRA (platelet-derived growth factor receptor alpha).3 Activation of either of these receptor tyrosine kinases plays a central role in the pathogenesis of GIST.4,5
When a GIST has a mutation that is not recognized by current tests, it is referred to as “wild type” (WT). Wild-type tumors, with no detectable KIT or PDGFRA mutations, account for 12% to 15% of all GIST.3
Treatment & Management of GIST
The management of gastrointestinal stromal tumors (GIST) involves close collaboration between pathologists, medical oncologists, surgeons, and imaging experts. Treatment may involve surgery and/or the use of a unique precision cancer medicine called a tyrosine kinase inhibitor (TKI).
Complete surgical removal of localized tumors appears to prolong survival and standard chemotherapy and radiation are rarely used. Patients should consider participation in a clinical trial utilizing new, innovative therapies also provides promising treatment.1,2,3
- Tyrosine Kinase Inhibitors
- Radiation Therapy
- Strategies to Improve Treatment
Understanding DNA Damage Response or DDR and Cancer Treatment
What is DNA Damage Response or DDR?
Surgery may be used as initial therapy to completely remove GIST and to remove metastatic tumors. Patients with large tumors or difficult-to-access small GIST that are considered difficult to remove may benefit from TKI therapy prior to surgery to shrink the tumor.3,4 This approach may allow some patients who were initially diagnosed with inoperable disease to undergo surgery once their cancer has responded to the TKI.
For patients with localized GIST, surgery is the standard treatment and should be performed whenever possible. Surgery is best performed by a surgical oncologist; a doctor that specializes in treating cancer with surgery.
The goal of surgery is complete removal of the tumor with an intact pseudocapsule and negative microscopic margins. Laparoscopic surgery in the management of GIST has also been performed and several studies, indicate a role for this surgical approach with gastric tumors.5,6,7
Surgery combined with targeted therapy: Patients with advanced GISTs who have limited progression or stable disease with targeted therapy have been shown to experience prolonged overall survival when they also undergo surgery to remove the majority of their remaining cancer, then continue with targeted therapy.
While surgery after targeted therapy appears to shrink the cancer so that it may be completely removed in some patients, research also shows that targeted therapy must be continued indefinitely to reduce the risk of relapse.3
Precision Treatment with TKI’s
Tyrosine kinase is a protein that is overproduced in GIST cells as a result of a genetic mutation and is responsible for helping the cancer cells survive and grow. A TKI is a precision cancer medicine that blocks tyrosine kinase activity slowing the growth of the cancer. TKI’s are the main medical treatment for GIST.
Gleevec® (imatinib mesylate): Gleevec was the first TKI approved for the treatment of GIST and has become the standard initial treatment. The results with Gleevec are quite remarkable given the fact that both chemotherapy and radiotherapy are ineffective in the treatment of GIST.2
Gleevec is given after surgery (called adjuvant therapy) and is usually given indefinitely because GIST has the ability to recur even after being surgically removed and can spread to other organs. Some GISTs have a higher risk of returning or spreading than others and clinical trials are still being performed to determine out how long Gleevec should be given after surgery to help delay or prevent a recurrence.
The usual dose of Gleevec is 400 milligrams daily. For some patients, the dose may be raised to 800 mg daily, especially for those who have an exon 9 genetic mutation in the KIT gene.
Sutent (sunitinib): Like Gleevec, Sutent inhibits the tyrosine kinase protein. Sutent appears to be an active treatment option for patients with GIST whose disease has progressed with Gleevec or who are unable to tolerate treatment with Gleevec. Results of clinical trials indicate that Sutent delayed the time it takes for existing or new tumors to grow in patients with Gleevec-resistant disease. On average, the time before tumor progression for patients treated with Sutent was more than six months (27 weeks) compared to six weeks for patients who were not treated. Sutent may also be used when the side effects of Gleeve are too serious.9
Stivarga (regorafenib): Stivarga is a multi-kinase inhibitor that targets multiple biological pathways involved in GIST development. It works in many different ways to slow tumor growth, including blockade of the KIT molecule and blocking blood vessel growth into tumors. Stivarga was approved in 2013 for people with later-stage GIST that could not be surgically removed or progressed after treatment with Gleevec and Sutent because it delayed the time to GIST recurrence and prolonged survival.6,7
Radiation therapy is the use of high-energy x-rays or other particles to destroy cancer cells and is only rarely used in for the treatment of GIST. A doctor who specializes in giving radiation therapy to treat cancer is called a radiation oncologist. The most common type of radiation treatment is called external-beam radiation therapy, which is radiation given from a machine outside the body. When radiation treatment is given using implants, it is called internal radiation therapy or brachytherapy.
Chemotherapy is the use of drugs to destroy cancer cells, usually by ending the cancer cells’ ability to grow and divide. However, standard chemotherapy is not effective for treating GIST and should not be used.1,2,3
When a recurrence occurs, a new cycle of genomic testing is required to learn as much as possible about the recurrence. After this testing is done a new treatment plan is developed based on the results of the tests. The treatment plan may include additional surgery, targeted therapy or participation in a clinical trial evaluating new ways to treat GIST.
Strategies to Improve Treatment
The purpose of precision cancer medicine is to define the genomic alterations in the GIST DNA that is driving growth of the cancer. Precision cancer medicine utilizes molecular diagnostic and genomic testing including DNA sequencing, to identify cancer-driving abnormalities in a cancer’s genome. Once a genetic abnormality is identified, a specific targeted therapy can be designed to attack a specific mutation or other cancer-related change in the DNA programming of the cancer cells.
Novel Precision Cancer Medicines
Ripretinib is a KIT and PDGFRα kinase switch control inhibitor specifically designed to improve the treatment of patients with GIST by inhibiting a broad spectrum of mutations in KIT and PDGFRα. Ripretinib is a KIT and PDGFRα inhibitor that inhibits initiating and secondary KIT mutations in exons 9, 11, 13, 14, 17, and 18, involved in GIST, as well as the primary D816V exon 17 mutation involved in SM. Ripretinib also inhibits primary PDGFRα mutations in exons 12, 14 and 18, including the exon 18 D842V mutation.10
Ayvakit (avapritinib) is approved for the treatment of adults with unresectable or metastatic gastrointestinal stromal tumor (GIST) harboring a PDGFRA exon 18 mutation.11
Pimitespib is a novel heat shock protein (HSP90) inhibitor that has shown prior anti-tumor activity in molecularly defined subgroups of solid tumors. Hsp90 is a highly abundant and ubiquitous molecular chaperone which plays an essential role in many cellular processes including cell cycle control, cell survival, hormone and other signaling pathways. It is important for the cell's response to stress and is a key player in maintaining cellular homeostasis. In a phase 2 study pimitespib demonstrated a median progression-free survival of 4.4 months in patients refractory to imatinib, sunitinib, and regorafenib.12,13
- 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.
- Judson I, Demetri G: Advances in the treatment of gastrointestinal stromal tumours. Ann Oncol 18 (Suppl 10): x20-4, 2007.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-ripretinib-advanced-gastrointestinal-stromal-tumor. Accessed May 15, 2020.
- FDA approves avapritinib for gastrointestinal stromal tumor with a rare mutation
- 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
- 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