GIST & KIT/PDGFRa Mutations Explained

A gastrointestinal stromal tumor, or GIST, starts in the wall of the digestive tract. Most begin in the stomach or the small intestine. They can occur anywhere from the esophagus to the rectum. They are thought to arise from interstitial cells of Cajal, the cells that help set the rhythm of gut movement.

Some GISTs are found by accident during surgery or a scan for something else. Others cause blood in the stool or vomit, dark or tarry stools, anemia and fatigue, abdominal pain, a feeling of fullness, or difficulty swallowing.

GIST is technically a sarcoma, which is a cancer of connective tissue. But treating it like other sarcomas would be a mistake. The chemotherapy drugs and radiation that work for other soft tissue sarcomas have little effect on GIST.

The reason is that most GISTs are driven by one overactive protein. Around 85 percent carry a mutation in either the KIT gene or the PDGFRA gene. Both genes make receptor proteins that normally switch on and off. When mutated, they stay on, and the cell is told to keep growing. Blocking that protein with a targeted pill turns the signal off. This is the single most important thing to understand about GIST treatment. It is also why it is worth asking to be seen by a team that treats GIST specifically.

Molecular testing of the tumor is standard. It changes decisions in concrete ways.

• KIT exon 11, the most common change, responds well to standard-dose imatinib.
• KIT exon 9 tumors often do better on a higher imatinib dose.
• PDGFRA D842V, the most common PDGFRA change, is resistant to imatinib. Avapritinib is used for these tumors instead.
• No KIT or PDGFRA mutation, sometimes called wild-type GIST, often involves the SDH genes. These behave differently, grow more slowly, and respond less well to imatinib. Referral to a specialist center or a clinical trial is commonly recommended.

If you do not know your mutation, ask. Starting the wrong drug wastes months.

For a GIST that has not spread, surgery to remove the tumor whole is the main treatment. Surgeons avoid cutting into the tumor, because that can spread cells. Removing nearby lymph nodes is usually unnecessary, since GIST rarely spreads to them.

Very small stomach GISTs found by chance, without worrying features, may be watched rather than removed. That decision rests on size, location and appearance on endoscopic ultrasound, a scan done with a probe passed into the gut.

Sometimes imatinib is given before surgery to shrink a tumor. That can make a smaller operation possible, or one that saves the organ.

Your pathology report gives three numbers that together estimate the risk of the cancer coming back. They are the tumor size, where it started, and the mitotic rate, which counts dividing cells. When that risk is high, imatinib after surgery lowers the chance of return. Trial evidence supports at least three years of treatment, and longer periods are under study.

For low-risk tumors, surgery alone may be enough.

For metastatic GIST, meaning GIST that has spread, imatinib is usually the first drug. It is taken daily and continued for as long as it controls the disease. Many people live for years on it.

If the disease progresses, the sequence generally moves to sunitinib, then regorafenib, then ripretinib. Avapritinib is used for PDGFRA D842V tumors. Repeat molecular testing at progression can sometimes show which resistance mutation has appeared. That can help guide the next choice.

Side effects across this drug class include swelling, especially around the eyes, plus muscle cramps, diarrhea, fatigue, low blood counts and skin changes. Most can be managed by adjusting the dose. It is better to report them than to stop the drug on your own.

GIST is often a long-term condition managed with a daily pill and regular scans. Taking the drug consistently matters, because the level in your blood affects how well it works. Ask about drug interactions, including with over-the-counter medicines and grapefruit.

Scans in GIST are read differently from other cancers. A tumor that stays the same size but becomes less dense on CT is often responding. Ask your team how they are judging response, so a stable-looking scan does not alarm you needlessly.

• Call 911 or go to an emergency department if you vomit blood, pass black or tarry stools, or get sudden severe pain in your abdomen. A GIST can bleed heavily into the gut, and NCI lists bright red or very dark blood in stool or vomit as a warning sign of the disease.
• Call your cancer team without delay if you develop a fever of 100.4°F (38°C) or higher or shaking chills while you are on imatinib or one of the related pills, or if you become newly short of breath. These drugs lower blood counts, and CDC treats a fever during cancer drug treatment as a medical emergency, so ring them at any hour. If you cannot get hold of anyone, go to an emergency department instead.
• Call your care team the same day if you spot fresh blood in the stool, or you gain weight suddenly with swelling of the face, hands or legs.
• Call your care team within a day or two if puffiness around the eyes, muscle cramps or loose stools are building instead of settling, or the skin starts peeling or blistering. Report these rather than stopping the drug yourself. The dose can usually be adjusted.

• NCI: GIST Treatment (PDQ®) Health Professional Version
• NCI drug information: imatinib mesylate
• NCI drug information: avapritinib
• NCI drug information: ripretinib
• NCI drug information: sunitinib malate
• NCI: GIST Treatment (PDQ®) Patient Version
• MedlinePlus: imatinib
• CDC: Fever During Chemotherapy Is a Medical Emergency