Presentation of Metastatic GIST

Jonathan Strosberg, MD:The case describes a 59-year-old woman who presented in August 2014 with acute abdominal pain. Scan showed an 11-cm tumor in the jejunum with a 3-cm liver metastasis. Needle biopsy showed a metastatic gastrointestinal stromal tumor (GIST) with a high mitotic rate greater than 5 mitoses/50 high-power fields and anexon 11mutation. The patient was started on imatinib, 400 mg daily.

So, this patient has a fairly aggressive GIST with a high mutation rate. When we deal with a small bowel GIST in a single liver metastasis, we may want to consider future resection even though it’s unlikely to be curative. Removing all sites of disease may result in better long-term outcomes. But certainly, I would agree with starting with imatinib based on the very substantial improvement in progression-free survival and overall survival associated with this drug.Exon 11mutations tend to be very sensitive to imatinib, and the dose of 400 mg is an appropriate starting dose for this mutation.

Imatinib has been a life-changing drug for patients with metastatic GISTs. The median survival durations used to be very short, somewhere on the order of 1 to 2 years. Now, they’re well in excess of 5 years. So, the gastrointestinal stromal tumors are one of the cancers that have responded extremely well to a targeted therapy, specifically because they tend to have a single activating mutation, which imatinib targets very well.

Most gastrointestinal stromal tumors have mutations inexon 11of theKITgene; that’s about 80%. Roughly, 10% to 15% have mutations inexon 9. A rare population have mutations in the platelet-derived growth receptor, or PDGFRA. Most are sensitive to imatinib, althoughexon 9mutations tend to be a little bit more resistant and there are certain data suggesting that progression-free survival and response rates are improved with higher doses of imatinib—400 mg twice a day rather than once a day. However, that did not translate into overall survival benefit. So, there’s not a great consensus as to the appropriate starting dose for patients withexon 9mutations.

Now there are mutations that are resistant to imatinib. For example, in PDGFRA, theD842Vmutation is known to be fairly resistant to imatinib. And then there’s a small population of patients who are wild-type, who have mutations in neither of these genes, and they also tend to be fairly resistant to imatinib.

There may be some additional tests. We would want to get a baseline in this case. A PET scan may be helpful, especially if we’re considering surgery. We want to try to identify all sites of disease. PET scans can also sometimes be useful for early assessment of response. Sometimes they go from positive to negative very quickly. However, it’s not absolutely a mandatory component of the initial evaluation.

Transcript edited for clarity.

August 2014

• A 59—year-old Caucasian female presented with acute onset abdominal pain
• Past medical history was remarkable for hyperlipidemia
  • Her performance status was ECOG 1
• Abdominal CT findings showed an 11-cm mass in the jejunum and a 3-cm lesion in the liver
  • Biopsy confirmed primary gastrointestinal stromal tumor (GIST) in the jejunum
  • The tumor was determined to be unresectable at the time because of its size and location
• IHC was positive for CD117 (c-KIT); molecular analysis demonstrated an exon 11 mutation
• Mitotic activity was high with >5 mitoses/50 high-power fields
• Treatment was initiated with imatinib 400 mg once daily
• No further disease progression was noted

​October 2016

• During routine follow-up, the patient complained of recurring abdominal pain
• Abdominal CT scan showed a slight increase in the primary tumor size and a new small metastatic tumor in the liver
  • Her ECOG performance status was 1
• The patient was switched to sunitinib 37.5 mg and showed stable disease on follow-up imaging at 3 months

March 2017

• At her 6-month follow-up, abdominal CT scan revealed additional metastases in the liver
• ECOG performance status had changed to 2
• The patient was subsequently referred to an academic center for treatment and was switched to regorafenib 160 mg on days 1-21 of every 28-day cycle
• Three weeks after initiating treatment with regorafenib, she complained of increased fatigue
• She presented with hand-foot skin reaction, which presented as tingling, burning sensations on her palms and a decreased tolerance for touching hot objects