GIST Diagnoses and Risk of Recurrence

Margaret von Mehren, MD: This particular patient is a relatively typical patient. We think, based on epidemiological data, that GIST [gastrointestinal stromal tumor] diagnoses are slightly more common in men than in women. He presents at the age of 55, which is a pretty typical age. His symptoms are not atypical, in the sense that he presents with somewhat vague abdominal complaints, some early satiety. And then, on work-up, finding of anemia is also common. He had a gastric GIST, for which we can understand why he might experience some early satiety as well as some abdominal discomfort. We believe that many of these tumors will bleed slightly, which is the reason for finding anemia. So his work-up, on the basis of his symptoms and his blood work, was very consistent.

On endoscopy, the finding of the mass in the stomach with ulceration is, again, consistent with this idea that he was probably having some bleeding from his tumor, which contributed to his anemia. The description of the ultrasound component of the endoscopy is consistent with a lesion that is likely to be malignant versus not. First of all, the size of the lesion being 5 cm or more, it is much more likely to be malignant. When we think about GISTs, we don’t necessarily think about them as benign or malignant. Rather, we think more about their behavior. But certainly, a 5-cm GIST is one that has the potential to be metastatic at some point. The description of the hypoechogenicity is very consistent with lesions that are much more likely to have a higher risk of recurrence, or have a more aggressive behavior.

I think those findings, in terms of noting on EUS [endoscopic ultrasound], are much more significant when you’re looking at a small tumor, such as one that’s 1.5 or 2 cm, in terms of the gastroenterologist trying to make a decision about how to monitor or address the lesion. Is this something for which the patient needs to go to surgery? Is this somebody I should be monitoring? Those findings that were described are more consistent with something that is more likely to be concerning.

I think the importance of the biopsy can’t be understated. In this particular biopsy, there was a sufficient amount of tissue to give us a mitotic rate. Oftentimes in small biopsies, we can’t collect this information. The information is helpful, certainly, in terms of thinking about this lesion being one that is potentially more aggressive. In somebody who has metastatic disease, the mitotic rate is less important. That feature is particularly important when you’re thinking about a primary tumor and assessing whether this is a candidate for adjuvant therapy.

The use of the tissue for mutational testing is very important, particularly now as we not only have Gleevec [imatinib] but have other drugs, particularly avapritinib, approved for patients with a specific mutation, [PDGFR-α] D842V. Really, with all of the other tyrosine kinases available that we are aware of with data—specifically imatinib, sunitinib, and regorafenib—there are no consistent data, or data suggestive that these drugs are effective against that mutation. So having that information is very important to say whether or not this is a patient for whom imatinib makes sense and the patient is going to derive benefit versus not. There are some other types of GISTs for which we think imatinib may not be the best agent, including for tumors that are found not to have a kinase mutation in KIT or PDGFR-α. Many of these tumors are found in the stomach, oftentimes in younger patients, and have loss of a protein called SDHB. These will have a very different biology. Those patients don’t particularly benefit from imatinib, but may have some benefit from Sutent [sunitinib] and regorafenib.

Less likely, there are some other mutations that are rarely associated with GIST, for which knowing the number of underpinnings would be of importance. We’ve found BRAF mutations. There are NTRK translocations that have been identified in some patients with GIST. Also, there are tumors that are associated with NF1. These are other mutations for which if KIT and PDGFR-α are negative, it’s important to pursue additional testing to understand what the tumor is and what therapeutic options might be available for treating your patient.

Transcript edited for clarity.

Case: A 68-Year-Old Man With Gastrointestinal Stromal Tumor

Initial presentation

• A 68-year-old man complains of a 5-month history early satiety and vague abdominal pain
• PMH: hypertension, medically controlled; colonoscopy at age 55 unremarkable; no family history of cancer
• PE: diffuse abdominal pain on palpation; otherwise unremarkable
  
  

Clinical workup

• Labs: Hb 10.1 g/dL, plt 100 x 109/L; other lab values WNL
• Endoscopy: showeda submucosal ~ 5 cm mass with ulceration
• EUS-FNA biopsy: irregular borders on extraluminal surfaces of the stomach with evidence of heterogeneous echogenicity
• Biopsy showed gastrointestinal tumor with mitotic activity showed >5 mitoses/50 HPFs
• Abdominal/pelvic CT confirmed a 5.4 cm lesion in the body of the stomach
• MRI showed evidence of peritoneal metastases
• IHC and genetic mutational analysis: KIT exon 11 mutation
• ECOG 0
  
  

Treatment

• He was started on imatinib 400 mg PO qDay, continued for 26 months until he complained of increased abdominal pain and decreased appetite
  • ECOG 1; Imatinib was discontinued due to progressive disease
• Treatment with sunitinib 50 mg PO qDay for 4 weeks, with a 2-week drug-free interval was started
  • Treatment was well tolerated for 9 cycles when he developed an altered sense of taste, occasional vomiting and diarrhea; sunitinib was discontinued
• Regorafenib 160 mg (four 40 mg tablets) PO qDay for the first 21 days of each 28-day cycle was started and tolerated except for hand-foot syndrome
  • Regorafenib was discontinued on progression of disease
• The patient was started on ripretinib 150 mg PO qDay