The Importance of Molecular Testing For Treatment Decision-Making in GIST
Michael Heinrich, MD, Oregon Health & Science University Knight Cancer Institute, Portland, Oregon, discusses the treatment course for a 52-year-old male with newly diagnosed gastrointestinal stromal tumors (GIST), highlighting the importance of molecular testing when considering medical therapies.
Transcript:
Hello, I'm Dr Michael Heinrich. I'm a Professor of Medicine and also a Professor of Cell Developmental and Cancer Biology at the Oregon Health & Science University Knight Cancer Institute in Portland, Oregon. I'm also director of our Cancer Institute's GIST (GI Stromal Tumor) Clinical and Translational Research Program.
Today's case is a 52-year-old male who presented with localized gastric GIST. GIST is the most common abdominal sarcoma, and some would argue the most common sarcoma overall. GIST arises in specialized cells in the gut wall called the interstitial cells of Cajal, which are pacemaker cells. The stomach is the most common primary site. About 70% of all GIST arise in the stomach. The next most common site is the small intestine.
Because these tumors arise in the wall, they can grow either endophytically, which is towards the lumen where the food is in the case of the stomach or exophytically into the abdominal cavity. Therefore, the clinical presentation depends on which way the tumor grows. If it grows primarily endophytically, tumors as they get larger will erode the mucosa and generally cause gastrointestinal bleeding, which can be occult or sometimes clinically apparent with melena. Therefore, many cases of GIST present to their primary care provider for workup of iron deficiency. If the tumor grows primarily exophytically, as in this case, they typically present later with symptoms that are related to tumor size.
In the case of gastric tumors, exophytic tumors can become quite large, as in this case, as they push around the surrounding organs and become pretty massive before they cause symptoms. Today's case features a tumor with both endophytic and exophytic growth.
The patient primarily presented with iron deficiency, but he also had some symptoms related to tumor mass. When a gastric mass is suspected to be a GIST, the appropriate next step is an upper endoscopy with biopsy. Even though you may do imaging that identifies a large mass, we don't want to do percutaneous biopsy, as in the case of GIST, these tumors are quite fragile, and needle biopsy can result in tumor rupture and actually disseminate the tumor. In this case, the diagnosis was made endoscopically.
Following diagnosis, additional staging with imaging is needed to define whether the patient has localized versus metastatic disease. In this case, abdominal pelvic imaging showed the mass to be a 15 centimeter, primarily exophytic mass arising from the greater curvature of the stomach with extension of the mass to the splenic hilum in contact with the body of spleen. Importantly though, there was no evidence of metastatic disease.
At this point, patients are generally referred to surgical and medical oncology to consider treatment options which were outlined in the questions associated with this case. The initial consideration would be whether primary surgery could be performed without excessive morbidity. Current concepts of GIST surgery include removing as little stomach as possible using wedge resection as wide margins are not needed, and removing too much stomach will reduce gastric capacity and lead to an unintentional weight loss operation.
In this case, the tumor is too large to consider primary surgery given concerns about the extent of gastric resection. Also, probable need for a splenectomy and possible need for distal pancreatectomy.
In this case, a consideration of neoadjuvant therapy to reduce tumor size should be appropriate. Although many but not all GIST tumors have a targetable mutation such as KIT or PDGFRA, about 10% of gastric GISTs are SDH deficient, and there is no active neoadjuvant agent for these. Therefore, the correct answer is B, perform SDHB immunohistochemistry (IHC) and obtain molecular testing. SDHB IHC would identify those tumors that are SDH deficient and are therefore very unlikely to respond to conventional GIST TKIs or tyrosine kinase inhibitors. Molecular testing will identify the presence and type of KIT or PDGFRA mutations and help the oncologist select the appropriate TKI. Beginning neoadjuvant imatinib in the absence of an identified imatinib-sensitive mutation, which is answer C, is incorrect. As stated before, perform molecular testing and then choose the appropriate medical therapy.
In the case of answer D, which is to use Imatinib 400 milligrams twice daily, there is no evidence to support this higher dose in the neoadjuvant setting, even if we found a sensitive mutation. This higher dose would be a more toxic option than standard dose imatinib.
If molecular testing identified the presence of the imatinib-resistant PDGFRA D842V mutation, then avapritinib could be considered in answer E. However, this mutation is only found in 5 to 10% of gastric tumors and the increased toxicity of avapritinib warrants proof that we need to use this agent before we started.
In this case, SDHB staining was retained, indicating that the tumor was not SDH deficient. A KIT exon 11 mutation was identified, which is a very sensitive mutation to imatinib. The patient received 6 months of neoadjuvant imatinib with tumor decreasing to 4 centimeters, and at surgery a clear margin with the spleen was obtained without need for splenectomy. The patient underwent a successful laparoscopic wedge resection with good recovery and no significant digestive abnormalities.
The takeaway from this case is that in any situation where you're considering medical therapy, first perform molecular testing. Thank you for listening to this patient case on gastrointestinal stromal tumors.
