GIST Location Predicts Tumor Mutation Profile and Drug Sensitivity

The mutational landscape of gastrointestinal stromal tumor (GIST) is associated with the tumor location, according to new evidence. It may then, in turn, provide direction for treatment decisions and selective confirmatory genomic testing when resources are limited.

The study, published in Clinical Cancer Research, was the first to highlight the anatomic-genomic landscape of gastric GIST, according to the authors.

“The most important takeaway for patients is that despite the fact there is a correlation between tumor location and mutation, I still think that mutational testing is critical to the management of patients,” said corresponding author Dr. Jason Sicklick, professor of surgery and co-leader of the sarcoma disease team at UC San Diego, in an interview with CURE®. “But I also recognize the fact that there are clinical situations and health systems where not everybody has access to mutational testing.”

He added that the data in the study can hopefully be used to identify correlations to guide situations where patients can request tumor mutation testing.

“I think it's a way for patients to advocate for themselves, especially in areas where they may not be just open to mutation testing,” Sicklick said.

The research stemmed from a clinical observation that patients with mutations varied based on the location of GIST in their stomachs, according to Sicklick. The researchers began looking into the database at UC San Diego and expanded to other institutions to validate their findings.

They performed a retrospective cohort study using the National Cancer Database (NCDB) to associate GIST location with tumor mutation profile, identifying 2,418 eligible patients. They then used a cohort from the TransAtlantic GIST Collaborative (TAGC) to further verify their findings, including 236 patients in another analysis of tumor characteristics and mutation profiles. These findings were consistent and suggested that mutation profiles of GIST are not evenly distributed.

“Tumors located in the proximal stomach were almost uniformly found to have a KIT mutation,” the study authors wrote. “Distal tumors were found to exhibit a more diverse and heterogenous mutational profile, with greater incidence of PDGFRA and SDHx subunit mutations.”

Despite the importance of genomic testing, as highlighted by the findings, only one in four patients with GIST in the U.S. undergo such testing. Sicklick explained that there is a common misconception that mutational testing is not cost effective, though this has been proven untrue in the metastatic setting. However, many patients still do not receive the testing out of the cost concern.

“There is also the misconception that all GISTs are driven by KIT mutations,” Sicklick said. Researchers are learning that some patients have other mutations and can be uniquely treated.

“GIST set the precedent early on for precision medicine in solid cancers, but we now learning that the mutations driving these tumor seem to have a geographic correlation,” he said. “Previously (this was) shown in the small intestine, but now we’re showing it not only within the stomach, but in specific regions of the stomach. The geographic correlations can help predict which drugs may or may not work for a patient.”

Sicklick added that physicians and patients should continue to advocate for the role of mutational testing, and that GIST should be described not only by the region of the GI tract but the portion of the stomach for those located within it.

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