Gastrointestinal stromal tumors (GISTs) ) represents the most common mesenchymal tumors of the gastrointestinal (GI) tract. Tumors are slow growing and usually located in the stomach or small intestine. In the United States, an estimated 4000 to 5000 new cases of GISTs are diagnosed annually. Data on worldwide frequency are limited, but in general, GISTs are equally distributed across all geographic and have no known racial proclivity. Recent SEER data reported a slightly higher prevalence in males versus females. It is most common in patients between the ages of 50 and 80. The vast majority of GIST are sporadic, but there are rare familial forms associated with the characteristic heritable mutations in the receptor tyrosine kinase KIT gene (or, rarely, in succinate dehydrogenase genes in Carney-Stratakis syndrome).

The most commonly used immunohistochemical marker for GIST is the KIT protein CD117 antigen, which is expressed by interstitial cells of Cajal, which are pacemakers for peristaltic contractions. Approximately 95% of GISTs have mutations of a growth factor receptor gene, KIT and about 3-5% of the remainder of KIT-negative GISTs contain PDGFR-alpha mutations. Whether GIST tumors have mutations in the KIT or PDGFRA gene and the location of those mutations has proven to be the most powerful predictor of how a patient will respond to treatment with targeted drugs such imatinib, sunitinib, sorafenib, and nilotinib.

Mutational testing should be considered standard practice for the treatment of GIST patients and is now recommended for metastatic and high-risk GIST patients (NCCN Task Force Report, 4-2010; ESMO clinical practice guidelines for diagnosis, treatment and follow-up, 2010). The information in genes is divided into coding regions or exons, and noncoding regions or introns (introns as intervening sequences and exons as expressed sequences). Mutations in the following exons of the KIT gene are known to occur in GIST.

  • Exon 11: This is the most commonly mutated exon in GIST. Exon 11 mutations are found in about 60% of cases. Mutations in exon 11 generally respond to treatment with Gleevec better than mutations in other exons.
  • Exon 9: Exon 9 mutations are the second most common mutation. Exon 9 mutations are found in about 10% of cases. In patients that have an exon 9 mutation, it occurs in the small bowel or colon about 98% of the time; however, they do not make up the majority of cases that occur in the small bowel or colon. GISTs with exon 9 mutations have a lower response rate to standard dose Imatinib therapy when compared to exon 11 mutations. As a result, a higher dose of Imatinib is generally recommended for patients with advanced/metastatic disease. They also seem to respond fairly well to Sunitinib.
  • Exon 13 and exon 17 mutations are rare in GIST.

These mutations result in ligand-independent kinase activation, which leads to the constitutive activation of the kinase. Mutations on the exon 11 include in-frame deletions, insertions, and substitutions, or combinations of these.

Wild-type GISTs (lack of KIT or PDGFRA mutations) are a heterogeneous group, of which some have alterations in BRAF, RAS or in the genes of the succinate dehydrogenase complex. Hence wild-type GISTs might respond better to other targeted agents, such as VEGFR inhibitors, and BRAF or MEK inhibitors.

Resistance to tyrosine kinase inhibitors (TKI) therapy such as imatinib can be divided into two types: primary and secondary. It’s estimated that 10% of patients with GISTs have primary resistance, which is defined as progression within the first 6 months of treatment. Whereas, secondary resistance develops after an initial benefit from imatinib.


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