New Therapeutic Options in Gastrointestinal Stromal Tumors

New Therapeutic Options in Gastrointestinal Stromal Tumors

Endoscopy image of GIST; source: Samir, Wikimedia Commons

ABSTRACT: Gastrointestinal stromal tumors have until recently had a uniformly poor prognosis with lack of effective drug therapies. These tumors usually have activating mutations in either KIT or PDGFR-α tyrosine kinase receptors. Over the past decade, imatinib (Gleevec), a selective tyrosine kinase inhibitor has become the standard of care for the first-line treatment of patients with unresectable and metastatic disease. For patients with imatinib-resistant disease or intolerant to the side effects of imatinib, sunitinib (Sutent), a multitargeted tyrosine kinase inhibitor was recently approved. For earlier-stage disease, status post–complete surgical excision, preliminary data seem encouraging for the role of adjuvant imatinib in prolonging patients' disease-free interval. The impact of neoadjuvant drug therapy needs to be further classified and explored. With additional evaluation of other tyrosine kinase inhibitors and novel therapies against other molecular markers, the treatment paradigm for this malignancy should continue to evolve.

Gastrointestinal stromal tumor (GIST), the most common mesenchymal tumor of the gastrointestinal tract, has until recently had a uniformly poor prognosis, with effective treatment options being limited to surgical resection. Conventional cytotoxic chemotherapy has led to minimal clinical responses. Since the initial establishment of GIST as an entity distinct from gastrointestinal (GI) smooth muscle and nerve sheath tumors,[1,2] the understanding of its molecular abnormalities and distinct biology has allowed for an increased accuracy in both diagnosis and treatment.

With the advent of small-molecule tyrosine kinase inhibitors, GIST has transformed from a malignancy with a poor prognosis, to a cancer with new and exciting therapeutic options that delay progression of disease and decrease mortality. This review provides a comprehensive overview of GIST with a focus on established and promising therapies in development for the treatment of this sarcomatous tumor.


Despite being a relatively uncommon neoplasm, GIST is the most common of the sarcomatous tumors of the gastrointestinal tract, with 3,000 to 6,000 new cases diagnosed each year in the United States.[3,4] That said, GISTs constitute less than 1% of all cancers.[3] Extremely small GISTs have been found in autopsy studies in 22.5% to 35% of individuals older than 50 years of age.[5,6] GISTs are typically neoplasms of older adults and show no sex bias, with the majority of men and women presenting after age 50, with a median age of 58 years.[7]

GISTs show a predilection for specific sites in the gastrointestinal tract, with 50% arising in the stomach, 25% in the small bowel, and 10% in the colon and rectum.[4] The remaining primary sites include the mesentery, omentum, and retroperitoneum. Lymphatic spread of GIST is extremely uncommon—so much so that current guidelines recommend against lymph node biopsy at the time of GIST resection.[8] Metastases typically occur in the abdominal cavity or liver. Extra-abdominal spread outside the abdominal cavity to lungs and bones is unusual and reflects an aggressive, more advanced disease process.[9]

At presentation, nonspecific clinical findings are typical. Bloating, fatigue, early satiety, obstruction, pain, and GI bleeding are all possible presentations for this tumor. A normal physical exam prompts further exploration with both endoscopy and computed tomography (CT) with final diagnosis confirmed by pathology.


Oncogenic mutations play a critical role in the development of sarcomas. KIT is a type III receptor tyrosine kinase that is important for the development of melanocytes, germ cells, mast cells, hematopoietic stem cells, as well as the interstitial cells of Cajal and the pacemaker cells of the GI tract, which GIST cells most closely resemble. GISTs are postulated to arise from either the interstitial cells of Cajal, the pacemaker cells that stimulate gut contraction in the myenteric plexus, or from a common precursor cell that gives rise to the interstitial cells of Cajal.[10,11] Given the intimate relation between GIST and the interstitial cells of Cajal, these tumors can arise only in organs where the interstitial cells of Cajal are located, and as such, further distinguish themselves from smooth muscle and peripheral nerve sheath tumors.

As a tyrosine kinase receptor, KIT (CD117) has cell growth regulatory functions. In normal cells, KIT ligand binds and activates two KIT receptors with subsequent phosphorylation and activation of signaling pathways that lead to cell growth and proliferation. As in other cancers, mutations in KIT lead to constitutive activation of KIT in the absence of ligand, unstoppable cell growth, and tumor formation. Most GISTs contain gain-of-function, an oncogenic mutation in KIT or in platelet-derived growth factor receptor–alpha (PDGFR-α), which appears to be the major initiating event that drives the pathogenesis of GIST. KIT-activating mutations are found in 85% to 90% of GISTs,[12,13] making this a distinguishing feature to further separate this tumor from leiomyomas, leiomyosarcomas, and schwannomas.

GISTs are associated with a KIT mutation that often involves exon 9 or 11, whereas mutations in the split kinase domains (exons 13 or 17) are uncommon (< 5%).[14] These mutations are not monolithic and include deletions, insertions, and missense mutations. Approximately 4% of GISTs completely lack KIT immunoreactivity. Most of these KIT-negative GISTs harbor activating mutations in PDGFR-α.[15,16] Of these mutations in PDGFR-α, 85% occur in the second kinase domain (exon 18), of which almost two-thirds consist of a single-point mutation. Although much less common, exon 12 (juxtamembrane domain) and exon 14 (first kinase domain) mutations have also been detected.[17]

Interestingly, nearly all PDGFR-α mutant GISTs arise in the stomach, omentum, or mesentery and show epithelioid morphology.[18-21] The different KIT or PDGFR-α mutations harbored by GISTs contribute to different molecular signatures at the level of gene expression, which further contributes to the complexity of GIST biology and variable responses to treatment.[22] GISTs with neither KIT nor PDGFR-α mutations are referred to as "wild- type" GISTs. In recent years, KIT mutational status has become important as a predictive marker of how well patients with GIST will respond to biologic therapies to counter their cancer.


Treatment options for GIST vary based on whether the tumor is local or metastatic, unresectable or accessible through surgery. For localized lesions that are deemed surgically resectable, treatment consists of complete surgical resection. Lymphatic dissection with lymphadenectomy is not recommended because of the rarity of GIST metastasizing through lymphatics. Complete surgical resection with negative margins is the mainstay of treatment and confers a 5-year survival rate of 20% to 44%.[23]

The prognosis for patients with newly diagnosed GIST has been well characterized and studied. The site and size of the primary tumor, as well as the mitotic index all contribute to risk of recurrent or metstatic disease. Tumors are stratified based on size less than 2 cm, 2 to 5 cm, 5 to 10 cm, or greater than 10 cm. Subsequent breakdowns include a mitotic index of less than or greater than 5 per 50 high-power fields and site of disease broken down to gastric, duodenum, jejunum, and ileum or rectum. The highest risk of recurrence is for large tumors with high mitotic indexes. By location, gastric tumors have the least progressive potential.[24,25]


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