MECHANISM OF DISEASE/ACTION OF GLIVEC

Cellular origins of GIST

GISTs are thought to arise from specialized cells in the wall of the gut known as interstitial cells of Cajal (ICCs). These cells serve as the "pacemaker" cells for gastrointestinal tract motility.¹

ICCs have been shown to express the KIT proto-oncogene receptor (KIT, CD117) on their surface. This receptor, a transmembrane tyrosine kinase, binds the stem cell factor and is believed to be essential for development of normal hematopoiesis, proliferation, and migration of primordial germ cells during embryogenesis, as well as for pacemaker functions in ICCs. Similarly, GISTs express the KIT protein tyrosine kinase receptor in most cases, unlike gastrointestinal leiomyomas and leiomyosarcomas, which do not express KIT receptors.^2,3

Histopathology

Histologic features of GIST are variable, depending to some degree on the site of the tumor.⁴

• A spindle cell pattern is the most common cytomorphology, occurring in 70% of cases¹
• Only 20% of GISTs have an epithelioid cell pattern, and 5% show mixed morphology¹
• GISTs in all GI sites frequently grow between bundles of smooth muscle fibers, often establishing a micronodular, plexiform pattern⁵

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Pathophysiology of GIST

Aberrant signal transduction

Cancers grow as a consequence of the disruption of the normal balance between the rate of cell division and cell growth and the rate of programmed cell death.⁶

Aberrant cellular signal transduction is a driving force on both sides of the equation as well as in the process of malignant transformation.⁶

Receptor tyrosine kinases

Receptor tyrosine kinases are among the most critical groups of signaling molecules involved in normal and malignant cell growth.⁷

The activity of receptor tyrosine kinases is normally tightly regulated. When receptor tyrosine kinase signaling is perturbed by mutations and other genetic alterations, dysregulated kinase activity and malignant transformation result.^3,5

The KIT protein is a type III receptor tyrosine kinase that is responsible at the molecular level for GIST tumorigenesis.^1,8

The KIT protein

Normal KIT activation occurs when the receptor is bound by stem cell factor, also referred to as Steel factor. This process activates cell signaling cascades that regulate cell behavior.⁹

GISTs have activating mutations in the KIT or PDGFRA genes. Approximately 95% of GISTs stain positive for KIT (CD117) in immunohistochemical tests and are designated as KIT positive (KIT+). A small percentage of GISTs are KIT negative. The pathology of these GISTs is not well understood.^10,11,12

The presence of the mutated KIT protein (also known as CD117 cell surface antigen) is the single most specific marker of GIST.¹³

The mutations that disrupt the KIT protein result in a constitutively activated KIT. These mutations disrupt critical downstream signaling mechanisms and result in activation of cell survival (antiapoptotic) proteins and cell proliferation-related proteins.^5,13

Normal cells

Cell with KIT defect (mutation)

Abnormal KIT+ cells multiply out of control, forming a tumor

GLIVEC mechanism of action in KIT+ GIST

GLIVEC competitively binds to the adenosine triphosphate (ATP)-binding pocket of KIT to prevent phosphorylation, interrupting proliferative and antiapoptotic intracellular signaling pathways.^8,14

GLIVEC specifically targets most activating mutations in KIT seen in patients with KIT+ GIST.¹⁰

Continuous KIT suppression with GLIVEC may prolong recurrence-free or progression-free survival.⁹

GIST IS A RARE AND COMPLEX SARCOMA THAT AFFECTS SOME 15 PEOPLE PER MILLION AROUND THE WORLD¹

GIST may develop anywhere along the GI tract; however, it is most often found in the stomach²

Distribution of GISTs Throughout the GI Tract3,a
Most GISTs occur in the stomach, but can occur throughout the GI tract3

a	Tumor location was reported in 97% of patients and not reported in 3% of patients.
b	Other includes 5% of patients with tumors reported in the appendix, gallbladder, pancreas, mesentery, omentum, and retroperitoneum, and 3% of patients with tumor location that was not reported.

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Diagnosing GIST remains a challenge

Symptoms may be absent, vague, or severe⁴

With small GISTs (under 5 cm), often no symptoms are observed. Often, they are detected incidentally during endoscopy, radiologic imaging, or abdominal exploration.^2,4

In general, patients with a suspected GIST may present with symptoms that include²:

• Abdominal discomfort from pain or swelling
• Early sensation of fullness when eating
• Fatigue secondary to anemia
• Intraperitoneal hemorrhage, intraluminal gastrointestinal bleeding

Some patients may present with an acute abdominal condition (as a result of tumor rupture, gastrointestinal obstruction, or appendicitis-like pain), which requires immediate medical attention.²

Unrelated tumors may simulate GISTs

GISTs have often been misdiagnosed in the past as⁵:

• Leiomyomas
• Leiomyosarcomas
• Schwannomas
• Leiomyoblastomas
• GI autonomic nerve tumors

Diagnostic tests

Available imaging modalities to evaluate GIST include:

• Computed tomography (CT) scan
• Endoscopic ultrasound
• Magnetic resonance imaging (MRI)
• Fluorine-18-fluorodeoxyglucose (FDG) positron emission tomography (PET)

Contrast-enhanced CT scan is the imaging modality of choice to visualize suspected abdominal masses and is used in staging and surgical planning. CT scanning also helps to guide tissue biopsy. A small tumor found incidentally during endoscopy may be evaluated using endoscopic ultrasound or CT.^5,6

MRI is the procedure of choice for imaging rectal GISTs, as it provides better preoperative staging information.⁶

PET may add functional imaging data that are complementary to the information obtained through CT and MRI.⁵

Certain machines provide a combination of CT and PET imaging.

KIT staining is integral to GIST diagnosis

• Staining for common tumor markers is utilized to confirm a differential diagnosis⁷
• Approximately 95% of GISTs stain positive for KIT (CD117)²

Immunohistochemical Stain of KIT (CD117) in GIST8

Localized versus metastatic disease

• Localized disease is restricted to one point in the GI tract and is usually a candidate for resection if the tumor is in an appropriate site⁹
• Localized recurrence is when a GIST that has been surgically removed recurs in the same location
• Metastatic GISTs have spread beyond the primary site of the cancer and have grown in size
  • Metastatic GIST typically appears within the soft tissues of the abdomen or the liver. Metastases to lymph nodes are rare²

SURGERY ALONE IN THE LOCALIZED RESECTABLE KIT+ GIST PATIENT MAY NOT PROTECT PATIENTS FROM RISK OF TUMOR RECURRENCE

GIST has malignant potential, even after resection¹

Surgical resection is the initial treatment approach, yet the threat of tumor recurrence for localized resectable GIST remains.²

• 1 in 2 patients will have tumor recurrence within 5 years following complete resection³
• Median time to recurrence is approximately 2 years, but GIST may recur even years later^2,4

Factors influencing risk of recurrence

• In accordance with current guidelines, mitotic rate, tumor site, and tumor size should be considered in risk assessments^5,6
  • Tumors localized in the small intestine are more aggressive than gastric tumors of equal size and mitotic count⁴
• Consider additional factors, including surgical margins, whether tumor rupture has occurred, mucosal invasion, and mutational status^5,7

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Depending on mitotic rate and anatomic location, a GIST of any size can have malignant potential.⁴

Rates of metastases or tumor-related death in GIST^4,a