Gastrointestinal Stromal Tumors and KIT

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GISTs are mesenchymal neoplasms that can arise from any organ in the gastrointestinal tract or from the mesentery or omentum. Although GISTs morphologically resemble leiomyosarcomas and nerve sheath tumors, they are a distinct entity (Fletcher et al. 2002). More than 90% of GISTs express KIT (Hirota et al. 1998), and biochemical evidence of KIT activation can be found in almost all GISTs (Rubin et al. 2001). In approximately 90% of cases, this activation is linked to somatic mutations of KIT, usually involving ex-ons 9 or 11 (Rubin et al. 2001). Several lines of evidence indicate that KIT mutations are an early pathogenetic event in GISTs: (1) a similar frequency and spectrum of mutations is seen in histologically benign vs malignant tumors and early/localized vs late/metastatic tumors; (2) familial syndromes of GIST are associated with germline mutations of KIT; (3) molecular studies suggest that KIT mutations are acquired before the development of cytoge-netic abnormalities (Rubin et al. 2001; Corless et al. 2002; Heinrich et al. 2002c).

The standard treatment for localized GISTs is complete resection (Blanke et al. 2001). Recurrence after complete resection is common, occurring in up to 90% of patients with larger tumors (Ng et al. 1992), and survival following recurrence is short. Patients with advanced GIST have historically done poorly, with a 30% 6-month progression-free survival following initial chemotherapy. The chemosensitivity of GISTs has been difficult to define because most published series have not adequately distinguished GISTs from leiomyosarcomas and neurogenic tumors. However, the published data suggest that the response rate of GISTs to single- or multi-agent chemotherapy is less than 5%.

The concept that patients with GISTs might benefit from treatment with imatinib was based on the above data and two additional experimental observations: (1) treatment of GIST cell lines with imatinib inhibited proliferation and induced apoptosis; (2) several GIST-associated mutant KIT iso-forms were potently inhibited by imatinib in vitro at concentrations similar to wild-type KIT (Heinrich et al. 2000; Tuveson et al. 2001). Based on the identification of mutated KIT as a therapeutic target in GIST and the lack of an effective conventional medical therapy, a patient with chemotherapy-resistant gastric GIST metastatic to omentum and liver was started on imatinib at 400 mg po daily in March 2000. The tumor in this patient expressed an exon 11 mutant KIT isoform and the patient responded dramatically to ima-tinib therapy (Joensuu et al. 2001).

The strong pre-clinical rationale, coupled with the clinical success in this solitary case, led to the development of two proof-of-principle GIST trials utilizing imatinib. An European Organization for Research and Treatment of Cancer (EORTC), dose-escalation study of imatinib included 40 patients, 36

of whom had advanced GIST. The imatinib dosage ranged from 400 mg daily to 500 mg twice daily. At the highest dose, 5 of 8 patients had grade 3 toxicity (nausea/vomiting in 3, edema in 1, and dyspnea in 1) and 400 mg twice daily was considered the maximally tolerated dose. Of the patients, 19 (53%) had objective partial responses, while 13 (36%) had stable disease and only 4 (11%) experienced frank progression (van Oosterom et al. 2001). Two patients who progressed on 400 mg subsequently responded to 800 mg. With a minimum follow-up of 11 months, 29/36 remained on treatment. None of the four patients in the trial with a non-GIST sarcoma responded to ima-tinib.

The GIST Working Group (a consortium of the Oregon Health and Science University Cancer Institute, the Fox Chase Cancer Center, the University of Turku, the University of Helsinki, and the Dana-Farber Cancer Institute) performed a phase II randomized trial of 400 mg daily vs 600 mg (Demetri et al. 2002): 147 patients with incurable GIST (51% pre-treated with systemic therapy) were accrued, with a median age of 54 and median performance status of 1. Of the patients, 94% had undergone previous surgery, often involving the stomach or other areas in the GI tract; therefore, drug absorption was a concern in this trial. Nevertheless, pharmacokinetic assessments showed that drug levels were actually higher than those seen in leukemia patients given imatinib. The half-life of the drug was 20 h.

Imatinib was highly effective in this advanced disease population: 62% of patients on 400 mg daily and 65% on 600 mg achieved a partial response (Demetri et al. 2002). Stable disease was seen in 19% and 20%, respectively, and 16% and 8% had primary resistance, manifested as initial disease progression. Of the patients that failed the lower dose, 28% responded when crossed over to the higher dose. With a median follow-up of 15 months, 73% of patients remained on study drug, with an overall median time-to-treatment failure of 72 weeks.

KIT mutation analysis was performed on pre-treatment tumor samples from 121 of the 147 patients in the GIST Working Group trial (Heinrich et al. 2002b). Using a combination of PCR amplification of tumor DNA, denaturing HPLC, and direct DNA sequencing, exons 9, 11, 13, and 17 of the KIT gene were examined for mutations. Activating mutations were found in 86% of cases, most commonly in exon 11. Despite the fact that previous studies had suggested KIT mutations in GIST were associated with a worse prognosis (Hirota et al. 1998), patients with an exon 11 mutation had a significantly higher partial response rate (72%) than those with no detectable mutations (9%), and time-to-treatment failure was statistically significantly longer as well. Patients whose tumor harbored an exon 9 mutation did less well than those with exon 11 mutation (partial rate of 32%), but responded better and had a longer time-to-treatment failure than those with no detectable mutation. Because the numbers of patients in the exon 9 mutation group and the no mutation group were relatively small, these findings need to be con firmed. It is currently recommended that imatinib be offered to all GIST patients who are candidates for systemic therapy. KIT mutation status may be helpful in assessing the risk-benefit ratio for adjuvant therapy, and might help identify patients with advanced disease who are likely to do poorly, so that alternative agents or combination therapies can be planned.

Several additional studies of imatinib in the treatment of GIST are ongoing. The EORTC enrolled a phase II trial treating GIST patients with 400 mg BID. Phase III trials of lower vs higher dose imatinib (400 vs 800 mg daily) were enrolled by a North American Intergroup and by a European Consortium (made up of the EORTC, ISG, and AGITG), and both trials accrued rapidly.

Given the high recurrence rate for GISTs, even following complete resection, and the sensitivity of the disease to imatinib, it is reasonable to test drug administration before or following surgery in higher-risk patients. At least three trials are assessing the neoadjuvant/adjuvant use of imatinib in GIST. As there is substantial evidence that KIT mutations are pathogenetic or at least occur before other molecular abnormalities, it is predicted that imatinib would be even more active in the early disease setting and may enhance surgical results by eliminating minimal residual disease (Heinrich et al. 2002c).

Besides GIST, a number of other human cancers are associated with KIT mutations, including mastocytosis, seminoma, and acute myeloid leukemia (AML). Although KIT mutations are found in almost all cases of mastocyto-sis, they are found in less than 10% of cases of seminoma and are rare in adult AML (Heinrich et al. 2002a). Unfortunately, the KIT mutation found in mastocytosis is biochemically resistant to imatinib (Ma et al. 2002), while the sensitivity of the mutations found in AML and seminoma have not been reported. Thus, it will be necessary to develop other KIT inhibitors with activity against the KIT mutation found in mastocytosis.

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