Gastrointestinal Stromal Tumors: Disease and Treatment Update

Abstract

Gastrointestinal stromal tumors (GISTs) are relatively rare mesenchymal neoplasms that can arise in any area of the gastrointestinal (GI) tract. In the past decade, significant advances have been made in the understanding of GIST biology and molecular pathogenesis. The identification of key signaling transduction pathways has led to the development of molecularly targeted therapies that have improved dramatically the prognosis for GIST patients. GISTs are soft tissue sarcomas that likely originate from the interstitial cells of Cajal, the intestinal pacemaker cells. They are the most common connective tissue tumors affecting the GI tract. GISTs are most often located in the stomach and the proximal small intestine, but can occur in any portion of the GI tract, including the omentum, mesentery, and peritoneum.1Gold J.S. Dematteo R.P. Combined surgical and molecular therapy: the gastrointestinal stromal tumor model.Ann Surg. 2006; 244: 176-184Crossref PubMed Scopus (221) Google Scholar There is no gender predominance. The peak age of onset is the late 50s, but GISTs can occur at any age. Studies on the incidence and prevalence of these tumors come mostly from population-based, histologic analyses using immunocytochemistry, retrospectively examining all cases of “potential GISTs.”2Goettsch W.G. Bos S.D. Breekveldt-Postma N. et al.Incidence of gastrointestinal stromal tumours is underestimated: results of a nation-wide study.Eur J Cancer. 2005; 41: 2868-2872Abstract Full Text Full Text PDF PubMed Scopus (254) Google Scholar, 3Tryggvason G. Gislason H.G. Magnusson M.K. et al.Gastrointestinal stromal tumors in Iceland, 1990-2003: the Icelandic GIST study, a population-based incidence and pathologic risk stratification study.Int J Cancer. 2005; 117: 289-293Crossref PubMed Scopus (287) Google Scholar, 4Nilsson B. Bumming P. Meis-Kindblom J.M. et al.Gastrointestinal stromal tumors: the incidence, prevalence, clinical course, and prognostication in the preimatinib mesylate era—a population-based study in western Sweden.Cancer. 2005; 103: 821-829Crossref PubMed Scopus (1029) Google Scholar GIST incidence ranges between 6 and 15 cases per million, with a prevalence of 129 cases per million.4Nilsson B. Bumming P. Meis-Kindblom J.M. et al.Gastrointestinal stromal tumors: the incidence, prevalence, clinical course, and prognostication in the preimatinib mesylate era—a population-based study in western Sweden.Cancer. 2005; 103: 821-829Crossref PubMed Scopus (1029) Google Scholar Historically, GISTs were thought to be of smooth muscle or neural origin.5Miettinen M. Virolainen M.Maarit-Sarlomo-Rikala. Gastrointestinal stromal tumors—value of CD34 antigen in their identification and separation from true leiomyomas and schwannomas.Am J Surg Pathol. 1995; 19: 207-216Crossref PubMed Scopus (503) Google Scholar In 1995, Huizinga et al6Huizinga J.D. Thuneberg L. Kluppel M. et al.W/kit gene required for interstitial cells of Cajal and for intestinal pacemaker activity.Nature. 1995; 373: 347-349Crossref PubMed Scopus (1262) Google Scholar confirmed that KIT played a key role in the development of interstitial cells of Cajal. In 1998, Hirota et al7Hirota S. Isozaki K. Moriyama Y. et al.Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors.Science. 1998; 279: 577-580Crossref PubMed Scopus (3834) Google Scholar demonstrated that KIT is also commonly expressed in GISTs. KIT is a receptor tyrosine kinase whose activity is normally regulated by binding of the endogenous ligand stem cell factor. Binding of stem cell factor to KIT results in receptor homodimerization, activation of its tyrosine kinase activity, and phosphorylation of downstream substrates leading to signal transduction.8Blume-Jensen P. Claesson-Welsh L. Siegbahn A. et al.Activation of the human c-kit product by ligand-induced dimerization mediates circular actin reorganization and chemotaxis.EMBO J. 1991; 10: 4121-4128Crossref PubMed Scopus (269) Google Scholar In >80% of GISTs, mutation in the KIT gene occurs, leading to constitutive activation. Most of the mutations in KIT affect exon 11 (60%) and less commonly exons 9 (15%), 13 or 17 (∼5%).9Heinrich M.C. Corless C.L. Demetri G.D. et al.Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor.J Clin Oncol. 2003; 21: 4342-4349Crossref PubMed Scopus (1959) Google Scholar, 10Corless C.L. Fletcher J.A. Heinrich M.C. Biology of gastrointestinal stromal tumors.J Clin Oncol. 2004; 22: 3813-3825Crossref PubMed Scopus (1017) Google Scholar In the subset of GISTs that are KIT wild type, a proportion have mutations in either exons 12 or 18 of the platelet-derived growth factor alpha (PDGFRA) gene (Figure 1) .11Heinrich M.C. Corless C.L. Duensing A. et al.PDGFRA activating mutations in gastrointestinal stromal tumors.Science. 2003; 299: 708-710Crossref PubMed Scopus (2003) Google Scholar Whereas mutations in exon 9 most commonly occur in GISTs arising within the small intestine and colon, the PDGFRA substitution D842V in exon 18 is found only in GISTs arising in the stomach, mesentery, and omentum. By contrast, all other KIT and PDGFRA mutations can be found in GISTs throughout the GI tract.12Corless C.L. Heinrich M.C. Molecular pathobiology of gastrointestinal stromal sarcomas.Annu Rev Pathol. 2008; 3: 557-586Crossref PubMed Scopus (281) Google Scholar Recently, there has been an increased awareness and recognition of the existence of small, clinically silent GISTs. Studies indicate that such lesions are present in up to 35% of the adult population. GISTlets harbor KIT and PDGFRA gene mutations at rates similar to overt tumors, indicating that oncogenic kinase mutations can contribute to the early development of GISTs.13Chetty R. Small and microscopically detected gastrointestinal stromal tumours: an overview.Pathology. 2008; 40: 9-12Crossref PubMed Scopus (32) Google Scholar Other cytogenetic aberrations, however, are also necessary in GIST development and the clinical progression of these tumors.10Corless C.L. Fletcher J.A. Heinrich M.C. Biology of gastrointestinal stromal tumors.J Clin Oncol. 2004; 22: 3813-3825Crossref PubMed Scopus (1017) Google Scholar The diagnosis of GIST is made on pathologic analysis of tumor specimens. The cellular morphology of GISTs falls into one of 3 categories: spindle cell type (70%), epithelioid type (20%), or mixed type (10%).10Corless C.L. Fletcher J.A. Heinrich M.C. Biology of gastrointestinal stromal tumors.J Clin Oncol. 2004; 22: 3813-3825Crossref PubMed Scopus (1017) Google Scholar Although GISTS are almost uniformly characterized by the expression of KIT (CD 117), approximately 5% of GISTs lack such expression. Recent studies have shown that DOG-1, a novel protein with unknown function, is a more sensitive immunohistochemical marker for GIST than KIT, with the additional benefit of detecting 36% of KIT-negative GISTs.14Liegl B. Hornick J.L. Corless C.L. et al.Monoclonal antibody DOG1.1 shows higher sensitivity than KIT in the diagnosis of gastrointestinal stromal tumors, including unusual subtypes.Am J Surg Pathol. 2009; 33: 437-446Crossref PubMed Scopus (218) Google Scholar Although 95% of GISTs express KIT and approximately 85% of GISTs have mutations in either KIT or PDGFRA, 12%–15% of all GISTs have no detectable mutations in either of these genes. The molecular pathogenesis of wild-type GISTs remains unknown. Phosphorylated KIT remains detectable in this subset of tumors, suggesting that KIT is still activated.15Duensing A. Joseph N.E. Medeiros F. et al.Protein kinase C theta (PKCtheta) expression and constitutive activation in gastrointestinal stromal tumors (GISTs).Cancer Res. 2004; 64: 5127-5131Crossref PubMed Scopus (115) Google Scholar The majority of GISTs seem to be sporadic. There is, however, a clear association between GISTs and type 1 neurofibromatosis.16Andersson J. Sihto H. Meis-Kindblom J.M. et al.NF1-associated gastrointestinal stromal tumors have unique clinical, phenotypic, and genotypic characteristics.Am J Surg Pathol. 2005; 29: 1170-1176Crossref PubMed Scopus (224) Google Scholar, 17Maertens O. Prenen H. Debiec-Rychter M. et al.Molecular pathogenesis of multiple gastrointestinal stromal tumors in NF1 patients.Hum Mol Genet. 2006; 15: 1015-1023Crossref PubMed Scopus (183) Google Scholar This subset of GISTs tends to arise in the small intestine, but very rarely metastasizes.16Andersson J. Sihto H. Meis-Kindblom J.M. et al.NF1-associated gastrointestinal stromal tumors have unique clinical, phenotypic, and genotypic characteristics.Am J Surg Pathol. 2005; 29: 1170-1176Crossref PubMed Scopus (224) Google Scholar Although they stain positively for KIT expression (CD 117), they essentially lack KIT and PDGFRA mutations.12Corless C.L. Heinrich M.C. Molecular pathobiology of gastrointestinal stromal sarcomas.Annu Rev Pathol. 2008; 3: 557-586Crossref PubMed Scopus (281) Google Scholar Most patients with GISTs present with nonspecific symptoms, such as early satiety and bloating. Spontaneous tumor bleeding may be observed. Patients may present also with secondary symptoms, such as bowel perforation or obstruction, or dysphagia.10Corless C.L. Fletcher J.A. Heinrich M.C. Biology of gastrointestinal stromal tumors.J Clin Oncol. 2004; 22: 3813-3825Crossref PubMed Scopus (1017) Google Scholar According to a large, population-based study, about one third of GISTs were detected incidentally during evaluation of other diseases.4Nilsson B. Bumming P. Meis-Kindblom J.M. et al.Gastrointestinal stromal tumors: the incidence, prevalence, clinical course, and prognostication in the preimatinib mesylate era—a population-based study in western Sweden.Cancer. 2005; 103: 821-829Crossref PubMed Scopus (1029) Google Scholar Fifteen percent to 47% of patients present with overt metastatic disease to the liver and peritoneum.18DeMatteo R.P. Lewis J.J. Leung D. et al.Two hundred gastrointestinal stromal tumors: recurrence patterns and prognostic factors for survival.Ann Surg. 2000; 231: 51-58Crossref PubMed Scopus (2168) Google Scholar The site of metastases may determine symptoms; patients with liver involvement may have pain, jaundice, and liver failure as their first manifestations. Lymph node, lung, and bone metastases are uncommon. Macroscopic complete surgical resection with negative microscopic margins remains the standard of care for patients with primary resectable GISTs. Neoadjuvant therapy for those with resectable disease is not recommended, but preoperative imatinib may be considered for patients with marginally resectable tumors and for those who have potentially resectable disease but with the risk of significant morbidity. Estimation of recurrence risk after resection of a GIST is of importance when selecting patients for adjuvant imatinib. It became evident that tumors showing the usual histologic characteristics for malignancy did not uniformly behave aggressively. Size, mitotic count, and anatomic location gained early acceptance as being predictive of outcome.19Fletcher C.D. Berman J.J. Corless C. et al.Diagnosis of gastrointestinal stromal tumors: a consensus approach.Int J Surg Pathol. 2002; 10: 81-89Crossref PubMed Scopus (337) Google Scholar In addition, tumor rupture, incomplete resection, and possibly KIT/PDGFR mutational status also impact disease-free survival.20Joensuu H. Risk stratification of patients diagnosed with gastrointestinal stromal tumor.Hum Pathol. 2008; 39: 1411-1419Abstract Full Text Full Text PDF PubMed Scopus (841) Google Scholar When compared with exon 11 mutants, the presence of exon 9 mutations and wild-type GIST were the strongest adverse prognostic factors for response, risk of progression, and death.21Dematteo R.P. Ballman K.V. Antonescu C.R. et al.Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled trial.Lancet. 2009; 373: 1097-1104Abstract Full Text Full Text PDF PubMed Scopus (1064) Google Scholar Questions remain regarding post-operative or adjuvant therapy. The American College of Surgeons Oncology Group conducted a randomized, phase III trial of adjuvant imantinib after operative resection of primary GIST. They randomly assigned 713 adults with a completely resected primary GIST ≥3 cm in size and immunohistochemically positive for KIT to 1 year of adjuvant imatinib (400 mg/d) or placebo. At a median follow-up of 20 months, 30 patients in the imatinib group had recurred or died, versus 70 given placebo. The 1-year recurrence-free survival was 98% versus 83%, favoring imatinib.21Dematteo R.P. Ballman K.V. Antonescu C.R. et al.Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled trial.Lancet. 2009; 373: 1097-1104Abstract Full Text Full Text PDF PubMed Scopus (1064) Google Scholar Based on these findings, imatinib was approved by the US Food and Drug Administration (FDA) for patients with completely resected GISTs ≥3 cm in size. However, the optimal duration of therapy for patients remains unclear. Two additional European trials have been completed and are awaiting data maturation. EORTC 62024 randomized patients with intermediate and high-risk GIST to 2 years of imatinib or observation alone, with overall survival (OS) as the primary endpoint. The Scandinavian Sarcoma Group trial XVIII randomized patients with high-risk disease patients to 1 or 3 years of adjuvant imatinib, with recurrence-free survival as the primary endpoint. Systemic chemotherapy for advanced GIST is highly ineffective, with response rates <10%.22Dematteo R.P. Heinrich M.C. El-Rifai W.M. et al.Clinical management of gastrointestinal stromal tumors: before and after STI-571.Hum Pathol. 2002; 33: 466-477Abstract Full Text Full Text PDF PubMed Scopus (567) Google Scholar Since the 2001 report of a solitary patient with rapidly progressive GIST exhibiting dramatic response,23Joensuu H. Roberts P.J. Sarlomo-Rikala M. et al.Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor.N Engl J Med. 2001; 344: 1052-1056Crossref PubMed Scopus (1833) Google Scholar many studies have confirmed the efficacy of tyrosine kinase inhibition in GIST patients. Imatinib blocks KIT/PDGFRA signaling by binding to the ATP-binding pocket required for phosphorylation and activation of the receptor. In vitro data demonstrated that, by inhibiting downstream phosphorylation, imatinib leads to interruption of cell proliferation.24Tuveson D.A. Willis N.A. Jacks T. et al.STI571 inactivation of the gastrointestinal stromal tumor c-KIT oncoprotein: biological and clinical implications.Oncogene. 2001; 20: 5054-5058Crossref PubMed Scopus (616) Google Scholar A large, multicenter, multinational, phase II trial (CSTIB2222) randomized 147 patients with incurable GIST to 400 or 600 mg of imatinib daily; 68.1% achieved an objective response (similar between arms), and 15% of patients experienced stable disease. The median time to progression (TTP) was 2 years, with a median OS of 57 months. Importantly, long-term results revealed that nearly half of the patients survived for >5 years and 28% of patients remained on long-term imatinib treatment.25Blanke C.D. Demetri G.D. von Mehren M. et al.Long-term results from a randomized phase II trial of standard- versus higher-dose imatinib mesylate for patients with unresectable or metastatic gastrointestinal stromal tumors expressing KIT.J Clin Oncol. 2008; 26: 620-625Crossref PubMed Scopus (833) Google Scholar On the basis of the results of this landmark trial, imatinib was approved by the FDA for the treatment of advanced GIST. European phase I/II results were similar.26Verweij J. van Oosterom A. Blay J.Y. et al.Imatinib mesylate (STI-571 Glivec, Gleevec) is an active agent for gastrointestinal stromal tumours, but does not yield responses in other soft-tissue sarcomas that are unselected for a molecular target Results from an EORTC Soft Tissue and Bone Sarcoma Group phase II study.Eur J Cancer. 2003; 39: 2006-2011Abstract Full Text Full Text PDF PubMed Scopus (400) Google Scholar Two randomized trials were conducted comparing 400 mg of imatinib daily with 800 mg. Preplanned combination of results revealed a small but statistically significant progression-free survival (PFS) advantage with higher dose therapy (hazard ratio [HR] for progression, 0.89; 95% confidence interval [CI], 0.79–1.0), but similar OS and best response (51% vs 54%) at a median follow-up of 45 months. The presence of a KIT exon 9 mutation was the only significant predictive factor for benefit from higher doses. Among the patients with an exon 9 mutation, PFS (HR, 0.58; 95% CI, 0.38–0.91) and overall response rate (47% vs 21%) were significantly higher with high-dose therapy.27Gastrointestinal Stromal Tumor Meta-Analysis Group (MetaGIST)Comparison of two doses of imatinib for the treatment of unresectable or metastatic gastrointestinal stromal tumors: a meta-analysis of 1,640 patients.J Clin Oncol. 2010; 28: 1247-1253Crossref PubMed Scopus (391) Google Scholar The median TTP on first-line imatinib is approximately 2–2.5 years. Dose escalation may be considered in patients started on imatinib 400 mg daily who have clear evidence of progression. The efficacy of this approach was demonstrated in the European dose-finding study. Among 133 of the 247 patients assigned to low-dose therapy (imatinib 400 mg/d) who crossed over to imatinib 400 mg twice daily, 3 patients demonstrated partial responses and 36 patients had prolonged periods of stable disease.28Zalcberg J.R. Verweij J. Casali P.G. et al.Outcome of patients with advanced gastro-intestinal stromal tumours crossing over to a daily imatinib dose of 800 mg after progression on 400 mg.Eur J Cancer. 2005; 41: 1751-1757Abstract Full Text Full Text PDF PubMed Scopus (330) Google Scholar Similar results were also found in the American trial.29Blanke C.D. Rankin C. Demetri G.D. et al.Phase III randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the kit receptor tyrosine kinase: S0033.J Clin Oncol. 2008; 26: 626-632Crossref PubMed Scopus (857) Google Scholar Sunitinib (Sutent) is a second-generation, multitargeted tyrosine kinase inhibitor (TKI). The role of sunitinib in the second-line setting was established by an international phase III trial of that drug versus best supportive care for patients intolerant to or with imatinib-resistant GIST. This trial revealed highly statistically significant benefits in terms of response rate (7% vs 0%; P = .006), TTP (27 vs 6 weeks; P < .0001), and OS (HR, 0.49; P = .007).30Demetri G.D. van Oosterom A.T. Garrett C.R. et al.Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial.Lancet. 2006; 368: 1329-1338Abstract Full Text Full Text PDF PubMed Scopus (2135) Google Scholar Although the US-approved dose was 50 mg/d for 4 consecutive weeks followed by 2 weeks off, George et al31George S. Blay J.Y. Casali P.G. et al.Clinical evaluation of continuous daily dosing of sunitinib malate in patients with advanced gastrointestinal stromal tumour after imatinib failure.Eur J Cancer. 2009; 45: 1959-1968Abstract Full Text Full Text PDF PubMed Scopus (309) Google Scholar demonstrated that continuously daily dosing at 37.5 mg was similarly effective but more tolerable. For limited localized progression, directed therapies such as operative resection and radiofrequency ablation can be considered. Hepatic arterial embolization or chemoembolization are viable alternatives for patients with liver metastases who have failed to respond to imatinib therapy. Hepatic arterial embolization is also the treatment of choice for liver-related bleeding.32Avritscher R. Gupta S. Gastrointestinal stromal tumor: role of interventional radiology in diagnosis and treatment.Hematol Oncol Clin North Am. 2009; 23: 129-137Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar Assessment of response to therapy in patients undergoing treatment for GISTs can be quite challenging. Radiographically, GISTs may actually enlarge during early treatment secondary to cystic degeneration or intratumoral hemorrhage, and as a result, patients evaluated for response using Response Evaluation Criteria in Solid Tumors (RECIST) may be prematurely taken off TKI therapy that is actually working well. By contrast, an important early marker of true antitumor activity is a decrease in tumor density as observed on computed tomography (CT).33Bechtold R.E. Chen M.Y. Stanton C.A. et al.Cystic changes in hepatic and peritoneal metastases from gastrointestinal stromal tumors treated with Gleevec.Abdom Imaging. 2003; 28: 808-814Crossref PubMed Scopus (59) Google Scholar Similarly, RECIST may not reflect tumor progression. Tumor progression may present as change in size or density of a known target lesion; only the prior would be classified as tumor progression by RECIST.34Shankar S. vanSonnenberg E. Desai J. et al.Gastrointestinal stromal tumor: new nodule-within-a-mass pattern of recurrence after partial response to imatinib mesylate.Radiology. 2005; 235: 892-898Crossref PubMed Scopus (133) Google Scholar Investigators at the M.D. Anderson Cancer Center proposed a new set of response evaluation criteria in which tumor response is defined as a 10% decrease in unidimensional tumor size or a 15% decrease in tumor density on CT.35Choi H. Charnsangavej C. Faria S.C. et al.Correlation of computed tomography and positron emission tomography in patients with metastatic gastrointestinal stromal tumor treated at a single institution with imatinib mesylate: proposal of new computed tomography response criteria.J Clin Oncol. 2007; 25: 1753-1759Crossref PubMed Scopus (1208) Google Scholar In a study of 98 patients receiving imatinib for the treatment of advanced GIST, these MDACC criteria were found to correlate with both disease-specific survival and TTP.36Benjamin R.S. Choi H. Macapinlac H.A. et al.We should desist using RECIST, at least in GIST.J Clin Oncol. 2007; 25: 1760-1764Crossref PubMed Scopus (474) Google Scholar Biomarkers may also be useful in assessing clinical outcomes in advanced GIST patients treated with sunitinib malate after imatinib failure. Demetri et al37Demetri G.D. Heinrich M.C. Fletcher J.A. et al.Molecular target modulation, imaging, and clinical evaluation of gastrointestinal stromal tumor patients treated with sunitinib malate after imatinib failure.Clin Cancer Res. 2009; 15: 5902-5909Crossref PubMed Scopus (106) Google Scholar demonstrated in a phase I/II trial that a decline in fludeoxyglucose-18F (FDG) avidity on positron emission tomography (FDG-PET) within 7 days of starting sunitinib correlated with subsequent clinical benefit (partial responses, complete responses, stable disease) on CT or magnetic resonance imaging (MRI) scans at ≥6 months. Demetri et al37Demetri G.D. Heinrich M.C. Fletcher J.A. et al.Molecular target modulation, imaging, and clinical evaluation of gastrointestinal stromal tumor patients treated with sunitinib malate after imatinib failure.Clin Cancer Res. 2009; 15: 5902-5909Crossref PubMed Scopus (106) Google Scholar found that 28% of patients with initial responses on PET did not show disease control on later CT/MRI scans.37Demetri G.D. Heinrich M.C. Fletcher J.A. et al.Molecular target modulation, imaging, and clinical evaluation of gastrointestinal stromal tumor patients treated with sunitinib malate after imatinib failure.Clin Cancer Res. 2009; 15: 5902-5909Crossref PubMed Scopus (106) Google Scholar Clinical variables negatively associated with outcome in GISTs include performance status, high neutrophil count, male gender for both OS and PFS, small bowel origin, and low hemoglobin for PFS and advanced age, low albumin and large lesions for OS.27Gastrointestinal Stromal Tumor Meta-Analysis Group (MetaGIST)Comparison of two doses of imatinib for the treatment of unresectable or metastatic gastrointestinal stromal tumors: a meta-analysis of 1,640 patients.J Clin Oncol. 2010; 28: 1247-1253Crossref PubMed Scopus (391) Google Scholar, 38Debiec-Rychter M. Sciot R. Le Cesne A. et al.KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumours.Eur J Cancer. 2006; 42: 1093-1103Abstract Full Text Full Text PDF PubMed Scopus (745) Google Scholar Recent data suggest that clinical behavior of GISTs might also be predicted by gene expression. Yamaguchi et al39Yamaguchi U. Nakayama R. Honda K. et al.Distinct gene expression-defined classes of gastrointestinal stromal tumor.J Clin Oncol. 2008; 26: 4100-4108Crossref PubMed Scopus (101) Google Scholar analyzed 32 surgical samples of untreated stomach and small bowel GISTs using oligonucleotide microarrays. Results revealed that CD 26 (T-cell activation antigen) was strongly correlated with poorer survival.39Yamaguchi U. Nakayama R. Honda K. et al.Distinct gene expression-defined classes of gastrointestinal stromal tumor.J Clin Oncol. 2008; 26: 4100-4108Crossref PubMed Scopus (101) Google Scholar Henrich et al40Heinrich M.C. Owzar K. Corless C.L. et al.Correlation of kinase genotype and clinical outcome in the North American Intergroup Phase III Trial of imatinib mesylate for treatment of advanced gastrointestinal stromal tumor: CALGB 150105 Study by Cancer and Leukemia Group B and Southwest Oncology Group.J Clin Oncol. 2008; 26: 5360-5367Crossref PubMed Scopus (482) Google Scholar examined tumor samples from the S0033 trial, a phase III trial comparison of imatinib 400 versus 800 mg/d. They reported that patients with exon 11 mutations are more likely to respond to imatinib compared with those with KIT exon 9 mutations or the wild-type KIT genotype (72% vs 44% vs 45%, respectively). Furthermore, exon 11 patients also have improved TTP (24.7 vs 16.7 vs 12.8 months) and OS (60 vs 38 vs 49 months) compared with those with exon 9 mutations and wild-type KIT patients.40Heinrich M.C. Owzar K. Corless C.L. et al.Correlation of kinase genotype and clinical outcome in the North American Intergroup Phase III Trial of imatinib mesylate for treatment of advanced gastrointestinal stromal tumor: CALGB 150105 Study by Cancer and Leukemia Group B and Southwest Oncology Group.J Clin Oncol. 2008; 26: 5360-5367Crossref PubMed Scopus (482) Google Scholar Similar results were reported in the study performed by the EORTC.38Debiec-Rychter M. Sciot R. Le Cesne A. et al.KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumours.Eur J Cancer. 2006; 42: 1093-1103Abstract Full Text Full Text PDF PubMed Scopus (745) Google Scholar Meta-GIST reported a statistically significant PFS in the subset of patients with KIT exon 9 mutations who received imatinib 800 mg/d. However, this finding was only confirmed in the EORTC dataset, but not in the North American dataset, likely owing to a greater proportion of patients with KIT exon 9 mutations enrolled in the European study (15% of analyzed patients in the EORTC study versus 8% in the North American study).27Gastrointestinal Stromal Tumor Meta-Analysis Group (MetaGIST)Comparison of two doses of imatinib for the treatment of unresectable or metastatic gastrointestinal stromal tumors: a meta-analysis of 1,640 patients.J Clin Oncol. 2010; 28: 1247-1253Crossref PubMed Scopus (391) Google Scholar Henrich et al41Heinrich M.C. Maki R.G. Corless C.L. et al.Primary and secondary kinase genotypes correlate with the biological and clinical activity of sunitinib in imatinib-resistant gastrointestinal stromal tumor.J Clin Oncol. 2008; 26: 5352-5359Crossref PubMed Scopus (600) Google Scholar also studied the relationship between the KIT/PDGFRA genotype and sunitinib treatment outcomes by examining tumor tissue from 78 patients previously enrolled in a phase I/II study of sunitinib (after progression on or intolerance to imatinib). These results revealed that patients with KIT exon 9 mutations or wild-type KIT or PDGFRA genotype have longer PFS and OS in comparison with those with KIT exon 11 mutations.41Heinrich M.C. Maki R.G. Corless C.L. et al.Primary and secondary kinase genotypes correlate with the biological and clinical activity of sunitinib in imatinib-resistant gastrointestinal stromal tumor.J Clin Oncol. 2008; 26: 5352-5359Crossref PubMed Scopus (600) Google Scholar As a result, the KIT/PDGFRA genotype predicts clinical outcomes to both imatinib and sunitinib. Furthermore, it is also useful clinically to determine up-front imatinib dosing. In summary, KIT mutation analysis should be performed on all patients. Imatinib therapy should be initiated at 400 mg/d if the tumor has an exon-11 mutation, PDGFRA mutation, or wild-type KIT. For tumors with exon 9 mutation, imatinib therapy should be initiated at 400 mg/d with escalation to 800 mg/d if the lower dose is well-tolerated. Imatinib should be continued until disease progression. Multiple drugs with potential activity against GIST have been developed and tested in recent years. Nilotinib and dasatinib are second-generation TKIs that target BCR-ABL, KIT, and the PDGFR, with dasatinib also inhibiting SRC. Nilotinib demonstrated disease stabilization and some evidence of tumor shrinkage when administered as a single agent (400 mg twice daily) or in combination with imatinib (400 mg/d) to imatinib-resistant GIST patients in early testing.42Weisberg E. Manley P.W. Breitenstein W. et al.Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl.Cancer Cell. 2005; 7: 129-141Abstract Full Text Full Text PDF PubMed Scopus (1289) Google Scholar Dasatinib, which is predicted from preclinical studies to be effective in imatinib-resistant KIT mutations, has also demonstrated some activity in early human trials.43Schittenhelm M.M. Shiraga S. Schroeder A. et al.Dasatinib (BMS-354825), a dual SRC/ABL kinase inhibitor, inhibits the kinase activity of wild-type, juxtamembrane, and activation loop mutant KIT isoforms associated with human malignancies.Cancer Res. 2006; 66: 473-481Crossref PubMed Scopus (427) Google Scholar Sorafenib (Nexavar, BAY 43-9006), a multitargeted TKI with potent activity against B-RAF tyrosine kinase, VEGFR, PDGFR, KIT, and FLT3, has been investigated in a phase II study involving 23 patients with imatinib- and sunitinib-resistant GIST. Partial response was observed in 3 patients and another 15 patients achieved disease stabilization. An overall PFS of 22.2 weeks was reported.44Wiebe L. Kasza K.E. Maki R.G. et al.Activity of sorafenib (SOR) in patients (pts) with imatinib (IM) and sunitinib (SU)-resistant (RES) gastrointestinal stromal tumors (GIST): a phase II trial of the University of Chicago Phase II consortium.J Clin Oncol. 2008; 26: 553sGoogle Scholar Other similar drugs in clinical trials include AZD 2171, OSI-930, and XL-820. Heat shock proteins (HSP) help to maintain malignant pathways by stabilizing mutated proteins, including KIT and PDGFRA. Inhibition of HSP 90 destroys the activated KIT/PDGFRA, potentially leading to a therapeutic effect in GIST patients. An international phase III randomized, double-blind, placebo-controlled registration trial of IPI-504 (RING trial) in patients with metastatic and/or unresectable GIST after failure of at least imatinib and sunitinib was initiated in May 2008 by Infinity. However, the trial was terminated on April 15, 2009, on the recommendation of the early review of safety data from the first 46 patients enrolled in the study, which showed higher than anticipated mortality rate among patients in the treatment arm. Other drugs in this class remain in clinical testing. Flavopiridol is an inhibitor of cyclin-dependent kinase (CDK2 and CDK1). In preclinical studies, flavopiridol induced a high level of apoptosis in GIST cells, at clinically achievable doses.45Sambol E.B. Ambrosini G. Geha R.C. et al.Flavopiridol targets c-KIT transcription and induces apoptosis in gastrointestinal stromal tumor cells.Cancer Res. 2006; 66: 5858-5866Crossref PubMed Scopus (74) Google Scholar A phase I trial involving a combination of flavopiridol and doxorubicin is currently underway for sarcoma (including GIST). Other druggable targets potentially useful in treatment of GISTs are downstream from KIT and PDGFRA activation. These include AKT and mammalian target of rapamycin (mTOR). AKT inhibitors are in phase II trials (usually in combination with other drugs) and at least 3 mTOR inhibitors, have undergone evaluation.46Schoffski P. Reichardt P. et al.A phase I-II study of everolimus (RAD001) in combination with imatinib in patients with imatinib-resistant gastrointestinal stromal tumors.Ann Oncol. 2010; 21: 1990-1998Crossref PubMed Scopus (100) Google Scholar, 47A Service of the US National Institutes of Health.http://clinicaltrials.gov/ct2/show/NCT00402415?term=sirolimus+AND+GIST&rank=2Google Scholar, 48A Service of the US National Institutes of Health.http://clinicaltrials.gov/ct2/show/NCT00087074?term=CCI-779+AND+gist&rank=1Google Scholar Although significant work has been done in GISTs over the past few years and advances have occurred, many questions remain unanswered. Despite the fact that most GISTS initially demonstrate response to imatinib, development of resistance over time is common. Currently, sunitinib is the only standard targeted therapy available in imatinib-refractory GISTs off study. Therefore, an urgent need for new drugs exists. GISTs remain a relatively rare disease. It may be difficult to accrue an adequate number of patients to clinical trials. Therefore, collaborations among medical centers across the world are crucial to test novel therapeutics.