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Keywords:

  • gastrointestinal stromal tumor (GIST);
  • KIT gene;
  • imatinib mesylate;
  • surgery;
  • review

Abstract

  1. Top of page
  2. Abstract
  3. Epidemiology
  4. Diagnosis
  5. Pathogenesis
  6. Imatinib Mesylate
  7. Treatment of Primary Disease
  8. Treatment of Metastatic Disease
  9. Evolving Biologic Advances in GIST
  10. Conclusions
  11. REFERENCES

There is now considerable interest in gastrointestinal stromal tumor (GIST) because it can be treated effectively with a targeted molecular agent. The majority of GISTs contain an activating mutation in the KIT protooncogene or, occasionally, in the platelet-derived growth factor-α (PDGFRA) gene. Five years ago, imatinib mesylate, a specific molecular inhibitor of the protein products of these 2 genes, was applied to metastatic GIST. Approximately 80% of patients with metastatic GIST benefit from imatinib, although acquired resistance to the agent may develop. For patients with primary GIST, surgery remains the treatment of choice, and whether outcome is improved by adjuvant imatinib is currently under broad investigation. A combination of imatinib therapy and surgery also may be effective in a subset of patients with metastatic or unresectable primary GIST. In this review, the authors summarize the new multimodality approach to GIST. The integration of surgery and molecular therapy in GIST will serve as a prototype for the management of other solid tumors for which targeted agents become available. Cancer 2005. © 2005 American Cancer Society.

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract. GIST is believed to originate from the interstitial cell of Cajal, an intestinal pacemaker cell.1 A recent study found an incidence of approximately 14.5 cases per million in Sweden, which suggests an annual U.S. incidence of 4000–5000.2 The exact incidence in the U.S. is difficult to determine because GIST has only recently become recognized as a distinct pathologic entity. Previously, it was confused with intestinal leiomyosarcoma, because both have a similar appearance by light microscopy. An immunohistochemical marker (CD117) for the KIT protein has greatly assisted pathologists in distinguishing GISTs from other spindle cell neoplasms of the gastrointestinal tract. Consequently, we now know that true leiomyomas and leiomyosarcomas of the gastrointestinal tract are rare. GIST has attracted widespread interest because the principal genetic mutation responsible for the pathogenesis of GIST has been identified to be a gain-of-function mutation in the c-KIT (KIT) protooncogene or, on occasion, in the platelet-derived growth factor-α (PDGFRA) gene. Moreover, a specific molecular inhibitor against these defects has been developed. Imatinib mesylate (STI571, Gleevec; Novartis Pharmaceuticals, Basel Switzerland) is a molecular inhibitor of the KIT and PDGFRA proteins.

Epidemiology

  1. Top of page
  2. Abstract
  3. Epidemiology
  4. Diagnosis
  5. Pathogenesis
  6. Imatinib Mesylate
  7. Treatment of Primary Disease
  8. Treatment of Metastatic Disease
  9. Evolving Biologic Advances in GIST
  10. Conclusions
  11. REFERENCES

GIST affects men slightly more often than women. At the time of diagnosis, the majority of patients are ages 40–80 years with a median age of 60 years.2, 3 Approximately 60% of the tumors occur in the stomach, 30% in the small intestine, 5% in the colon and rectum, and 5% in the esophagus. On rare occasions, GIST develops outside of the gastrointestinal tract in the mesentery, omentum, or retroperitoneum.

There is a broad range of patient presentation in GIST. Small GISTs (measuring less than 2 cm) usually do not produce symptoms and are detected incidentally on endoscopy, radiologic imaging, or abdominal exploration. Similar to other sarcomas, GISTs tend to displace adjacent structures without invading them. Therefore, they can become quite large before causing symptoms. Most patients present with nonspecific symptoms such as nausea, emesis, abdominal discomfort, pain, or increased abdominal girth. Often, a GIST may erode into the lumen of the intestinal tract and produce gastrointestinal bleeding. Infrequently, it may rupture into the peritoneal cavity and cause life-threatening intraperitoneal hemorrhage. Other symptoms are particular to the site of tumor origin. A recent population-based study demonstrated that approximately 70% of GISTs were associated with symptoms, 20% were not, and 10% were detected at autopsy.2 The median tumor size for each of these categories was 8.9 cm, 2.7 cm, and 3.4 cm, respectively.

Diagnosis

  1. Top of page
  2. Abstract
  3. Epidemiology
  4. Diagnosis
  5. Pathogenesis
  6. Imatinib Mesylate
  7. Treatment of Primary Disease
  8. Treatment of Metastatic Disease
  9. Evolving Biologic Advances in GIST
  10. Conclusions
  11. REFERENCES

GIST is frequently diagnosed only after the pathologic examination of a resected specimen, because most physicians have little experience recognizing this tumor. Abdominal computed tomography (CT) scanning is useful to evaluate the primary tumor as well as to detect metastases. Typically, primary GIST is a well circumscribed and highly vascular tumor arising from the stomach or elsewhere in the gastrointestinal tract and growing in an extraluminal manner. Large tumors may have a necrotic center. GIST also can be detected as a submucosal mass during endoscopy. Endoscopic ultrasound may be useful to determine the extent of a small tumor. GIST usually demonstrates intense uptake on18 fluorodeoxyglucose-positron emission tomography (18FDG-PET) scanning, as do many other intraabdominal malignancies.

Because of the risk of tumor rupture, which may lead to tumor dissemination and hemorrhage, the routine use of preoperative biopsy is controversial. In addition, most pathologists cannot reliably render a diagnosis of GIST from a percutaneous biopsy, especially when only a fine-needle aspirate is obtained or a necrotic portion of the tumor is sampled. We generally avoid preoperative biopsy of a primary GIST, unless there is a possibility that the diagnosis may be lymphoma or when neoadjuvant therapy is desirable.

GIST has 3 microscopic morphologies: spindle cell type (70%), epithelioid type (20%), or a combination of these 2 morphologies.4 Spindle cell GISTs are usually comprised of relatively uniform eosinophilic cells in short fascicles or whorls. The epithelioid subtype is comprised of rounded cells with variably eosinophilic or clear cytoplasm. On immunohistochemistry, in contrast to true smooth muscle tumors, GISTs are positive for expression of the KIT receptor tyrosine kinase (CD117 antigen) in 95% of cases. Otherwise, approximately 60–70% of GISTs stain for CD34, 30–40% react to antismooth muscle actin (SMA), and approximately 5% demonstrate immunopositivity for S-100 protein.4

Extensive retrospective analyses have been performed to identify factors that determine the risk of GIST metastasis. The general consensus is that mitotic rate, tumor size, and tumor site are the most important predictors, although to our knowledge prospective data are lacking.5 Gastric GIST tends to have a more favorable outcome than GIST of the small intestine. Gastric GIST is considered to be low risk when measuring < 5 cm with fewer than 5 mitoses (per 50 high-power fields) and intermediate risk when measuring 5–10 cm with fewer than 5 mitoses. Intestinal GIST is believed to be low risk when measuring < 2 cm with fewer than 5 mitoses and intermediate risk when measuring 2–5 cm with fewer than 5 mitoses. All GISTs should be considered to have malignant potential, with the possible exception of very small tumors (tumors measuring < 1 cm).

Pathogenesis

  1. Top of page
  2. Abstract
  3. Epidemiology
  4. Diagnosis
  5. Pathogenesis
  6. Imatinib Mesylate
  7. Treatment of Primary Disease
  8. Treatment of Metastatic Disease
  9. Evolving Biologic Advances in GIST
  10. Conclusions
  11. REFERENCES

The KIT protooncogene encodes for KIT protein, a transmembrane glycoprotein. KIT protein is expressed by the interstitial cells of Cajal (from which GISTs are believed to derive), hematopoietic cells, mast cells, and germ cells. The natural ligand for KIT has multiple names including KIT ligand, stem cell factor, steel factor, and mast cell growth factor. KIT functions in differentiation, cell growth, and survival. Binding of the KIT ligand induces dimerization and autophosphorylation of KIT, which initiates a cascade of intracellular signaling involved in tumorigenesis, including proliferation, adhesion, and differentiation. In GIST, a gain-of-function mutation often occurs in KIT, resulting in ligand-independent activation of its tyrosine kinase function.6KIT mutation has been shown to be sufficient to induce GIST in a transgenic mouse model.7KIT mutation occurs in up to 90% of GISTs.8 The most frequent sites of mutation are in exon 11 (70% of GISTs) or exon 9 (10% of GISTs), whereas exons 13 or 17 rarely are involved.8–11 Approximately 3% of all GISTs have been shown instead to have a mutation in the related receptor tyrosine kinase PDGFRA.12 Approximately 10% of patients do not have a detectable mutation in either KIT or PDGFRA. At the chromosomal level, several abnormalities have been identified in GIST, including early loss of chromosomes 14p and 22q.13–15

Imatinib Mesylate

  1. Top of page
  2. Abstract
  3. Epidemiology
  4. Diagnosis
  5. Pathogenesis
  6. Imatinib Mesylate
  7. Treatment of Primary Disease
  8. Treatment of Metastatic Disease
  9. Evolving Biologic Advances in GIST
  10. Conclusions
  11. REFERENCES

The development of imatinib mesylate has revolutionized the treatment of GIST. Imatinib selectively inhibits specific tyrosine kinases, including KIT, ABL, BCR-ABL, and platelet-derived growth factor receptor (PDGFR). Imatinib initially was developed as a PDGFR inhibitor. Imatinib was first used in patients with chronic myeloid leukemia (CML), which is characterized by a balanced translocation between chromosomes 9 and 22. The resulting Philadelphia chromosome produces the BCR-ABL fusion protein, which has uncontrolled tyrosine kinase activity. Imatinib has been found to induce a complete response in nearly all patients in the chronic phase of CML.16

The first patient with metastatic GIST began treatment with imatinib in 2000, after failing several other therapies. The patient achieved a major objective radiologic response and18FDG-PET activity virtually disappeared.17 The remarkable response noted in the first patient prompted several clinical trials. It now is apparent that up to 80% of patients with metastatic GIST achieve a partial response or stable disease while receiving imatinib. The toxicities of imatinib are usually controllable and include edema, rash, diarrhea, nausea, abdominal pain, and fatigue.

Treatment of Primary Disease

  1. Top of page
  2. Abstract
  3. Epidemiology
  4. Diagnosis
  5. Pathogenesis
  6. Imatinib Mesylate
  7. Treatment of Primary Disease
  8. Treatment of Metastatic Disease
  9. Evolving Biologic Advances in GIST
  10. Conclusions
  11. REFERENCES

The standard therapy for primary GIST remains complete surgical resection (Fig. 1). In general, only a segmental resection of the organ in which the tumor originates is necessary. When GIST adheres to contiguous organs, consideration should be given to an en bloc resection. There is no apparent benefit to obtaining wider surgical margins. Every effort should be made to achieve negative resection margins, although the importance of negative surgical margins is uncertain for GISTs measuring > 10 cm, which may shed tumor cells into the peritoneum from anywhere along their surface. Because GISTs are soft and fragile, meticulous surgical technique is necessary to avoid tumor rupture, which increases the risk of peritoneal recurrence. Lymphadenectomy generally is not indicated unless the regional lymph nodes are enlarged because GIST rarely metastasizes to the lymph nodes. A thorough abdominal exploration should be performed to evaluate for early metastasis to the liver or peritoneum. Complete resection is accomplished in approximately 85% of patients with primary disease.3 Nevertheless, tumor recurrence is common and the 5-year survival after removal of primary localized GIST is approximately 50%.3, 18 It should be noted that to our knowledge there are no prospective data regarding the outcome of patients with primary GIST.

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Figure 1. Treatment algorithm for patients with primary or recurrent gastrointestinal stromal tumor. Postop: postoperative.

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The use of adjuvant imatinib after complete resection of primary GIST is currently being evaluated (Table 1). The American College of Surgeons Oncology Group (ACOSOG) is leading a Phase II intergroup trial sponsored by the Cancer Therapy Evaluation Program (CTEP) and Novartis testing the value of adjuvant imatinib given at a dose of 400 mg/day for 12 months after complete macroscopic surgical resection in patients with high-risk primary GIST. High risk is defined as a tumor size ≥10 cm, intraperitoneal tumor rupture or hemorrhage, or multifocal (< 5) tumors. Survival in this study will be compared with that of historical controls. The trial completed accrual in 2003 and the patients currently are being followed for overall survival. The initial data from this trial have shown that imatinib is well tolerated in the adjuvant setting. There were no CTC Grade 4 or Grade 5 toxicities reported, 18% of patients had Grade 3 adverse events, and 83% of the patients completed the 12 months of imatinib therapy.19 In addition, a Phase III ACOSOG intergroup trial is open for patients with tumors measuring at least 3 cm (Fig. 2). It is a randomized, double-blinded trial in which patients receive imatinib (400 mg/day) or placebo for 1 year after undergoing complete resection of their primary GIST. Patients assigned to the placebo arm will cross over to imatinib therapy in the event of tumor recurrence. The primary endpoint is recurrence-free survival between the two arms. There currently are two other adjuvant trials ongoing in Europe. A preoperative (neoadjuvant) Phase II trial for primary GIST is also in progress and is being led by the Radiation Therapy Oncology Group (RTOG). Neoadjuvant therapy is particularly attractive for patients with large or poorly placed tumors that are marginally resectable or tumors that would require extensive sacrifice of normal tissue. For instance, neoadjuvant imatinib may convert the resection of a rectal GIST from an abdominoperineal resection to a low anterior resection. It should be noted that positive KIT staining on immunohistochemistry is an inclusion criterion for all these trials

Table 1. Clinical Trials Testing Adjuvant or Neoadjuvant Imatinib and Surgery for Primary GIST
Group/TrialDiseaseImatinib therapyEligibilityDoseAccruala
  • GIST: gastrointestinal stomal tumor; ACOSOG:- American College of Surgeons Oncology Group; SSG: Scandinavian Sarcoma Group; mets: metastases; Mit rate: mitotic rate expressed per 50 high-power fields; EORTC - European Organization for the Research and Treatment of Cancer; RTOG:- Radiation Treatment Oncology Group; preop: preoperatively; postop: postoperatively.

  • a

    As of March 2005.

  • b

    Accrual completed.

  • c

    Study just initiated.

ACOSOG Z9000PrimaryAdjuvantAny of the following:400 mg/day × 12 mos; open label106/89b
    Tumor ≥ 10 cm  
    Rupture/hemorrhage  
    Multifocal tumors (< 5)  
   Complete macroscopic resection  
ACOSOG Z9001PrimaryAdjuvantTumor ≥ 3 cm400 mg/d versus placebo × 1 yr; double-blind320/672
   Complete macroscopic resection  
SSG XVIIIPrimary ± metsAdjuvantAny of the following:400mg/d × 12 or 36 mos; open label65/240
    Tumor ≥ 10 cm  
    Mitotic rate > 10  
    Tumor > 5 cm and mitotic rate > 5  
    Tumor rupture  
    Primary tumor plus liver/peritoneal mets  
   Complete macroscopic resection  
EORTC 62024PrimaryAdjuvantAny of the following:400 mg/day vs. no treatment × 2 years open label*c/400
    Tumor > 5 cm  
    Mitotic rate >10  
    Tumor < 5 cm and mitotic rate 6–10  
   Complete macroscopic resection  
RTOG S0132AnyNeoadjuvantEither of the following:600 mg/day × 8–10 wks preop and 600 mg/day × 24 mos postop; open label44/63
    Primary tumor ≥ 5 cm 
    Recurrent tumor ≥ 2 cm  
    Potentially resectable  
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Figure 2. Phase III American College of Surgeons Oncology Group(ACOSOG) Z9001 intergroup trial testing adjuvant imatinib mesylate after surgical resection of primary gastrointestinal stromal tumor (GIST).

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There is no standard postoperative follow-up in patients who undergo surgical resection of a primary GIST. In fact, there is no proof that the earlier detection of recurrent GIST improves survival. However, because there is now an effective treatment for patients with recurrent or metastatic disease, it appears reasonable to perform routine postoperative surveillance. The National Comprehensive Cancer Network (NCCN) consensus panel recommends CT scans of the abdomen and pelvis with intravenous contrast every 3–6 months during the first 3–5 years and possibly yearly thereafter (available at URL: www.NCCN.com [accessed May 1, 2005]).

Treatment of Metastatic Disease

  1. Top of page
  2. Abstract
  3. Epidemiology
  4. Diagnosis
  5. Pathogenesis
  6. Imatinib Mesylate
  7. Treatment of Primary Disease
  8. Treatment of Metastatic Disease
  9. Evolving Biologic Advances in GIST
  10. Conclusions
  11. REFERENCES

The majority of patients will experience tumor recurrence despite undergoing complete resection of their primary tumor.3, 20 The median time to recurrence after surgery is reported to range from 18–24 months. The first site of recurrence of GIST is usually within the abdomen and involves the peritoneum and/or the liver. Peritoneal tumors tend to sit on the intestine, mesentery, omentum, or undersurface of the abdominal wall. At the time of disease recurrence, approximately two-thirds of patients have liver involvement and half have peritoneal disease.3 Extraabdominal metastases (e.g., lung or bone) may develop later in the course of the disease.

Surgery by itself has limited efficacy in recurrent GIST. Removal of peritoneal metastases is usually followed by subsequent recurrence. Typically, peritoneal disease is found to be more extensive than shown on preoperative imaging. Liver metastases from GIST are usually multifocal but approximately 26% of patients have resectable disease.21 However, essentially all patients will develop a subsequent recurrence after hepatectomy. Conventional chemotherapy is also of minimal value because the response rate is only approximately 5%.22

The first-line treatment of metastatic GIST is now imatinib (Fig. 1). Of course, there are exceptions. Patients who have primary GIST with synchronous, low-volume metastatic disease may be considered for surgical resection first, especially if they are symptomatic. Imatinib is reported to produce a partial tumor response in 45% of patients and stable disease in approximately 30% (Table 2).23–27 Remarkably, the 2-year survival of patients with metastatic disease is now reported to be approximately 70%.27 By contrast, before the introduction of imatinib, the median survival after surgical resection of recurrent GIST was only 15 months.28 The optimal dose of imatinib therapy has not been determined to date, but 400 mg daily is considered the standard starting dose. Randomized studies have demonstrated no difference in response induction between 400 mg given once a day versus twice a day; however, 1 study suggests a longer progression-free survival at the higher dose.26, 27 There is clearly more toxicity at the higher dose. Little is known regarding the effect of imatinib on c-KIT KIT-negative GIST, which comprises approximately 5% of all GIST cases, but there appears to be clinical benefit.29

Table 2. Results of Imatinib Therapy for Metastatic GIST
TrialPhaseNo. of patientsDose in (mg/day)Follow-upBest response (%)
CRPRSDPDPFS
  1. GIST: gastrointestinal stomal tumor; CR: complete response; PR: partial response; SD: stable disease; PD: progressive disease; PFS: progression-free survival; EORTC: European Organization for the Research and Treatment of Cancer; NR: no response.

EORTC25I35400–1000> 10 mosNR5131882
U.S. multicenter23II7340021 mosNR66171765
  74600      
EORTC27III47040025 mos5%45321356
  472800 6%4832950
U.S. Intergroup26III36140014NR4332NR80
  360800mos 4132 82

CT is the preferred method to follow response in GIST. However, tumor size alone is an unreliable indicator of the efficacy of imatinib. A better marker of treatment response is tumor density.30 Tumors that respond often change in appearance from hypervascular to hypoattenuating and homogeneous (Fig. 3). Therapeutic response to imatinib also can be observed within a few days of the initiation of therapy by using serial18FDG-PET scans, which demonstrate diminished uptake.

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Figure 3. Acquired resistance to imatinib after initial response in a patient with gastrointestinal stromal tumor metastases to the liver. The patient had multiple liver metastases that responded to imatinib therapy. The response could be observed at 6 months on computed tomography scan through the reduction in contrast enhancement. The treated tumors became largely hypodense, but there was a small nodule (solid arrow) that represented residual tumor. After 10 months of therapy, the amount of viable tumor increased (solid arrow) and the tumor now extended down the right hepatic vein (open arrow).

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The value of combining surgery and imatinib therapy for patients with metastatic GIST is unclear (Fig. 1). The rationale to resect metastatic GIST in conjunction with imatinib therapy is that the agent rarely induces a complete response and the median time to disease progression with imatinib therapy is 2 years.27 We propose that the likelihood of developing imatinib resistance is proportional to the amount of residual viable GIST. Therefore, once maximal response to imatinib occurs (generally after 2–6 mos of therapy), we evaluate patients for complete surgical resection. Imatinib therapy is continued postoperatively to delay or prevent subsequent disease recurrence, although the optimal duration of therapy is unknown. A recent study showed an increase in the rate of progressive disease when imatinib was interrupted.31 Alternatives to surgery for residual GIST liver metastases include radiofrequency ablation and hepatic artery embolization.

In patients who develop focal resistance to imatinib (i.e., one specific tumor begins to grow again), surgery should be considered, although the benefit is unknown. There is general agreement that multifocal resistance to imatinib should be treated with another targeted agent such as SU11248 (Pfizer, New York, NY), which has activity against KIT and PDGFRA as well as the vascular endothelial cell growth factor (VEGF) and fms-related tyrosine kinase 3 (Flt3) receptors. In 48 patients who were treated with SU11248 after disease progression with imatinib therapy, there were 20 patients with stable disease and 6 who achieved a partial response.32 Other agents in clinical trials include the multikinase inhibitor AMG706 (Amgen, Inc., Thousand Oaks, CA), the mTOR inhibitor RAD001 (Novartis) in combination with imatinib, and the protein kinase C inhibitor PKC412 (Novartis) in combination with imatinib. The combination of imatinib and other new agents such as bevacizumab (Genentech, Inc., South San Francisco, CA) also is attractive. Dose escalation of imatinib also may be attempted because it temporizes disease progression in some patients.

Evolving Biologic Advances in GIST

  1. Top of page
  2. Abstract
  3. Epidemiology
  4. Diagnosis
  5. Pathogenesis
  6. Imatinib Mesylate
  7. Treatment of Primary Disease
  8. Treatment of Metastatic Disease
  9. Evolving Biologic Advances in GIST
  10. Conclusions
  11. REFERENCES

A greater understanding of the biology of GIST and how it interacts with imatinib will provide the rationale for the design of additional therapeutic strategies in GIST. A few fundamental correlative questions are addressed below.

Does the type of KIT mutation predict the response to imatinib?

Several studies have shown that the type of mutation in GIST correlates with the clinical outcome after imatinib therapy.33, 34 In 324 patients with advanced GIST on the U.S. Phase III trial of a 400-mg dose versus a 800-mg dose of imatinib per day, 86% were found to have an activating mutation of KIT whereas 1% had a PDGFRA mutation.35 It is interesting to note that patients with a KIT mutation in exon 11 had the best outcome, with an objective response rate of 67%. In contrast, patients with an exon 9 mutation had a 40% response rate and those without a kinase (KIT or PDGFRA) mutation were found to have a 39% response rate. Accordingly, patients with an exon 11 mutation had a significantly longer median time to treatment failure (576 days) compared with those with an exon 9 mutation (308 days) or no detectable kinase mutation (251 days).

Can the gene expression profile of a particular GIST predict its clinical behavior and response to therapy?

GISTs have a homogeneous gene expression profile that distinguishes them as a group from other sarcomas.36–38 Nevertheless, there is considerable transcriptional heterogeneity when comparing different GISTs.39 Gene expression in GIST depends on KIT genotype and tumor location. Genes involved in KIT signaling are differentially expressed among wild-type and mutant GISTs and there is a striking difference in gene expression between gastric and small bowel GISTs. Similarly, the gene expression profile is distinct between GISTs with KIT or PDGFRA mutations.40 These findings may explain the variable clinical behavior and response to therapy, but currently do not have an impact on clinical management.

What are the underlying mechanisms that mediate tumor resistance to imatinib?

A minority (< 15%) of patients have primary (i.e., immediate) resistance to imatinib. Patients who initially respond or achieve stable disease with imatinib therapy may subsequently acquire resistance (Fig. 3), typically after more than 1 year of therapy. The mechanism of acquired resistance to imatinib in patients with GIST has been reported by several groups and is often due to secondary KIT mutation (Table 3).41–44 This is consistent with the predominant mechanism of imatinib resistance in CML, which has been shown to be due to second-site mutation in BCR-ABL.45, 46 It is interesting to note that many of the secondary mutations in GIST occur at novel sites of mutation in exons 13, 14, and 17. Recently, one patient was found to have acquired four different secondary exon 17 mutations in four different tumors while another patient acquired three secondary mutations (exons 13, 14, and 17) in three separate tumors.47

Table 3. Secondary Mutations in Patients with Acquired Resistance to Imatinib
SeriesNo. of patients2nd mutationExon 13Exon 14Exon 17PDGFRAKIT amplification
  • a

    Novel mutations that have not been reported as primary mutations in gastrointestinal stromal tumor.

  • b

    The study included one patient with primary resistance. There also was one patient with a D716N mutation, which has not been previously reported in gastrointestinal stromal tumor.

  • c

    One patient had both KIT and PDGFR amplification.

  • d

    This patient later was found to have a D822K mutation in a subsequent recurrence.

Fletcher et al., 200341134 (31%)    2/13 (15%)
Chen et al., 20044255 (100%)5 V654Aa   0/5
Debiec-Rychter et al., 20054326b13 (50%)4 V654Aa3 T670Ia1 D816Ga1 D842V2/26 (8%)c
     1 D820Y  
     1 D820Ea  
     1 N822K  
Antonescu et al., 200544157 (46%)1 V654Aad1 T6701a3 N822K 0/4
     2 D820Y  
     1 Y823D  

Conclusions

  1. Top of page
  2. Abstract
  3. Epidemiology
  4. Diagnosis
  5. Pathogenesis
  6. Imatinib Mesylate
  7. Treatment of Primary Disease
  8. Treatment of Metastatic Disease
  9. Evolving Biologic Advances in GIST
  10. Conclusions
  11. REFERENCES

The development of imatinib heralds the era of targeted cancer therapy. Since the application of imatinib to the treatment of GIST 5 years ago, patient outcomes have improved dramatically. Further advances will result from a better understanding of imatinib resistance and the development of second-line tyrosine kinase inhibitors or the use of other biologic agents. Furthermore, the integration of surgery and targeted therapy may reduce the development of GIST recurrence or decrease the risk of disease progression in patients with metastatic disease. Although uncommon, GIST now serves as a paradigm for the multimodality management of other solid malignancies.

REFERENCES

  1. Top of page
  2. Abstract
  3. Epidemiology
  4. Diagnosis
  5. Pathogenesis
  6. Imatinib Mesylate
  7. Treatment of Primary Disease
  8. Treatment of Metastatic Disease
  9. Evolving Biologic Advances in GIST
  10. Conclusions
  11. REFERENCES
  • 1
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  • 18
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  • 19
    DeMatteo RP, Antonescu CR, Chadaram V, et al. Adjuvant imatinib mesylate in patients with primary high risk gastrointestinal stromal tumor (GIST) following complete resection: safety results from the U.S. Intergroup Phase II trial ACOSOG Z9000 [abstract 9009]. Proc Am Soc Clin Oncol. 2005; 23: 818S.
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