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Recent advances and novel agents for gastrointestinal stromal tumor (GIST).

ABSTRACT: The discovery of CD117 mutation in almost all gastrointestinal stromal tumors (GISTs) marked a milestone. Other spindle cell neoplasms arising from the GI tract including lipoma, schwannoma, hemangioma, leiomyoma, and leiomyosarcoma are typically CD117-negative. GIST research and clinical care now represent a paradigm of translating discoveries in the molecular pathogenesis of cancer into highly effective targeted therapies that selectively inhibit etiologic "driver" pathways, leading to dramatically improved clinical outcomes. A series of investigations and trials are underway to develop novel and effective ways to treat patients with GIST. In this review, we discuss the highlights of recent advances and novel agents for GIST therapy.

SUBMITTER: Lamba G

PROVIDER: S-EPMC3405472 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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Recent advances and novel agents for gastrointestinal stromal tumor (GIST).

Lamba Gurpreet G Ambrale Samir S Lee Byung B Gupta Ridhi R Rafiyath Shamudheen M SM Liu Delong D

Journal of hematology & oncology 20120508

The discovery of CD117 mutation in almost all gastrointestinal stromal tumors (GISTs) marked a milestone. Other spindle cell neoplasms arising from the GI tract including lipoma, schwannoma, hemangioma, leiomyoma, and leiomyosarcoma are typically CD117-negative. GIST research and clinical care now represent a paradigm of translating discoveries in the molecular pathogenesis of cancer into highly effective targeted therapies that selectively inhibit etiologic "driver" pathways, leading to dramati ...[more]

PMID: 22569033

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Project description:Introduction: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasm of the gastrointestinal (GI) system. Most GISTs originate from the interstitial cells of Cajal (ICC), the pacemaker cell situated between the circular and longitudinal layers of the muscularis propria along the GI tract. In this population-based study using the SEER database, we sought to identify demographic, clinical, and pathologic factors that affect the prognosis and survival of patients with this neoplasm. Molecular genetic advances, current management guidelines, and advances in targeted therapy are discussed. Methods: Demographic and clinical data from GIST patients were retrieved from the SEER research plus database for the period 2000−2018. Statistical analysis was performed with IBM SPSS® v20.2 software using the Chi-square test, paired t-test, multivariate analysis, and Kaplan−Meier functions. Results: A total of 10,833 patients with GIST were identified. Most patients were between 60−74 years of age: 40%, Caucasian: 68%, and the male to female ratio was 1.1:1. The most common primary tumor sites were stomach: 63%, small intestine: 30%, rectum: 3%, and esophagus: 0.7%. When reported, the grade of differentiation was well: 38%, moderately: 32%, undifferentiated: 19%, poorly: 12%. The size of most tumors ranged between 6−10 cm: 36% and they were treated by surgical intervention: 82% and/or chemotherapy/targeted therapy: 39%. The stage was localized: 66%, advanced: 19%, and regional: 15%. The 5-year survival was 74% (95% confidence interval (95% CI) = 72.6−74.7), and the 5-year cause-specific survival 82% (95% CI = 80.7−82.6). The 5-year cause-specific survival by treatment included surgery at 86% (95% CI = 85.4−87.3), chemotherapy/targeted therapy with or without surgery at 77% (95% CI = 75.7−78.9), and radiation at 75% (95% CI = 74.5−80). On multivariable analysis tumor size > 5 cm, poorly and undifferentiated grade, age > 60, and distant metastases at presentation were associated with worse overall survival. Conclusion: GISTs comprise 1−2% of malignancies of the GI tract, usually affect male Caucasians between the ages of 60 and 74 years, most tumors occur in the stomach and small intestine, and are usually >5 cm, but still localized, at the time of diagnosis. Most tumors receive multimodality surgical and chemotherapy/targeted therapy treatment, with a 5-year overall survival of 74% and cause-specific survival of 82%. GIST patients would benefit from enrollment in large clinical trials to establish better therapy guidelines for unresectable, treatment-refractory, and recurrent tumors.

Project description:BackgroundGastrointestinal stromal tumor (GIST) is the most common primary mesenchymal neoplasm of the gastrointestinal tract. Mutations of KIT and platelet-derived growth factor receptor alpha have been well characterized in GISTs. Patients with KIT mutations are generally sensitive to treatment with tyrosine kinase inhibitors. However, some patients with GIST, while initially sensitive to TKIs, gain resistance in later stages of treatment. Heterologous rhabdomyomsarcomatous dedifferentiation of advanced GISTs after long-term imatinib mesylate (IM) therapy has been reported. In these cases, the underlying molecular mechanism of tumor progression and transformation is unclear.Case presentationWe report one such patient with rhabdomyosarcomatous dedifferentiation of a GIST without metastatic disease after brief 3-month therapy with IM. The tumor was composed of two distinct phenotypes, a CD117 negative region with rhabdomyosarcomatous differentiation directly adjacent to a CD117 positive classic GIST region. Molecular analysis identified the activating KIT exon 11 mutation in both regions, indicating a common origin for both phenotypes. Additionally, the dedifferentiated component contained two synonymous variants in platelet-derived growth factor receptor alpha and KIT. The increased number of synonymous variants in the rhabdomyosarcomatous region may reflect increased genetic instability of this tumor that may have resulted in the loss of CD117 expression in the dedifferentiated component.ConclusionThis study adds to the growing consensus that rhabdomyosarcomatous GIST progresses from a common GIST primary tumor. The role of IM in this progression is uncertain; however short duration of IM treatment in this study supports the hypothesis that rhabdomyosarcomatous GIST progression is not a consequence of IM therapy. Furthermore, we provide additional information supporting the observation that CD117 negative rhabdomyosarcomatous transformation maintains the activating KIT variant without KIT expression.

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Recent advances and novel agents for gastrointestinal stromal tumor (GIST).

Publications

Recent advances and novel agents for gastrointestinal stromal tumor (GIST).

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