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Gastrointestinal Stromal Tumors: From Molecular Pathogenesis to Therapy
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
Joaquina Baranda, Stafinur Atay, Andrew K. Godwin
Gastrointestinal stromal tumors (GISTs), the archetypal and commonest mesenchymal neoplasms of the digestive tract, occur most regularly in the stomach (60%) and small bowel (25%) but may occur at sites in the gut or even elsewhere in the abdomen [1–3]. They classically manifest in older adults as single, well-circumscribed masses that are composed (in decreasing frequency) of spindle cell histology, epithelioid histology or a combination of those types. GISTs demonstrate widely ranging clinical behavior, which currently may be predicted by a risk stratification system that combines their location as well as two morphologic features, their size and mitotic rate [3]. Typically, small GISTs (2 cm or less) with low mitotic counts behave very indolently while larger mitotically active GISTs may act more aggressively. In the latter scenario, they may metastasize, usually to the abdominal cavity and liver and can even be fatal.
Metastatic Gastrointestinal Stromal Tumor with Bleeding
Published in Savio George Barreto, Shailesh V. Shrikhande, Dilemmas in Abdominal Surgery, 2020
Inian Samarasam, K. Senthilnathan
Gastrointestinal stromal tumors are more common in males and are encountered in the fourth or fifth decades of life. These tumors are commonly asymptomatic but clinical presentation of these gastrointestinal stromal tumors may range from indolent vague abdominal pain, chronic anemia, palpable abdominal masses, and dysphagia. Abdominal pain and intestinal bleeding are the most common clinical presentations in symptomatic patients [2].
Familial Gastrointestinal Stromal Tumor Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Gastrointestinal stromal tumor (GIST) is a relatively uncommon malignancy of the gastrointestinal tract that affects the stomach (60%), small intestine (30%), colon–rectum (5%), greater omentum and mesentery (4%), and esophagus (1%). While sporadic GIST makes up 95% of cases that likely evolve from sporadic events without apparent family connection, familial (syndromic) GIST represent about 5% of cases due to autosomal dominant inheritance of germline mutations. Clinically, sporadic GIST typically produces solitary lesions, although it may also cause multiple sporadic lesions (so-called synchronous or metachronous tumors) in association with familial syndromes. By contrast, familial (syndromic) GIST often presents with multiple lesions, hyperpigmentation, mast cell tumor, and ICC hyperplasia-associated dysphagia in patients younger than their counterparts with sporadic GIST. Molecularly, GIST is attributed to de novo or germline mutations involving the KIT (75%), PDGFRA (∼10%), SDH (5%), NF1 (1.5%), and other genes. The fact that KIT and PDGFRA all encode receptor tyrosine kinases enables the use of receptor tyrosine kinase inhibitors for treating 85% of GIST cases. However, for the remaining 15% of KIT/PDGFRA intact cases (wild-type GIST), specific treatment is still lacking. This clearly calls for further experimental investigation into the molecular mechanisms of wild-type GIST, with the goal of identifying novel, specific therapeutic agents for improved management of GIST.
Chemotherapy and targeted treatments of breast sarcoma by histologic subtype
Published in Expert Review of Anticancer Therapy, 2021
Stefania Kokkali, Athina Stravodimou, Jose Duran-Moreno, Nektarios Koufopoulos, Ioannis a Voutsadakis, Antonia Digklia
During the last few years, exciting new targeted therapeutics have been introduced advancing the goal of personalized medicine for cancer. Unfortunately, besides the success story of Gastrointestinal Stromal Tumors (GIST) in which targeted effective therapies have been developed, the sarcoma field has not enjoyed its fair share in these developments and the majority of patients with STS and also BS are still treated with chemotherapy, mostly independently of primary site, histologic sub-type or underlying molecular defects. The results of chemotherapy in STS are sub-optimal and most patients progress rapidly. Introduction of novel chemotherapeutics, such as eribulin and trabectedin, has produced modest benefits beyond the first-line treatment but their ability to change the natural course of metastatic STS is minimal. It is unlikely that chemotherapy will contribute significantly in the future to the improvement of outcomes in STS. Despite the disappointing results so far, targeted therapies based on the results from rationally designed clinical trials hold the most realistic hope. In addition to identifying a molecular target and the availability of a targeted drug, it is very important to confirm the tumor dependency on the target of interest. This has not been very successfully accomplished in targeted therapy development in the past and may be the cause of failures in sarcoma therapeutics.
New insights into the clinical management of advanced gastrointestinal stromal tumors
Published in Expert Opinion on Pharmacotherapy, 2021
The discovery of molecular abnormalities involved in the pathogenesis of gastrointestinal stromal tumors (GISTs) provided evidence for the concept of targeted therapeutics. Indeed, the vast majority of GISTs are characterized by activating mutations in the KIT or PDGFRA receptor, and these types of mutations occur very early in tumorigenesis. The inhibition of these receptors by small tyrosine kinase inhibitor molecules, such as imatinib or sunitinib, has resulted in spectacular therapeutic results, in which conventional cytotoxic drugs had little to no effectiveness. These molecular abnormalities are also correlated with the anatomo-clinical profile, spontaneous prognosis, and treatment of GISTs. In addition, the evolution of the molecular profile of these tumors largely explains the emergence of resistance to tyrosine kinase inhibitors. The aim of this review is to focus on the latest knowledge about the molecular abnormalities of GISTs and their impact on the current and future management of patients with this disease.
Systemic therapy of advanced/metastatic gastrointestinal stromal tumors: an update on progress beyond imatinib, sunitinib, and regorafenib
Published in Expert Opinion on Investigational Drugs, 2021
Mahmoud Mohammadi, Hans Gelderblom
Although gastrointestinal stromal tumors (GISTs) are a rare type of cancer with an incidence of around 15 patients per million per year [1], they are the most prevalent mesenchymal neoplasm. Reported incidence rates of GIST are variable across different geographical regions, although most population-based studies share similar epidemiological features of GIST around the globe [2]. At diagnosis, patients have a median age of mid-sixties with a slight predominance in males [1]. While GIST can arise along the entire gastrointestinal tract, most primary are found in the stomach (56%) and in the small intestine (32%). The minority of GISTs is located in the colon and rectum (6.0%), esophagus (0.7%), and other sites (5.5%) [2]. The recognition of overexpression of the KIT protein, a receptor tyrosine kinase, also known as CD-117 was crucial for accurately diagnosing GIST more than two decades ago. Simultaneously, the discovery of a gain of function mutation resulting in uncontrolled activation of KIT was a practice-changing breakthrough [3]. These mutations in KIT or platelet-derived growth factor receptor (PDGFRA) genes lead via activation of sustained growth, proliferation, and inhibition of apoptosis to – development of GIST [3,4]. Approximately 80% of GISTs arise from oncogenic KIT mutations while PDGFRA mutations are in 10–15% responsible for GIST. In the remaining 5–10% of GIST, the formally so-called wild-type GIST, other stigmata such as SDH-deficiency, NF1 mutation, and occasional NTRK and BRAF mutations are identified.