Gastrointestinal stromal tumors : Where do we stand?

Gastrointestinal Stromal Tumors: Disease and Treatment Update

Gastrointestinal stromal tumors (GISTs) are rare tumors of the gastrointestinal (GI) tract yet represent the most common GI sarcomas. Most GISTs are driven by activating mutations of the KIT and/or PDGFRA genes. Prior to the development of tyrosine kinase inhibitors (TKIs), GISTs were associated with a poor prognosis because conventional cytotoxic chemotherapy was relatively ineffective. However, TKIs that inhibit the most common driver mutations in KIT or PDGFRA have revolutionized the treatment of GISTs over the past two decades. Notwithstanding, ongoing management challenges relate to the development of secondary mutations in these genes, resulting in tumor progression. Due to both the intra- and inter-patient heterogeneity of these secondary mutations in GISTs, optimal treatment requires an agent that blocks as many mutant genes as possible. Ripretinib – a novel switch-control TKI – inhibits many of the most common primary and secondary activating KIT and PDGFRA mutants involved in GIST progression through a dual mechanism of action. In the pivotal INVICTUS phase III trial, patients with advanced GIST that had progressed on at least imatinib, sunitinib, and regorafenib and who received ripretinib experienced significantly longer progression-free survival (primary endpoint) as well as prolongation of overall survival, compared with those receiving placebo. Treatment with ripretinib was associated with durable improvements in quality-of-life indices and a manageable toxicity profile. The most frequent side effects were common to the class of TKIs used in the management of GIST. These results led to the approval of ripretinib for treatment of advanced GIST in adults who have received three or more TKIs, including imatinib. Ripretinib is also under investigation in the second-line treatment of advanced GIST in a phase III trial (INTRIGUE) comparing ripretinib with sunitinib in patients with advanced GIST after treatment with imatinib.Plain language summaryUse of ripretinib for the treatment of gastrointestinal stromal tumors (GISTs)Gastrointestinal stromal tumors (GISTs) are a rare type of tumor most commonly located in the stomach and small intestine but can develop anywhere throughout the gastrointestinal tract. The symptoms of GISTs vary in extent depending on location of the primary tumor and include a feeling of fullness, abdominal pain, intestinal bleeding, and fatigue. Since these symptoms are nonspecific, making a diagnosis can be challenging. Most GISTs carry initial mutations in genes that control specific enzymes called tyrosine kinases. Historically, treatment of GISTs was limited because traditional chemotherapy is ineffective against these tumors. However, with the introduction of drugs that inhibit tyrosine kinases [i.e., tyrosine kinase inhibitors (TKIs)], survival has been extended substantially. However, many GISTs go on to develop secondary mutations that render them resistant to a given TKI. Prior to the approval of ripretinib, four TKIs were available for the treatment of GIST: imatinib; sunitinib; regorafenib; and, recently, avapritinib. Each drug is used until resistance develops or patients are unable to tolerate the side effects of treatment, after which the next drug is started. Ripretinib was recently approved by the FDA as the fourth drug in the usual treatment sequence recommended for patients with advanced GIST who have progressed (or are treatment intolerant) after receiving three or more TKIs, including imatinib. Approval of ripretinib was based on the results of the INVICTUS trial, which demonstrated that the drug significantly improves the time patients have without progression of the disease or death compared with placebo. The most common side effects related to ripretinib were hair loss, muscle pain, nausea, fatigue, hand-foot syndrome, and diarrhea, although most events were not very severe. Ripretinib is being further studied as the second TKI used in patients with GIST who have progressed on or could not tolerate first-line treatment with imatinib.

The great success of tyrosine kinase receptor inhibitor (TKI) in gastrointestinal stromal tumors(GIST) has promoted it to become a classic model of targeted cancer therapy in the era of precision medicine. Multidisciplinary diagnosis and treatment and whole-process scientific management are the key to clinical diagnosis and treatment of GIST. There are many expert consensuses or guidelines on diagnosis and treatment of GIST in the world. The English version of expert consensuses on diagnosis and treatment of GIST has been issued by the East Asian countries represented by Japan, Korea and China, respectively, in combination with their own clinical practice. In 2016, the first edition of the Asian Expert Consensus on Diagnosis and Treatment of GIST was formulated jointly by the above - mentioned countries. This paper aims to explore the similarities and differences between Chinese and Asian Consensus on the diagnosis and treatment of GIST, to improve the understanding of GIST, and to bridge the gap and explore clues for future cooperation among these countries. The overall framework of both consensuses includes the pathological diagnosis, surgery and drug treatment of GIST. The differences include the following three aspects: (1) The different focus of pathological diagnosis of GIST. The Chinese Consensus has highlighted the requirements for the management of pathological specimens of GIST and the pathological evaluation after targeted therapy. The Chinese Consensus has also tried to clarify the algorithm of diagnosis of wild-type GIST, while wild-type GIST is introduced in very few words in the Asian Consensus. (2) The difference of surgical treatment of GIST focuses on the field of minimally invasive techniques, especially the application of endoscopy in the treatment of GIST. The Asian Consensus is cautious about laparoscopic surgery and has no comments on endoscopic resection at all. At present, the Chinese Consensus does not recommend routine endoscopic treatment in GIST, but the indications have been expanded to a certain extent, reflecting the clinical needs and development trends of endoscopic therapy in China. (3) The recommendation degree of medication for GIST varies. The difference includes the indication of adjuvant therapy, the recommendation after failure of first-line treatment, and discontinuation of TKIs preoperatively, and duration of postoperative adjuvant therapy. The difference between the Chinese Consensus and the Asian Consensus reflects the gap in the practice and clinical research of GIST between China and other Asian countries (e.g. Japan and Korea). Cooperation is the main theme in the field of medical science in the 21st century. China, Japan and South Korea are all located in East Asia and have certain shared features in terms of genetic and biological background, living habits and social environment, medical system and scientific research mode. It is a good entry point to carry out international cooperation research in the field of GIST. In view of some pending problems in the diagnosis and treatment of GIST, the cooperative research between China, Japan and Korea may focus on the following aspects: (1) The value of surgery in the treatment of advanced GIST. (2) The detection of imatinib blood concentration in East Asian population and optimized rational use of targeted drugs in the oriental population. (3) Chinese researchers should optimize the strategy of endoscopic treatment of GIST, design rigorous domestic multi-center clinical trials, and provide convincing data, so as to obtain international recognition. (4) Other related studies may include the diagnosis and treatment of wild-type GIST, the value of Ki-67 in the pathological evaluation of GIST, laparoscopic surgery for gastric GIST, and the optimal duration of imatinib adjuvant therapy. Researchers in China should attach importance to the value of clinical trials, especially cooperative clinical research. Starting with improving data quality, we should welcome cooperation with an open and confident attitude and strive to promote the clinical practice and research of GIST to a new height.

Differential Properties of Current Tyrosine Kinase Inhibitors in Gastrointestinal Stromal Tumors

Background: Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract. The majority of GISTs have a gain-of-function mutation of the c-kit or PDGFRA gene in the interstitial cells of Cajal. Although surgery is the most effective treatment for resectable primary GISTs, postoperative recurrence or metastasis has been observed after surgical resection in 40-90% of patients without adjuvant therapy. Metastatic GISTs are found most commonly in the liver, which are difficult to cure with surgical treatment alone. Although tyrosine kinase inhibitor (TKI) imatinib mesylate (Gleevec) is thought to be the most effective agent for treating GISTs, secondary resistance often arises during therapy due to secondary mutations. In this era of TKIs, control of liver metastasis remains to be an important issue in the treatment of GISTs and mechanisms of liver metastasis need to be elucidated. In this study, we compared gene expression and micro RNA (miRNA) expression profiles between gastric GISTs and metastatic liver GISTs to address mechanisms of GIST liver metastasis and to detect novel molecular markers for prediction of the postoperative prognosis of GIST patients. Methods: Frozen tissue specimens of three gastric GISTs and four metastatic liver GISTs were utilized for cDNA microarray analysis. None of the patients had received imatinib therapy before surgery. Formalin-fixed paraffin-embedded (FFPE) tissues of 104 primary GISTs and 13 metastatic GISTs from 107 patients who had undergone surgery were included for immunohistochemistry investigations. GIST cells were isolated from FFPE tissues of five gastric GISTs at low risk, five gastric GISTs at high risk and six metastatic liver GISTs surgically resected, and miRNA expression was analyzed using TaqMan miRNA array. Results: Expression levels were higher for 165 genes and lower for 146 genes in metastatic liver GIST. The upregulation of five oncogenes including versican and downregulation of four tumor suppressor genes, Cadherin8, Protocadherin10, NRCAM and CD9 were confirmed by qRT-PCR. Immunohistochemistry in 117 GISTs revealed that protein levels of versican and CD9 were higher and lower, respectively, in metastatic GIST. High expression of versican and low expression of CD9 in 104 primary gastric GISTs correlated with poor disease-free survival (P= 0.0078 and P= 0.0018). In miRNA array analysis, miR-122 was the most highly expressed in liver metastasis compared with primary gastric GISTs, consistent with our earlier papers that showed the overexpression of miR-122 and concomitant suppression of CAT1 in colorectal liver metastasis (Cancer Sci 104,624-30,2013). Conclusions: In addition to the c-kit gene mutation, genetic or epigenetic changes other than c-kit and alteration of miRNA expression such as miR-122 play important roles in the metastatic process of gastric GIST. Citation Format: Hirotoshi Kikuchi, Ichirota Iino, Shinichiro Miyazaki, Yusuke Ozaki, Yoshihiro Hiramatsu, Manabu Ohta, Kinji Kamiya, Takanori Sakaguchi, Satoshi Baba, Haruhiko Sugimura, Mitsutoshi Setou, Hiroyuki Konno. cDNA and miRNA microarray analysis comparing gastric and metastatic liver gastrointestinal stromal tumors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4008. doi:10.1158/1538-7445.AM2014-4008

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract and have gained considerable research and treatment interest, especially in the last two decades. GISTs are driven by mutations commonly found in the KIT gene and less commonly in the platelet-derived growth factor receptor alpha gene, BRAF gene and succinate dehydrogenase gene. GISTs behave in a spectrum of malignant potential, and both the tumor size and mitotic index are the most commonly used prognostic criteria. Whilst surgical resection can offer the best cure, targeted therapy in the form of tyrosine kinase inhibitors (TKIs) has revolutionized the management options. As the first-line TKI, imatinib offers treatment for advanced and metastatic GISTs, adjuvant therapy in high-risk GISTs and as a neoadjuvant agent to downsize large tumors prior to resection. The emergence of drug resistance has altered some treatment options, including prolonging the first-line TKI from 1 to 3 years, increasing the dose of TKI or switching to second-line TKI. Other newer TKIs, such as sunitinib and regorafenib, may offer some treatment options for imatinib-resistant GISTs. New molecular targeted therapies are being evaluated, such as inhibitors of BRAF, heat shock protein 90, glutamine and mitogen-activated protein kinase signaling, as well as inhibitors of apoptosis proteins antagonist and even immunotherapy. This editorial review summarizes the recent research trials and potential treatment targets that may influence our future patient-specific management of GISTs. The current guidelines in GIST management from Europe, North America and Asia are highlighted.

The c-KIT receptor tyrosine kinase is constitutively activated and oncogenic in the majority of gastrointestinal stromal tumors. The identification of selective inhibitors of c-KIT, such as imatinib, has provided a novel therapeutic approach in the treatment of this chemotherapy refractory tumor. However, despite the clinical importance of these findings and the potential it provides as a model system for understanding targeted therapy, this approach has not yielded curative outcomes in most patients, and the biochemical pathways connecting c-KIT inhibition to cell death are not completely understood. Here, we show that inhibition of c-KIT with imatinib in gastrointestinal stromal tumors (GISTs) triggered the up-regulation of the proapoptotic protein BIM via both transcriptional and post-translational mechanisms. The inhibition of c-KIT by imatinib increased levels of the dephosphorylated and deubiquitinated form of BIM as well as triggered the accumulation of the transcription factor FOXO3a on the BIM promoter to activate transcription of BIM mRNA. Furthermore, using RNA interference directed against BIM, we demonstrated that BIM knockdown attenuated the effects of imatinib, suggesting that BIM functionally contributes to imatinib-induced apoptosis in GIST. The identification and characterization of the pathways that mediate imatinib-induced cell death in GIST provide for a better understanding of targeted therapy and may facilitate the development of new therapeutic approaches to further exploit these pathways.

Gastrointestinal stromal tumors (GISTs), historically misclassified as leiomyomas, leiomyosarcomas, or schwannomas, are the most common mesenchymal neoplasms found in the gastrointestinal (GI) tract. The cornerstone in the treatment of GISTs has always been surgical resection, yet historically this has been associated with suboptimal overall survival and recurrence rates [1, 2]. However, there was a major breakthrough in 1998 when it was discovered that GISTs arise from the interstitial cell of Cajal and are molecularly characterized principally by mutations in the c-KIT and PDGFRA genes [3]. Since then, multiple clinical trials have evaluated the efficacy of imatinib mesylate, an oral tyrosine kinase inhibitor (TKI), as a treatment modality for GIST with excellent results [2, 4–7]. Today, imatinib plays a critical role in both the neoadjuvant and adjuvant treatment of GISTs, and in addition to other TKIs such as sunitinib and regorafenib, these drugs have fundamentally altered the natural history of both localized and metastatic GIST. Given that TKI therapy is costly and is associated with long-term adverse effects, it is critical to understand the natural history of localized GISTs as well as the prognostic factors for recurrence in order to identify those patients who would benefit most from TKI therapy. In this chapter, we review the natural history and prognosis of localized GISTs before the introduction of imatinib, the landmark trials demonstrating its efficacy, and the improved prognosis of localized GISTs after the introduction of imatinib.

This review describes the pathologic and epidemiologic features of gastrointestinal stromal tumor (GIST) as well as the contemporary management of this tumor. The integration of surgery and treatment with targeted molecular agents in the treatment of GIST is highlighted. GIST is the most common mesenchymal tumor of the gastrointestinal tract. Its cellular origin from the interstitial cell of Cajal and distinctness from smooth muscles tumors were only recently appreciated. The discovery of the centrality of KIT proto-oncogene mutations in the pathogenesis of this tumor, and the development of imatinib mesylate, a specific inhibitor of KIT tyrosine kinase function have revolutionized the treatment of GIST. We conducted a review of the English literature on GIST. The pathology, epidemiology, diagnosis, and treatment of this tumor are summarized with particular emphasis on recent developments in the field. GIST is a rare tumor that usually arises from the stomach or small intestine. It is characterized by immunohistochemical staining for KIT. Treatment of primary localized tumors is surgical. The benefit of adjuvant treatment with the KIT tyrosine kinase inhibitor imatinib is the subject of investigation. The treatment of unresectable, recurrent, or metastatic GIST is primarily imatinib treatment. The integration of surgery or ablative modalities is often employed, particularly when all disease is amenable to gross resection or destruction, or when GIST becomes resistant to imatinib. Newer tyrosine kinase inhibitors, such as sunitinib are the subject of ongoing investigation. The treatment paradigm for GIST has required the integration of surgery and molecular therapy and this will likely serve as a paradigm for the treatment of other solid tumors as targeted agents are developed.

Current treatment of gastrointestinal stromal tumours

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. Activating mutations of KIT or the platelet-derived growth factor receptor alpha gene (PDGFRA) have been identified in the vast majority of GISTs. The respective oncoproteins exhibit constitutive tyrosine kinase activity and promote cell growth. KIT and PDGFRA mutations are rarely found in GISTs in patients with neurofibromatosis type 1 (NF1) suggesting that the pathogenesis of GIST in NF1 patients is different from that in non-NF1 patients. Endoscopic diagnosis of GIST is usually difficult. Endoscopic ultrasonography (EUS)-guided fine-needle aspiration biopsy (EUS-FNAB) is a useful method for the diagnosis of GIST and for the detection of KIT or PDGFRA mutations. Imatinib mesylate, a tyrosine kinase inhibitor known to inhibit the activities of BCR-ABL, KIT, and PDGFR, is currently being used for the treatment of both chronic myeloid leukemia and metastatic GIST. The clinical response to imatinib therapy correlates with the types of mutations of KIT and PDGFRA, and the determination of KIT and PDGFRA mutations is useful for predicting the effect of imatinib. Resistance to imatinib after an initial response has been reported; secondary point mutations in KIT or PDGFRA that confer imatinib resistance are the most common mechanisms responsible for acquired resistance to imatinib. The continued development of target-specific therapies should increase the probability of cure in most patients with GISTs.

The availability of the tyrosine kinase inhibitor (TKI) small molecule imatinib has revolutionized the systemic treatment for gastrointestinal stromal tumor (GIST), historically one of the most chemoresistant solid malignancies. Prior to imatinib availability approximately 14 years ago, surgery was the only effective treatment modality. Imatinib is now accepted as the first-line systemic treatment for advanced GIST and subsequently has become the standard systemic treatment for GIST in the neoadjuvant and adjuvant settings. Sunitinib and regorafenib have been approved for second- and third-line treatments, respectively, for patients with advanced GIST progressing on imatinib. The dramatic and continuing efficacy of TKIs targeting oncogenic driver pathways such as KIT, platelet-derived growth factor receptor alpha (PDGFR〈), and vascular epithelial growth factor receptors (VEGFs), in advanced GIST supports the utility of targeted therapy in oncogene addicted solid malignancies. Molecular mutational diagnostics has further defined subpopulations of responders. Although significant gains have been made in the treatment of GIST patients, future research is still warranted to help further improve clinical outcomes of patients with GIST.

In the last decade a tremendous amount has been learned about the biology and treatment of gastrointestinal stromal tumor (GIST). Imatinib mesylate has revolutionized the treatment of metastatic GIST. In addition, the role of imatinib in localized GIST has gained much interest and may improve patient outcomes. Additionally, research efforts aimed at understanding the biology and the molecular heterogeneity of GIST both at initial presentation and at the time of resistance to imatinib, has helped guide rational approaches to treatment as well as future efforts aimed at treating imatinib-resistant GIST.

Imatinib for chronic myeloid leukaemia: a NICE mess

Gastrointestinal stromal tumours (GISTs) are soft-tissue sarcomas of the gastrointestinal tract. Surgery is the standard treatment for localised disease, but the risk of relapse and progression to more advanced disease is substantial. Following the discovery of the molecular mechanisms underlying GISTs, targeted therapies for advanced GIST were developed, with the first being the tyrosine kinase inhibitor (TKI) imatinib. Imatinib is recommended in international guidelines as first-line therapy to reduce the risk of GIST relapse in high-risk patients, and for locally advanced, inoperable and metastatic disease. Unfortunately, imatinib resistance frequently occurs and, therefore, second-line (sunitinib) and third-line (regorafenib) TKIs have been developed. Treatment options are limited for patients with GIST that has progressed despite these therapies. A number of other TKIs for advanced/metastatic GIST have been approved in some countries. Ripretinib is approved as fourth-line treatment of GIST and avapritinib is approved for GIST harbouring specific genetic mutations, while larotrectinib and entrectinib are approved for solid tumours (including GIST) with specific genetic mutations. In Japan, pimitespib, a heat shock protein 90 (HSP90) inhibitor, is now available as a fourth-line therapy for GIST. Clinical studies of pimitespib have indicated that it has good efficacy and tolerability, importantly not displaying the ocular toxicity of previously developed HSP90 inhibitors. Additional approaches for advanced GIST have been investigated, including alternative uses of currently available TKIs (such as combination therapy), novel TKIs, antibody–drug conjugates, and immunotherapies. Given the poor prognosis of advanced GIST, the development of new therapies remains an important goal.