Therapy For Gastrointestinal Stromal Tumors Research Articles

ISY-13-5 - SCRUM for sarcoma

Soft tissue sarcomas are rare tumors arising from soft tissue anywhere in body with more than 100 subtypes. Among them gastrointestinal stromal tumor (GIST) is a distinct tumor type characterized by the driver oncogene c-KIT mutations and corresponding molecular-targeted agents such as imatinib, sunitinib, and regorafenib. Imatinib is the established first line therapy for metastatic or recurrent GIST and shows activity with response rate of approximately 60%. Resistance to imatinib occurs primarily or secondarily. Most of the primary resistant GIST lack c-KIT mutations and called ‘wild-type GIST’. Instead of c-KIT mutations, they occasionally possess BRAF, KRAS, NF-1, or SDH alterations. Therefore multiplex test for several mutations is useful to investigate wild-type GISTs. SCRUM-Japan is a nationwide cancer genome screening for orphan-fractionated cancer. Recently the program included GIST patients and expected to show its utility. In secondary resistant GISTs, secondary c-KIT mutations in addition to the primary mutations are seen in approximately 70% of cases and the types of secondary mutations are reported to be predictive for response to the following treatment. In such cases sequential analysis for mutation during the course of the treatment could be useful. Investigator-initiated study ‘RESET’ explores correlation between secondary mutations and regorafenib.

Pazopanib: a new therapeutic option for advanced gastrointestinal stromal tumors

Gastrointestinal stromal tumors (GIST) are the most common mesenchymal malignancy of the alimentary tract, with an annual incidence of 6,000 new cases in the United States (1). Surgery has been the mainstay of treatment for GIST, but a significant number of patients develop unresectable or metastatic disease. Since most GISTs are driven by constitutively active receptor tyrosine kinases (KIT in 85% and PDGFRA in 10%) (2,3), systemic therapy for advanced GIST consists primarily of tyrosine kinase inhibitors (TKIs). Imatinib, a multi-targeted TKI with activity against KIT and PDGFRA, was the first of these to show significant efficacy against unresectable or metastatic GIST, with a median progression-free survival (PFS) of 24 months (4). However, over 80% of patients eventually develop imatinib resistance. Sunitinib, another multi-targeted TKI, was shown to confer a median PFS of 24 weeks for imatinib-resistant/intolerant patients (5), and it has now become the second-line therapy for advanced GIST. Unfortunately, almost all of these patients also subsequently develop sunitinib resistance over time.

Genetic alteration and mutation profiling of circulating cell-free tumor DNA (cfDNA) for diagnosis and targeted therapy of gastrointestinal stromal tumors.

Gastrointestinal stromal tumors (GISTs) have been recognized as a biologically distinctive type of tumor, different from smooth muscle and neural tumors of the gastrointestinal tract. The identification of genetic aberrations in proto-oncogenes that drive the growth of GISTs is critical for improving the efficacy of cancer therapy by matching targeted drugs to specific mutations. Research into the oncogenic mechanisms of GISTs has found that these tumors frequently contain activating gene mutations in either platelet-derived growth factor receptor A (PDGFRA) or a receptor tyrosine protein associated with a mast cell growth factor receptor encoded by the KIT gene. Mutant cancer subpopulations have the potential to disrupt durable patient responses to molecularly targeted therapy for GISTs, yet the prevalence and size of subpopulations remain largely unexplored. Detection of the cancer subpopulations that harbor low-frequency mutant alleles of target proto-oncogenes through the use of molecular genetic methods, such as polymerase chain reaction (PCR) target amplification technology, is hampered by the high abundance of wild-type alleles, which limit the sensitivity of detection of these minor mutant alleles. This is especially true in the case of mutant tumor DNA derived “driver” and “drug-resistant” alleles that are present in the circulating cell-free tumor DNA (cfDNA) in the peripheral blood circulation of GIST patients. So-called “liquid biopsy” allows for the dynamic monitoring of the patients’ tumor status during treatment using minimally invasive sampling. New methodologies, such as a technology that employs a xenonucleic acid (XNA) clamping probe to block the PCR amplification of wild-type templates, have allowed improved molecular detection of these low-frequency alleles both in tissue biopsy samples and in cfDNA. These new methodologies could be widely applied for minimally invasive molecular testing in the therapeutic management of GISTs.

Asian Consensus Guidelines for the Diagnosis and Management of Gastrointestinal Stromal Tumor.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors originating in the gastrointestinal tract. With the introduction of molecular-targeted therapy for GISTs which has yielded remarkable outcomes, these tumors have become a model of multidisciplinary oncological treatment. Although Western clinical guidelines are available for GISTs, such as those published by the National Comprehensive Cancer Network (NCCN) and the European Society of Medical Oncology (ESMO), the clinical situations in Asian countries are different from those in Western countries in terms of diagnostic methods, surgical approach, and availability of new targeted agents. Accordingly, we have reviewed current versions of several GIST guidelines published by Asian countries (Japan, Korea, China, and Taiwan) and the NCCN and ESMO and discussed the areas of dissensus. We here present the first version of the Asian GIST consensus guidelines that were prepared through a series of meetings involving multidisciplinary experts in the four countries. These guidelines provide an optimal approach to the diagnosis and management of GIST patients in Asian countries.

An Unusual Case of Central Retinal Vein Occlusion and Review of the Toxicity Profile of Regorafenib in GIST Patients

Gastrointestinal stromal tumor (GIST) is the most common sarcoma of the gastrointestinal tract with around 5000 new cases per year. Outcomes for patients with GIST dramatically improved after the development of tyrosine kinase inhibitors targeted against the aberrant signaling pathways that drive GIST oncogenesis. Majority of patients derive benefit from first-line imatinib, and the type of driver mutation is predictive of response. However, almost half of the patients eventually develop resistance to initial targeted therapy and further lines of treatment do not have the same impact. Regorafenib is an oral multi-kinase inhibitor approved as a third-line therapy for advanced GIST and though its efficacy is limited in comparison to imatinib, it has activity across the various driver mutation categories in GISTevenin the setting of imatinib resistance. Herein, we describe a case of central retinal vein occlusion (CRVO) secondary to regorafenib and review regorafenib's efficacy and toxicity profile.

Advanced gastrointestinal stromal tumors : What role does surgery currently play in multimodal concepts?

Gastrointestinal stromal tumors (GIST) have an incidence of 1-2/100,000 and thus constitute the most common mesenchymal neoplasm of the digestive tract. Their specific tumor biology with mutations in the protooncogenes c-KIT and PDGFR α acting as drivers of tumor growth facilitate targeted therapy with tyrosine kinase inhibitors. In this context, there are several specific indications for surgery in patients with advanced GIST. This article discusses the importance of surgery within multimodal therapeutic concepts for advanced GIST. The results of a selective literature search including own studies and case reports are presented. For large GIST at unfavorable anatomical locations, which are not amenable to organ-sparing resection, neoadjuvant imatinib therapy is the standard upfront treatment prior to surgery in the case of imatinib-sensitive mutations in the c-KIT protooncogene. This usually reduces the extent of resection without increasing perioperative morbidity. In the metastatic setting, surgery can constitute a significant part of multimodal therapy in patients with a generalized response to drug therapy by resection of residual tumor masses, although there are no prospective studies to prove a beneficial effect on overall survival. In patients with focal progression on anti-proliferative therapy, local therapeutic measures can make an important contribution to multimodal tumor control. In patients with generalized progression, an operation should only be performed in highly selected cases with the goal of symptom control. Local ablative therapies, such as radiofrequency ablation (RFA), irreversible electroporation (IRE) and selective internal radiotherapy (SIRT) are a therapeutic option particularly for liver metastases. Surgery plays an important role in the multimodal therapy of advanced GIST particularly in the neoadjuvant setting. Its role is more limited in metastatic stages where systemic treatment represents the frontline therapeutic approach.

Management approach and surgical strategies for retrorectal tumours: a systematic review.

The management strategy for retrorectal tumours is complex. Due to their rarity, few surgeons have expertise in management. A systematic literature review was conducted using the PubMed database. English language publications in the years 2011-2015 that assessed preoperative management, surgical strategies and chemoradiotherapy for presacral tumours were included. Two hundred and fifty-one abstracts were screened of which 88 met the inclusion criteria. After review of the full text, this resulted in a final list of 42 studies eligible for review. In all, 932 patients (63.2% female, 36.8% male; P < 0.01) with a retrorectal tumour were identified. Most were benign (65.9% vs. 33.7%, P < 0.01). Imaging distinguished benign from malignant lesions in 88.1% of cases; preoperative biopsy was superior to imaging in providing an accurate definitive diagnosis (91.3% vs. 61.4%, P < 0.05) with negligible seeding risk. Biopsy should be performed in solid tumours. It is useful in guiding neoadjuvant therapy for gastrointestinal stromal tumours, sarcomas and desmoid type fibromatosis and may alter the management strategy in cases of diffuse large B-cell lymphoma and metastases. Biopsies for cystic lesions are not recommended. The gold standard in imaging is MRI. The posterior Kraske procedure is the most common surgical approach. Overall, the reported recurrence rate was 19.7%. This review evaluated the management strategies for retrorectal tumours. A preoperative biopsy should be performed for solid tumours. MRI is the most useful imaging modality. Surgery is the mainstay of treatment. There is limited information on robotic surgery, single-port surgery, transanal endoscopic microsurgery, chemoradiotherapy and reconstruction.

The safety of regorafenib for the treatment of gastrointestinal stromal tumors

Introduction: The management of gastrointestinal stromal tumors (GIST) evolved due to effective molecularly targeted therapy with imatinib and sunitinib which are used first- and second-line, respectively. However, due to the development of resistance to those drugs in the majority of patients, the need for third-line therapy arose.Areas covered: Regorafenib, an oral multitargeted inhibitor with activity against multiple kinases including KIT, RET, RAF1, BRAF, angiogenesis (VEGFR, TIE-2) and those involved in tumor microenvironment (PDGFR and FGFR) was introduced after the successful Phase III GRID (GIST – Regorafenib In progressive Disease) clinical trial. This study showed significant improvement in progression-free survival for patients receiving regorafenib compared to placebo (4.8 months vs 0.9 months). The treatment was reasonably well tolerated, with arterial hypertension, hand-foot syndrome, diarrhea being the most common grade ≥3 adverse events, which could be managed by dose reduction and supportive treatment. The aim of this paper is to describe, assess and advise on the safety of regorafenib as third-line therapy in GIST.Expert opinion: Regorafenib has demonstrated clinical benefit in GIST patients after progression on prior treatment with at least imatinib/sunitinib and currently it is the approved standard third-line option in therapy of advanced GIST. The safety profile is similar to other multikinase inhibitors with anti-VEGFR activity and is manageable.

Abstract A13: Establishment and characterization of patient-derived xenograft models of gastrointestinal stromal tumor resistant to standard tyrosine kinase inhibitors

Abstract BACKGROUND: The prognosis of gastrointestinal stromal tumor (GIST) has been dramatically improved after introduction of imatinib which can inhibit the driver mutated oncoproteins,KIT or PDGFRa. However, most patients eventually develop resistance to the tyrosine kinase inhibitors (TKIs) targeting these oncoproteins including imatinib, sunitinib, or regorafenib. The paucity of TKIs-resistant commercially available GIST cell lines hampers development of effective therapy for drug-resistant GIST. Therefore, we established patient-derived xenograft (PDX) models that faithfully recapitulate the genetic and phenotypic features of drug-resistant GIST. METHODS: PDXs have been established in NOD-SCID mice with tumor fragments of patients with metastatic and/or unresectable GIST after failure of at least imatinib and/or sunitinib. The histological and genomic similarities between all xenografts and the parental tumors have been confirmed using H&amp;E and KIT staining, and short tandem repeat (STR) analysis, respectively. Mutation was detected by whole exome sequencing of patients' tumors on a HiSeq2000 and validated by Sanger sequencing of patients tumors and PDXs. After sequential passaging to BALB/c nude mouse, drug sensitivity assay (imatininb, sunitinib, and regorafenib) was conducted in established PDX models along with Western blotting regarding to KIT and FGFR signaling pathway. As an imatinib-sensitive control model, a xenograft established with GIST-T1 cell line was used. RESULTS: Three GIST PDX models were established from an imatinib/sunitinib/sorafenib-resistant GIST harboring KIT exon 11 (p.Y570-L576del) and 17 (p.D816E) mutations (AMC-GX1), an imatinib-resistant GIST harboring KIT exon 11 (p.K550_K558del) and 14 (p.T670I) mutations (AMC-GX2), and an imatinib/sunitinib-resistant GIST harboring KIT exon 11 (p.565-577GNNYVVIDPTQLP&amp;gt;Q) and 17 (p.D820Y) mutations (AMC-GX3). Histologic and genetic similarities were confirmed between primary patients' tumors and PDXs. The mutation status of GIST PDXs was consistent with primary tumors. The GIST PDX models showed TKI sensitivity profiles comparable to clinical responses in patients. At day 21 after treatmemt with imatinib, tumor growth was inhibited by 17.8, 53.9, and 12.6% in AMC-GX1, GX2, and GX3, respectively, while by 80.0% in GIST-T1 xenografts. Western blotting analysis showed that KIT phosphorylation was inhibited by imatinib treatment in AMC-GX1 similar to GIST-T1, but not in AMC-GX2 and AMC-GX3. In contrast to GIST-T1, PI3K downstream of KIT was not inhibited with imatinib in AMC-GX1, GX2, and GX3. In addition, TKIs-resistant PDX models showed FGFR1 activation at baseline which was not evident in GIST-T1 xenografts. CONCLUSION: We have established 3 TKI-resistant GIST PDX models harboring variable KIT mutations which show different KIT and FGFR signaling features from imatinib-sensitive models. The established GIST PDX models will play a role for further studies on mechanisms of resistance to TKI and evaluation of novel targeted therapies in GIST. Citation Format: Young-Soon Na, Min-Hee Ryu, Sook Ryun Park, Ju-Kyung Lee, Hanui Kim, Chae-Won Lee, Sun Young Lee, Young-Kyoung Shin, Ja-Lok Ku, Sung-Min Ahn, Yoon-Koo Kang. Establishment and characterization of patient-derived xenograft models of gastrointestinal stromal tumor resistant to standard tyrosine kinase inhibitors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A13.

Endoscopic band ligation versus endoscopic submucosal dissection and laparoscopic resection for small gastric stromal tumors.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. Previous studies have addressed the safety and feasibility of endoscopic band ligation (EBL) for the treatment of small gastric GISTs. However, published reports comparing EBL with other interventions are limited. This current study evaluates the efficacy of EBL and compares EBL to both endoscopic submucosal dissection (ESD) and laparoscopic resection (LAP) for small gastric GISTs less than 15mm. A total of 339 patients who underwent endoscopic therapy or laparoscopic resection for gastric GISTs between 1998 and 2012 were retrospectively identified and collected from medical records in our hospital. The parameters measured for each procedure type includes clinicopathological characteristics, length of stay, hospitalization expense and surgical outcomes. Among the 147 patients included in our study, 72 (48.98%) received EBL, 27 (18.37%) received ESD, and 48 (32.65%) received LAP. The demographic and clinical characteristics of the patients such as gender, age, tumor site and size were well balanced between the study groups. There was also no significant difference in follow-up time between the study groups. The mean operating time was significantly shorter in the patients receiving EBL than patients receiving ESD and LAP (p<0.001). The estimated blood loss was significantly different between the three groups (p<0.001). Complications occurred in 1.39% of the patients receiving EBL, 18.52% of the patients receiving ESD and 4.17% of the patients receiving LAP (p=0.004), and recurrence rate in 15.00, 9.10 and 11.76%, respectively (p=0.705). There was also significant difference about mean hospital stay and hospital cost between three groups (p<0.001). Our results show a significant advantage in the short-term outcome for EBL compared to ESD and LAP. However, long-term randomized controlled trials are needed to compare the three methods for the treatment of small GISTs.

Adjuvant therapy with imatinib mesilate in a patient with intermediate risk GIST

The presented case regards a 63-year-old male patient who underwent radical surgery for an intermediate risk gastrointestinal stromal tumor (GIST) and thereafter was treated with imatinib mesilate at a daily dose of 400 mg for one year. Adjuvant therapy for primary GIST has proven benefit in extending relapse free survival in randomised controlled phase III trials; the advantage in overall survival, however, is yet to be proved. Defined risk factors for recurrence are based on GIST size, location, and mitotic rate provide useful guidelines for selecting patients for adjuvant therapy considerations. Nevertheless, it is currently unclear how to select those patients who would benefit the most, which is the optimal dose and treatment duration, and, importantly, if the use of adjuvant imatinib could enhance the chance of cure. The case report will be used as a paradigmatic springboard for further discussion.

Prognostic factors after imatinib secondary resistance: survival analysis in patients with unresectable and metastatic gastrointestinal stromal tumors.

Patients undergoing imatinib therapy for gastrointestinal stromal tumors (GISTs) show drug resistance during treatment in the late stages. The aims of this study were to determine survival after the appearance of imatinib secondary resistance (ISR) and to identify the prognostic factors. Eligible were patients with unresectable and metastatic GISTs who were diagnosed with ISR and/or underwent treatment for ISR in our institution between 2001 and 2012. A total of 48 patients were enrolled and overall survival was retrospectively analyzed. The Cox proportional hazards model was used to identify the independent prognostic factors. Median follow-up time was 58 months. As of the cutoff date, 41 of the 48 patients with ISR had died, of which 39 died of GISTs. The overall 1-, 3-, and 5-year survival rates of the 48 patients were 64.6, 32.8, and 20.4 %, respectively, and median survival time was 22 months. The favorable independent prognostic factors identified were long progression-free survival in first-line imatinib therapy (P = 0.04), small diameter of progressive disease (PD) (P = 0.02), and surgical resection of PD (P = 0.01). Surgical resection of PD in selected cases could improve prognosis in ISR patients undergoing GIST treatment.

Abstract 791: BLU-285, the first selective inhibitor of PDGFRα D842V and KIT Exon 17 mutants

Abstract The advent of imatinib therapy in gastrointestinal stromal tumor (GIST) has been transformative, altering the treatment of advanced disease in the majority of patients from supportive care and poor prognosis to a median 24-month progression free survival in the first line setting. However, for 20% of patients with gastric GIST, imatinib shows no therapeutic benefit. These patients are characterized by the amino acid substitution D842V in the PDGFRα protein; this mutation results in ligand-independent activation of PDGFRα and is insensitive to all small molecule inhibitors approved for GIST. When metastatic, the prognosis for PDGFRα D842V GIST is dire, with median overall survival of 12 months. Starting with a novel chemical library optimized for kinase selectivity and potency, we have identified BLU-285, a small molecule kinase inhibitor that potently inhibits PDGFRα D842V mutant activity in vitro (IC50 = 0.5 nM) and PDGFRα D842V autophosphorylation in the cellular setting (IC50 = 30 nM). We have observed that in addition to PDGFRα D842V, BLU-285 is also a potent inhibitor of the analogous KIT mutation, D816V in KIT Exon 17 (IC50 = 0.5nM). KIT D816 mutations have been identified in several human diseases such as systemic mastocytosis (SM), acute myeloid leukemia (AML), and as resistance mutations in second and third line GIST, after imatinib and sunitinib failure. Cellular assays measuring inhibition of KIT mutant autophosphorylation confirm the activity of BLU-285 against the KIT D816 mutants D816V (HMC1.2 cells, IC50 = 3 nM) and D816Y (P815 cells, IC50 = 22 nM) as well as other KIT Exon 17 mutants such as N822K (Kasumi cells, IC50 = 40 nM) found in treatment-refractory GIST. In vivo, BLU-285 is a well-tolerated, orally bioavailable agent that achieves dose dependent tumor growth inhibition in a D816Y-driven xenograft model. A PK-PD-efficacy relationship with BLU-285 has been established demonstrating that tumor regression results from &amp;gt;90% target suppression and is observed with 30 mg/kg once daily dosing. Furthermore, in non-clinical toxicology studies, projected human efficacious exposures were well tolerated. With potent activity against PDGFRα D842V and KIT Exon 17 mutants, BLU-285 targets previously unaddressed genomic drivers of disease and provides promise for the treatment of PDGFRα D842V-driven GIST or SM, where more than 90% of patients carry the KIT D816V mutation. Besides single agent activity, the highly selective BLU-285 offers an opportunity for combination with other agents in GIST to cover the entirety of KIT primary and resistance mutants. This approach of pairing potent, selective kinase inhibitors with defined disease-driving kinase mutants is designed to fulfill the promise of personalized medicine and, if clinically proven, may provide maximum benefit to patients. BLU-285 is scheduled to enter first-in-human phase 1 clinical trials for both the GIST and SM patient populations in the first half of 2015. Citation Format: Erica K. Evans, Brian L. Hodous, Alexandra K. Gardino, Alison Davis, Julia Zhu, Adam Shutes, Joseph L. Kim, Kevin J. Wilson, Doug Wilson, Yulian Zhang, Tat Chu, Nancy E. Kohl, Vivek Kadambi, Timothy Guzi, Christoph Lengauer. BLU-285, the first selective inhibitor of PDGFRα D842V and KIT Exon 17 mutants. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 791. doi:10.1158/1538-7445.AM2015-791

Clinicopathological features of small gastrointestinal stromal tumors

To investigate the clinicopathological features of small gastrointestinal stromal tumors(GISTs) and to evaluate the efficacy of endoscopic therapy for GISTs. Clinicopathological and follow-up data of 418 patients with GISTs undergoing endoscopic therapy in the Zhongshan Hospital between January 2009 and July 2014 were analyzed retrospectively. All the cases were evaluated by the NIH risk classification and AIFP classification, and were grouped according to the tumor size and location. Nuclear atypia and mitotic count were used to evaluate the biological behavior of small GIST. Efficacy of endoscopic therapy was analyzed with follow-up data. Out of 418 patients, GISTs located in the esophagus was 14(3.3%), in the stomach 389(93.1%), in the duodenum 5(1.2%), in the rectum 10(2.4%). A total of 412(98.6%) patients were mainly spindle cells, and mitosis was not found in 320(76.5%) patients. In 389 small stomach GIST, 245(58.6%) were in fundic region. Cases were divided into four groups according to the size and the result revealed the bigger the size, the more the mitotic count. Nuclear atypia in the 1.5-1.9 cm group was significantly higher compared to other groups. Cases were divided into four groups according to the location and the result revealed the mitotic count was not associated to the location. While the nuclear atypia of stomach GIST was significantly higher than that of esophageal GIST and the nuclear atypia of rectum GIST was significantly higher than that of other positions. The median follow-up was 32(4-69) months. One case(gastric fundus GIST, >1.5 cm) presented local recurrence 23 months after operation and underwent endoscopic resection again. No recurrence or metastasis was found in other patients. Endoscopic resection technique is effective for small GISTs patients. The small GISTs with 0.4 cm diameter or less are often benign and should be followed up for long time. The small GISTs with 0.5 cm diameter or more possess the risk of malignancy, then surgical resection should be performed. Rectum small GISTs (except for 0.4 cm diameter or less) have worse biological behavior and should be removed.

Targeted Therapy for Gastrointestinal Stromal Tumor: Emerging concepts in oncogenetics and therapy sequencing

Targeted Therapy for Gastrointestinal Stromal Tumor: Emerging concepts in oncogenetics and therapy sequencing

The importance of mutational status in prognosis and therapy of GIST

GIST (gastrointestinal stromal tumor) are the most common mesenchymal tumors in gastrointestinal tract and are thought to derive from the cells of Cajal or their precursors that have a constitutional mutation in KIT and PDGFRA genes. There are KIT and PDGFRA genes mutations detected before the start of therapy that are believed to be related to GIST pathogenesis and some secondary mutations causing drug resistance and progression of disease. The most common KIT mutations are detected in exon 11 (66-71%), exon 9 (10-13%), exon 13,14,17 (1% each). PDGFRA mutations (8%) are described in exon 18 (5-6%), 12 (1%) and 14 (1%). No mutations are detected in 5-10% of tumors and those subtypes are called wild type GIST (WT). Imatinib mesilate is a selective inhibitor of KIT and PDGFRA with an antityrosine kinase activity (TKI) used in advanced or metastatic GIST as well as in adjuvant setting after complete resection of neoplasm. Imatinib has radically changed the therapy and prognosis of GIST, but sensitivity of the disease is different on the basis of leading mutations. GIST KIT exon 11 mutated manifests response rate in 80% of cases, exon 9 in 40% and GIST WT in 14%. PDGFRA shows a mild sensitivity to drug (66%) except the exon 18 D842 V mutation which is totally resistant. Unfortunately up to 15% of GIST have a primary resistance to imatinib that means progression of the disease within 6-12 months after the start of therapy. Another 40-50% of GIST develops a secondary resistance after >24 months of TKI treatment. Biopsy of progressing GIST shows multiple clonal origins with distinct mutational changes. Secondary resistance occurs almost exclusively in KIT mutated GIST with the appearances of T670I gatekeeper secondary mutation and less common in 14, 17, 18 exons. After progression of disease second line therapy is represented by sunitinib malate that overcomes the most common resistant mutations excepted PGDFRA D842V. Again, after few months of treatment, new different mutations appear and the disease progresses. Regorafenib is the third line therapy but too few data relates mutational status and regorafenib activity. In adjuvant setting only imatinib has a role. Two important studies (the USA ACOSOG Z 9001 and the German-Scandinavian study) fail to demonstrate that a specific mutation can predict a better DFS and OS in treated patients. On the contrary, volume of the tumor, number of mitosis and site of GIST are strong prognostic and predictive factors. In conclusion mutational analysis in GIST is at present more useful in metastatic setting than in adjuvant therapy. The insurgence of primary and secondary mutations during therapy is a fundamental step for disease progression.

A Case of Disseminated Intra-abdominal Gastrointestinal Stromal Tumor Managed with Low Dose Imatinib

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract. Imatinib mesylate is recommended as adjuvant therapy for GIST after surgical resection. However, drug-related adverse events are common. A 74-year-old female with metastatic GIST who was managed with imatinib experienced severe adverse events, including skin rashes, tremor, and alopecia, etc. The imatinib dose was reduced and the size of the metastatic GIST continued to decrease and adverse events showed significant improvement.

Single-center experience of surgically resected gastrointestinal stromal tumors: A report of six cases, including a rare case involving the lower esophagus.

Gastrointestinal stromal tumors (GISTs) are rare, but remain the most common GI mesenchymal neoplasms. In the present study, six cases of GIST are reported, and one of these cases, a patient with esophageal GIST, is reported in-depth. Certain recent developments in the clinical therapy of GISTs are also discussed. The records of all surgically-resected GI stromal tumors treated at the Al-Hada Military Hospital between January 2007 and December 2012 were reviewed. There were six cases of surgically resected GISTs during this time period, three males and three females, with a mean age of 69.3±16.4 years. The stomach was involved in 66.7% of cases, the small intestine in 16.7% and the esophagus, which is an extremely rare site, in 16.7% of cases. The most common symptom at presentation was abdominal pain, followed by GI bleeding. The mean tumor size was 8.7±6.3 cm. Surgery was indicated by the presence of the aforementioned symptoms or a tumor size >5 cm. All tumors were completely resected with histologically negative margins. The diagnoses were established by immunohistochemistry. Four patients were classified as possessing a high-grade variant, and were administered with tyrosine kinase inhibitors (TKIs). Following a mean follow up of 31 months, no recurrence or mortality was detected. Complete surgical resection with tumor-free margins is the standard treatment for GISTs, and TKIs should be used as adjuvant therapy if the risk of progressive disease is high.

Genomic index predicts clinical outcome of intermediate-risk gastrointestinal stromal tumours, providing a new inclusion criterion for imatinib adjuvant therapy

PurposeImatinib mesylate is the front-line targeted therapy for gastrointestinal stromal tumours (GISTs). Patient’s eligibility to adjuvant imatinib after primary tumour resection is currently based on histological and clinical risk assessment. While therapeutic options are clear for the very-low, low and high-risk subpopulations, no standard is actually available for the tumours classified as intermediate. Since we recently validated genomic index (GI), a measure of the level of genomic alterations, as a strong predictor of clinical outcome in GIST, we asked whether it could also represent a novel prognostic factor for the intermediate subgroup. Experimental design82 intermediate risk patients were selected based on the Armed Forces Institute of Pathology (AFIP) classification for genomic profiling. ResultsData revealed that even if studied samples generally harboured a combination of the typical genetic aberrations found in GIST, i.e. 1p, 14q 22q deletions and frequently lost CDKN2A locus on chromosome 9, they profoundly differed from each other on the total number of genomic changes and GI value. Kaplan–Meier analyses of metastatic-free survival unveiled that stratification of the tumours by the GI value at a cutoff of 10 separated the good from the poor prognosis patients, proven that metastatic-risk in GIST intermediate patients is strongly associated with high GI values and genome complexity. ConclusionGI is validated here as a robust marker to predict intermediate-GIST clinical outcome. Applicable in numerous Pathology Laboratories already using array comparative genomic hybridisation (CGH) with formalin-fixed paraffin-embedded (FFPE) samples, this assay presently stands as an efficient tool for the clinical management of intermediate GIST-patients.

Hepatic Artery Embolization for Liver Metastasis of Gastrointestinal Stromal Tumor Following Imatinib and Sunitinib Therapy

The purpose of the study is to determine the efficacy of hepatic artery embolization (HAE) as a therapy for gastrointestinal stromal tumor (GIST) in patients who are refractory to imatinib and sunitinib. After institutional review board approval, a retrospective review revealed 11 patients with GIST metastatic to the liver who underwent 15 HAEs between February 2002 and May 2013. These patients were stratified into two groups according to the previous treatment: (a) those treated with HAE as second-line treatment after failing first-line imatinib (n = 3) and (b) those treated with HAE as third-line therapy after failing first-line imatinib and second-line sunitinib (n = 8). Initial therapeutic response, overall survival (OS), progression-free survival (PFS), and safety were evaluated. Initial therapeutic response rates at 3months after HAE were 27.3% (95% confidence interval (CI), 6.0-61.0%) by Response Evaluation Criteria in Solid Tumor (RECIST) version 1.0 and 45.5% (95% CI, 16.7-76.6%) by modified RECIST (mRECIST). The median OS and PFS after HAE were 14.9 and 3.9months in group A and 23.8 and 3.4months in group B, respectively. No procedure-related mortality or major complication was observed. HAE is an effective and well-tolerated therapeutic option for GIST liver metastases. Although larger studies are necessary, HAE should be considered as an alternative or adjuvant to third-line or even second-line systemic treatment.