Therapy For Gastrointestinal Stromal Tumors Research Articles

S3032 Extra-Gastrointestinal Stromal Tumor (EGIST): An Unusual Case of Worsening Exertional Dyspnea

INTRODUCTION: Gastrointestinal stromal tumors (GISTs) are mesenchymal tumors of the gut. GISTs are rare, composing 0.1-3% of all gastrointestinal tumors. Exceedingly rare cases of GISTs have been identified outside of the GI tract and named extra-gastrointestinal stromal tumors (EGISTs). Here, we present a case of a large EGIST with multiple metastasis that initially presented with worsening exertional dyspnea. CASE DESCRIPTION/METHODS: An 83-year-old female with past medical history significant for hypertension and breast cancer status post lumpectomy and radiation therapy presented with worsening shortness of breath on exertion for 6 weeks. She also reported mild left upper quadrant abdominal pain, weakness, and decreased appetite. On physical exam, her abdomen was distended with splenomegaly noted. CTA of the chest shows right-sided pulmonary emboli without right ventricular strain and intra-abdominal ascites with a markedly enlarged spleen. US of lower extremities was positive for right femoral deep vein thrombosis. The patient was placed on heparin drip, which was later changed to Lovenox. Abdominal US shows multiple intrahepatic lesions and epigastric mass. CT of the abdomen and pelvis shows a large mass occupying a majority of the abdominal and pelvic cavities and multiple metastasis noted to liver and adrenal glands. Core biopsy of the abdominal mass showed high grade (Grade 2, x > 5 mitotic figures per 5 mm) GIST with necrosis. Tumor cells were positive for DOG1, CD117, and CD34. EGD revealed antral gastritis with biopsy positive for H. pylori. She was discharged and placed on Imatinib with repeat imaging after several months of Imatinib to evaluate for possible resection of disease. DISCUSSION: EGISTs are rare mesenchymal tumors that have been identified in the retroperitoneum and pelvis. GISTs result from activating mutations of proto-oncogenes c-KIT (CD117) or PDGFR-alpha. These activated proto-oncogenes increase tyrosine kinase receptor activity and result in stem cell proliferation. Roughly one third of GISTs have malignant potential and are prone to metastatic spread. GIST prognosis is multifactorial, depending on tumor size, mitotic potential, and metastatic invasion. Imatinib, a tyrosine kinase inhibitor, is the first-line therapy of metastatic GIST. In addition, surgical resection is the mainstay of therapy, especially in cases where the lesion is > 2 cm. In the 3 to 5 years post-treatment, close surveillance is warranted due to high risk of GIST recurrence.Figure 1.: Abdominal and Pelvic GIST on CT of the abdomen and pelvis.Figure 2.: Abdominal and Pelvic GIST on CT of the abdomen and pelvis.

Characteristics and targeted therapy of wild-type gastrointestinal stromal tumor

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor in the gastrointestinal tract. Approximately 10%-15% of GIST does not harbor any mutation in C-kit/PDGFRA genes and is defined as wild-type GIST. There are significant differences in molecular mechanisms and clinical characteristics between wild-type GIST and C-kit/PDGFRA-mutant GIST. Wild-type GIST can be divided into SDH-deficient GIST, NF1-related GIST, BRAF-mutant GIST, KRAS-mutant GIST and quadruple wild-type GIST according to different pathogenesis. We elucidate the clinical features and targeted therapy of wild-type GIST in order to provide reference for clinical practice.

Research advance of liquid biopsy in gastrointestinal stromal tumors

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumors in the gastrointestinal tract. Surgical resection is the only curative treatment, while imatinib is the first-line therapy for recurrent, metastatic, and unresectable GIST. However, more than half of GIST patients suffer from secondary resistance to imatinib within 2 years after treatment initiation. Therefore, early diagnosis, drug resistance and recurrence surveillance are critical for GIST patients. Liquid biopsy is a new method which utilizes the detection of tumor biomarkers in peripheral blood for early diagnosis and therapeutic efficacy assessment. In recent years, liquid biopsy has achieved significant research progress in several kinds of malignancy. This review aims at presenting an overview on research advance of liquid biopsy in GIST and may provide a new method for early diagnosis and therapeutic efficacy assessment of GIST.

Model-based Dose Individualization of Sunitinib in Gastrointestinal Stromal Tumors.

Various biomarkers have been proposed for sunitinib therapy in gastrointestinal stromal tumor (GIST). However, the lack of "real-life" comparative studies hampers the selection of the most appropriate one. We, therefore, set up a pharmacometric simulation framework to compare each proposed biomarker. Models describing relations between sunitinib exposure, adverse events (hand-foot syndrome, fatigue, hypertension, and neutropenia), soluble VEGFR (sVEGFR)-3, and overall survival (OS) were connected to evaluate the differences in survival and adverse events under different dosing algorithms. Various fixed dosing regimens [4/2 (weeks on/weeks off) or 2/1 (50 mg), and continuous daily dosing (37.5 mg)] and individualization approaches [concentration-adjusted dosing (CAD), toxicity-adjusted dosing (TAD), and sVEGFR-3-adjusted dosing (VAD)] were explored following earlier suggested blood sampling schedules and dose-reduction criteria. Model-based forecasts of biomarker changes were evaluated for predictive accuracy and the advantage of a model-based dosing algorithm was evaluated for clinical implementation. The continuous daily dosing regimen was predicted to result in the longest survival. TAD (24.5 months) and VAD (25.5 months) increased median OS as compared with a fixed dose schedule (19.9 and 21.5 months, respectively) and CAD (19.7 and 21.3 months, respectively), without markedly raising the risk of intolerable toxicities. Changes in neutrophil count and sVEGFR-3 were accurately forecasted in the majority of subjects (>65%), based on biweekly blood sampling. Dose adjustments based on the pharmacodynamic biomarkers neutrophil count and sVEGFR-3 can increase OS while retaining drug safety. Future efforts could explore the possibility of incorporating a model-based dose approach in clinical practice to increase dosing accuracy for these biomarkers.

Abstract 5181: Therapeutic targeting of GPR20, selectively expressed in gastrointestinal stromal tumor (GIST), with DS-6157a, an antibody-drug conjugate (ADC)

Abstract More than 85% of GISTs are driven by activating mutations in KIT proto-oncogene receptor tyrosine kinase (KIT) or platelet-derived growth factor receptor alpha (PDGFRA). Currently, the only approved treatments for GIST are KIT directed tyrosine kinase inhibitors (TKIs). However, treatment with approved TKIs eventually results in disease progression most often due to the development of secondary resistance mutations in KIT. In addition, these agents have limited activity in PDGFRA mutant GIST and KIT/PDGFRA wild type (WT) GIST as primary therapy. Therefore, it is essential to develop novel therapeutic strategies with different modes of action in advanced GIST. G protein-coupled receptor 20 (GPR20) is an orphan GPCR selectively and abundantly expressed in GIST. GPR20 expression is regulated by FOXF1 and ETV1, transcription factors that play critical roles in KIT-driven GIST initiation, proliferation, and survival. We hypothesize that GPR20 is a potential therapeutic target for ADC development for the treatment of GIST. In this study, 1) GPR20 and KIT protein expression was assessed by IHC staining on GIST samples from DFCI (n=144) and NCCHE (n=100) as well as on normal and malignant tissue microarrays obtained commercially, and 2) an anti-GPR20 ADC (DS-6157a) was generated to evaluate antitumor activity in GIST models and to assess safety. GPR20 was expressed in more than 88% of the GIST samples analyzed, with higher expression levels in samples that: (I) received multiple treatment lines compared to naïve/early treated samples, (II) expressed higher KIT levels, (III) were small intestinal GIST, and/or (IV) had no KIT mutation, including succinate dehydrogenase (SDH) deficient GIST and neurofibromatosis type 1 (NF1)-associated GIST. The interstitial cells of Cajal were the only normal cells positive for GPR20. Normal mast cells expressed KIT but not GPR20. DS-6157a is an ADC composed of a humanized anti-GPR20 antibody, a Gly-Gly-Phe-Gly tetra-peptide-based linker, and a DNA topoisomerase I (TOP1) inhibitor Dxd. DS-6157a exhibited GPR20 expression-dependent cell growth-inhibitory activity and induced tumor regression with dosing at 3 to 10 mg/kg in multiple GIST xenograft models. In addition, DS-6157a showed antitumor activity in a GIST patient-derived xenograft model that was resistant to imatinib, sunitinib, and regorafenib. In vitro, DS-6157a induced TOP1 inhibitor-associated markers of DNA damage (phosphorylation of Chk1) and apoptosis (cleaved PARP) in GPR20 expressing cells. In preclinical toxicology studies using rats and cynomolgus monkeys, the pharmacokinetics and safety profile of DS-6157a were favorable at up to 200 mg/kg and 30 mg/kg, respectively. These data support the clinical development of DS-6157a as a potential novel GIST therapy with activity in patients that are resistant, refractory, or intolerant to approved TKIs. Citation Format: Kenji Iida, Amr H. Abdelhamid, Akiko Kawano Nagatsuma, Tomoko Shibutani, Satoru Yasuda, Michiko Kitamura, Chiharu Hattori, Manabu Abe, Jun Hasegawa, Takuma Iguchi, Tsuyoshi Karibe, Takashi Nakada, Koichiro Inaki, Reiko Kamei, Yuki Abe, Jessica L. Andersen, Sandro Santagata, Matthew L. Hemming, Suzanne George, Toshihiko Doi, Atsushi Ochiai, George D. Demetri, Toshinori Agatsuma. Therapeutic targeting of GPR20, selectively expressed in gastrointestinal stromal tumor (GIST), with DS-6157a, an antibody-drug conjugate (ADC) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5181.

Inhibition of FGF2-Mediated Signaling in GIST-Promising Approach for Overcoming Resistance to Imatinib.

Inhibition of KIT-signaling is a major molecular target for gastrointestinal stromal tumor (GIST) therapy, and imatinib mesylate (IM) is known as the most effective first-line treatment option for patients with advanced, unresectable, and/or metastatic GISTs. We show here for the first time that the inhibition of KIT-signaling in GISTs induces profound changes in the cellular secretome, leading to the release of multiple chemokines, including FGF-2. IM increased migration, invasion, and colony formation of IM-resistant GISTs in an FGF2-dependent manner, whereas the use of blocking anti-FGF2 antibodies or BGJ398, a selective FGFR inhibitor, abolished these effects, thus suggesting that the activation of FGF2-mediated signaling could serve as a compensatory mechanism of KIT-signaling inhibited in GISTs. Conversely, FGF-2 rescued the growth of IM-naive GISTs treated by IM and protected them from IM-induced apoptosis, consistent with the possible involvement of FGF-2 in tumor response to IM-based therapy. Indeed, increased FGF-2 levels in serum and tumor specimens were found in IM-treated mice bearing IM-resistant GIST xenografts, whereas BGJ398 used in combination with IM effectively inhibited their growth. Similarly, increased FGF-2 expression in tumor specimens from IM-treated patients revealed the activation of FGF2-signaling in GISTs in vivo. Collectively, the continuation of IM-based therapy for IM-resistant GISTs might facilitate disease progression by promoting the malignant behavior of tumors in an FGF2-dependent manner. This provides a rationale to evaluate the effectiveness of the inhibitors of FGF-signaling for IM-resistant GISTs.

Retrospective analysis of prognostic factors affecting the recurrence and disease-free survival following surgical management of gastrointestinal stromal tumors.

The aim of this study was to evaluate the prognostic factors effecting recurrence risk and disease-free survival of the patients who were diagnosed as gastrointestinal stromal tumor after complete resection of the tumor with or without adjuvant therapy. Between the years 2005 and 2013, data of 71 patients including clinical and demographic features, tumor localizations, pathologic examinations, survival and recurrence rates were enrolled into this retrospective study. Male/female ratio was 1.71, and mean age was 60.27 ± 14.65 years. Forty-two (59.2%) patients had tumor in stomach, 16 (22.5%) in small bowel, whereas 12 (16.9%) had extra-gastrointestinal system and one patient (%1.4) had rectal localization. Modified NIH risk stratification scheme categorized 9 (12.68%) patients in very low-, 12 (16.90%) in low-, 21 (29.58%) patients in moderate-and 29 (40.85%) patients in high-risk group. Twenty-four (33.8%) patients had a metastatic disease at follow-up while 13 (18.3%) patients were metastatic at admission. R0 resection was successfully performed in 51 (71.8%) patients, while R1 resection in 9 (12.7%) and R2 resection in 11 (15.5%) were achieved. Mean follow-up time was 47.12 ± 33.52 months (range, 1-171 months). Nineteen (26.8%) patients demonstrated recurrence with a mean time of 22.16 ± 15.89 months (range, 3-57 months). During follow-up 17 (23.9%) patients were deceased. In univariate analysis, high-risk group, small bowel and extra-gastrointestinal system localization, R1-2 resection, necrosis, positive resection margin and invasion of surrounding tissues, metastatic disease and adjuvant therapy were statistically significant in terms of recurrence. Multivariate analysis presented small bowel and extra-gastrointestinal system localization, R2 resection, mitoses count, invasion and adjuvant therapy as independent prognostic risk factors affecting disease-free survival rates. The 1, 3 and 5 years of disease-free survival rates of the patients were 89.6%, 75.4%, 64.3%, respectively. As mentioned in the literature, the mainstay of curative therapy of gastrointestinal stromal tumor is surgery. In our study, not only small bowel, extra-gastrointestinal system localization and invasion of surrounding tissues by tumor, but also R2 resection that complicate the local control of the disease were represented as independent adverse prognostic factors for disease-free survival. Unfavourable clinical outcomes of adjuvant therapy over the disease-free survival was linked to higher tumor stage with metastatic disease and emphasized that prospective trials with more cases should be practiced.

Genomic characterizations of KIT and PDGFRA in Chinese pan-cancer patients.

e13654 Background: KIT and PDGFRA gene mutations have been identified as biomarkers for targeted therapy in gastrointestinal stromal tumor. Mutations and amplification of KIT and PDGFRA are also considered as potential targets in solid tumors in clinical trials. We assessed the characteristics of KIT and PDGFRA alterations in a variety of cancers and tried to provide genomic landscape of these genes. Methods: Formalin-fixed, paraffin-embedded (FFPE) tumors and their matched blood samples were collected from 10,010 patients for 450 cancer genes targeted next-generation sequencing (NGS) panel.The testing was carried out in a College of American Pathologists (CAP) accredited and Clinical Laboratory Improvement Amendments (CLIA) certified laboratory. Genomic alterations including single nucleotide variations, short and long insertions/deletions, copy number variations, and gene rearrangements were assessed. Results: Alterations of KIT and PDGFRA were detected 2.1% and 1.6% respectively in Chinese pan-cancer patients. KIT alterations was detected most frequently in gastrointestinal stromal tumor (68.8%), soft tissue sarcoma (10.8%), melanoma (10.3 %), thymic tumors (7.7%) and small cell lung cancer (5.1%), and PDGFRA alterations was detected in gastrointestinal stromal tumor (18.7%), melanoma (5.2 %), primary hepatic carcinoma (4.3%), bone sarcoma (4.2%) and soft tissue sarcoma (3.4%). Particularly, KIT and PDGFRA amplifications accounted for 0.68% and 0.58% respectively in pan-cancer patients and were highly co-existed. Conversely, KIT and PDGFRA mutations were mutually exclusive which indicated an independent role of driver genes. Furthermore, tumor with microsatellite instability high (MSI-H) status had a significantly higher rate of KIT or PDGFRA mutations compared to microsatellite stable (MSS) tumors (p < 0.001). Conclusions: KIT and PDGFRA alterations occurred in 2.1% and 1.6% respectively in Chinese pan-cancer patients and mutually exclusive with known driver genes. KIT and PDGFRA alterations may act as driving oncogenic factors across cancers and warrant drug development strategy.

Outcomes of patients (pts) with advanced gastro-intestinal stromal tumors (GIST) treated with multi-kinase inhibitors other than imatinib (IM) as first-line treatment.

11532 Background: IM is the standard first-line therapy in advanced GIST, with a median progression-free survival (PFS) of 30 months. Recent multi-kinase inhibitors (MKIs) such as nilotinib, dasatinib or masitinib have been tested as first-line therapies in phase II/III studies. This might theoretically result in increased PFS (by the addition of a new line of treatment), or in early emergence of resistance to approved MKIs. Methods: A retrospective chart review was performed in GIST pts who received investigational MKIs (in phase II/III trials) as first-line treatment, followed by IM as second line. Data on demographics, molecular profile, PFS, and overall survival (OS) were collected in two French referral centers. Results: Of 47 pts, (57% females), 22 (47%) had a KIT exon 11 mutation, one a KIT exon 9 mutation (2%), one a PDGFR D842V mutation (2%). Five patients were wild-type for KIT and PDGFR. The mutational status was unknown in 18 pts (38 %). From 2005 to 2011, 21 pts (45%) received masitinib, 18 (38%) received dasatinib and 8 pts (17%) received nilotinib. Median PFS on first-line treatment was 18.9 months [95%IC: 9.0-26.0]. Median time-to-failure (TTF) with IM was 19.7 months [95%IC: 14.8-53.4]. Median time to second relapse was 50.2 months [95%IC: 31.2-92.2]. Thirty-five patients (74.5%) were dead at the end of follow-up. The median OS from time of initial diagnosis was 5.9 years [95%IC: 4.5-8.2]. Conclusions: GIST pts who received MKIs other than IM as first-line treatment and IM as second-line had a time to second relapse longer than that observed historically with IM in first line. This suggests that using MKIs other than IM in first line does not decrease IM efficacy in second line. Further comparative studies are needed to confirm these findings, but this is encouraging to further develop studies with other MKIs in the first line setting.

Preoperative adjuvant therapy for locally advanced and recurrent/metastatic gastrointestinal stromal tumors: a retrospective study

BackgroundPreoperative imatinib mesylate therapy for gastrointestinal stromal tumors (GISTs) is controversial. This study aimed to explore the clinical efficacy and optimal duration of preoperative imatinib mesylate (IM) therapy in patients with locally advanced and recurrent/metastatic GISTs.MethodsWe retrospectively examined patients who received preoperative imatinib mesylate therapy from January 2013 to December 2018 at Xiangya Hospital, Central South University and the Second Xiangya Hospital of Central South University, China. Clinical data, including the results of tests for mutations in KIT and PDGFR, findings from regularly conducted re-examinations, abdominal-enhanced computed tomography/magnetic resonance imaging data, responses to imatinib, progression-free survival, and overall cancer-specific survival, were recorded.ResultsA total of 25 patients were enrolled in our study, including 18 with a locally advanced GIST and 7 with recurrent or metastatic GISTs. Their ages ranged from 22 to 70 years (M:F = 1.6:0.9), with a mean age of 50.48 ± 12.51 years. The tumor locations included the stomach (56.0%), rectum (16.0%), enterocoelic/retroperitoneal sites (12.0%), and the small intestine (12.0%). Based on testing for mutations in KIT and PDGFR, 22 patients received 400 mg/day KIT, and 3 patients received 600 mg/day PDGFR. The median duration of preoperative IM therapy was 8.96 ± 4.81 months, ranging from 3 to 26 months. According to the Choi criteria, 24 patients achieved a partial response (PR), and 1 patient had stable disease (SD). All patients underwent surgery after preoperative IM therapy, and no postoperative complications appeared. The 2-year PFS and 5-year PFS were 92% and 60%, respectively, and the total 5-year cancer-specific survival (CSS) was 92%.ConclusionPreoperative imatinib therapy is feasible for locally advanced and recurrent/metastatic GISTs and can effectively shrink the tumor size, allow organ sparing, and avoid extensive organ resection. Moreover, the optimal duration of preoperative IM therapy in patients with locally advanced and recurrent/metastatic GISTs was 8.96 ± 4.81 months, ranging from 3 to 26 months, and gastric GISTs had a better response to preoperative IM therapy than did non-gastric GISTs.

Pretreatment Tumor DNA Sequencing of KIT and PDGFRA in Endosonography-Guided Biopsies Optimizes the Preoperative Management of Gastrointestinal Stromal Tumors

BackgroundNeoadjuvant tyrosine kinase inhibitor (TKI) therapy increases the chance of organ-preserving, radical resection in selected patients with gastrointestinal stromal tumors (GISTs). We aimed to evaluate systematic, immediate DNA sequencing of KIT and PDGFRA in pretreatment GIST tissue to guide neoadjuvant TKI therapy and optimize preoperative tumor response.MethodsAll patients who were candidates for neoadjuvant therapy of a suspected GIST [the study cohort (SC)] were prospectively included from January 2014 to March 2018. Patients were subjected to pretreatment endosonography-guided fine-needle biopsy (EUS-FNB) or transabdominal ultrasound-guided needle biopsy (TUS-NB), followed by immediate tumor DNA sequencing (< 2 weeks). A historic (2006–2013) reference cohort (RC) underwent work-up without sequencing before neoadjuvant imatinib (n = 42). The rate of optimal neoadjuvant therapy (TherapyOPTIMAL) was calculated, and the induced tumor size reduction (Tumor RegressionMAX, %) was evaluated by computed tomography (CT) scan.ResultsThe success rate of pretreatment tumor DNA sequencing in the SC (n = 81) was 77/81 (95%) [EUS-FNB 71/74 (96%); TUS-NB 6/7 (86%)], with mutations localized in KIT (n = 58), PDGFRA (n = 18), or neither gene, wild type (n = 5). In patients with a final indication for neoadjuvant therapy, the TherapyOPTIMAL was higher in the SC compared with the RC [61/63 (97%) versus 33/42 (79%), p = 0.006], leading to a significantly higher Tumor RegressionMAX in patients treated with TKI (27% vs. 19%, p = 0.015).ConclusionsPretreatment endosonography-guided biopsy sampling followed by immediate tumor DNA sequencing of KIT and PDGFRA is highly accurate and valuable in guiding neoadjuvant TKI therapy in GIST. This approach minimizes maltreatment with inappropriate regimens and leads to improved tumor size reduction before surgery.Electronic supplementary materialThe online version of this article (10.1007/s40291-020-00451-0) contains supplementary material, which is available to authorized users.

Possibilities of targeted neoadjuvant therapy for gastrointestinal stromal tumors

Possibilities of targeted neoadjuvant therapy for gastrointestinal stromal tumors

Anticancer effects of dietary administration of secoisolariciresinol diglucoside in a patient of gastrointestinal stromal tumor: a case report

Introduction: Gastrointestinal stromal tumor (GIST) is among the leading malignancies of the digestive system. GIST is not susceptible to chemotherapies and is prone to recurrence or metastasis after surgical operation. Secoisolariciresinol diglucoside (SDG) was suggested to have potential anticancer effects, but no clinical evidence had been available. Here we report successful treatment of a postoperative GIST case with dietary SDG. Presentation of Case: The patient was a 58-year-old man. He had GIST and received resection of small intestinal lesions 1 year before. He was diagnosed with postoperation of GIST and presented with high level of serum carbohydrate antigen 72-4 (CA72-4). The patient was then treated with dietary administration of SDG with his voluntary acceptance for 5 months, and underwent 2 serum CA72-4 measurements during this period. CA72-4 level of the patient was restored to normal range after treatment with dietary SDG for 1 month. There was no aberrant CA72-4 level, recurrence or metastasis after the treatment with dietary SDG. Discussion: This is to our knowledge the first report on application of dietary SDG on a postoperative GIST patient with aberrant level of serum CA72-4. SDG can be transformed into active substances with antitumor effects by human gut bacteria. Dietary SDG might inhibit tumorigenicity and malignant behavior of GIST cells. Conclusion: The excellent effects suggest dietary SDG to be a potential therapy for GIST, especially against recurrence or metastasis.

Genetic Characterization of Molecular Targets in Korean Patients with Gastrointestinal Stromal Tumors.

PurposeGastrointestinal stromal tumors (GISTs) frequently harbor activating gene mutations in either KIT or platelet-derived growth factor receptor A (PDGFRA) and are highly responsive to several selective tyrosine kinase inhibitors. In this study, a targeted next-generation sequencing (NGS) assay with an Oncomine Focus Assay (OFA) panel was used for the genetic characterization of molecular targets in 30 Korean patients with GIST.Materials and MethodsUsing the OFA that enables rapid and simultaneous detection of hotspots, single nucleotide variants (SNVs), insertion and deletions (Indels), copy number variants (CNVs), and gene fusions across 52 genes relevant to solid tumors, targeted NGS was performed using genomic DNA extracted from formalin-fixed and paraffin-embedded samples of 30 GISTs.ResultsForty-three hotspot/other likely pathogenic variants (33 SNVs, 8 Indels, and 2 amplifications) in 16 genes were identified in 26 of the 30 GISTs. KIT variants were most frequent (44%, 19/43), followed by 6 variants in PIK3CA, 3 in PDGFRA, 2 each in JAK1 and EGFR, and 1 each in AKT1, ALK, CCND1, CTNNB1, FGFR3, FGFR4, GNA11, GNAQ, JAK3, MET, and SMO. Based on the mutation types, majority of the variants carried missense mutations (60%, 26/43), followed by 8 frameshifts, 6 nonsense, 1 stop-loss, and 2 amplifications.ConclusionsOur study confirmed the advantage of using targeted NGS with a cancer gene panel to efficiently identify mutations associated with GISTs. These findings may provide a molecular genetic basis for developing new drugs targeting these gene mutations for GIST therapy.

Renal Clearable Theranostic Nanoplatforms for Gastrointestinal Stromal Tumors.

Advances in molecular imaging modalities have accelerated the diagnosis and treatment of human diseases. However, tumors less than 1 cm in size still remain difficult to localize by conventional means because of the difficulty in specific targeting/delivery to the tumor site. Furthermore, high nonspecific uptake in the major organs and persistent background retention results in low tumor-to-background ratio. The targeting and therapy of gastrointestinal stromal tumors (GIST) using nonsticky and renal clearable theranostic nanoparticles (a.k.a. H-Dots) are demonstrated. H-Dots not only target GIST for image-guided surgery, but also tailor the fate of anticancer drugs such as imatinib (IM) to the tumor site resulting in efficient treatment of unresectable GIST. In addition, H-Dots can monitor targetability, pharmacokinetics, and drug delivery, while also showing therapeutic efficacy in GIST-bearing xenograft mice following surgical resection. More importantly, IM loaded H-Dots exhibit lower uptake into the immune system, improved tumor selectivity, and increased tumor suppression compared to free IM, which accumulates in the spleen/liver. Precisely designed H-Dots can be used as a promising theranostic nanoplatform that can potentially reduce the side effects of conventional chemotherapies.

Individualization of Drug Therapy Mode in a Patient with Disseminated Form of GIST by Determining Active Metabolites of the Drug (Tyrosine Kinase Inhibitor) in Blood Plasma

An own experience of effective treatment of a patient with a disseminated form of gastrointestinal stromal tumor (GIST) with a preparation from the group of tyrosine kinase inhibitors (imatinib) is presented.Relevance. Therapy of gastrointestinal stromal tumors is still a complex problem of modern oncology. Since 2001, a breakthrough has occurred in the treatment of patients with GISTO due to the successful use of a targeted drug from the group of tyrosine kinase inhibitors — imatinib, which is effective in the first line of inoperable and / or metastatic GISTs, and is also used for the neoadjuvant, adjuvant therapy of localized GISTs. The lack of response to therapy and, consequently, the progression of the disease, may be associated with a decrease in the therapeutic concentration of imatinib in the blood plasma. Determining the concentration of active metabolites of imatinib in the serum allows timely identification of potential causes of insufficient response to therapy and individual correction of the dose of the drug.Materials and methods. In order to determine the significance of the correlation between increasing / decreasing the dose of imatinib and achieving a therapeutic response, we used a laboratory method of high performance liquid chromatography to determine the concentration of imatinib in serum.Conclusion. Determination of the reduced concentration of active metabolites of imatinib in the blood plasma by high performance liquid chromatography with the detection of tandem mass spectrometry in a patient with disseminated form of GIST allowed to correct the dose of the drug and achieve a positive effect.

Gastrointestinal stromal tumors – Summary of mutational status of the primary/secondary KIT/PDGFRA mutations, BRAF mutations and SDH defects

The most important findings revealing pathogenesis, molecular characteristics, genotyping and targeted therapy of gastrointestinal stromal tumors (GISTs) are activated oncogenic mutations in KIT and PDGFRA genes. Imatinib mesylate (IM), which inhibits both KIT and PDGFRA receptors, significantly improved treatment of advanced (metastatic, recurrent, and/or inoperable) GISTs. However, in a significant number of patients the treatment fails due to the primary or secondary resistance to targeted therapy. Most common cause of secondary resistance is a presence of secondary mutations. Approximately 15% of adult patients with GISTs are negative for mutations in KIT or PDGFRA genes. These so-called wild-type GISTs appear to be characterized by other oncogenetic drivers, including mutations in BRAF, RAS, NF1 genes, and subunits of succinate dehydrogenase (SDH) complex.In the present study we investigated 261 tumour specimens from 239 patients with GIST. Primary mutations were detected in 82 % tumor specimens. 66 of them were in KIT, and 16 % in PDGFRA genes. Remaining 18 % were KIT/PDGFRA wild-type. Secondary KIT mutations were detected in 10 from 133 (7 %) patients treated with IM. We examined secondary KIT mutations in exons 13 and 17 and secondary PDGFRA mutation in exon 18 in sixteen progressive tumors and/or metastasis (from overall 22 samples). We identified BRAF V600E point mutation in 4 % of KIT/PDGFRA wild-type GIST patients. Moreover, we analysed SDH complex mutations in 4 younger patients (15, 33, 37, and 45 years old) from 44 patients without KIT, PDGFRA, and BRAF mutations. Two patients (a 37-year old man, and a 33-year old woman) had defects of the SDH complex.Our findings of mutational status of the primary and secondary KIT/PDGFRA mutations in patients with GIST confirm mechanisms of primary and secondary resistance, and also intralesional and interlesional heterogeneity of secondary mutations within and between progressive lesions. Moreover, detection of V600E BRAF mutation and defects of SDH complex in KIT/PDGFRA wild-type GISTs confirm their activation and allow for a selection of targeted therapy.

Regorafenib as second line therapy for imatinib-resistant gastrointestinal stromal tumor (GIST): A phase II study

Abstract Background Standard first line treatment for metastatic/recurrent gastrointestinal stromal tumor (GIST) is imatinib; however eventually almost all the GISTs become resistant to imatinib. Secondary mutation in KIT is the most relevant cause of imatinib-resistant, as high as 70% of cases. Sunitinib is the current standard second line treatment for imatinib-resistant GIST with median progression-free survival (PFS) of 24.6 weeks; however, in a preclinical study sunitinib is not active for approximately half of secondary mutant GIST. Regorafenib is active for some secondary mutations resistant to sunitinib in the preclinical study. Therefore, we conducted a prospective phase II study of regorafenib as second line therapy for imatinib-resistant GIST. Method Patients with imatinib-resistant metastatic/recurrent GIST were eligible for the current study. Other key inclusion criteria included patients with ECOG performance status of 0-1 and adequate organ function. Patients treated with sunitinib were excluded. The primary endpoint was PFS rate at 24 weeks. Tumor response, safety, and biomarkers were also analyzed. Results A total of 38 patients were enrolled as planned. Median age was 64.5 (39 - 80). Twenty-five patients were male. Primary site was stomach in 17, small intestine in 16. Best overall response was PR for 5 (13%), SD for 24 (63%) and PD for 6 (16%) patients, with response rate of 13%. Grade 3 or more adverse events (AE) were observed in 25 (66%) patients. Common grade 3 or more AE were hand-foot syndrome (n = 9), hypertension (n = 9), hepatotoxicity (n = 4), thrombocytopenia (n = 2), and proteinuria (n = 2). There was one treatment-related death (cerebral attack). The primary endpoint of PFS will be presented at the conference. Conclusion Regorafenib demonstrated promising activity in patients with imatinib-resistant GIST as second line therapy with acceptable toxicity.

Real world study and its application in gastrointestinal stromal tumor

Gastrointestinal stromal tumor (GIST) is a relatively rare type of gastrointestinal tract tumors. Thus, it is difficult to perform randomized controlled trials (RCTs) of GIST in a single center, which are often plagued by a small number of participants. Real world study (RWS) is a complement to the evidence derived from traditional RCT. Emerging sources of real world data offer enormous opportunity for deeper understanding of why treatments work (or not) and for whom. Evidence generated from RWD can help clarify best use of treatments for individuals and populations, and care value. Thus, RWS of GIST has attracted much attention. RWS helps us better understand the diagnosis, treatment, prognosis and outcome prediction of GIST in clinical practice. GIST is often misdiagnosed as other tumor. A diagnostic test provides evidence on how well a test correctly identifies or rules out GIST. Therapeutic research aims to evaluate the effectiveness and/or safety of a therapy for GIST. Prognostic research aims to forecast the likely outcome of GIST, explore the factors affecting the outcome, and analyze quality of life. Predictive research aims to quantify the probability of identification or health outcome of GIST based on a set of predictors. Pharmacoeconomic data in real world can evaluate the cost-effectiveness of medicinal products for GISTs and serve as a guidance tool for optimal healthcare resource allocation. Attaching importance to data sourse and data quality, strenthening communicate with a qualified statistician, and the implementation of a standardized process are necessary for performing a high-quality RWS.

Targeted therapy and personalized medicine in gastrointestinal stromal tumors: drug resistance, mechanisms, and treatment strategies.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract. Since the discovery that the KIT and PDGFRA receptor tyrosine kinases are the primary oncogenic drivers in the vast majority of GISTs, targeted therapy with tyrosine kinase inhibitors has been the mainstay of treatment for this disease. Using molecular profiling of tumor specimens, researchers also discovered that KIT and PDGFRA mutations are non-random and occur in specific regions of the receptors, and furthermore, that particular genotypes predicted response or resistance to targeted therapy. Imatinib, the first tyrosine kinase inhibitor used to treat GIST, remains the first-line therapy in advanced GIST and the only therapy confirmed through clinical trials in the adjuvant or neoadjuvant setting for resectable disease. Resistance to imatinib is well described and is either primary or secondary. Primary resistance is associated with specific tumor genotypes, so genotyping of individual patient tumors helps guide decision-making into whether to offer imatinib and at what dose. Secondary resistance occurs due to the acquisition of secondary mutations during therapy. Currently, the main strategy to combat imatinib resistance is to switch to another tyrosine kinase inhibitor, because imatinib-resistant GIST is usually still oncogenically addicted to KIT/PDGFRA signaling. Surgery can also be used to combat resistant disease in select settings. Unfortunately, progression-free and overall survival remains dismal for patients who develop imatinib-resistant disease, and further research into alternative strategies is still needed.