Gastrointestinal Stromal Tumors Research Articles

Computed tomography radiogenomics: A potential tool for prediction of molecular subtypes in gastric stromal tumor

BACKGROUND Preoperative knowledge of mutational status of gastrointestinal stromal tumors (GISTs) is essential to guide the individualized precision therapy. AIM To develop a combined model that integrates clinical and contrast-enhanced computed tomography (CE-CT) features to predict gastric GISTs with specific genetic mutations, namely KIT exon 11 mutations or KIT exon 11 codons 557-558 deletions. METHODS A total of 231 GIST patients with definitive genetic phenotypes were divided into a training dataset and a validation dataset in a 7:3 ratio. The models were constructed using selected clinical features, conventional CT features, and radiomics features extracted from abdominal CE-CT images. Three models were developed: ModelCT sign, modelCT sign + rad, and model CTsign + rad + clinic. The diagnostic performance of these models was evaluated using receiver operating characteristic (ROC) curve analysis and the Delong test. RESULTS The ROC analyses revealed that in the training cohort, the area under the curve (AUC) values for modelCT sign, modelCT sign + rad, and modelCT sign + rad + clinic for predicting KIT exon 11 mutation were 0.743, 0.818, and 0.915, respectively. In the validation cohort, the AUC values for the same models were 0.670, 0.781, and 0.811, respectively. For predicting KIT exon 11 codons 557-558 deletions, the AUC values in the training cohort were 0.667, 0.842, and 0.720 for modelCT sign, modelCT sign + rad, and modelCT sign + rad + clinic, respectively. In the validation cohort, the AUC values for the same models were 0.610, 0.782, and 0.795, respectively. Based on the decision curve analysis, it was determined that the modelCT sign + rad + clinic had clinical significance and utility. CONCLUSION Our findings demonstrate that the combined modelCT sign + rad + clinic effectively distinguishes GISTs with KIT exon 11 mutation and KIT exon 11 codons 557-558 deletions. This combined model has the potential to be valuable in assessing the genotype of GISTs.

Efficacy and histologic frequencies of endoscopic ultrasonography‐guided tissue acquisition using conventional fine‐needle aspiration needles for gastric subepithelial hypoechoic mass

AbstractIntroduction/PurposeFor gastric subepithelial lesions (GSELs) showing a hypoechoic mass (HM) on endoscopic ultrasonography (EUS) imaging, the utility of EUS‐guided tissue acquisition using conventional fine‐needle aspiration needles (EUS‐TA‐CFNAN) and the frequency of histological types remain unclear. This study aimed to examine this issue.MethodsThis prospective observational study enrolled 291 consecutive patients who underwent EUS‐TA‐CFNAN for GSELs showing an HM (GSELHM) on EUS imaging. Immunohistochemical analysis was performed for all EUS‐TA‐CFNAN and surgically resected specimens. The main outcome measures were the technical results of EUS‐TA‐CFNAN and the frequency of histological types in GSELHM.ResultsThe endoscopic ultrasound‐guided tissue acquisition using conventional fine‐needle aspiration needle diagnosis rate for GSELHM was 80.1% (95% confidence interval [CI]: 75.0–84.5, 233/291). It was significantly lower for antrum (P = 0.004) and lesions smaller than 2 cm (P = 0.003). There were no adverse events. The immunohistochemical diagnoses of EUS‐TA‐CFNAN included 149 cases of gastrointestinal stromal tumour (GIST) (51.2%), 48 cases of leiomyoma (16.5%), 11 cases of schwannoma (3.8%), 8 cases of the ectopic pancreas (2.7%), 5 cases of subepithelial lesion like cancer (1.7%), 12 cases of other lesions (4.1%), and 58 cases of undiagnosable lesions (19.9%). The frequency of malignant or potentially malignant tumour in GSELHM was 55.0% (95% CI: 49.1–60.8, 160/291). Surgery was performed in 149 patients according to the conclusive EUS‐TA‐CFNAN results, in which the diagnostic accuracy of EUS‐TA‐CFNAN was 97.3% (95% CI: 94.7–99.9, 145/149).ConclusionThe use of EUS‐TA‐CFNAN for GSELHMs is safe and accurate. Gastric subepithelial lesions showing a hypoechoic mass have a reasonably high possibility of containing malignant or potentially malignant tumours, including GISTs.

English version of Japanese Clinical Practice Guidelines 2022 for gastrointestinal stromal tumor (GIST) issued by the Japan Society of Clinical Oncology.

The Japan Society of Clinical Oncology Clinical Practice Guidelines 2022 for gastrointestinal stromal tumor (GIST) have been published in accordance with the Minds Manual for Guideline Development 2014 and 2017. A specialized team independent of the working group for the revision performed a systematic review. Since GIST is a rare type of tumor, clinical evidence is not sufficient to answer several clinical and background questions. Thus, in these guidelines, we considered that consensus among the experts who manage GIST, the balance between benefits and harms, patients' wishes, medical economic perspective, etc. are important considerations in addition to the evidence. Although guidelines for the treatment of GIST have also been published by the National Comprehensive Cancer Network (NCCN) and the European Society for Medical Oncology (ESMO), there are some differences between the treatments proposed in those guidelines and the treatments in the present guidelines because of the differences in health insurance systems among countries.

Comparable long‑term survival outcomes of endoscopic treatment versus surgical treatment for gastrointestinal stromal tumors with a diameter of 5–10 cm

Currently, endoscopic treatment for small gastrointestinal stromal tumors (GIST) has been widely accepted. However, for tumors larger than 5 cm, endoscopic treatment has not been recognized by national guidelines as the standard therapy due to concerns about safety and adverse tumor outcomes. Therefore, this study compares the long-term survival outcomes of endoscopic treatment and surgical treatment for GIST in the range of 5–10 cm. We selected patients with GIST from the Surveillance, Epidemiology, and End Results (SEER) database between 2004 and 2015. Kaplan–Meier analysis and the log-rank test were employed to compare the long-term survival outcomes between endoscopic treatment and surgical treatment. A multivariate Cox proportional hazards model was used for analysis to identify risk factors influencing patient prognosis. To balance baseline data, we performed 1:1 propensity score matching (PSM). A total of 1223 GIST patients were included, with 144 patients (11.8%) received endoscopic treatment and 1079 patients (88.2%) received surgical treatment. Before PSM, there was no significant difference in the long-term survival rates between the two groups [5-year OS (86.5% vs. 83.5%, P = 0.42), 10-year OS (70.4% vs. 66.7%, P = 0.42)]. After adjusting for covariates, we found that the overall survival (HR = 1.26, 95% CI 0.89–1.77, P = 0.19) and cancer-specific survival (HR = 1.69, 95% CI 0.99–2.89, P = 0.053) risks were comparable between the endoscopic treatment group and the surgical treatment group. In the analysis after PSM, there was no significant difference between the endoscopic treatment group and the surgical treatment group. Our study found that for GIST patients with tumor sizes between 5 and 10 cm, the long-term OS and CSS outcomes were similar between the endoscopic treatment group and the surgical treatment group.

Imaging Gigantic Small Bowel Gastrointestinal Stromal Tumours Through Different Radiological Lenses: A Case Report

Gastrointestinal stromal tumours (GIST) account for 1–3% of all the gastrointestinal (GI) neoplasms. It is the most common mesenchymal tumour in the Gl tract. The majority of GISTs are KIT gene positive; however, it is necessary to diagnose them pre-operatively. Here, the authors report the case of a 65-year-old male who presented with pain and a lump in the umbilical region for the last 2 years. On abdominal ultrasound, there was a heterogeneously hypoechoic mass in the umbilical region, with lobulated margins and central necrotic areas. On small bowel series, the core of the mass showed faint contrast opacification. Contrast-enhanced CT of the abdomen showed a heterogeneously enhancing, lobulated exophytic lesion arising from the small bowel loops, the central core of the lesion demonstrating an air-contrast level. Under ultrasound guidance, the lesion was biopsied. Histopathological findings were suggestive of a spindle cell tumour. The sample was c-KIT positive. Hence, the diagnosis of GIST was confirmed. The patient was given imatinib after resection of the mass. Usually, a GIST of larger size has higher malignant and metastatic potential; however, this article shows a gigantic small bowel GIST with cavitation and heterogeneity in different imaging modality, and still has no metastasis on imaging or high mitotic activity, and nuclear atypia on histopathology. A radiologist should also know the imaging pattern on conventional imaging and ultrasound, apart from usual cross-sectional imaging.

The advent of the first electric driven EUS-guided 17 gauge core needle biopsy – A pilot study on subepithelial lesions

Background and aims This pilot study aimed to evaluate safety and tissue sampling from subepithelial lesions (SEL) in the upper gastrointestinal tract with a novel electric motor driven endoscopic ultrasonography (EUS)-guided 17-gauge (G) size core needle biopsy (CNB) instrument. Methods An investigator-led prospective open label, performance and safety control study, including seven patients (female n = 4, median 71 y, range 28–75) with a determined SEL (median size 30 mm, range 17–150 mm) in the upper digestive tract (stomach n = 6, duodenum n = 1) were eligible and later followed up 14 days after index procedure. All investigations were completed according to protocol with three FNB 22-G passes with four fanning strokes and two EndoDrill® 17-G passes with three fanning strokes. Results Quality of samples as ‘visible pieces’ (>5 mm): FNB (n = 5/7) (fragmented/blood imbibed n = 1, poor tissue quantity n = 1) compared with 17-G CNB (n = 7/7). Histological result which led to final diagnosis (leiomyoma n = 2, adenocarcinoma n = 1, schwannoma n = 1, neuroendocrine tumour n = 1, desmoid tumour n = 1 and gastrointestinal stromal tumour (GIST) n = 1) could be obtained with the 17-G CNB instrument in all seven patients. FNB technique reached correct diagnosis in six patients. No serious adverse event were recorded. Conclusions By using an electric driven 17-G biopsy device, a true cylinder of core tissue can be obtained in one single puncture from the area of interest reducing the need for a second sampling. The absolute benefit of EUS-guided CNB is that the sample can be handled and histologically prepared in the same manner as standard percutaneous core needle sample, e.g., breast and prostate cancer.

Financial difficulties experienced by patients with gastrointestinal stromal tumours (GIST) in the Netherlands: data from a cross-sectional multicentre study

PurposeThis study aims to (1) explore the prevalence of patient-reported financial difficulties among GIST patients, differentiating between those currently undergoing tyrosine kinase inhibitor (TKI) treatment and those who are not; (2) investigate associations between financial difficulties and sociodemographic and clinical characteristics, work, cancer-related concerns, anxiety and depression and (3) study the impact of financial difficulties on health-related quality of life.MethodsA cross-sectional study was conducted among Dutch GIST patients diagnosed between 2008 and 2018, who were invited to complete a one-time survey between September 2020 and June 2021. Patients completed nine items of the EORTC item bank regarding financial difficulties, seven work-related questions, the Hospital Anxiety and Depression Scale, Cancer Worry Scale and EORTC QLQ-C30.ResultsIn total, 328 GIST patients participated (response rate 63.0%), of which 110 (33.8%) were on TKI treatment. Patients currently treated with TKIs reported significantly more financial difficulties compared to patients not on TKIs (17.3% vs 8.7%, p = 0.03). The odds of experiencing financial difficulties was 18.9 (95% CI 1.7–214.7, p = 0.02) times higher in patients who were less able to work due to their GIST diagnosis. Patients who experienced financial difficulties had significantly lower global quality of life and functioning, and more frequently reported psychological symptoms as compared to patients who did not report financial difficulties.ConclusionEven in a country where the costs of TKIs and follow-up care are covered by health insurance, financial difficulties can be present in GIST patients, especially in patients on TKI treatment, and may negatively influence the quality of life.

The application of artificial intelligence in EUS

ABSTRACT Artificial intelligence (AI) is an epoch-making technology, among which the 2 most advanced parts are machine learning and deep learning algorithms that have been further developed by machine learning, and it has been partially applied to assist EUS diagnosis. AI-assisted EUS diagnosis has been reported to have great value in the diagnosis of pancreatic tumors and chronic pancreatitis, gastrointestinal stromal tumors, esophageal early cancer, biliary tract, and liver lesions. The application of AI in EUS diagnosis still has some urgent problems to be solved. First, the development of sensitive AI diagnostic tools requires a large amount of high-quality training data. Second, there is overfitting and bias in the current AI algorithms, leading to poor diagnostic reliability. Third, the value of AI still needs to be determined in prospective studies. Fourth, the ethical risks of AI need to be considered and avoided.

Imaging of pediatric gastrointestinal tumors: A tertiary center experience over 19 years

PurposeGastrointestinal tract (GIT) tumors in children are rare and there is a scarcity of data on their imaging features. The purpose of this study was to determine thefrequency of various GIT tumor types in children and to identify key imaging characteristics. MethodsThis retrospective, single-center study was approved by the local ethics committee. Children with histologically proven GIT tumours (malignantand benign) who had imaging available on the institutional PACS between May 1, 2000 and Dec 31, 2019 were included. Demographic data and available imaging was reviewed by two blinded radiologists. ResultsIn total, 90 children (45 male, mean age 9.3 ± 4.3 years) with GIT tumours were included. The final diagnoses included polyps (n = 28), lymphomas/PTLD (n = 27), neuroendocrine tumours (n = 16), adenocarcinoma (n = 6), adenoma (n = 5), gastrointestinal stromal tumor (GIST) (n = 3), inflammatory myofibroblastic tumours (n = 2) and lastly leiomyoblastoma, leiomyoma and lipoma (1 each). All GIT segments were affected, but overall the small and large bowel had most lesions. Eighty-one percent children had a single lesion while remaining 19 % had multiple lesions. The neoplastic process manifested as intra-luminal lesion (58 %) or wall thickening (42 %) on imaging. Multiple cystic areas and vascular pedicle for polyps; and hypoechogenecity of the mass or wall thickening and aneurysmal dilatation for lymphomas, were the characteristic imaging features. None of the neuroendocrine tumours affecting appendix were seen on pre-resection imaging. ConclusionsVariety of benign and malignant tumors are seen throughout the childhood. Polyps, lymphomas and appendiceal neuroendocrine tumors are common lesions. Characteristic imaging features of juvenile polyps and lymphomas on ultrasound may help narrowing the differentials, and guide further work up.

Expression of TGF-β1 in Gastrointestinal Stromal Tumor (GIST) and the Occurrence of Frequent Desmoplasia.

Gastrointestinal stromal tumors (GISTs) are mesenchymal neoplasms with variable behavior characterized by differentiation toward the interstitial cells of Cajal occurring anywhere in the gastrointestinal stromal tract. Frequently, GISTs have fibrous stroma within tumor cell proliferation areas, which is unlike other types of malignant tumors. If this desmoplasia is active, there is a possibility that some sort of transmitter exists between GIST cells and cells related to fibrosis in the tumor cell proliferation areas. Transforming growth factor (TGF)-β isoforms, particularly TGF-β1, are critical for fibrosis pathogenesis. TGF-β1 regulation of myofibroblasts and fibroblasts during fibrosis is well described. The induced fibroblast activation resulting in myofibroblast differentiation has been reported as an important source of collagen, glycoproteins, proteoglycans, and matrix metallopeptidases in wound healing and fibrosis. However, there are a few reports on the relationship between TGF-β1 and GISTs. This study aims to clarify TGF-β1 expression in 30 gastric GISTs using immunohistochemistry and reverse transcription polymerase chain reaction (RT-PCR). For comparison, we also enrolled 30 samples of gastric tubular adenocarcinoma (GTAC). We confirmed TGF-β1 expression (H-score ≥50 points) in 57% of GIST and 13% of GTAC samples, a significant difference between the 2 tumor types (P=0.001). We examined the TGF-β1 mRNA expression of 3 representative GIST samples, each having their respective immunostained areas detected by RT-PCR. Finding TGF-β1 expression may indicate that this cytokine plays a part in the formation of desmoplasia within GIST cell proliferative areas.

[Gastrointestinal stromal tumors : Where do we stand?]

For more than 20 years gastrointestinal stromal tumors (GIST) have been aparadigm for atargeted treatment with tyrosine kinase inhibitors. Afundamental prerequisite for aneoadjuvant or adjuvant treatment of localized GIST or an additive treatment of metastatic GIST is the molecular typing of tumors, ideally at the initial diagnosis. In addition, the possibility of ahereditary or syndromic predisposition must be considered because this results in consequences for the treatment and adifferent follow-up strategy.

Abstract CT290: Trial in progress: Evaluation of the safety, tolerability, whole-body distribution, radiation dosimetry and antitumor activity of 177Lu-NeoB in patients with advanced solid tumors expressing gastrin-releasing peptide receptor (GRPR)

Abstract Introduction: Many common cancers such as breast, lung, and prostate, plus several less common malignancies such as gastrointestinal stromal tumors (GIST) and glioblastoma (GBM) express or are associated with the Gastrin-Releasing Peptide Receptor (GRPR). Therefore, GRPR could be utilized for the development of innovative approaches to tumor imaging and therapeutic interventions. NeoB is a new generation bombesin analog, which binds to GRPR with high affinity/specificity. The structure of NeoB permits radiolabeling with gallium-68 [68Ga] (for imaging) or lutetium-177 [177Lu] (for therapy), making it suitable for theranostics. Pre-clinical and early phase clinical data confirmed the utility of [68Ga]-NeoB for identification of GRPR-expressing tumors and demonstrated the in vitro and in vivo antitumor activity of [177Lu]-NeoB. In the Phase IIa part of this first-in-human study of [177Lu]-NeoB (NeoRay; NCT03872778), we aim to characterize the safety, tolerability, whole-body distribution, radiation dosimetry and antitumor activity of [177Lu]-NeoB in patients with selected advanced solid tumors known to express GRPR. Methods: The Phase IIa part of this Phase I/IIa multi-center, open-label study will enroll approximately 50 adult patients (age ≥18 years old) with advanced/metastatic cancers and for whom no standard therapy is available, tolerated or appropriate. Patients will be enrolled across 4 cohorts: HR-positive, HER2-negative breast cancer (Cohort A), prostate cancer (Cohort B), GIST (Cohort C) or any solid tumor overexpressing GRPR including recurrent GBM, and who have moderate renal impairment (CrCl ≥30 mL/min - <60 mL/min; Cohort D). Eligible patients must have at least one measurable lesion with confirmed uptake of [68Ga]-NeoB and have an ECOG performance status of ≤1. Patients will be treated with [177Lu]-NeoB at the recommended Phase II dose (9.25 GBq [250 mCi]) for a minimum of 2 treatment cycles, each lasting 6 weeks. The primary endpoints are assessment of the disease control rate with [177Lu]-NeoB in cohorts A, B and C, and evaluation of the pharmacokinetics (PK), biodistribution and radiation dosimetry in patients with impaired renal function (Cohort D). Secondary endpoints include assessment of the antitumor activity, PK, distribution, radiation dosimetry, and impact on the quality of life of patients in the [177Lu]-NeoB cohorts (A, B and C) as well as the safety and tolerability of both [177Lu]-NeoB and [68Ga]-NeoB across all cohorts. Citation Format: Erik Mittra, Andrei Iagaru, Astrid Van der Veldt, Luigi Aloj, Jeffrey Wong, Loic Djaileb, Dhrubajyoti Pathak, Yongmin Liu, Lilja Solnes. Trial in progress: Evaluation of the safety, tolerability, whole-body distribution, radiation dosimetry and antitumor activity of 177Lu-NeoB in patients with advanced solid tumors expressing gastrin-releasing peptide receptor (GRPR) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT290.

Abstract CT089: A phase 1 multi-center, open label, dose escalation study to evaluate the safety, pharmacokinetics (PK) and anti-tumor activity of T-1301, a novel small molecular multi-target kinase inhibitor, in patients with advanced solid tumors

Abstract Background: T-1301 is a novel small molecule multi-target kinase inhibitor, it also exhibited potent inhibitory activity against both wild type and mutant forms of various kinases, i.e., ABL1, FLT3, c-KIT, PDFGRA, RET, and TRKA. In in vitro studies, T-1301 effectively inhibited growth of acute myeloid leukemia (AML) as well as gastrointestinal stromal tumor (GIST) cells carrying mutations that are resistant to KIT-targeting tyrosine kinase inhibitors (TKIs) in clinical use. In animal studies, tumor regressions were observed in AML and GIST xenograft models, while growth inhibition were observed in various other types of solid tumor models. Method: This is an open label, multi-centered Phase 1 dose escalating study (NCT05156203). The primary objectives are to establish the maximal tolerated dose (MTD) and recommended Phase 2 dose (RP2D), and to assess the safety and tolerability of T-1301. The secondary objectives are to evaluate the pharmacokinetics (PK) and therapeutic response after receiving treatment. Eligible Patient should have histologically and cytologically confirmed advanced solid tumors (including lymphoma) with measurable or evaluable target lesion(s) per RICEST v1.1 and refractory to or without standard treatments, ECOG performance status 0-1, and adequate organ function. The dose escalation begins with accelerated titration and switch to the Bayesian Optimal Interval (BOIN) design when either one of the following events is observed in Cycle 1: the first instance of DLT, or any Grade 2 or higher drug-related adverse event (AE) in any patient. Then, at least 2 additional subjects are treated at the current dose level and the dose escalation will follow the Bayesian Optimal Interval (BOIN) design with cohorts of size 3-6.T-1301 is orally administered daily in a 28-day cycle (a 21-day consecutive dosing followed by a 7-day rest). The dosing schedule is once daily (QD) at the initial dose level and could be QD or twice daily starting with the second dose level according to the safety review committee (SRC) decision after reviewing the safety and PK data from each dose level. AEs are assessed according to CTCAE v5.0 and occurrence of dose limiting toxicity (DLT) is determined during the first cycle of treatment. The safety findings are reviewed by the SRC, which will determine the MTD and RP2D. Tumor response evaluation is performed after 2 cycles of treatment and assessed according to RECIST v1.1 criteria. For those who benefit from the study medication after 2 treatment cycles, intra-subject dose escalation for multiple times is allowed in extension study period. Patient recruitment began in December 2021 and is ongoing in Taiwan. Citation Format: Jen-Shi Chen, Ming-Huang Chen, Yi-Chang Liu, Wen-Chi Chou, Nai-Jung Chiang, Hui-Ching Wang, Ta-Sen Yeh, Shih-Feng Cho, Cheng-Hsu Wang, I-Fang Lee, Li-Tzong Chen. A phase 1 multi-center, open label, dose escalation study to evaluate the safety, pharmacokinetics (PK) and anti-tumor activity of T-1301, a novel small molecular multi-target kinase inhibitor, in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT089.

Treatment Access for Gastrointestinal Stromal Tumor in Predominantly Low- and Middle-Income Countries

Gastrointestinal stromal tumor (GIST) is a rare cancer treated with the tyrosine kinase inhibitors imatinib mesylate or sunitinib malate. In general, in low- and middle-income countries (LMICs), access to these treatments is limited. To describe the demographic characteristics, treatment duration, and survival of patients with GIST in LMICs treated with imatinib and sunitinib through The Max Foundation programs. This retrospective database cohort analysis included patients in 2 access programs administered by The Max Foundation: the Glivec International Patient Assistance Program (GIPAP), from January 1, 2001, to December 31, 2016, and the Max Access Solutions (MAS) program, January 1, 2017, to October 12, 2020. Sixty-six countries in which The Max Foundation facilitates access to imatinib and sunitinib were included. Participants consisted of patients with approved indications for imatinib, including adjuvant therapy in high-risk GIST by pathologic evaluation of resected tumor or biopsy-proven unresectable or metastatic GIST. All patients were reported to have tumors positive for CD117(c-kit) by treating physicians. A total of 9866 patients received treatment for metastatic and/or unresectable disease; 2100 received adjuvant imatinib; 49 received imatinib from another source and were only included in the sunitinib analysis; and 53 received both imatinib and sunitinib through The Max Foundation programs. Data were analyzed from October 13, 2020, to January 30, 2024. Demographic and clinical information was reported by treating physicians. Kaplan-Meier analysis was used to estimate time to treatment discontinuation (TTD) and overall survival (OS). An imputation-based informed censoring model estimated events for patients lost to follow-up after treatment with adjuvant imatinib. Patients who were lost to follow-up with metastatic or unresectable disease were presumed deceased. A total of 12 015 unique patients were included in the analysis (6890 male [57.6%]; median age, 54 [range, 0-100] years). Of these, 2100 patients were treated with imatinib in the adjuvant setting (median age, 54 [range 8-88] years) and 9866 were treated with imatinib for metastatic or unresectable disease (median age, 55 [range, 0-100] years). Male patients comprised 5867 of 9866 patients (59.5%) with metastatic or unresectable disease and 1023 of 2100 patients (48.7%) receiving adjuvant therapy. The median OS with imatinib for unresectable or metastatic disease was 5.8 (95% CI, 5.6-6.1) years, and the median TTD was 4.2 (95% CI, 4.1-4.4) years. The median OS with sunitinib for patients with metastatic or unresectable GIST was 2.0 (95% CI, 1.5-2.5) years; the median TTD was 1.5 (95% CI, 1.0-2.1) years. The 10-year OS rate in the adjuvant setting was 73.8% (95% CI, 67.2%-81.1%). In this cohort study of patients with GIST who were predominantly from LMICs and received orally administered therapy through the GIPAP or MAS programs, outcomes were similar to those observed in high-resource countries. These findings underscore the feasibility and relevance of administering oral anticancer therapy to a molecularly defined population in LMICs, addressing a critical gap in cancer care.

Duodenal gastrointestinal stromal tumor masquerading as an uncinate process pancreatic neoplasm.

Duodenal gastrointestinal stromal tumor masquerading as an uncinate process pancreatic neoplasm.

Laparoscopic Resection of Gastric GIST Tumor

After a patient is found to have a gastrointestinal stromal tumor (GIST), David Rattner, MD performs a laparoscopic resection, carefully avoiding the nerves of Latarjet. He then confirms the success of the procedure with an upper GI endoscopy.

Genomic and clinical characterization of a familial GIST kindred intolerant to imatinib

Familial gastrointestinal stromal tumors (GIST) are rare. We present a kindred with multiple family members affected with multifocal GIST who underwent whole genome sequencing of the germline and tumor. Affected individuals with GIST harbored a germline variant found within exon 13 of the KIT gene (c.1965T>G; p.Asn655Lys, p.N655K) and a variant in the MSR1 gene (c.877 C > T; p.Arg293*, pR293X). Multifocal GISTs in the proband and her mother were treated with preoperative imatinib, which resulted in severe intolerance. The clinical features of multifocal GIST, cutaneous mastocytosis, allergies, and gut motility disorders seen in the affected individuals may represent manifestations of the multifunctional roles of KIT in interstitial cells of Cajal or mast cells and/or may be suggestive of additional molecular pathways which can contribute to tumorigenesis.

Abstract 3142: NN3201, a novel c-Kit targeting ADC, exhibits robust preclinical anti-tumor efficacy in SCLC and GIST models

Abstract c-Kit (CD117) is a type III receptor tyrosine kinase (RTK), which is known to be activated upon binding to its cognate ligand stem cell factor (SCF) to induce critical signaling pathways involved in cell proliferation, survival, and differentiation. Indicative of poor prognosis, overexpression and activating mutations of c-Kit have been implicated in a variety of human cancers including small cell lung cancer (SCLC), gastrointestinal stromal tumors (GIST), and acute myelogenous leukemia (AML). While imatinib, a small molecule c-Kit inhibitor, has been a beneficial treatment for GIST, resistance eventually develops to the drug, moreover, shows limited efficacy in c-Kit overexpressing tumors such as SCLC. Herein, we developed NN3201, a novel c-Kit targeting antibody-drug conjugate (ADC), comprised of fully human 2G4 antibody with a picomolar binding affinity to c-Kit and cytotoxic monomethyl auristatin E (MMAE) as the payload. NN3201 displayed potent in vitro cytotoxicity in various wild-type and mutant c-Kit positive SCLC and GIST cell lines with IC50 in the nanomolar range. In addition, NN3201 was rapidly internalized and inhibited c-Kit-mediated signaling., NN3201 treatment resulted in the increased proportions of the sub G1 and G2/M in the c-Kit positive cancer cell lines, indicating that release of MMAE induced cell cycle arrest. Moreover, bystander effect was confirmed by co-culturing c-Kit high and negative cell lines. Most importantly, in mouse xenograft models, NN3201 showed a remarkable tumor growth inhibition of several wild type, mutant c-Kit positive, and imatinib resistant SCLC and GIST cell lines. Enhanced anti-tumor activity and delayed tumor growth were observed in an SOC-treated (etoposide and carboplatin) SCLC xenograft model, by NN3201 in comparison to second line SOC (topotecan or irinotecan). In the GLP study, repeated intravenous administration of NN3201 was well tolerated at all doses (0.5, 1, 2 mg/kg Q3Wx3) without unscheduled death. Dose-dependent, yet transient, cytotoxicity of NN3201 was observed in the bone marrow. We confirmed HNSTD (Highest Non-Severely Toxic Dose) of NN3201 to be 2 mg/kg through exploratory and GLP repeat dose toxicity studies as no serious irreversible toxicity was observed. Accumulating data suggest that NN3201 is a promising therapeutic alternative for the treatment of SCLC and GIST regardless of wild-type or activating mutations in c-Kit. Citation Format: Chansik Kim, Jin Gu Cho, TaeMin Wi, Jiwoo Moon, Han-Jik Ko, Jina Lee, Jin Woo Park, Yeonjy Lee, Sanghee Kim, Jin-Ock Kim, Jaeyoung Song, Sun-Hwa Lee, Sang Gyu Park. NN3201, a novel c-Kit targeting ADC, exhibits robust preclinical anti-tumor efficacy in SCLC and GIST models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3142.

Abstract 3928: Genomic landscape and estimation of immune infiltration of soft tissue sarcoma histology subtypes from the ORIEN network

Abstract Sarcomas encompass a group of malignant diseases arising from mesenchymal origins. Given their rarity and diversity, a fundamental understanding of the genomic underpinnings for many sarcoma subtypes is still lacking. Studies are often limited to one or several of the more common subtypes or a narrow evaluation of a broader sampling. We therefore report on one of the largest comprehensive omics evaluation in sarcomas to date, including whole exome sequencing (WES; n = 1170) and RNA-sequencing (n = 983) of tissues from 29 different sarcoma histologic subtypes collected at 13 institutions in the US as part of the Oncology Research Information Exchange Network (ORIEN). We identified recurrent somatic mutations previously identified in sarcomas (e.g. TP53, KIT) as well as other cancer types (e.g. BRCA1). The burden of putatively pathogenic driver point mutations was higher in metastatic samples (median = 3) as compared to primary tumor samples (median = 2; p < 0.001). We observed frequent copy number alterations including whole genome doubling more commonly in metastatic compared to primary tumors (23.4% vs. 16.9%; p = 0.0.25). Inspection of gene expression dimensionality reduction (UMAP) showed separation of gastrointestinal stromal tumors (GISTs), leiomyosarcomas, myxoid liposarcomas, and well/de-differentiated liposarcomas from the other histologies. Differential expression analysis for these four histologies with gene set enrichment analysis highlights the diversity of disease-specific pathways and need for sarcoma subtype-specific translational focus. Estimation of immune cell abundances based on RNA-seq followed by hierarchical clustering identified five immune subtypes. The subtypes ranged from low (clusters A, B) to high (clusters D, E) immune infiltration with higher abundance of T, B, Natural Killer (NK), and myeloid cells (FDR < 0.01). Intermediate immune group C was predominantly composed by GISTs and marked by an enrichment for NK cells (FDR < 0.01) compared to all groups except the immune “hot” group E; however, this immune group exhibited modest infiltration by other immune cell types. Notably, we observed significant differences in the overall survival of patients with sarcomas in immune enriched (C, D, E) compared to immune depleted clusters (A, B; p = 0.002). In summary, we report the genomic and expressional landscape of over 1000 sarcomas, representing one of the largest comprehensive profiling efforts in this disease. We identify the mutational and copy number variation landscape and observe differences between primary and metastatic samples. We highlight expression pathways that are enriched in histologic subtypes that cluster most distinctly from others, providing a subtype-specific roadmap for further translational efforts. Finally, we define immune enriched or depleted sarcoma subgroupings that carry a prognostic impact. Citation Format: Alex C. Soupir, Oscar E. Ospina, Dale Hedges, Jamie K. Teer, Michael D. Radmacher, David M. McKean, Nathan Seligson, Martin McCarter, Breelyn Wilkey, Greg Riedlinger, John Groundland, Benjamin J. Miller, Bryan Schneider, Reema Patel, Abdul Rafeh-Naqash, Stephen Edge, Bodour Salhia, Chris Moskaluk, Maggy Johns, Michelle L. Churchman, Oliver Hampton, David Liebner, Brooke L. Fridley, Andrew S. Brohl. Genomic landscape and estimation of immune infiltration of soft tissue sarcoma histology subtypes from the ORIEN network [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3928.

Abstract 1771: NYU Langone Genome PACT - Genome Profiling of Actionable Cancer Targets (LG-PACT) for clinical patient molecular diagnostics and treatment

Abstract Next-generation sequencing (NGS) for the detection of somatic variants has become the tool of choice in a variety of molecular oncology fields and in the clinic. Its use ranges from sequencing entire tumor genomes and transcriptomes to targeted clinical diagnostic gene panels. The NYU Langone Genome PACT assay is a qualitative in vitro diagnostic test that uses targeted next generation sequencing of formalin-fixed paraffin-embedded (FFPE) tumor tissue matched with normal specimens from patients to detect gene alterations in a 607-gene panel. Indications for testing are cancer (solid tumors or hematological malignancies) where a mutational profile from multiple genes would be informative for disease stratification, prognosis, or treatment options including targeted therapies and eligibility for clinical trials. The test is intended to provide information on somatic mutations including point mutations, copy number aberrations, and small insertions/deletions (indels) for diagnostic and treatment decisions. LG-PACT is a United States Food and Drug Administration (FDA) approved diagnostic test. The clinical interpretation of sequencing data of molecular tumor markers from NGS encompasses automated variant calling tools with human interpretation. The final mostly manual review of data is intensive, involving highly trained scientists, encompassing literature review, interpretation and tier classification by pathologists, who then provide a complete molecular diagnostic report to the treating oncologists. Since January 2022 to present (October 2023) we have provided clinical genomic reports for 1029 oncological cases from 124 different cancers and their subtypes, including Brain (489 cases incl. meningioma, glioma and glioblastoma), Gastrointestinal (123), Lung (114), among others. We first present the technical challenges of validating an NGS oncological diagnostic targeted assay for appropriate clinical grade accuracy and sensitivity acceptable for patient care. We show how copy number alterations provide a more comprehensive description of the tumors genomic profile. We then outline the actionability of targeted panel sequencing for our current patient cohort. Where analysis of variant detection has led to 47% (490) of our clinical tumor samples containing known tier 1 therapeutic variants. We conclude with presenting case studies that identify both the clinical utility and informatic challenges of variant calling specific to gene panel sequencing e.g., i) the capture of potential targetable rare and novel indels and multivariant mutations in exons 19 and 20 of EGFR, and ii) a unique KIT tandem duplication event in a gastrointestinal stromal tumor (GIST). We demonstrate the value in precision oncology for multiple cancer types and how the capture of unique variants can provide better targeted treatment options to cancer patients. Citation Format: Varshini Vasudevaraja, Yiying Yang, Jonathan Serrano, Kazimierz Wrzeszczynski, Matija Snuderl. NYU Langone Genome PACT - Genome Profiling of Actionable Cancer Targets (LG-PACT) for clinical patient molecular diagnostics and treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1771.