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1
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Hohenberger P, Rathmann N, Büsing K, Menge F, Jakob J, Pink D, Wardelmann E, Schoenberg SO, Diehl SJ. Selective internal radiation with Y-90 resin microspheres (SIRT) for liver metastases of gastro-intestinal stromal tumors (GIST) resistant to tyrosine kinase inhibitor (TKI) therapy. Br J Cancer 2025; 132:716-724. [PMID: 40044980 DOI: 10.1038/s41416-025-02952-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Revised: 12/20/2024] [Accepted: 01/31/2025] [Indexed: 04/16/2025] Open
Abstract
BACKGROUND Hepatic metastases of GIST might be the dominant site of progression and resistant to available tyrosine kinase inhibitors (TKIs). Selective internal radiation therapy (SIRT) offers treatment by intratumoral radiation up to 200 Gy. We analyzed the hepatic progression-free survival (H-PFS) in a consecutive patient cohort. METHODS Twenty-six patients (median age 57.6 years) with biopsy proven liver metastases of GIST were treated by SIRT. All had RECIST documented tumor progression, and 24/26 patients had up to four lines of pretreatment. Mutational status was 'quadruple wildtype' (q-wt, n = 5), KIT exon 11/9/13 in n = 15/4/1 cases and PDGFRα (n = 1). Median follow-up of this retrospective analysis of a prospectively kept database is 33.6 months. RESULTS Median H-PFS was 16 months (range, 4-54+ months, 95% CI 6.5-25.4 months) and OS after SIRT was 28 months (95% CI 17.2-28.7 months). Best H-PFS was observed in patients with 'q-wt' at 25 months (range, 6+-54 months, 95% CI 16.2-33.8 months). The worst outcome was for KIT exon 11 mutations plus secondary mutations with 7 months (range, 4-33 months, 95% CI, 4.2-9.8 months). CONCLUSIONS 90Y-SIRT is a potent treatment for patients with liver metastases of GIST resistant to TKI therapy. In patients with 'q-wt' GIST, SIRT is an option for first-line use.
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Affiliation(s)
- Peter Hohenberger
- Division of Surgical Oncology and Thoracic Surgery, University Medical Center Mannheim, Medical Faculty Mannheim - Heidelberg University, Heidelberg, Germany.
| | - Nils Rathmann
- Institute of Clinical Radiology and Nuclear Medicine, University Medical Center Mannheim, Medical Faculty Mannheim - Heidelberg University, Heidelberg, Germany
| | - Karen Büsing
- Institute of Clinical Radiology and Nuclear Medicine, University Medical Center Mannheim, Medical Faculty Mannheim - Heidelberg University, Heidelberg, Germany
| | - Franka Menge
- Division of Surgical Oncology and Thoracic Surgery, University Medical Center Mannheim, Medical Faculty Mannheim - Heidelberg University, Heidelberg, Germany
| | - Jens Jakob
- Department of Surgery Mannheim University Medical Center, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Daniel Pink
- Sarkomzentrum Berlin-Brandenburg, HELIOS Klinikum Berlin-Buch, Berlin, Germany
| | - Eva Wardelmann
- Sarkomzentrum Berlin-Brandenburg, HELIOS Klinikum Berlin-Buch, Berlin, Germany
- Gerhard Domagk Institute of Pathology, University Hospital Muenster, Muenster, Germany
| | - Stefan O Schoenberg
- Institute of Clinical Radiology and Nuclear Medicine, University Medical Center Mannheim, Medical Faculty Mannheim - Heidelberg University, Heidelberg, Germany
| | - Steffen J Diehl
- Institute of Clinical Radiology and Nuclear Medicine, University Medical Center Mannheim, Medical Faculty Mannheim - Heidelberg University, Heidelberg, Germany
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Flicek KT, Nehra AK, Fidler JL, Sheedy SP. Imaging of the Small Bowel Tumors. Radiol Clin North Am 2025; 63:345-359. [PMID: 40221179 DOI: 10.1016/j.rcl.2024.11.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/14/2025]
Abstract
Small bowel tumors are rare gastrointestinal tumors. Neuroendocrine tumors are the most common and demonstrate unique subtypes depending on their location. Adenocarcinomas are most common in the duodenum demonstrating luminal narrowing and irregularity. Gastrointestinal stromal tumors are heterogeneously enhancing lesions with endophytic and/or exophytic growth patterns. Immunotherapy is a unique treatment of these tumors with tumoral response best assessed with both routine computed tomography (CT) and PET/CT. Primary small bowel lymphoma has many imaging patterns, most commonly being aneurysmal dilation and thickening of the small bowel. Metastases are common and may present as polypoid lesions, focal wall thickening, or serosal deposits.
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Affiliation(s)
- Kristina T Flicek
- Department of Radiology, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905, USA.
| | - Avinash K Nehra
- Department of Radiology, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905, USA
| | - Jeff L Fidler
- Department of Radiology, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905, USA
| | - Shannon P Sheedy
- Department of Radiology, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905, USA
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Dedousis D, Gadra E, Van Galen J, von Mehren M. Recent Advances in Succinate Dehydrogenase Deficient Gastrointestinal Stromal Tumor Systemic Therapies. Curr Treat Options Oncol 2025; 26:227-240. [PMID: 40045030 DOI: 10.1007/s11864-025-01304-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/15/2025] [Indexed: 04/02/2025]
Abstract
OPINION STATEMENT Gastrointestinal stromal tumors (GIST) are the most common gastrointestinal soft tissue sarcomas, with an incidence of about 15 cases per million person-years. Approximately 15% of GIST develop due to succinate dehydrogenase deficiency (SDH-Def), and such tumors do not respond well to the tyrosine kinase inhibitors (TKIs) used to treat other GIST. Due to its indolent nature SDH-Def GIST can often be surveilled if asymptomatic. In our current practice we typically treat advanced symptomatic SDH-Def GIST with the anti-angiogenic TKIs, sequentially treating with sunitinib, regorafenib and pazopanib. This practice is based on limited data. This systematic review provides an update on new data (12/21/2021 to 9/26/2024) for systemic treatment of SDH-Def GIST, both with agents generally used to treat other GIST subtypes and with agents approved in other malignancies. Olverembatinib and rogaratinib have shown promising activity in pre-clinical models and small SDH-Def GIST cohorts. Other agents whose benefits are explored here include the immune checkpoint inhibitors (ICI) ipilimumab and nivolumab and temozolomide, whether as monotherapy or in combination with INBRX-109 (a pro-apoptotic antibody) or olaparib. Additional research into TKI agents with anti-vascular endothelial growth factor receptor (VEGFR) and anti-fibroblast growth factor receptor (FGFR) activity in this clinical setting is needed. Patients with SDH-Def will benefit more broadly from ongoing explorations of treatments with alternative mechanisms of action, especially those that exploit cellular pathways involved in SDH-Def GIST tumorigenesis.
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Affiliation(s)
- Demitrios Dedousis
- Department of Hematology/Oncology, Fox Chase Cancer Center, 333 Cottman Avenue , Philadelphia, PA, 19111, USA
| | - Elyse Gadra
- Lewis Katz School of Medicine, Temple University, Philadelphia, USA
| | - Joseph Van Galen
- Department of Hematology/Oncology, Fox Chase Cancer Center, 333 Cottman Avenue , Philadelphia, PA, 19111, USA
| | - Margaret von Mehren
- Department of Hematology/Oncology, Fox Chase Cancer Center, 333 Cottman Avenue , Philadelphia, PA, 19111, USA.
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4
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Yip D, Zalcberg J, Blay JY, Eriksson M, Espinoza D, Price T, Marreaud S, Italiano A, Steeghs N, Boye K, Underhill C, Gebski V, Simes J, Gelderblom H, Joensuu H. Imatinib alternating with regorafenib compared to imatinib alone for the first-line treatment of advanced gastrointestinal stromal tumor: The AGITG ALT-GIST intergroup randomized phase II trial. Br J Cancer 2025:10.1038/s41416-025-02983-w. [PMID: 40133509 DOI: 10.1038/s41416-025-02983-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Revised: 02/14/2025] [Accepted: 03/11/2025] [Indexed: 03/27/2025] Open
Abstract
BACKGROUND To determine if an alternating regimen of the tyrosine kinase inhibitors imatinib and regorafenib improved outcomes in patients with advanced gastrointestinal stromal tumors. METHODS ALTGIST (NCT02365441) was a randomized phase II study of standard treatment of imatinib (Arm A) compared with an experimental alternating regimen of imatinib and regorafenib (Arm B). Primary outcome was best objective tumor response (OTR) at nine months. RESULTS Seventy-six eligible patients (Arm A 36, Arm B 40) enrolled were evaluable. Median follow-up was 46.0 months (range 6.5-64.6). Best responses and OTR were similar at 9 months. Eighteen (50.0%) Arm A patients and twelve (30.0%) Arm B patients discontinued treatment due to progressive disease. No Arm A patients stopped protocol therapy due to unacceptable toxicity, with 12 (30.0%) stopping in Arm B. Twelve (33.2%) Arm A patients and 12 (30.0%) Arm B patients experienced at least one serious adverse event, mostly grade 3. Secondary endpoints of PFS at 1 and OS at 1 year were not statistically different. CONCLUSIONS Alternation of imatinib and regorafenib did not impact on 9 months objective response nor on the secondary objectives of PFS and OS. Patients in the alternating arm experienced more toxicity and protocol discontinuations. CLINICAL TRIAL REGISTRATION NCT02365441.
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Affiliation(s)
- Desmond Yip
- The Canberra Hospital and Australian National University, Canberra, ACT, Australia.
| | - John Zalcberg
- School of Public Health, Monash University, Melbourne, VIC, Australia
| | | | | | - David Espinoza
- NHMRC Clinical Trials Centre, The University of Sydney, Sydney, NSW, Australia
| | - Timothy Price
- Queen Elizabeth Hospital, University of Adelaide, Adelaide, SA, Australia
| | - Sandrine Marreaud
- European Organisation for Research and Treatment of Cancer (EORTC), Brussels, Belgium
| | | | - Neeltje Steeghs
- Department of Medical Oncology, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands
| | | | - Craig Underhill
- Albury-Wodonga Regional Cancer Centre, Albury-Wodonga, NSW, Australia
| | - Val Gebski
- NHMRC Clinical Trials Centre, The University of Sydney, Sydney, NSW, Australia
| | - John Simes
- NHMRC Clinical Trials Centre, The University of Sydney, Sydney, NSW, Australia
| | - Hans Gelderblom
- Leiden University Medical Centre, Department of Medical Oncology, Leiden, The Netherlands
| | - Heikki Joensuu
- Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland
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Schulz T, Gontla R, Teuber A, Beerbaum M, Fletcher BS, Mühlenberg T, Kaitsiotou H, Hardick J, Jeyakumar K, Keul M, Müller MP, Sievers S, Bauer S, Rauh D. Design, Synthesis, and SAR of Covalent KIT and PDGFRA Inhibitors─Exploring Their Potential in Targeting GIST. J Med Chem 2025; 68:3238-3259. [PMID: 39841084 DOI: 10.1021/acs.jmedchem.4c02472] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2025]
Abstract
Gastrointestinal stromal tumors (GIST), driven by KIT and PDGFRA mutations, are the most common mesenchymal tumors of the gastrointestinal tract. Although tyrosine kinase inhibitors (TKIs) have advanced treatment, resistance mutations and off-target toxicity limit their efficacy. This study develops covalent TKIs targeting drug-resistant GIST through structure-based design, synthesis, and biological evaluation. SAR studies provided key insights into mutant KIT and PDGFRA interactions, and the first crystal structure of PDGFRA bound to a covalent inhibitor is reported. These findings highlight the promise of covalent inhibitors for overcoming resistance and advancing safer, more effective therapies for advanced GIST.
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Affiliation(s)
- Tom Schulz
- Department of Chemistry and Chemical Biology, TU Dortmund University and Drug Discovery Hub Dortmund (DDHD), Zentrum für Integrierte Wirkstoffforschung (ZIW), Otto-Hahn-Strasse 4a, Dortmund 44227, Germany
| | - Rajesh Gontla
- Department of Chemistry and Chemical Biology, TU Dortmund University and Drug Discovery Hub Dortmund (DDHD), Zentrum für Integrierte Wirkstoffforschung (ZIW), Otto-Hahn-Strasse 4a, Dortmund 44227, Germany
| | - Alina Teuber
- Department of Chemistry and Chemical Biology, TU Dortmund University and Drug Discovery Hub Dortmund (DDHD), Zentrum für Integrierte Wirkstoffforschung (ZIW), Otto-Hahn-Strasse 4a, Dortmund 44227, Germany
| | - Maria Beerbaum
- Department of Chemistry and Chemical Biology, TU Dortmund University and Drug Discovery Hub Dortmund (DDHD), Zentrum für Integrierte Wirkstoffforschung (ZIW), Otto-Hahn-Strasse 4a, Dortmund 44227, Germany
| | - Benjamin S Fletcher
- Department of Medical Oncology and Sarcoma Center, West German Cancer Center, and DKTK partner site Essen, German Cancer Consortium (DKTK), University Duisburg-Essen, Medical School, Hufelandstraße 55, Essen 45122, Germany
| | - Thomas Mühlenberg
- Department of Medical Oncology and Sarcoma Center, West German Cancer Center, and DKTK partner site Essen, German Cancer Consortium (DKTK), University Duisburg-Essen, Medical School, Hufelandstraße 55, Essen 45122, Germany
| | - Helena Kaitsiotou
- Department of Chemistry and Chemical Biology, TU Dortmund University and Drug Discovery Hub Dortmund (DDHD), Zentrum für Integrierte Wirkstoffforschung (ZIW), Otto-Hahn-Strasse 4a, Dortmund 44227, Germany
| | - Julia Hardick
- Department of Chemistry and Chemical Biology, TU Dortmund University and Drug Discovery Hub Dortmund (DDHD), Zentrum für Integrierte Wirkstoffforschung (ZIW), Otto-Hahn-Strasse 4a, Dortmund 44227, Germany
| | - Kirujan Jeyakumar
- Department of Chemistry and Chemical Biology, TU Dortmund University and Drug Discovery Hub Dortmund (DDHD), Zentrum für Integrierte Wirkstoffforschung (ZIW), Otto-Hahn-Strasse 4a, Dortmund 44227, Germany
| | - Marina Keul
- Department of Chemistry and Chemical Biology, TU Dortmund University and Drug Discovery Hub Dortmund (DDHD), Zentrum für Integrierte Wirkstoffforschung (ZIW), Otto-Hahn-Strasse 4a, Dortmund 44227, Germany
| | - Matthias P Müller
- Department of Chemistry and Chemical Biology, TU Dortmund University and Drug Discovery Hub Dortmund (DDHD), Zentrum für Integrierte Wirkstoffforschung (ZIW), Otto-Hahn-Strasse 4a, Dortmund 44227, Germany
| | - Sonja Sievers
- Max Planck Institute of Molecular Physiology, Compound Management and Screening Center (COMAS), Otto-Hahn-Straße 11, Dortmund 44227, Germany
| | - Sebastian Bauer
- Department of Medical Oncology and Sarcoma Center, West German Cancer Center, and DKTK partner site Essen, German Cancer Consortium (DKTK), University Duisburg-Essen, Medical School, Hufelandstraße 55, Essen 45122, Germany
| | - Daniel Rauh
- Department of Chemistry and Chemical Biology, TU Dortmund University and Drug Discovery Hub Dortmund (DDHD), Zentrum für Integrierte Wirkstoffforschung (ZIW), Otto-Hahn-Strasse 4a, Dortmund 44227, Germany
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6
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Cicala CM, Matito J, Quindos M, Gómez-Peregrina D, Romero-Lozano P, Fernández-Suárez P, Valverde C, González M, Landolfi S, Pérez-Albert P, Gros L, Vivancos A, Serrano C. Targeted Next-Generation Sequencing in Succinate Dehydrogenase-Deficient GI Stromal Tumor Identifies Actionable Alterations in the PI3K/mTOR Pathway. JCO Precis Oncol 2025; 9:e2400497. [PMID: 39787462 DOI: 10.1200/po-24-00497] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Revised: 10/29/2024] [Accepted: 11/22/2024] [Indexed: 01/12/2025] Open
Abstract
PURPOSE Less than 5% of GI stromal tumors (GISTs) are driven by the loss of the succinate dehydrogenase (SDH) complex, resulting in a pervasive DNA hypermethylation pattern that leads to unique clinical features. Advanced SDH-deficient GISTs are usually treated with the same therapies targeting KIT and PDGFRA receptors as those used in metastatic GIST. However, these treatments display less activity in the absence of alternative therapeutic options. Therefore, it is critical to identify novel actionable alterations in SDH-deficient GIST. PATIENTS AND METHODS We performed a single-center, retrospective analysis of patients with SDH-deficient GIST together with next-generation sequencing (NGS) analysis from their respective tumor samples to identify mutations and copy number alterations and chromosomal alterations. NGS-tailored treatment was implemented whenever possible. RESULTS Seventeen tumor samples from 14 patients with SDH-deficient GIST underwent NGS. Mutational load was low, although three patients (21%) displayed molecular events in relapse samples leading to PI3K/mTOR pathway hyperactivation. mTOR inhibition with everolimus obtained a sustained tumor response in a heavily pretreated patient. Other alterations, largely present in late-stage patients, uncovered genes involved in cell cycle regulation, telomere maintenance, and DNA damage repair. Chromosomal arm-level alterations differed from the canonical cytogenetic progression in KIT/PDGFRA-mutant GIST. CONCLUSION This molecular landscape of SDH-deficient GIST uncovers novel molecular alterations, mostly in relapse and/or previously pretreated patients. The identification of genetic events leading to PI3K/mTOR dysregulation together with the remarkable activity of everolimus in one patient showcases the clinical relevance of this pathway, validates the utility of NGS in this population, and poses everolimus as a novel therapeutic alternative. Several other alterations were found at the genetic and genomic levels, underscoring novel biological processes likely involved during tumor evolution.
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Affiliation(s)
- Carlo María Cicala
- Sarcoma Translational Research Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
- Department of Medical Oncology, Vall d'Hebron University Hospital, Barcelona, Spain
| | - Judit Matito
- Cancer Genomics Group, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - María Quindos
- Medical Oncology Department, Complexo Hospitalario Universitario de A Coruña. Biomedical Research Institute (INIBIC), A Coruña, Spain
| | - David Gómez-Peregrina
- Sarcoma Translational Research Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Paula Romero-Lozano
- Vall d'Hebron Institute of Research (VHIR), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - Paula Fernández-Suárez
- Abdominal Imaging, Radiodiagnostic Department, Complexo Hospitalario Universitario de A Coruña, A Coruña, Spain
| | - Claudia Valverde
- Department of Medical Oncology, Vall d'Hebron University Hospital, Barcelona, Spain
| | - Macarena González
- Department of Medical Oncology, Vall d'Hebron University Hospital, Barcelona, Spain
| | - Stefania Landolfi
- Pathology Department, Vall d'Hebron University Hospital, Barcelona, Spain
| | - Paula Pérez-Albert
- Paediatric Oncology and Hematology Department, Vall d'Hebron University Hospital, Barcelona, Spain
- Childhood Cancer and Blood Disorders Group, Vall d'Hebron Institute of Research (VHIR), Barcelona, Spain
| | - Luis Gros
- Paediatric Oncology and Hematology Department, Vall d'Hebron University Hospital, Barcelona, Spain
- Childhood Cancer and Blood Disorders Group, Vall d'Hebron Institute of Research (VHIR), Barcelona, Spain
| | - Ana Vivancos
- Cancer Genomics Group, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - César Serrano
- Sarcoma Translational Research Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
- Department of Medical Oncology, Vall d'Hebron University Hospital, Barcelona, Spain
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7
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Cai W, Guo K, Chen Y, Shi Y, Chen J. Sub-regional CT Radiomics for the Prediction of Ki-67 Proliferation Index in Gastrointestinal Stromal Tumors: A Multi-center Study. Acad Radiol 2024; 31:4974-4984. [PMID: 39033048 DOI: 10.1016/j.acra.2024.06.036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Revised: 06/18/2024] [Accepted: 06/22/2024] [Indexed: 07/23/2024]
Abstract
RATIONALE AND OBJECTIVES The objective was to assess and examine radiomics models derived from contrast-enhanced CT for their predictive capacity using the sub-regional radiomics regarding the Ki-67 proliferation index (PI) in patients with pathologically confirmed gastrointestinal stromal tumors (GIST). METHODS In this retrospective study, a total of 412 GIST patients across three institutions (223 from center 1, 106 from center 2, and 83 from center 3) was enrolled. Radiomic features were derived from various sub-regions of the tumor region of interest employing the K-means approach. The Least Absolute Shrinkage and Selection Operator (LASSO) regression was employed to identify features correlated with Ki-67 PI level in GIST patients. A support vector machine (SVM) model was then constructed to predict the high level of Ki-67 (Ki-67 index >8%), drawing on the radiomics features from each sub-region within the training cohort. RESULTS After features selection process, 6, 9, 9, 7 features were obtained to construct SVM models based on sub-region 1, 2, 3 and the entire tumor, respectively. Among different models, the model developed by the sub-region 1 achieved an area under the receiver operating characteristic curve (AUC) of 0.880 (95% confidence interval [CI]: 0.830 to 0.919), 0.852 (95% CI: 0.770-0.914), 0.799 (95% CI: 0.697-0.879) in the training, external test set 1, and 2, respectively. CONCLUSION The results of the present study suggested that SVM model based on the sub-regional radiomics features had the potential of predicting Ki-67 PI level in patients with GIST.
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Affiliation(s)
- Wemin Cai
- Department of Emergency, Wenzhou Hospital of Integrated Traditional Chinese and Western Medicine, Wenzhou 325000, China; Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Kun Guo
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Yongxian Chen
- Department of Chest cancer, Xiamen Second People's Hospital, Xiamen 36100, China
| | - Yubo Shi
- Department of Pulmonary, Yueqing People's Hospital, Wenzhou 325000, China
| | - Junkai Chen
- Department of Emergency, Wenzhou Hospital of Integrated Traditional Chinese and Western Medicine, Wenzhou 325000, China.
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Meyer M, Ota H, Messiou C, Benson C, Henzler T, Mattonen SA, Marin D, Bartsch A, Schoenberg SO, Riedel RF, Hohenberger P. Prospective evaluation of quantitative response parameter in patients with Gastrointestinal Stroma Tumor undergoing tyrosine kinase inhibitor therapy-Impact on clinical outcome. Int J Cancer 2024; 155:2047-2057. [PMID: 39023303 DOI: 10.1002/ijc.35094] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Revised: 05/18/2024] [Accepted: 06/04/2024] [Indexed: 07/20/2024]
Abstract
The purpose of this study was to determine if dual-energy CT (DECT) vital iodine tumor burden (ViTB), a direct assessment of tumor vascularity, allows reliable response assessment in patients with GIST compared to established CT criteria such as RECIST1.1 and modified Choi (mChoi). From 03/2014 to 12/2019, 138 patients (64 years [32-94 years]) with biopsy proven GIST were entered in this prospective, multi-center trial. All patients were treated with tyrosine kinase inhibitors (TKI) and underwent pre-treatment and follow-up DECT examinations for a minimum of 24 months. Response assessment was performed according to RECIST1.1, mChoi, vascular tumor burden (VTB) and DECT ViTB. A change in therapy management could be because of imaging (RECIST1.1 or mChoi) and/or clinical progression. The DECT ViTB criteria had the highest discrimination ability for progression-free survival (PFS) of all criteria in both first line and second line and thereafter treatment, and was significantly superior to RECIST1.1 and mChoi (p < .034). Both, the mChoi and DECT ViTB criteria demonstrated a significantly early median time-to-progression (both delta 2.5 months; both p < .036). Multivariable analysis revealed 6 variables associated with shorter overall survival: secondary mutation (HR = 4.62), polymetastatic disease (HR = 3.02), metastatic second line and thereafter treatment (HR = 2.33), shorter PFS determined by the DECT ViTB criteria (HR = 1.72), multiple organ metastases (HR = 1.51) and lower age (HR = 1.04). DECT ViTB is a reliable response criteria and provides additional value for assessing TKI treatment in GIST patients. A significant superior response discrimination ability for median PFS was observed, including non-responders at first follow-up and patients developing resistance while on therapy.
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Affiliation(s)
- Mathias Meyer
- Department of Radiology and Nuclear Medicine, University Medical Center Mannheim, Medical Faculty Mannheim-Heidelberg University, Mannheim, Germany
- Department of Radiology, Duke University Medical Center, Durham, North Carolina, USA
- Department of Diagnostic and Interventional Radiology and Nuclear Medicine, University Hospital Hamburg-Eppendorf, Hamburg, Germany
| | - Hideki Ota
- Department of Diagnostic Radiology, Tohoku University Hospital, Miyagi, Japan
| | - Christina Messiou
- Department of Radiology, Royal Marsden Hospital and Institute of Cancer Research, London, UK
| | | | - Thomas Henzler
- Department of Radiology and Nuclear Medicine, University Medical Center Mannheim, Medical Faculty Mannheim-Heidelberg University, Mannheim, Germany
| | - Sarah A Mattonen
- Department of Medical Biophysics, Western University, London, Canada
| | - Daniele Marin
- Department of Radiology, Duke University Medical Center, Durham, North Carolina, USA
| | - Anna Bartsch
- Department of Radiology and Nuclear Medicine, University Medical Center Mannheim, Medical Faculty Mannheim-Heidelberg University, Mannheim, Germany
- Department of Orthopedics and Traumatology, University Hospital Basel, Basel, Switzerland
| | - Stefan O Schoenberg
- Department of Radiology and Nuclear Medicine, University Medical Center Mannheim, Medical Faculty Mannheim-Heidelberg University, Mannheim, Germany
| | - Richard F Riedel
- Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina, USA
| | - Peter Hohenberger
- Division of Surgical Oncology and Thoracic Surgery, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany
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9
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Kanda T, Ichikawa H, Ishikawa T, Muneoka Y, Kano Y, Naito T, Suzuki S, Wakai T. Fourteen-year follow-up results of imatinib therapy in patients with unresectable and metastatic gastrointestinal stromal tumors. Int J Clin Oncol 2024; 29:1870-1877. [PMID: 39343814 DOI: 10.1007/s10147-024-02631-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Accepted: 09/17/2024] [Indexed: 10/01/2024]
Abstract
BACKGROUND Imatinib therapy is the gold standard for the treatment of unresectable and metastatic gastrointestinal stromal tumors (GISTs). However, few studies have reported the long-term outcomes of the treatment. METHODS Seventy patients who underwent imatinib therapy for unresectable and metastatic GISTs were enrolled between 2001 and 2009, and follow-up data were collected until October 2023. One hundred and sixty-eight months had passed since the final enrollment. The outcome measures were patient survival and the status of GIST and imatinib therapy. The cumulative incidence of disease progression (PD) and the chronological changes in PD hazard rate (HR) were also analyzed. RESULTS The 5-, 10-, 15-, and 20-year overall survival rates were 64.3%, 30.0%, 16.8%, and 12.2%, respectively. Sixty of the 70 enrolled patients died before the data cutoff date: 47 (78.3%) patients died of GIST progression while the remaining 13 (21.7%) died of diseases other than GISTs. The cumulative incidence of PD logarithmically increased, and PD continued even after 10 years of treatment. PD HR decreased over time to reach the lowest value at 9.6 years after the initiation of treatment (HR 0.00027; 95% CI 0.00007-0.00174) and after that formed a small peak at 13 years (HR 0.00144; 95% CI 0.00043-0.00436). CONCLUSIONS Imatinib therapy showed high clinical efficacy in terms of long-term survival in GIST patients. However, patients undergoing imatinib therapy were at continuous risk of PD even after the 10-year treatment. Long-term treatment and follow-up beyond 10 years are necessary for unresectable and metastatic GIST patients.
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Affiliation(s)
- Tatsuo Kanda
- Department of Gastroenterology, Southern TOHOKU General Hospital, 7-115 Yatsuyamada, Koriyama, Fukushima, 963-8563, Japan.
| | - Hiroshi Ichikawa
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Niigata, Japan
| | - Takashi Ishikawa
- Department of Surgery, Saiseikai Niigata Kenoh Kikan Hospital, Sanjo, Niigata, Japan
| | - Yusuke Muneoka
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Niigata, Japan
| | - Yosuke Kano
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Niigata, Japan
| | - Tetsuya Naito
- Department of Surgery, Nagaoka Red Cross Hospital, Nagaoka, Niigata, Japan
| | - Satoshi Suzuki
- Department of Surgery, Tsuruoka Municipal Shonai Hospital, Tsuruoka, Yamagata, Japan
| | - Toshifumi Wakai
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Niigata, Japan
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10
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Haller V, Reiff C, Hamacher R, Kostbade K, Kaths M, Treckmann J, Bertram S, Zaun Y, Bauer S, Falkenhorst J. Overall survival of patients with KIT-mutant metastatic GIST in the era of multiple kinase inhibitor availability. J Cancer Res Clin Oncol 2024; 150:489. [PMID: 39516299 PMCID: PMC11549121 DOI: 10.1007/s00432-024-05965-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Accepted: 09/19/2024] [Indexed: 11/16/2024]
Abstract
PURPOSE The prognosis of patients with metastatic GIST and imatinib-sensitive primary mutations has significantly improved. However, limited data are available to inform patients about outcomes across different lines of treatment. This retrospective analysis aims to evaluate patient outcomes at a large German GIST referral center over the past 15 years. PATIENTS AND METHODS Overall survival (OS) and progression-free survival (PFS) were analyzed in patients with metastatic GIST, with diagnosis of metastases between 2008 and 2021, when at least three lines of treatment were available in Germany (n = 174). RESULTS The median overall survival far exceeds historical data for patients with primary exon 11 and exon 9 mutations (median OS in palliative treatment with imatinib: 7.1 years; median OS in second-line palliative treatment with sunitinib: 2.9 years; median OS in third-line palliative treatment with regorafenib: 1.9 years). Among those patients who received palliative imatinib treatment, no significant difference in median OS survival was observed between those who had received perioperative imatinib for localized disease and those who did not. Furthermore, the location of metastases significantly impacted survival, whereas the time between the initial diagnosis and the diagnosis of metastases had no significant effect on survival. CONCLUSION In conclusion, this study provides a novel, real-world reference for survival outcomes in patients with metastatic GIST.
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Affiliation(s)
- Valerie Haller
- Department of Medical Oncology and Sarcoma Center, West German Cancer Center, University Hospital Essen, Essen, Germany
- German Cancer Consortium (DKTK), Partner Site University Hospital Essen, Essen, Germany
| | - Carina Reiff
- Department of Medical Oncology and Sarcoma Center, West German Cancer Center, University Hospital Essen, Essen, Germany
- German Cancer Consortium (DKTK), Partner Site University Hospital Essen, Essen, Germany
| | - Rainer Hamacher
- Department of Medical Oncology and Sarcoma Center, West German Cancer Center, University Hospital Essen, Essen, Germany
- German Cancer Consortium (DKTK), Partner Site University Hospital Essen, Essen, Germany
| | - Karina Kostbade
- Department of Medical Oncology and Sarcoma Center, West German Cancer Center, University Hospital Essen, Essen, Germany
- German Cancer Consortium (DKTK), Partner Site University Hospital Essen, Essen, Germany
| | - Moritz Kaths
- German Cancer Consortium (DKTK), Partner Site University Hospital Essen, Essen, Germany
- Department of Visceral and Transplantation Surgery, University Hospital Essen, Essen, Germany
| | - Juergen Treckmann
- German Cancer Consortium (DKTK), Partner Site University Hospital Essen, Essen, Germany
- Department of Visceral and Transplantation Surgery, University Hospital Essen, Essen, Germany
| | - Stefanie Bertram
- German Cancer Consortium (DKTK), Partner Site University Hospital Essen, Essen, Germany
- Department of Pathology, University Hospital Essen, Essen, Germany
| | - Yasmin Zaun
- Department of Medical Oncology and Sarcoma Center, West German Cancer Center, University Hospital Essen, Essen, Germany
- German Cancer Consortium (DKTK), Partner Site University Hospital Essen, Essen, Germany
| | - Sebastian Bauer
- Department of Medical Oncology and Sarcoma Center, West German Cancer Center, University Hospital Essen, Essen, Germany.
- German Cancer Consortium (DKTK), Partner Site University Hospital Essen, Essen, Germany.
| | - Johanna Falkenhorst
- Department of Medical Oncology and Sarcoma Center, West German Cancer Center, University Hospital Essen, Essen, Germany
- German Cancer Consortium (DKTK), Partner Site University Hospital Essen, Essen, Germany
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11
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Habringer S, Ihlow J, Kleo K, Klostermann A, Schmidt M, Chai L, Knödler M, Leyvraz S, Sigler C, Sinn B, Maschmeyer G, Jegodka Y, Benary M, Ott CE, Tinhofer I, Schäfer R, Möbs M, Keller U, Keilholz U, Rieke DT. A diagnostic challenge of KIT p.V559D and BRAF p.G469A mutations in a paragastric mass. Oncologist 2024; 29:908-912. [PMID: 38886160 PMCID: PMC11448896 DOI: 10.1093/oncolo/oyae137] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Accepted: 05/15/2024] [Indexed: 06/20/2024] Open
Abstract
A patient with gastrointestinal stroma tumor (GIST) and KIT p.V559D and BRAF p.G469A alterations was referred to our institutional molecular tumor board (MTB) to discuss therapeutic implications. The patient had been diagnosed with B-cell chronic lymphocytic leukemia (CLL) years prior to the MTB presentation. GIST had been diagnosed 1 month earlier. After structured clinical annotation of the molecular alterations and interdisciplinary discussion, we considered BRAF/KIT co-mutation unlikely in a treatment-naïve GIST. Discordant variant allele frequencies furthermore suggested a second malignancy. NGS of a CLL sample revealed the identical class 2 BRAF alteration, thus supporting admixture of CLL cells in the paragastric mass, leading to the detection of 2 alterations. Following the MTB recommendation, the patient received imatinib and had a radiographic response. Structured annotation and interdisciplinary discussion in specialized tumor boards facilitate the clinical management of complex molecular findings. Coexisting malignancies and clonal hematopoiesis warrant consideration in case of complex and uncommon molecular findings.
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Affiliation(s)
- Stefan Habringer
- Department of Hematology, Oncology and Cancer Immunology, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin 12203, Germany
- German Cancer Consortium (DKTK), Berlin 10115, Germany
| | - Jana Ihlow
- Berlin Institute of Health (BIH), Charité - Universitätsmedizin Berlin, Berlin 10178, Germany
- Institute of Pathology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin 10117, Germany
| | - Karsten Kleo
- Institute of Pathology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin 10117, Germany
| | - Anna Klostermann
- Charité Comprehensive Cancer Center, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin 10117, Germany
| | - Max Schmidt
- Charité Comprehensive Cancer Center, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin 10117, Germany
| | - Lidan Chai
- Charité Comprehensive Cancer Center, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin 10117, Germany
| | - Maren Knödler
- Charité Comprehensive Cancer Center, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin 10117, Germany
| | - Serge Leyvraz
- Charité Comprehensive Cancer Center, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin 10117, Germany
| | - Christian Sigler
- Charité Comprehensive Cancer Center, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin 10117, Germany
| | - Bruno Sinn
- Institute of Pathology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin 10117, Germany
| | - Georg Maschmeyer
- Department of Hematology, Oncology and Cancer Immunology, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin 12203, Germany
| | - Yvette Jegodka
- Charité Comprehensive Cancer Center, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin 10117, Germany
| | - Manuela Benary
- Berlin Institute of Health (BIH), Charité - Universitätsmedizin Berlin, Berlin 10178, Germany
- Charité Comprehensive Cancer Center, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin 10117, Germany
| | - Claus-Eric Ott
- Institut für Medizinische Genetik und Humangenetik, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin 13353, Germany
| | - Ingeborg Tinhofer
- Department of Radiooncology and Radiotherapy, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin 10115, Germany
| | - Reinhold Schäfer
- Charité Comprehensive Cancer Center, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin 10117, Germany
| | - Markus Möbs
- Institute of Pathology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin 10117, Germany
| | - Ulrich Keller
- Department of Hematology, Oncology and Cancer Immunology, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin 12203, Germany
- German Cancer Consortium (DKTK), Berlin 10115, Germany
| | - Ulrich Keilholz
- German Cancer Consortium (DKTK), Berlin 10115, Germany
- Charité Comprehensive Cancer Center, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin 10117, Germany
| | - Damian T Rieke
- Department of Hematology, Oncology and Cancer Immunology, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin 12203, Germany
- German Cancer Consortium (DKTK), Berlin 10115, Germany
- Charité Comprehensive Cancer Center, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin 10117, Germany
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12
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Tsai HJ, Shan YS, Yang CY, Hsiao CF, Tsai CH, Wang CC, Lin MT, Ting CF, Chan DC, Chen TH, Yen CC, Chen YY, Lin HY, Yeh TS, Ho CL, Shieh TY, Bai LY, Hsu JT, Chen IS, Chen LT, Yeh CN. Survival of advanced/recurrent gastrointestinal stromal tumors treated with tyrosine kinase inhibitors in Taiwan: a nationwide registry study. BMC Cancer 2024; 24:828. [PMID: 38992597 PMCID: PMC11238460 DOI: 10.1186/s12885-024-12567-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2023] [Accepted: 06/26/2024] [Indexed: 07/13/2024] Open
Abstract
BACKGROUND Most gastrointestinal stromal tumors (GISTs) harbor c-KIT or PDGFRA mutations. Administration of tyrosine kinase inhibitors (TKIs) has significantly improved the survival of patients with GISTs. We aimed to evaluate the clinical outcome of advanced or recurrent GIST patients in Taiwan. METHODS Patients diagnosed between 2010 and 2020 were enrolled. The collected data included baseline characteristics, treatment pattern, treatment outcome, genetic aberrations and survival status. Progression-free survival (PFS) and overall survival (OS) were analyzed and plotted with the Kaplan-Meier method. Cox regression analysis was used to analyze the prognostic factors of survival. RESULTS A total of 224 patients with advanced or recurrent GISTs treated with TKIs were enrolled. All patients received imatinib treatment. Ninety-three and 42 patients received sunitinib and regorafenib treatment, respectively. The 48-month PFS and OS rates for patients treated with imatinib were 50.5% and 79.5%, respectively. c-KIT exon 9 and PDGFRA mutations were prognostic factors for a poor PFS and PDGFRA mutation was a prognostic factor for a poor OS in patients treated with imatinib in multivariate Cox regression analysis. The median PFS of patients who received sunitinib treatment was 12.76 months (95% confidence interval (CI), 11.01-14.52). Patients with c-KIT exon 9 mutations had a longer PFS than those with other genetic aberrations. The median PFS of patients treated with regorafenib was 7.14 months (95% CI, 3.39-10.89). CONCLUSIONS We present real-world clinical outcomes for advanced GIST patients treated with TKIs and identify mutational status as an independent prognostic factor for patient survival.
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Affiliation(s)
- Hui-Jen Tsai
- National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan
- Department of Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Division of Hematology and Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Yan-Shen Shan
- Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Ching-Yao Yang
- Department of Surgery, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Chin-Fu Hsiao
- Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan
| | - Chung-Hsin Tsai
- Department of Surgery, MacKay Memorial Hospital and Mackay Medical College, Taipei, Taiwan
| | - Chuan-Cheng Wang
- Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan
| | - Ming-Tsan Lin
- Department of Surgery, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Chun-Fu Ting
- Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - De-Chuan Chan
- Division of General Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Te-Hung Chen
- Department of Surgery, China Medical University Hospital, China Medical University, Taichung, Taiwan
| | - Chueh-Chuan Yen
- Division of Medical Oncology, Center for Immuno-Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan
- Division of Clinical Research, Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan
- School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Institute of Biopharmaceutical Sciences, College of Pharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Yen-Yang Chen
- Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Hsuan-Yu Lin
- Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan
| | - Ta-Sen Yeh
- Division of General Surgery, Department of Surgery, Chang Gung Memorial Hospital, Linkou, Chang Gung University, Taoyuan, Taiwan
| | - Ching-Liang Ho
- Division of Hematology and Oncology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
- Division of Hematology and Oncology, Medical Department, Taipei Tzu Chi Hospital, Taipei, Taiwan
| | - Tze-Yu Shieh
- Division of Gastroenterology, Department of Internal Medicine, Mackay Memorial Hospital, Taipei, Taiwan
| | - Li-Yaun Bai
- Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Jun-Te Hsu
- Division of General Surgery, Department of Surgery, Chang Gung Memorial Hospital, Linkou, Chang Gung University, Taoyuan, Taiwan
| | - I-Shu Chen
- Division of General Surgery, Department of Surgery, Kaohsiung Veterans General Hospital and National Yang Ming Chiao Tung University, Kaohsiung, Taiwan
| | - Li-Tzong Chen
- National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan.
- Department of Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
- Center for Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan.
- Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
| | - Chun-Nan Yeh
- Division of General Surgery, Department of Surgery, Chang Gung Memorial Hospital, Linkou, Chang Gung University, Taoyuan, Taiwan.
- Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital at Linkou, Chang Gung University, Taoyuan, Taiwan.
- School of Medicine, National Tsing Hua University, Hsinchu, Taiwan.
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13
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Kim M, Shim HS, Kim S, Lee IH, Kim J, Yoon S, Kim HD, Park I, Jeong JH, Yoo C, Cheon J, Kim IH, Lee J, Hong SH, Park S, Jung HA, Kim JW, Kim HJ, Cha Y, Lim SM, Kim HS, Lee CK, Kim JH, Chun SH, Yun J, Park SY, Lee HS, Cho YM, Nam SJ, Na K, Yoon SO, Lee A, Jang KT, Yun H, Lee S, Kim JH, Kim WS. Clinical practice recommendations for the use of next-generation sequencing in patients with solid cancer: a joint report from KSMO and KSP. J Pathol Transl Med 2024; 58:147-164. [PMID: 39026440 PMCID: PMC11261170 DOI: 10.4132/jptm.2023.11.01] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Revised: 10/31/2023] [Accepted: 11/01/2023] [Indexed: 07/20/2024] Open
Abstract
In recent years, next-generation sequencing (NGS)-based genetic testing has become crucial in cancer care. While its primary objective is to identify actionable genetic alterations to guide treatment decisions, its scope has broadened to encompass aiding in pathological diagnosis and exploring resistance mechanisms. With the ongoing expansion in NGS application and reliance, a compelling necessity arises for expert consensus on its application in solid cancers. To address this demand, the forthcoming recommendations not only provide pragmatic guidance for the clinical use of NGS but also systematically classify actionable genes based on specific cancer types. Additionally, these recommendations will incorporate expert perspectives on crucial biomarkers, ensuring informed decisions regarding circulating tumor DNA panel testing.
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Affiliation(s)
- Miso Kim
- Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Hyo Sup Shim
- Department of Pathology, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Sheehyun Kim
- Department of Genomic Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - In Hee Lee
- Department of Oncology/Hematology, Kyungpook National University Chilgok Hospital, School of Medicine, Kyungpook National University, Daegu, Korea
| | - Jihun Kim
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Shinkyo Yoon
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Hyung-Don Kim
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Inkeun Park
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Jae Ho Jeong
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Changhoon Yoo
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Jaekyung Cheon
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - In-Ho Kim
- Division of Medical Oncology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jieun Lee
- Division of Medical Oncology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Sook Hee Hong
- Division of Medical Oncology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Sehhoon Park
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Hyun Ae Jung
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jin Won Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
| | - Han Jo Kim
- Division of Oncology and Hematology, Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Korea
| | - Yongjun Cha
- Division of Medical Oncology, Center for Colorectal Cancer, National Cancer Center, Goyang, Korea
| | - Sun Min Lim
- Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
| | - Han Sang Kim
- Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
| | - Choong-Kun Lee
- Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
| | - Jee Hung Kim
- Division of Medical Oncology, Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Sang Hoon Chun
- Division of Medical Oncology, Department of Internal Medicine, Bucheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jina Yun
- Division of Hematology/Oncology, Department of Medicine, Soonchunhyang University Bucheon Hospital, Bucheon, Korea
| | - So Yeon Park
- Department of Pathology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
| | - Hye Seung Lee
- Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Yong Mee Cho
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Soo Jeong Nam
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Kiyong Na
- Department of Pathology, Kyung Hee University Hospital, Kyung Hee University College of Medicine, Seoul, Korea
| | - Sun Och Yoon
- Department of Pathology, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Ahwon Lee
- Department of Hospital Pathology, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Kee-Taek Jang
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Hongseok Yun
- Department of Genomic Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Sungyoung Lee
- Department of Genomic Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Jee Hyun Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
| | - Wan-Seop Kim
- Department of Pathology, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, Korea
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14
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Kim M, Shim HS, Kim S, Lee IH, Kim J, Yoon S, Kim HD, Park I, Jeong JH, Yoo C, Cheon J, Kim IH, Lee J, Hong SH, Park S, Jung HA, Kim JW, Kim HJ, Cha Y, Lim SM, Kim HS, Lee CK, Kim JH, Chun SH, Yun J, Park SY, Lee HS, Cho YM, Nam SJ, Na K, Yoon SO, Lee A, Jang KT, Yun H, Lee S, Kim JH, Kim WS. Clinical Practice Recommendations for the Use of Next-Generation Sequencing in Patients with Solid Cancer: A Joint Report from KSMO and KSP. Cancer Res Treat 2024; 56:721-742. [PMID: 38037319 PMCID: PMC11261187 DOI: 10.4143/crt.2023.1043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Accepted: 11/17/2023] [Indexed: 12/02/2023] Open
Abstract
In recent years, next-generation sequencing (NGS)-based genetic testing has become crucial in cancer care. While its primary objective is to identify actionable genetic alterations to guide treatment decisions, its scope has broadened to encompass aiding in pathological diagnosis and exploring resistance mechanisms. With the ongoing expansion in NGS application and reliance, a compelling necessity arises for expert consensus on its application in solid cancers. To address this demand, the forthcoming recommendations not only provide pragmatic guidance for the clinical use of NGS but also systematically classify actionable genes based on specific cancer types. Additionally, these recommendations will incorporate expert perspectives on crucial biomarkers, ensuring informed decisions regarding circulating tumor DNA panel testing.
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Affiliation(s)
- Miso Kim
- Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Hyo Sup Shim
- Department of Pathology, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Sheehyun Kim
- Department of Genomic Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - In Hee Lee
- Department of Oncology/Hematology, Kyungpook National University Chilgok Hospital, School of Medicine, Kyungpook National University, Daegu, Korea
| | - Jihun Kim
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Shinkyo Yoon
- Department of Oncology,Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Hyung-Don Kim
- Department of Oncology,Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Inkeun Park
- Department of Oncology,Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Jae Ho Jeong
- Department of Oncology,Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Changhoon Yoo
- Department of Oncology,Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Jaekyung Cheon
- Department of Oncology,Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - In-Ho Kim
- Division of Medical Oncology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jieun Lee
- Division of Medical Oncology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Sook Hee Hong
- Division of Medical Oncology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Sehhoon Park
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Hyun Ae Jung
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jin Won Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
| | - Han Jo Kim
- Division of Oncology and Hematology, Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Korea
| | - Yongjun Cha
- Division of Medical Oncology, Center for Colorectal Cancer, National Cancer Center, Goyang, Korea
| | - Sun Min Lim
- Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
| | - Han Sang Kim
- Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
| | - Choong-kun Lee
- Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
| | - Jee Hung Kim
- Division of Medical Oncology, Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Sang Hoon Chun
- Division of Medical Oncology, Department of Internal Medicine, Bucheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jina Yun
- Division of Hematology/Oncology, Department of Medicine, Soonchunhyang University Bucheon Hospital, Bucheon, Korea
| | - So Yeon Park
- Department of Pathology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
| | - Hye Seung Lee
- Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Yong Mee Cho
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Soo Jeong Nam
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Kiyong Na
- Department of Pathology, Kyung Hee University Hospital, Kyung Hee University College of Medicine, Seoul, Korea
| | - Sun Och Yoon
- Department of Pathology, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Ahwon Lee
- Department of Hospital Pathology, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Kee-Taek Jang
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Hongseok Yun
- Department of Genomic Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Sungyoung Lee
- Department of Genomic Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Jee Hyun Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
| | - Wan-Seop Kim
- Department of Pathology, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, Korea
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15
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Li J, Huang Z, Zhou H, Li H, Zhang J. Survival outcomes and prognostic factors of advanced gastrointestinal stromal tumors: in the era of multiple tyrosine kinase inhibitors. J Gastrointest Oncol 2024; 15:931-945. [PMID: 38989429 PMCID: PMC11231870 DOI: 10.21037/jgo-24-63] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Accepted: 04/26/2024] [Indexed: 07/12/2024] Open
Abstract
Background Tyrosine kinase inhibitors (TKIs) have shown great efficacy in the treatment of advanced gastrointestinal stromal tumors (GISTs), significantly prolonging the survival of patients. In the era of imatinib, a few studies reported some prognostic factors for patients with advanced GISTs, such as age, sex, performance status, diameter of the largest lesions, KIT exon mutations, and some hematological examination results. However, with the advent of more TKIs, the prognostic factors for patients with advanced GISTs have not been fully understood in the era of multiple TKIs. In this study, we aimed to identify independent prognostic factors associated with the survival of patients diagnosed with advanced GISTs. Methods Data on clinicopathologic characteristics, treatment approaches, and survival were retrospectively collected for patients with primary unresectable or recurrent GISTs treated from January 2010 to July 2023 at the First Affiliated Hospital of Chongqing Medical University, China. Univariable and multivariable Cox proportional hazards regression models were used to identify independent prognostic factors of survival. Results A total of 194 patients were included in the analysis. The median follow-up duration was 59.9 months (range, 2.7-141.7 months). The median overall survival (mOS) in this cohort was 76.5 months (95% confidence interval, 63.4 to 89.6 months). All patients received TKI therapy during the follow-up period, and 56.2% received two or more types of TKIs. In multivariable Cox analysis, younger age, a single lesion at enrollment, no previous use of TKIs, smaller tumor burden, good Eastern Cooperative Oncology Group performance status (ECOG PS ≤1), and lesions limited to the liver were independent prognostic factors for better survival. Conclusions We found that a single lesion at enrollment, no previous use of TKIs, a smaller tumor burden, and lesions limited to the liver were associated with better survival. Drug resistance is a severe challenge for advanced GISTs, and several factors mentioned above may be correlated with the development of drug resistance, leading to the poor survival of patients.
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Affiliation(s)
- Jinjin Li
- Department of Gastrointestinal Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Zhen Huang
- Department of Gastrointestinal Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Hui Zhou
- Department of Gastrointestinal Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Haitao Li
- Department of Gastrointestinal Surgery, Nanchuan People’s Hospital, Chongqing, China
| | - Jun Zhang
- Department of Gastrointestinal Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
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16
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Zhang L, Zhang S, Cao X, Shi J, Zhao S, Tian J, Xiao K, Wang M, Liu J, Wang C, Zhou L, Yu Y, Zhao H, Li S, Sun J. RAF1 facilitates KIT signaling and serves as a potential treatment target for gastrointestinal stromal tumor. Oncogene 2024; 43:2078-2091. [PMID: 38760447 DOI: 10.1038/s41388-024-03063-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2023] [Revised: 05/08/2024] [Accepted: 05/09/2024] [Indexed: 05/19/2024]
Abstract
The aberrant activation of RAS/RAF/MEK/ERK signaling is important for KIT mutation-mediated tumorigenesis of gastrointestinal stromal tumor (GIST). In this study, we found that inhibition of RAF1 suppresses the activation of both wild-type KIT and primary KIT mutations in GIST, with primary KIT mutations showing greater sensitivity. This suggests a positive feedback loop between KIT and RAF1, wherein RAF1 facilitates KIT signaling. We further demonstrated that RAF1 associates with KIT and the kinase activity of RAF1 is necessary for its contribution to KIT activation. Accordingly, inhibition of RAF1 suppressed cell survival, proliferation, and cell cycle progression in vitro mediated by both wild-type KIT and primary KIT mutations. Inhibition of RAF1 in vivo suppressed GIST growth in a transgenic mouse model carrying germline KIT/V558A mutation, showing a similar treatment efficiency as imatinib, the first-line targeted therapeutic drug of GIST, while the combination use of imatinib and RAF1 inhibitor further suppressed tumor growth. Acquisition of drug-resistant secondary mutation of KIT is a major cause of treatment failure of GIST following targeted therapy. Like wild-type KIT and primary KIT mutations, inhibition of RAF1 suppressed the activation of secondary KIT mutation, and the cell survival, proliferation, cell cycle progression in vitro, and tumor growth in vivo mediated by secondary KIT mutation. However, the activation of secondary KIT mutation is less dependent on RAF1 compared with that of primary KIT mutations. Taken together, our results revealed that RAF1 facilitates KIT signaling and KIT mutation-mediated tumorigenesis of GIST, providing a rationale for further investigation into the use of RAF1 inhibitors alone or in combination with KIT inhibitor in the treatment of GIST, particularly in cases resistant to KIT inhibitors.
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Affiliation(s)
- Liangying Zhang
- NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Science and Technology Center, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China
| | - Shaoting Zhang
- NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Science and Technology Center, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China
| | - Xu Cao
- NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Science and Technology Center, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China
| | - Jun Shi
- NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Science and Technology Center, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China
| | - Sien Zhao
- NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Science and Technology Center, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China
| | - Jinhai Tian
- NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Science and Technology Center, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China
| | - Kun Xiao
- NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Science and Technology Center, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China
| | - Ming Wang
- NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Science and Technology Center, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China
| | - Jing Liu
- Department of Pediatrics, the General Hospital of Ningxia Medical University, Yinchuan, China
| | - Chengdong Wang
- Key Laboratory for Regenerative Medicine, Ministry of Education, School of Biomedical Sciences, Faculty of Medicine, the Chinese University of Hong Kong, Hong Kong SAR, China
| | - Liangji Zhou
- Key Laboratory for Regenerative Medicine, Ministry of Education, School of Biomedical Sciences, Faculty of Medicine, the Chinese University of Hong Kong, Hong Kong SAR, China
| | - Yuanyuan Yu
- Department of Emergency, the General Hospital of Ningxia Medical University, Yinchuan, China
| | - Hui Zhao
- Key Laboratory for Regenerative Medicine, Ministry of Education, School of Biomedical Sciences, Faculty of Medicine, the Chinese University of Hong Kong, Hong Kong SAR, China.
| | - Shujing Li
- NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Science and Technology Center, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China.
- Department of Pediatrics, the General Hospital of Ningxia Medical University, Yinchuan, China.
| | - Jianmin Sun
- NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Science and Technology Center, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China.
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17
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Cicala CM, Olivares-Rivas I, Aguirre-Carrillo JA, Serrano C. KIT/PDGFRA inhibitors for the treatment of gastrointestinal stromal tumors: getting to the gist of the problem. Expert Opin Investig Drugs 2024; 33:159-170. [PMID: 38344849 DOI: 10.1080/13543784.2024.2318317] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Accepted: 02/09/2024] [Indexed: 02/15/2024]
Abstract
INTRODUCTION Approximately 90% of gastrointestinal stromal tumors (GISTs) are driven by activating mutations in receptor tyrosine-kinases KIT or PDGFRA. Despite the outstanding results of first-line imatinib in advanced GIST, resistance ultimately occurs mainly through secondary mutations in KIT/PDGFRA. Other tyrosine-kinase inhibitors (TKIs) with a broader spectrum of activity against these mutations are approved after imatinib failure. However, response rates and progression-free survival are drastically lower compared to imatinib. Notably, imatinib also triggers early tolerance adaptation mechanisms, which precede the occurrence of secondary mutations. AREAS COVERED In this review, we outline the current landscape of KIT inhibitors, discuss the novel agents, and present additional biological pathways that may be therapeutically exploitable. EXPERT OPINION The development of broad-spectrum and highly selective TKIs able to induce a sustained KIT/PDGFRA inhibition is the pillar of preclinical and clinical investigation in GIST. However, it is now recognized that the situation is more intricate, with various factors interacting with KIT and PDGFRA, playing a crucial role in the response and resistance to treatments. Future strategies in the management of advanced GIST should integrate driver inhibition with the blockade of other molecules to enhance cell death and establish enduring responses in patients.
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Affiliation(s)
- Carlo María Cicala
- Sarcoma Translational Research Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
- Department of Medical Oncology, Vall d'Hebron University Hospital, Barcelona, Spain
| | - Iván Olivares-Rivas
- Sarcoma Translational Research Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | | | - César Serrano
- Sarcoma Translational Research Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
- Department of Medical Oncology, Vall d'Hebron University Hospital, Barcelona, Spain
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18
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Wallander K, Öfverholm I, Boye K, Tsagkozis P, Papakonstantinou A, Lin Y, Haglund de Flon F. Sarcoma care in the era of precision medicine. J Intern Med 2023; 294:690-707. [PMID: 37643281 DOI: 10.1111/joim.13717] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 08/31/2023]
Abstract
Sarcoma subtype classification is currently mainly based upon histopathological morphology. Molecular analyses have emerged as an efficient addition to the diagnostic workup and sarcoma care. Knowledge about the sarcoma genome increases, and genetic events that can either support a histopathological diagnosis or suggest a differential diagnosis are identified, as well as novel therapeutic targets. In this review, we present diagnostic, therapeutic, and prognostic molecular markers that are, or might soon be, used clinically. For sarcoma diagnostics, there are specific fusions highly supportive or pathognomonic for a diagnostic entity-for instance, SYT::SSX in synovial sarcoma. Complex karyotypes also give diagnostic information-for example, supporting dedifferentiation rather than low-grade central osteosarcoma or well-differentiated liposarcoma when detected in combination with MDM2/CDK4 amplification. Molecular treatment predictive sarcoma markers are available for gastrointestinal stromal tumor (GIST) and locally aggressive benign mesenchymal tumors. The molecular prognostic markers for sarcomas in clinical practice are few. For solitary fibrous tumor, the type of NAB2::STAT6 fusion is associated with the outcome, and the KIT/PDGFRA pathogenic variant in GISTs can give prognostic information. With the exploding availability of sequencing technologies, it becomes increasingly important to understand the strengths and limitations of those methods and their context in sarcoma diagnostics. It is reasonable to believe that most sarcoma treatment centers will increase the use of massive-parallel sequencing soon. We conclude that the context in which the genetic findings are interpreted is of importance, and the interpretation of genomic findings requires considering tumor histomorphology.
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Affiliation(s)
- Karin Wallander
- Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
| | | | - Kjetil Boye
- Department of Oncology, Oslo University Hospital, Oslo, Norway
| | - Panagiotis Tsagkozis
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
| | - Andri Papakonstantinou
- Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
- Department of Breast Cancer, Endocrine Tumors and Sarcoma, Karolinska University Hospital and Karolinska Comprehensive Cancer Centre, Stockholm, Sweden
| | - Yingbo Lin
- Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
| | - Felix Haglund de Flon
- Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
- Department of Pathology and Cancer diagnostics, Karolinska University Hospital, Stockholm, Sweden
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Klein O, Palmer J, Behren A, Cebon J, Kee D. Durable response to combination immunotherapy using nivolumab and ipilimumab in metastatic succinate dehydrogenase (SDH)-deficient gastrointestinal stroma tumour. Eur J Cancer 2023; 194:113351. [PMID: 37827066 DOI: 10.1016/j.ejca.2023.113351] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2023] [Revised: 09/04/2023] [Accepted: 09/10/2023] [Indexed: 10/14/2023]
Affiliation(s)
- Oliver Klein
- Department of Medical Oncology, Austin Health, Melbourne, Victoria, Australia; Olivia Newton-John Cancer Research Institute, Melbourne, Victoria, Australia.
| | - Jodie Palmer
- Olivia Newton-John Cancer Research Institute, Melbourne, Victoria, Australia; School of Cancer Medicine, La Trobe University, Melbourne, Victoria, Australia
| | - Andreas Behren
- Olivia Newton-John Cancer Research Institute, Melbourne, Victoria, Australia; School of Cancer Medicine, La Trobe University, Melbourne, Victoria, Australia
| | - Jonathan Cebon
- Department of Medical Oncology, Austin Health, Melbourne, Victoria, Australia; Olivia Newton-John Cancer Research Institute, Melbourne, Victoria, Australia; School of Cancer Medicine, La Trobe University, Melbourne, Victoria, Australia
| | - Damien Kee
- Department of Medical Oncology, Austin Health, Melbourne, Victoria, Australia; Olivia Newton-John Cancer Research Institute, Melbourne, Victoria, Australia; Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
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20
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Abdellateif MS, Bayoumi AK, Mohammed MA. c-Kit Receptors as a Therapeutic Target in Cancer: Current Insights. Onco Targets Ther 2023; 16:785-799. [PMID: 37790582 PMCID: PMC10544070 DOI: 10.2147/ott.s404648] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2023] [Accepted: 09/19/2023] [Indexed: 10/05/2023] Open
Abstract
c-Kit is a type III receptor tyrosine kinase (RTK) that has an essential role in various biological functions including gametogenesis, melanogenesis, hematopoiesis, cell survival, and apoptosis. c-KIT aberrations, either overexpression or loss-of-function mutations, have been implicated in the pathogenesis and development of many cancers, including gastrointestinal stromal tumors, mastocytosis, acute myeloid leukemia, breast, thyroid, and colorectal cancer, making c-KIT an attractive molecular target for the treatment of cancers. Therefore, a lot of effort has been put into investigating the utility of tyrosine kinase inhibitors for the management of c-KIT mutated tumors. This review of the literature illustrates the role of c-KIT mutations in many cancers, aiming to provide insights into the role of TKIs as a therapeutic option for cancer patients with c-KIT aberrations. In conclusion, c-KIT is implicated in different types of cancer, and it could be a successful molecular target; however, proper detection of the underlying mutation type is required before starting the appropriate personalized therapy.
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Affiliation(s)
- Mona S Abdellateif
- Medical Biochemistry and Molecular Biology, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, 11796, Egypt
| | - Ahmed K Bayoumi
- Paediatric Oncology Department, National Cancer Institute, Cairo University, Cairo, 11796, Egypt
- Children’s Cancer Hospital 57357, Cairo, 11617, Egypt
| | - Mohammed Aly Mohammed
- Medical Biochemistry and Molecular Biology, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, 11796, Egypt
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21
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Hu X, Su P, Liu B, Guo J, Wang Z, He C, Wang Z, Kou Y. Characterization of a Human Gastrointestinal Stromal Tumor Cell Line Established by SV40LT-Mediated Immortalization. Int J Mol Sci 2023; 24:13640. [PMID: 37686448 PMCID: PMC10487453 DOI: 10.3390/ijms241713640] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Revised: 08/20/2023] [Accepted: 08/25/2023] [Indexed: 09/10/2023] Open
Abstract
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors in the digestive tract and originate from the interstitial cells of Cajal (ICC), which is the pacemaker for peristaltic movement in the gastrointestinal tract. Existing GIST cell lines are widely used as cell models for in vitro experimental studies because the mutation sites are known. However, the immortalization methods of these cell lines are unknown, and no Chinese patient-derived GIST cell lines have been documented. Here, we transfected simian virus 40 large T antigen (SV40LT) into primary GIST cells to establish an immortalized human GIST cell line (ImGIST) for the first time. The ImGIST cells had neuronal cell-like irregular radioactive growth and retained the fusion growth characteristics of GIST cells. They stably expressed signature proteins, maintained the biological and genomic characteristics of normal primary GIST cells, and responded well to imatinib, suggesting that ImGIST could be a potential in vitro model for research in GIST to explore the molecular pathogenesis, drug resistance mechanisms, and the development of new adjuvant therapeutic options.
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Affiliation(s)
- Xiangchen Hu
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang 110004, China; (X.H.)
| | - Peng Su
- Medical Research Center, Shengjing Hospital of China Medical University, Shenyang 117005, China
| | - Bo Liu
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang 110004, China; (X.H.)
| | - Jingwei Guo
- Department of Pathology, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Zitong Wang
- Department of Pathology, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Cai He
- Department of Pathology, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Zhe Wang
- Department of Pathology, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Youwei Kou
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang 110004, China; (X.H.)
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22
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Martin-Broto J, Valverde C, Hindi N, Vincenzi B, Martinez-Trufero J, Grignani G, Italiano A, Lavernia J, Vallejo A, Tos PD, Le Loarer F, Gonzalez-Campora R, Ramos R, Hernández-Jover D, Gutierrez A, Serrano C, Monteagudo M, Letón R, Robledo M, Moura DS, Martin-Ruiz M, López-Guerrero JA, Cruz J, Fernandez-Serra A, Blay JY, Fumagalli E, Martinez-Marin V. REGISTRI: Regorafenib in first-line of KIT/PDGFRA wild type metastatic GIST: a collaborative Spanish (GEIS), Italian (ISG) and French Sarcoma Group (FSG) phase II trial. Mol Cancer 2023; 22:127. [PMID: 37559050 PMCID: PMC10413507 DOI: 10.1186/s12943-023-01832-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Accepted: 07/26/2023] [Indexed: 08/11/2023] Open
Abstract
BACKGROUND Approximately 15% of adult GIST patients harbor tumors that are wild-type for KIT and PDGFRα genes (KP-wtGIST). These tumors usually have SDH deficiencies, exhibit a more indolent behavior and are resistant to imatinib. Underlying oncogenic mechanisms in KP-wtGIST include overexpression of HIF1α high IGFR signaling through the MAPK pathway or BRAF activating mutation, among others. As regorafenib inhibits these signaling pathways, it was hypothesized that it could be more active as upfront therapy in advanced KP-wtGIST. METHODS Adult patients with advanced KP-wtGIST after central confirmation by NGS, naïve of systemic treatment for advanced disease, were included in this international phase II trial. Eligible patients received regorafenib 160 mg per day for 21 days every 28 days. The primary endpoint was disease control rate (DCR), according to RECIST 1.1 at 12 weeks by central radiological assessment. RESULTS From May 2016 to October 2020, 30 patients were identified as KP-wtGIST by Sanger sequencing and 16 were confirmed by central molecular screening with NGS. Finally, 15 were enrolled and received regorafenib. The study was prematurely closed due to the low accrual worsened by COVID outbreak. The DCR at 12 weeks was 86.7% by central assessment. A subset of 60% experienced some tumor shrinkage, with partial responses and stabilization observed in 13% and 87% respectively, by central assessment. SDH-deficient GIST showed better clinical outcome than other KP-wtGIST. CONCLUSIONS Regorafenib activity in KP-wtGIST compares favorably with other tyrosine kinase inhibitors, especially in the SDH-deficient GIST subset and it should be taken into consideration as upfront therapy of advanced KP-wtGIST. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02638766.
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Affiliation(s)
- Javier Martin-Broto
- Health Research Institute-Fundación Jiménez Díaz University Hospital, Universidad Autonoma de Madrid (IIS-FJD, UAM), 28040, Madrid, Spain.
- Medical Oncology Department, Fundación Jimenez Diaz University Hospital, Av. de los Reyes Católicos, 2, 28040, Madrid, Spain.
- General de Villalba University Hospital, 28400, Madrid, Spain.
| | - Claudia Valverde
- Medical Oncology department, Vall d'Hebron University Hospital, 08035, Barcelona, Spain
| | - Nadia Hindi
- Health Research Institute-Fundación Jiménez Díaz University Hospital, Universidad Autonoma de Madrid (IIS-FJD, UAM), 28040, Madrid, Spain
- Medical Oncology Department, Fundación Jimenez Diaz University Hospital, Av. de los Reyes Católicos, 2, 28040, Madrid, Spain
- General de Villalba University Hospital, 28400, Madrid, Spain
| | - Bruno Vincenzi
- Medical Oncology, University Campus Bio-Medico and Fondazione Policlinico Universitario Campus Bio-Medico, 00128, Rome, Italy
| | | | - Giovanni Grignani
- Medical Oncology Unit, Città della Salute e della Scienza Hospital, 10126, Turin, Italy
| | - Antoine Italiano
- Medical Oncology department, Institute Bergonié, 33076, Bordeaux, France
| | - Javier Lavernia
- Medical Oncology department, Fundación Instituto Valenciano de Oncologia, 46009, Valencia, Spain
| | - Ana Vallejo
- Pathology department, Hospital Regional Universitario de Malaga, 29010, Malaga, Spain
| | - Paolo Dei Tos
- Department of Medicine, School of Medicine, University of Padua, 35122, Padua, Italy
| | | | | | - Rafael Ramos
- Pathology department, University Hospital Son Espases, 07120, Mallorca, Spain
| | | | - Antonio Gutierrez
- Hematology department, University Hospital Son Espases, 07120, Mallorca, Spain
| | - Cesar Serrano
- Medical Oncology department, Vall d'Hebron University Hospital, 08035, Barcelona, Spain
| | - Maria Monteagudo
- Hereditary Endocrine Cancer Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
| | - Rocio Letón
- Hereditary Endocrine Cancer Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
| | - Mercedes Robledo
- Hereditary Endocrine Cancer Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Institute of Health Carlos III (ISCIII), Madrid, Spain
| | - David S Moura
- Health Research Institute-Fundación Jiménez Díaz University Hospital, Universidad Autonoma de Madrid (IIS-FJD, UAM), 28040, Madrid, Spain
| | - Marta Martin-Ruiz
- Health Research Institute-Fundación Jiménez Díaz University Hospital, Universidad Autonoma de Madrid (IIS-FJD, UAM), 28040, Madrid, Spain
| | - Jose A López-Guerrero
- Molecular Biology department, Fundación Instituto Valenciano de Oncologia, 46009, Valencia, Spain
| | - Julia Cruz
- Pathology department, Fundación Instituto Valenciano de Oncologia, 46009, Valencia, Spain
| | - Antonio Fernandez-Serra
- Molecular Biology department, Fundación Instituto Valenciano de Oncologia, 46009, Valencia, Spain
| | - Jean-Yves Blay
- Medicine Department, Centre Léon Bérard, 69008, Lyon, France
| | - Elena Fumagalli
- Medicine Department, Fondazione IRCCS - Istituto Nazionale dei Tumori, 20133, Milan, Italy
| | - Virginia Martinez-Marin
- Department of Medical Oncology, Hospital Universitario La Paz-IdiPAZ, P. Castellana, 261, 28046, Madrid, Spain
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23
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Catalano F, Cremante M, Dalmasso B, Pirrone C, Lagodin D’Amato A, Grassi M, Comandini D. Molecular Tailored Therapeutic Options for Advanced Gastrointestinal Stromal Tumors (GISTs): Current Practice and Future Perspectives. Cancers (Basel) 2023; 15:cancers15072074. [PMID: 37046734 PMCID: PMC10093725 DOI: 10.3390/cancers15072074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Revised: 03/23/2023] [Accepted: 03/28/2023] [Indexed: 04/03/2023] Open
Abstract
Gastrointestinal stromal tumors (GISTs) are one of the most common mesenchymal tumors characterized by different molecular alterations that lead to specific clinical presentations and behaviors. In the last twenty years, thanks to the discovery of these mutations, several new treatment options have emerged. This review provides an extensive overview of GISTs’ molecular pathways and their respective tailored therapeutic strategies. Furthermore, current treatment strategies under investigation and future perspectives are analyzed and discussed.
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Affiliation(s)
- Fabio Catalano
- Medical Oncology Unit 1, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy
| | - Malvina Cremante
- Medical Oncology Unit 1, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy
| | - Bruna Dalmasso
- Genetica dei Tumori Rari, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy
| | - Chiara Pirrone
- Medical Oncology Unit 1, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy
| | | | - Massimiliano Grassi
- Medical Oncology Unit 1, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy
- Correspondence:
| | - Danila Comandini
- Medical Oncology Unit 1, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy
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Bleckman R, Roets E, IJzerman NS, Mohammadi M, Bonenkamp HJ, Gelderblom H, Mathijssen RH, Steeghs N, Reyners AK, van Etten B. Local recurrence in primary localized resected gastro-intestinal stromal tumors A registry observational national cohort study including 912 patients. Eur J Cancer 2023; 186:113-121. [PMID: 37062209 DOI: 10.1016/j.ejca.2023.03.007] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Revised: 03/10/2023] [Accepted: 03/10/2023] [Indexed: 03/17/2023]
Abstract
BACKGROUND AND OBJECTIVES Previous literature showed a high risk of recurrence following surgical treatment in patients with gastrointestinal stromal tumours (GISTs). However, little is known about the patient- and treatment characteristics of local recurrences (LRs) in GIST patients. Therefore, this study aimed to better understand patterns of LR in surgically treated localised GIST and to describe treatment options based on our Dutch GIST Registry (DGR). METHODS Data of primary surgically treated localised GIST between January 2009 until July 2021 were retrospectively retrieved from the DGR. RESULTS Of 1452 patients registered in the DGR, 912 patients were included in this study. Only 3.8% (35/912) of patients developed LR, including 20 patients with LR only and 15 patients with simultaneous LR and distant metastases (DM). Median time to LR was 30 (interquartile range 8-53) months from date of surgery. Eleven percent (100/912) of patients developed only DM. A total of 2.3% (6/259) of patients treated with adjuvant treatment developed an LR during adjuvant therapy. Seventy percent of patients with LR only (14/20) were treated with surgery (85.7% R0), which was mostly combined with systemic treatment. CONCLUSIONS Patients with primary surgically treated localised GIST have a limited risk of developing recurrence. Fifteen percent developed recurrence, of which one quarter developed an LR. Therefore, less intensified follow-up schedules could be considered, especially during treatment with adjuvant imatinib. In patients with LR only, potentially curative treatment strategies, including surgical (re-)resection, are often possible as treatment for LR.
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25
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Molecular Mechanisms of Gastrointestinal Stromal Tumors and Their Impact on Systemic Therapy Decision. Cancers (Basel) 2023; 15:cancers15051498. [PMID: 36900287 PMCID: PMC10001062 DOI: 10.3390/cancers15051498] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Revised: 02/23/2023] [Accepted: 02/24/2023] [Indexed: 03/08/2023] Open
Abstract
Gastrointestinal stromal tumors (GISTs) are soft tissue sarcomas that mostly derive from Cajal cell precursors. They are by far the most common soft tissue sarcomas. Clinically, they present as gastrointestinal malignancies, most often with bleeding, pain, or intestinal obstruction. They are identified using characteristic immunohistochemical staining for CD117 and DOG1. Improved understanding of the molecular biology of these tumors and identification of oncogenic drivers have altered the systemic treatment of primarily disseminated disease, which is becoming increasingly complex. Gain-of-function mutations in KIT or PDGFRA genes represent the driving mutations in more than 90% of all GISTs. These patients exhibit good responses to targeted therapy with tyrosine kinase inhibitors (TKIs). Gastrointestinal stromal tumors lacking the KIT/PDGFRA mutations, however, represent distinct clinico-pathological entities with diverse molecular mechanisms of oncogenesis. In these patients, therapy with TKIs is hardly ever as effective as for KIT/PDGFRA-mutated GISTs. This review provides an outline of current diagnostics aimed at identifying clinically relevant driver alterations and a comprehensive summary of current treatments with targeted therapies for patients with GISTs in both adjuvant and metastatic settings. The role of molecular testing and the selection of the optimal targeted therapy according to the identified oncogenic driver are reviewed and some future directions are proposed.
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26
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Thirasastr P, Somaiah N. Emerging Data on the Safety and Efficacy of Ripretinib for the Treatment of Gastrointestinal Stromal Tumors. Clin Exp Gastroenterol 2023; 16:11-19. [PMID: 36798653 PMCID: PMC9926989 DOI: 10.2147/ceg.s351839] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Accepted: 01/18/2023] [Indexed: 02/18/2023] Open
Abstract
In patients with gastrointestinal stromal tumors (GIST), systemic treatment after disease progression on imatinib is challenging. Sunitinib and regorafenib are approved in the second- and third-line setting, respectively, with activity against certain secondary mutations with comparatively much lower response rates and survival increment compared to imatinib. All three of these drugs were serendipitously found to have activity in GIST, starting with imatinib, which was formulated for its ability to inhibit BCR-ABL in chronic myelogenous leukemia. Ripretinib is a drug that was specifically developed as a more potent KIT tyrosine kinase inhibitor (TKI), with broad-spectrum activity against the mutations encountered in GIST. Encouraging responses in early and later lines of treatment in the Phase 1 trial of ripretinib in GIST led to the rapid development of this novel drug. In a Phase 3 randomized clinical trial with cross-over, ripretinib demonstrated superior PFS and overall survival (OS) in 4th-line treatment and beyond compared to placebo. This established 150 mg once daily ripretinib as the standard of care in this setting. Ripretinib is generally well tolerated, with common adverse effects of hair loss, diarrhea, cramps, fatigue and nausea. The favorable safety profile and efficacy of ripretinib prompted its evaluation in a randomized phase 3 trial in the 2nd-line treatment setting. However, it did not result in a longer PFS duration than sunitinib. Although the efficacy of ripretinib in this unselected patient population was not significantly different from that of sunitinib, the tolerability profile was better. This review article aims to review the efficacy and tolerability profile of ripretinib, together with its role in the setting of unresectable or metastatic GIST.
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Affiliation(s)
- Prapassorn Thirasastr
- Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Neeta Somaiah
- Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA,Correspondence: Neeta Somaiah, Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 0450, Houston, TX, 77030, USA, Tel +1 713 792-3626, Email
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27
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Ligon JA, Sundby RT, Wedekind MF, Arnaldez FI, del Rivero J, Wiener L, Srinivasan R, Spencer M, Carbonell A, Lei H, Shern J, Steinberg SM, Figg WD, Peer CJ, Zimmerman S, Moraly J, Xu X, Fox S, Chan K, Barbato MI, Andresson T, Taylor N, Pacak K, Killian JK, Dombi E, Linehan WM, Miettinen M, Piekarz R, Helman LJ, Meltzer P, Widemann B, Glod J. A Phase II Trial of Guadecitabine in Children and Adults with SDH-Deficient GIST, Pheochromocytoma, Paraganglioma, and HLRCC-Associated Renal Cell Carcinoma. Clin Cancer Res 2023; 29:341-348. [PMID: 36302175 PMCID: PMC9851965 DOI: 10.1158/1078-0432.ccr-22-2168] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 09/22/2022] [Accepted: 10/25/2022] [Indexed: 01/22/2023]
Abstract
PURPOSE Succinate dehydrogenase (dSDH)-deficient tumors, including pheochromocytoma/paraganglioma, hereditary leiomyomatosis and renal cell cancer-associated renal cell carcinoma (HLRCC-RCC), and gastrointestinal stromal tumors (GIST) without KIT or platelet-derived growth factor receptor alpha mutations are often resistant to cytotoxic chemotherapy, radiotherapy, and many targeted therapies. We evaluated guadecitabine, a dinucleotide containing the DNA methyltransferase inhibitor decitabine, in these patient populations. PATIENTS AND METHODS Phase II study of guadecitabine (subcutaneously, 45 mg/m2/day for 5 consecutive days, planned 28-day cycle) to assess clinical activity (according to RECISTv.1.1) across three strata of patients with dSDH GIST, pheochromocytoma/paraganglioma, or HLRCC-RCC. A Simon optimal two-stage design (target response rate 30% rule out 5%) was used. Biologic correlates (methylation and metabolites) from peripheral blood mononuclear cells (PBMC), serum, and urine were analyzed. RESULTS Nine patients (7 with dSDH GIST, 1 each with paraganglioma and HLRCC-RCC, 6 females and 3 males, age range 18-57 years) were enrolled. Two patients developed treatment-limiting neutropenia. No partial or complete responses were observed (range 1-17 cycles of therapy). Biologic activity assessed as global demethylation in PBMCs was observed. No clear changes in metabolite concentrations were observed. CONCLUSIONS Guadecitabine was tolerated in patients with dSDH tumors with manageable toxicity. Although 4 of 9 patients had prolonged stable disease, there were no objective responses. Thus, guadecitabine did not meet the target of 30% response rate across dSDH tumors at this dose, although signs of biologic activity were noted.
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Affiliation(s)
- John A Ligon
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA,Department of Pediatrics, Division of Hematology/Oncology, University of Florida, Gainesville, FL
| | - R. Taylor Sundby
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Mary F Wedekind
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | | | - Jaydira del Rivero
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA,Developmemtal Therapeutics Branch, CCR, NCI, Bethesda, MD
| | - Lori Wiener
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | | | - Melissa Spencer
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Amanda Carbonell
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Haiyan Lei
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - John Shern
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | | | | | - Cody J Peer
- Clinical Pharmacology Program, NCI/NIH, Bethesda, MD
| | | | - Josquin Moraly
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA,Laboratory of physiopathology and treatment of Hematological malignancies, Institut imagine, INSERM U1153, Université de Paris, Paris, France
| | - Xia Xu
- Cancer Research Technology Program, Protein Characterization Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD
| | - Stephen Fox
- Cancer Research Technology Program, Protein Characterization Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD
| | - King Chan
- Cancer Research Technology Program, Protein Characterization Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD
| | - Michael I Barbato
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Thorkell Andresson
- Cancer Research Technology Program, Protein Characterization Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD
| | - Naomi Taylor
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Karel Pacak
- Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD
| | | | - Eva Dombi
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | | | | | - Richard Piekarz
- Cancer Therapy Evaluation Program, Division of Cancer Treatments and Diagnosis, NCI, Bethesda, MD
| | | | | | - Brigitte Widemann
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - John Glod
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
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Eng L, Brual J, Nagee A, Mok S, Fazelzad R, Chaiton M, Saunders DP, Mittmann N, Truscott R, Liu G, Bradbury PA, Evans WK, Papadakos J, Giuliani ME. Reporting of tobacco use and tobacco-related analyses in cancer cooperative group clinical trials: a systematic scoping review. ESMO Open 2022; 7:100605. [PMID: 36356412 PMCID: PMC9646674 DOI: 10.1016/j.esmoop.2022.100605] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2022] [Revised: 09/21/2022] [Accepted: 09/23/2022] [Indexed: 11/09/2022] Open
Abstract
BACKGROUND Continued smoking after a diagnosis of cancer negatively impacts cancer outcomes, but the impact of tobacco on newer treatments options is not well established. Collecting and evaluating tobacco use in clinical trials may advance understanding of the consequences of tobacco use on treatment modalities, but little is known about the frequency of reporting and analysis of tobacco use in cancer cooperative clinical trial groups. PATIENTS AND METHODS A comprehensive literature search was conducted to identify cancer cooperative group clinical trials published from January 2017-October 2019. Eligible studies evaluated either systemic and/or radiation therapies, included ≥100 adult patients, and reported on at least one of: overall survival, disease/progression-free survival, response rates, toxicities/adverse events, or quality-of-life. RESULTS A total of 91 studies representing 90 trials met inclusion criteria with trial start dates ranging from 1995 to 2015 with 14% involving lung and 5% head and neck cancer patients. A total of 19 studies reported baseline tobacco use; 2 reported collecting follow-up tobacco use. Seven studies reported analysis of the impact of baseline tobacco use on clinical outcomes. There was significant heterogeneity in the reporting of baseline tobacco use: 7 reported never/ever status, 10 reported never/ex-smoker/current smoker status, and 4 reported measuring smoking intensity. None reported verifying smoking status or second-hand smoke exposure. Trials of lung and head and neck cancers were more likely to report baseline tobacco use than other disease sites (83% versus 6%, P < 0.001). CONCLUSIONS Few cancer cooperative group clinical trials report and analyze trial participants' tobacco use. Significant heterogeneity exists in reporting tobacco use. Routine standardized collection and reporting of tobacco use at baseline and follow-up in clinical trials should be implemented to enable investigators to evaluate the impact of tobacco use on new cancer therapies.
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Affiliation(s)
- L Eng
- Division of Medical Oncology and Hematology, Department of Medicine, Princess Margaret Cancer Centre/University Health Network and University of Toronto, Toronto, Canada.
| | - J Brual
- Cancer Education Program, Princess Margaret Cancer Centre, Toronto, Canada
| | - A Nagee
- Cancer Education Program, Princess Margaret Cancer Centre, Toronto, Canada
| | - S Mok
- Cancer Education Program, Princess Margaret Cancer Centre, Toronto, Canada
| | - R Fazelzad
- Library and Information Services, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
| | - M Chaiton
- Centre for Addiction and Mental Health, University of Toronto, Toronto, Canada
| | - D P Saunders
- Northeast Cancer Centre of Health Sciences North, Northern Ontario School of Medicine, Sudbury, Canada
| | - N Mittmann
- Canadian Agency for Drugs and Technologies in Health, Toronto, Canada
| | - R Truscott
- Division of Prevention Policy and Stakeholder Engagement, Ontario Health (Cancer Care Ontario), Toronto, Canada
| | - G Liu
- Division of Medical Oncology and Hematology, Department of Medicine, Princess Margaret Cancer Centre/University Health Network and University of Toronto, Toronto, Canada
| | - P A Bradbury
- Division of Medical Oncology and Hematology, Department of Medicine, Princess Margaret Cancer Centre/University Health Network and University of Toronto, Toronto, Canada
| | - W K Evans
- Department of Oncology, McMaster University, Hamilton, Canada
| | - J Papadakos
- Cancer Education Program, Princess Margaret Cancer Centre, Toronto, Canada; Patient Education, Ontario Health (Cancer Care Ontario), Toronto, Canada
| | - M E Giuliani
- Cancer Education Program, Princess Margaret Cancer Centre, Toronto, Canada; Department of Radiation Oncology, Princess Margaret Cancer Centre, Toronto, Canada.
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29
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von Mehren M, Kane JM, Riedel RF, Sicklick JK, Pollack SM, Agulnik M, Bui MM, Carr-Ascher J, Choy E, Connelly M, Dry S, Ganjoo KN, Gonzalez RJ, Holder A, Homsi J, Keedy V, Kelly CM, Kim E, Liebner D, McCarter M, McGarry SV, Mesko NW, Meyer C, Pappo AS, Parkes AM, Petersen IA, Poppe M, Schuetze S, Shabason J, Spraker MB, Zimel M, Bergman MA, Sundar H, Hang LE. NCCN Guidelines® Insights: Gastrointestinal Stromal Tumors, Version 2.2022. J Natl Compr Canc Netw 2022; 20:1204-1214. [PMID: 36351335 PMCID: PMC10245542 DOI: 10.6004/jnccn.2022.0058] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Gastrointestinal stromal tumors (GIST) are the most common type of soft tissue sarcoma that occur throughout the gastrointestinal tract. Most of these tumors are caused by oncogenic activating mutations in the KIT or PDGFRA genes. The NCCN Guidelines for GIST provide recommendations for the diagnosis, evaluation, treatment, and follow-up of patients with these tumors. These NCCN Guidelines Insights summarize the panel discussion behind recent important updates to the guidelines, including revised systemic therapy options for unresectable, progressive, or metastatic GIST based on mutational status, and updated recommendations for the management of GIST that develop resistance to specific tyrosine kinase inhibitors.
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Affiliation(s)
| | | | | | | | - Seth M Pollack
- 5Robert H. Lurie Comprehensive Cancer Center of Northwestern University
| | | | | | | | - Edwin Choy
- 9Massachusetts General Hospital Cancer Center
| | - Mary Connelly
- 10The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute
| | - Sarah Dry
- 11UCLA Jonsson Comprehensive Cancer Center
| | | | | | | | - Jade Homsi
- 14UT Southwestern Simmons Comprehensive Cancer Center
| | | | | | | | - David Liebner
- 10The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute
| | | | | | - Nathan W Mesko
- 20Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute
| | - Christian Meyer
- 21The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
| | - Alberto S Pappo
- 22St. Jude Children's Research Hospital/University of Tennessee Health Science Center
| | | | | | - Matthew Poppe
- 25Huntsman Cancer Institute at the University of Utah
| | | | - Jacob Shabason
- 27Abramson Cancer Center at the University of Pennsylvania
| | - Matthew B Spraker
- 28Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine
| | - Melissa Zimel
- 29UCSF Helen Diller Family Comprehensive Cancer Center; and
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30
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Schaefer IM, Hemming ML, Lundberg MZ, Serrata MP, Goldaracena I, Liu N, Yin P, Paulo JA, Gygi SP, George S, Morgan JA, Bertagnolli MM, Sicinska ET, Chu C, Zheng S, Mariño-Enríquez A, Hornick JL, Raut CP, Ou WB, Demetri GD, Saka SK, Fletcher JA. Concurrent inhibition of CDK2 adds to the anti-tumour activity of CDK4/6 inhibition in GIST. Br J Cancer 2022; 127:2072-2085. [PMID: 36175617 PMCID: PMC9681737 DOI: 10.1038/s41416-022-01990-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Revised: 09/07/2022] [Accepted: 09/12/2022] [Indexed: 11/09/2022] Open
Abstract
BACKGROUND Advanced gastrointestinal stromal tumour (GIST) is characterised by genomic perturbations of key cell cycle regulators. Oncogenic activation of CDK4/6 results in RB1 inactivation and cell cycle progression. Given that single-agent CDK4/6 inhibitor therapy failed to show clinical activity in advanced GIST, we evaluated strategies for maximising response to therapeutic CDK4/6 inhibition. METHODS Targeted next-generation sequencing and multiplexed protein imaging were used to detect cell cycle regulator aberrations in GIST clinical samples. The impact of inhibitors of CDK2, CDK4 and CDK2/4/6 was determined through cell proliferation and protein detection assays. CDK-inhibitor resistance mechanisms were characterised in GIST cell lines after long-term exposure. RESULTS We identify recurrent genomic aberrations in cell cycle regulators causing co-activation of the CDK2 and CDK4/6 pathways in clinical GIST samples. Therapeutic co-targeting of CDK2 and CDK4/6 is synergistic in GIST cell lines with intact RB1, through inhibition of RB1 hyperphosphorylation and cell proliferation. Moreover, RB1 inactivation and a novel oncogenic cyclin D1 resulting from an intragenic rearrangement (CCND1::chr11.g:70025223) are mechanisms of acquired CDK-inhibitor resistance in GIST. CONCLUSIONS These studies establish the biological rationale for CDK2 and CDK4/6 co-inhibition as a therapeutic strategy in patients with advanced GIST, including metastatic GIST progressing on tyrosine kinase inhibitors.
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Affiliation(s)
- Inga-Marie Schaefer
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
| | - Matthew L Hemming
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA
- Sarcoma Center, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Boston, MA, USA
| | - Meijun Z Lundberg
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Matthew P Serrata
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA
| | - Isabel Goldaracena
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA
| | - Ninning Liu
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA
| | - Peng Yin
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA
| | - Joao A Paulo
- Department of Cell Biology, Harvard Medical School, Boston, MA, USA
| | - Steven P Gygi
- Department of Cell Biology, Harvard Medical School, Boston, MA, USA
| | - Suzanne George
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA
- Sarcoma Center, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Boston, MA, USA
| | - Jeffrey A Morgan
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA
- Sarcoma Center, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Boston, MA, USA
| | - Monica M Bertagnolli
- Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Ewa T Sicinska
- Department of Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Chen Chu
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
| | - Shanshan Zheng
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
| | - Adrian Mariño-Enríquez
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Jason L Hornick
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
- Sarcoma Center, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Boston, MA, USA
| | - Chandrajit P Raut
- Sarcoma Center, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Boston, MA, USA
- Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Wen-Bin Ou
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
- Zhejiang Provincial Key Laboratory of Silkworm Bioreactor and Biomedicine, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, China
| | - George D Demetri
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA
- Sarcoma Center, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Boston, MA, USA
- Ludwig Center at Harvard, Harvard Medical School, Boston, MA, USA
| | - Sinem K Saka
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA
- European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany
| | - Jonathan A Fletcher
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
- Sarcoma Center, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Boston, MA, USA
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Sutton TL, Walker BS, Billingsley KG, Corless CL, Sheppard BC, Heinrich MC, Mayo SC. Ten-Year Survivorship in Patients with Metastatic Gastrointestinal Stromal Tumors. Ann Surg Oncol 2022; 29:7123-7132. [PMID: 35829795 PMCID: PMC10038195 DOI: 10.1245/s10434-022-12063-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Accepted: 06/04/2022] [Indexed: 11/18/2022]
Abstract
INTRODUCTION Patients developing metastatic gastrointestinal stromal tumors (mGIST) have heterogenous disease biology and oncologic outcomes; prognostic factors are incompletely characterized. We sought to evaluate predictors of 10-year metastatic survivorship in the era of tyrosine kinase inhibitor (TKI) therapy. METHODS We reviewed patients with mGIST treated at our Comprehensive Cancer Center from 2003 to 2019, including only patients with either mortality or 10 years of follow-up. Ten-year survivorship was evaluated with logistic regression. RESULTS We identified 109 patients with a median age of 57 years at mGIST diagnosis. Synchronous disease was present in 57% (n = 62) of patients; liver (n = 48, 44%), peritoneum (n = 40, 37%), and liver + peritoneum (n = 18, 17%) were the most common sites. Forty-six (42%) patients were 10-year mGIST survivors. Following mGIST diagnosis, radiographic progression occurred within 2 years in 53% (n = 58) of patients, 2-5 years in 16% (n = 17), and 5-10 years in 16% (n = 17), with median survival of 32, 76, and 173 months, respectively. Seventeen (16%) patients had not progressed by 10 years. Fifty-two (47%) patients underwent metastasectomy, which was associated with improved progression-free survival (hazard ratio 0.63, p = 0.04). In patients experiencing progression, factors independently associated with 10-year survivorship were age (odds ratio [OR] 0.96, p = 0.03) and time to progression (OR 1.71/year, p < 0.001). CONCLUSIONS Ten-year survivorship is achievable in mGIST in the era of TKIs and is associated with younger age and longer time to first progression, while metastasectomy is associated with longer time to first progression. The role of metastasectomy in the management of patients with disease progression receiving TKI therapy merits further study.
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Affiliation(s)
- Thomas L Sutton
- Department of Surgery, Division of General Surgery, Oregon Health & Science University, Portland, OR, USA
| | - Brett S Walker
- Department of Surgery, Division of General Surgery, Oregon Health & Science University, Portland, OR, USA
| | | | | | - Brett C Sheppard
- Department of Surgery, Division of General Surgery, Oregon Health & Science University, Portland, OR, USA
| | - Michael C Heinrich
- Department of Medicine, Division of Hematology/Oncology, Portland VA Health Care System and Oregon Health & Science University, Knight Cancer Institute, Portland, OR, USA
| | - Skye C Mayo
- Department of Surgery, Division of Surgical Oncology, Oregon Health & Science University, Knight Cancer Institute, Portland, OR, USA.
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32
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Sun J, Zhang Q, Sun X, Xue A, Gao X, Shen K. THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours. Cell Commun Signal 2022; 20:138. [PMID: 36076237 PMCID: PMC9454178 DOI: 10.1186/s12964-022-00928-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Accepted: 07/05/2022] [Indexed: 11/19/2022] Open
Abstract
Background Gastrointestinal stromal tumours (GISTs) are the most common mesenchymal tumours of the gastrointestinal tract and are characterized by activating mutations of c-KIT or PDGFRa receptor tyrosine kinases (RTKs). Despite the clinical success of tyrosine kinase inhibitors (TKIs), more than half of GIST patients develop resistance due to a second mutation. Cyclin-dependent kinase 7 (CDK7) is the catalytic subunit of CDK-activating kinase (CAK), and it plays an important role in the regulation of cell cycle transitions and gene transcription. THZ1, a CDK7 inhibitor, exhibits a dose-dependent inhibitory effect in various cancers. Methods Data from the public GEO database and tissue microarray were used to analyse the gene expression levels of CDKs in GISTs. The impact of CDK7 knockdown and the CDK7 inhibitor THZ1 on GIST progression was investigated in vitro using CCK-8, colony formation, and flow cytometry assays and in vivo using a xenograft mouse model. RNA sequencing was performed to investigate the mechanism of GIST cell viability impairment mediated by THZ1 treatment. Results Our study demonstrated that CDK7 is relatively overexpressed in high-risk GISTs and predicts a poor outcome. A low concentration of THZ1 exhibited a pronounced antineoplastic effect in GIST cells in vivo and in vitro. Moreover, THZ1 exerted synergistic anticancer effects with imatinib. THZ1 treatment resulted in transcriptional modulation by inhibiting the phosphorylation of Ser2, Ser5, and Ser7 within RNA polymerase II (RNAPII). c-KIT, an oncogene driver of GIST, was transcriptionally repressed by THZ1 treatment or CDK7 knockdown. Transcriptome sequencing analysis showed that OSR1 acts as a downstream target of CDK7 and regulates c-KIT expression. Taken together, our results highlight elevated CDK7 expression as a predictor of poor outcome in GIST and present the combination of CDK7 and RTK inhibitors as a potent therapeutic strategy to improve the efficacy of GIST treatment.
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