News - PDGFR wild-type

21d

Comprehensive Genomic Assessment of Advanced-Stage GI Stromal Tumors Using the Japanese National Center for Cancer Genomics and Advanced Therapeutics Database. (PubMed, JCO Precis Oncol)

This study highlights the genomic landscape of advanced GISTs and the important role of CGP in identifying rational molecular-targeted therapeutic options.

21 days ago

Retrospective data • Journal • Tumor mutational burden • PD(L)-1 Biomarker • Stroma • Metastases

HER-2 (Human epidermal growth factor receptor 2) • TP53 (Tumor protein P53) • TMB (Tumor Mutational Burden) • NTRK3 (Neurotrophic tyrosine kinase, receptor, type 3) • STK11 (Serine/threonine kinase 11) • HRD (Homologous Recombination Deficiency) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • RB1 (RB Transcriptional Corepressor 1) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha) • ETV6 (ETS Variant Transcription Factor 6) • CDKN2B (Cyclin Dependent Kinase Inhibitor 2B) • SDHB (Succinate Dehydrogenase Complex Iron Sulfur Subunit B) • NTRK (Neurotrophic receptor tyrosine kinase) • SDHA (Succinate Dehydrogenase Complex Flavoprotein Subunit A)

TMB-H • NTRK3 fusion • HRD • ETV6-NTRK3 fusion • PDGFRA mutation • PDGFR wild-type

Keytruda (pembrolizumab)

Oncogenetic Panel and Integrated Clinical Data Registry Study for Wild Type Gastrointestinal Stromal Tumor Patients (clinicaltrials.gov)

P=N/A; Trial primary completion date: Dec 2025 --> Dec 2024

1 month ago

Trial primary completion date • Stroma

KIT (KIT proto-oncogene, receptor tyrosine kinase) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha)

PDGFRA mutation • KIT wild-type • PDGFR wild-type

OncoPanel™ Assay

2ms

Exploration of the immunologic characteristics of KIT/PDGFRA wild-type gastrointestinal stromal tumor as a candidate for neoantigen vaccination. (PubMed, Chin Med J (Engl))

No abstract available

2 months ago

Journal • Stroma

KIT (KIT proto-oncogene, receptor tyrosine kinase) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha)

PDGFR wild-type

6ms

Utility of Clinical Next Generation Sequencing Tests in KIT/PDGFRA/SDH Wild-Type Gastrointestinal Stromal Tumors. (PubMed, Cancers (Basel))

Compared to KIT/PDGFRA-mutant GIST, limited benefit was observed with imatinib in triple-negative GIST. In depth molecular profiling can be helpful in identifying driver mutations and guiding therapy.

6 months ago

Journal • Next-generation sequencing • Stroma

BRAF (B-raf proto-oncogene) • TP53 (Tumor protein P53) • PTEN (Phosphatase and tensin homolog) • KIT (KIT proto-oncogene, receptor tyrosine kinase) • NTRK3 (Neurotrophic tyrosine kinase, receptor, type 3) • FGFR1 (Fibroblast growth factor receptor 1) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha) • NF1 (Neurofibromin 1) • ETV6 (ETS Variant Transcription Factor 6) • CHEK2 (Checkpoint kinase 2) • FANCA (FA Complementation Group A) • SDHB (Succinate Dehydrogenase Complex Iron Sulfur Subunit B) • AURKA (Aurora kinase A) • SDHC (Succinate Dehydrogenase Complex Subunit C) • SDHD (Succinate Dehydrogenase Complex Subunit D) • SDHA (Succinate Dehydrogenase Complex Flavoprotein Subunit A)

TP53 mutation • BRAF V600E • BRAF V600 • NTRK3 fusion • PTEN deletion • PTEN mutation • NF1 mutation • ETV6-NTRK3 fusion • CHEK2 mutation • PDGFRA mutation • FANCA mutation • FGFR1 fusion • FANCA deletion • PDGFR wild-type

imatinib

7ms

TIMP-3 Alleviates White Matter Injury After Subarachnoid Hemorrhage in Mice by Promoting Oligodendrocyte Precursor Cell Maturation. (PubMed, Cell Mol Neurobiol)

The data indicates TIMP-3 could promote the differentiation and maturation of OPCs and subsequently improve neurological outcomes after SAH. Therefore, TIMP-3 could be beneficial for repair after white matter injury and could be a potential therapeutic target in SAH.

7 months ago

Preclinical • Journal

PDGFRB (Platelet Derived Growth Factor Receptor Beta) • TIMP3 (TIMP Metallopeptidase Inhibitor 3)

PDGFR wild-type

7ms

Pediatric-type high-grade gliomas with PDGFRA amplification in adult patients with Li-Fraumeni syndrome: clinical and molecular characterization of three cases. (PubMed, Acta Neuropathol Commun)

These data suggest that high-grade gliomas developed in adult patients with LFS may be involved in pHGG H3-/IDH-wt. PDGFRA and homozygous alterations in TP53 may play pivotal roles in the development of this type of glioma in adult patients with LFS.

7 months ago

Journal

EGFR (Epidermal growth factor receptor) • TP53 (Tumor protein P53) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha) • TERT (Telomerase Reverse Transcriptase)

TP53 mutation • EGFR mutation • EGFR amplification • TERT mutation • IDH wild-type • TERT promoter mutation • PDGFR wild-type

10ms

Avapritinib-based SAR studies unveil a binding pocket in KIT and PDGFRA. (PubMed, Nat Commun)

Against this background, we solve the crystal structures of avapritinib in complex with wild-type and mutant PDGFRA and stem cell factor receptor (KIT), which provide evidence and understanding of inhibitor binding and lead to the identification of a sub-pocket (Gα-pocket). We utilize this information to design, synthesize and characterize avapritinib derivatives for the determination of key pharmacophoric features to overcome drug resistance and limit potential blood-brain barrier penetration.

10 months ago

Journal

KIT (KIT proto-oncogene, receptor tyrosine kinase) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha)

PDGFRA D842V • PDGFRA mutation • PDGFR wild-type

Ayvakit (avapritinib)

10ms

Molecular and clinicopathological features of KIT/PDGFRA wild-type gastrointestinal stromal tumors. (PubMed, Cancer Sci)

NF1-GISTs involved multifocal spindle cell tumors in the small intestine. SDH-GISTs occurred in young patients and were multifocal in the stomach and clinically indolent.

10 months ago

Journal • Stroma

BRAF (B-raf proto-oncogene) • TP53 (Tumor protein P53) • KIT (KIT proto-oncogene, receptor tyrosine kinase) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha) • NF1 (Neurofibromin 1) • CHEK2 (Checkpoint kinase 2) • CREBBP (CREB binding protein) • SDHB (Succinate Dehydrogenase Complex Iron Sulfur Subunit B) • SDHA (Succinate Dehydrogenase Complex Flavoprotein Subunit A)

TP53 mutation • BRAF V600E • BRAF V600 • NF1 mutation • CHEK2 mutation • PDGFRA mutation • SDHB mutation • PDGFR wild-type

1year

A Phase 1, Multicenter, Open-Label, First-in-Human Study of DS-6157a in Patients With Advanced Gastrointestinal Stromal Tumor. (PubMed, Clin Cancer Res)

Targeting GPR20 with DS-6157a was tolerated in patients with advanced GIST with tumor shrinkage demonstrated in KIT/PDGFRA wild type GIST. However, the study did not proceed further due to lower efficacy outcomes than anticipated.

1 year ago

P1 data • Journal • Stroma • Metastases

KIT (KIT proto-oncogene, receptor tyrosine kinase) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha) • GPR20 (G Protein-Coupled Receptor 20)

PDGFR wild-type

DS-6157

1year

GENOMIC ALTERATIONS IN ADVANCED GASTROINTESTINAL STROMAL TUMORS AS REVEALED BY COMPREHENSIVE GENOMIC PROFILING TESTS (CTOS 2023)

Fifty-four patients (38%) underwent CGP tests using specimens obtained before initiating treatment with imatinib and 90 (63%) using specimens obtained after imatinib. The present study highlights that approximately 25% and 50% of patients in each KIT/PDGFRA and wild-type group exhibit targetable GAs, thereby illustrating the clinical utility of CGP tests in identifying therapeutic targets in advanced GISTs.

1 year ago

Tumor mutational burden • PD(L)-1 Biomarker • MSi-H Biomarker • BRCA Biomarker • Stroma • Metastases

HER-2 (Human epidermal growth factor receptor 2) • KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • TMB (Tumor Mutational Burden) • NRAS (Neuroblastoma RAS viral oncogene homolog) • BRCA2 (Breast cancer 2, early onset) • PTEN (Phosphatase and tensin homolog) • KIT (KIT proto-oncogene, receptor tyrosine kinase) • NTRK3 (Neurotrophic tyrosine kinase, receptor, type 3) • STK11 (Serine/threonine kinase 11) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • RB1 (RB Transcriptional Corepressor 1) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha) • NF1 (Neurofibromin 1) • PALB2 (Partner and localizer of BRCA2) • ETV6 (ETS Variant Transcription Factor 6) • CDKN2B (Cyclin Dependent Kinase Inhibitor 2B) • SDHB (Succinate Dehydrogenase Complex Iron Sulfur Subunit B) • TSC1 (TSC complex subunit 1) • SDHA (Succinate Dehydrogenase Complex Flavoprotein Subunit A)

TP53 mutation • BRAF V600E • TMB-H • MSI-H/dMMR • HER-2 amplification • BRAF V600 • NTRK3 fusion • STK11 mutation • ETV6-NTRK3 fusion • PDGFRA D842V • PDGFRA mutation • TSC1 mutation • PDGFR wild-type

FoundationOne® CDx • OncoGuide™ NCC Oncopanel System

Keytruda (pembrolizumab) • Vitrakvi (larotrectinib) • Rozlytrek (entrectinib) • imatinib

1year

EFFICACY OF RIPRETINIB IN A MULTICENTER EXPANDED ACCESS PROGRAM IN PATIENTS WITH ADVANCED GASTROINTESTINAL STROMAL TUMORS HARBOURING NON-KIT EXON 11 MUTATIONS. (CTOS 2023)

Objective: There remains an unmet need for effective and well tolerated systemic therapy for metastatic gastrointestinal stromal tumors (GISTs) after disease progression on imatinib is challenging. In the real world setting, ripretinib has durable benefit in metastatic GISTs harbouring non KIT exon 11 primary mutations. Ripretinib at a dose of 150 mg BD can be safely administered. Ripretinib is generally well tolerated with toxicity profile consistent with previous reports.

1 year ago

Clinical • Stroma • Metastases

KIT (KIT proto-oncogene, receptor tyrosine kinase) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha)

KIT exon 11 mutation • PDGFRA D842V • PDGFRA mutation • PDGFR wild-type

imatinib • Qinlock (ripretinib)

1year

CLINICO-GENOMIC ANALYSIS OF KIT/PDGFRA/SDH WILD-TYPE GASTROINTESTINAL STROMAL TUMORS IDENTIFIES POTENTIAL DRIVER MUTATIONS (CTOS 2023)

The patient with ETV6-NTRK3 fusion was treated with larotrectinib for 28.7 months prior to progression, likely due to acquired NTRK3 gatekeeper mutation (F617L) rendering resistance to larotrectinib, then was on a second generation NTRK inhibitor, selitrectinib, for 16.5 months prior to progression. Triple negative GISTs comprise a diverse cohort with different driver mutations. Compared to KIT/PDGFRA mutant GIST, limited benefit was observed with imatinib in triple negative GIST. In depth molecular profiling can be helpful in identifying driver mutations and guiding therapy.

1 year ago

Genomic analysis • Stroma • Omic analysis

PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • PTEN (Phosphatase and tensin homolog) • KIT (KIT proto-oncogene, receptor tyrosine kinase) • NTRK3 (Neurotrophic tyrosine kinase, receptor, type 3) • FGFR1 (Fibroblast growth factor receptor 1) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha) • NF1 (Neurofibromin 1) • ETV6 (ETS Variant Transcription Factor 6) • CHEK2 (Checkpoint kinase 2) • SDHB (Succinate Dehydrogenase Complex Iron Sulfur Subunit B) • AURKA (Aurora kinase A) • NTRK (Neurotrophic receptor tyrosine kinase) • SDHC (Succinate Dehydrogenase Complex Subunit C) • SDHD (Succinate Dehydrogenase Complex Subunit D) • SDHA (Succinate Dehydrogenase Complex Flavoprotein Subunit A)

BRAF V600E • PIK3CA mutation • BRAF V600 • NTRK3 fusion • PTEN deletion • PTEN mutation • NF1 mutation • ETV6-NTRK3 fusion • CHEK2 mutation • PDGFRA mutation • FGFR1 fusion • PIK3CA I391M • PDGFR wild-type

Vitrakvi (larotrectinib) • imatinib • selitrectinib (BAY 2731954)

over1year

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. (PubMed, Mol Cancer)

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.

over 1 year ago

P2 data • Journal • Metastases

BRAF (B-raf proto-oncogene) • KIT (KIT proto-oncogene, receptor tyrosine kinase) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha) • HIF1A (Hypoxia inducible factor 1, alpha subunit)

BRAF mutation • HIF1A overexpression • PDGFR wild-type

imatinib • Stivarga (regorafenib)

over1year

A registry-based analysis of the projected genomic landscape among unclassified KIT/PDGFRA wildtype mutations in patients with gastrointestinal stromal tumors (ESMO 2023)

Table: 1977P Known and projected mutation distribution Conclusions By using the methods described, we were able to project the frequency of mutations in LRG registry patients and identified a higher frequency of unclassified mutations. A well-defined mutation can provide important information to optimize clinical decision-making, including diagnosis, prognosis, treatment selection, and monitoring treatment response.

over 1 year ago

Clinical • Stroma

BRAF (B-raf proto-oncogene) • KIT (KIT proto-oncogene, receptor tyrosine kinase) • NTRK3 (Neurotrophic tyrosine kinase, receptor, type 3) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha) • NF1 (Neurofibromin 1) • ETV6 (ETS Variant Transcription Factor 6) • PTCH1 (Patched 1) • NTRK (Neurotrophic receptor tyrosine kinase)

NTRK3 fusion • KIT mutation • ETV6-NTRK3 fusion • PDGFRA mutation • KIT wild-type • PDGFR wild-type

over1year

Deep learning predicts patients outcome and mutations from digitized histology slides in gastrointestinal stromal tumor. (PubMed, NPJ Precis Oncol)

DL models yielded comparable results to the Miettinen classification for relapse-free-survival prediction in localized GIST without adjuvant Imatinib (C-index=0.83 in cross-validation and 0.72 for independent testing)...Additionally, novel histological criteria predictive of patients' outcome and mutations were identified by reviewing the tiles selected by the models. As a proof of concept, our study showed the possibility of implementing DL with digitized WSI and may represent a reproducible way to improve tailoring therapy and precision medicine for patients with GIST.

over 1 year ago

Journal • Stroma

KIT (KIT proto-oncogene, receptor tyrosine kinase) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha)

KIT mutation • PDGFRA D842V • PDGFRA mutation • PDGFRA exon 18 mutation • PDGFR wild-type

imatinib

over1year

Wild-type gastrointestinal stromal tumors with NTRK gene fusions (ESMO-GI 2023)

The incidence of NTRK fusion in GIST is extremely low (<1%), but an increased incidence has been reported in wild-type GIST (6% in this study and 5% to 25% in other studies), which established the necessity of detecting NTRK fusion in wild-type GIST. NGS or FISH may be preferred to Pan-TRK IHC to diagnose NTRK fusion GIST. Compared with classic GIST, NTRK fusion GIST showed significant difference in clinicopathological features: more common in men, younger at diagnosis, more common in colorectum and higher recurrence risk, which may indicate a higher malignant tendency.

over 1 year ago

Stroma

KIT (KIT proto-oncogene, receptor tyrosine kinase) • NTRK1 (Neurotrophic tyrosine kinase, receptor, type 1) • NTRK3 (Neurotrophic tyrosine kinase, receptor, type 3) • NTRK2 (Neurotrophic tyrosine kinase, receptor, type 2) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha) • NTRK (Neurotrophic receptor tyrosine kinase)

NTRK1 fusion • NTRK3 fusion • NTRK2 fusion • NTRK fusion • PDGFR wild-type

over1year

MSI analysis in patients with GIST with Lynch syndrome. (ASCO 2023)

For the first time we observed in Lynch Syndrome MSH2 mutated, simolutaneous GIST and colon cancer in the same site of ileum and PCR analisys detected a rare exemple of microsatellite instability in GIST.

over 1 year ago

Clinical • MSi-H Biomarker

BRAF (B-raf proto-oncogene) • MSI (Microsatellite instability) • NTRK1 (Neurotrophic tyrosine kinase, receptor, type 1) • NTRK3 (Neurotrophic tyrosine kinase, receptor, type 3) • NTRK2 (Neurotrophic tyrosine kinase, receptor, type 2) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha) • MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2) • PMS2 (PMS1 protein homolog 2) • NTRK (Neurotrophic receptor tyrosine kinase)

MSI-H/dMMR • NTRK2 fusion • KIT mutation • BRAF wild-type • KIT exon 11 mutation • MSH2 mutation • PDGFR wild-type

EasyPGX® ready MSI

over1year

Multi-omic characterization of gastrointestinal stromal tumor (GIST) in a large real-world patient cohort. (ASCO 2023)

This series provides unprecedented resolution of KIT/PDGFRAmut GIST with features of clinical aggressiveness associated with KIT exon 11 indels and resistance mutations, illustrating a specific cytogenetic genotype with more aggressive growth and malignant behavior. Identification of less common molecular alterations that drive kinase activation and impaired DNA damage repair warrant further investigation.

over 1 year ago

Real-world evidence • Clinical • BRCA Biomarker • Real-world • Stroma

BRAF (B-raf proto-oncogene) • TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • TMB (Tumor Mutational Burden) • BRCA1 (Breast cancer 1, early onset) • PTEN (Phosphatase and tensin homolog) • KIT (KIT proto-oncogene, receptor tyrosine kinase) • NTRK3 (Neurotrophic tyrosine kinase, receptor, type 3) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • RB1 (RB Transcriptional Corepressor 1) • ARID1A (AT-rich interaction domain 1A) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha) • NF1 (Neurofibromin 1) • CHEK2 (Checkpoint kinase 2) • TSC1 (TSC complex subunit 1) • SETD2 (SET Domain Containing 2, Histone Lysine Methyltransferase) • DEPDC5 (DEP Domain Containing 5, GATOR1 Subcomplex Subunit) • MAX (MYC Associated Factor X)

PIK3CA mutation • NTRK3 fusion • PTEN mutation • KIT mutation • NF1 mutation • KIT exon 11 mutation • CHEK2 mutation • PDGFRA mutation • TSC1 mutation • PDGFR wild-type

MI Tumor Seek™

over1year

Outcomes in patients with advanced gastrointestinal stromal tumor who did not have baseline ctDNA detected in the INTRIGUE study. (ASCO 2023)

Background: Ripretinib is a switch-control tyrosine kinase inhibitor approved for patients (pts) with gastrointestinal stromal tumor (GIST) who received prior treatment with ≥3 kinase inhibitors, including imatinib. Pts with ctDNA-ND had better efficacy outcomes vs pts with ctDNA-D in both treatment arms; PFS was numerically higher with ripretinib vs sunitinib in pts with ctDNA-ND. Although little is known about the biology driving ctDNA in GIST, these data suggest pts may have improved outcomes and different treatment sensitivity based on ctDNA detectability. Clinical trial information: NCT03673501.

over 1 year ago

Clinical • Circulating tumor DNA • Stroma • Metastases

KIT (KIT proto-oncogene, receptor tyrosine kinase) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha)

KIT mutation • KIT exon 11 mutation • KIT exon 9 mutation • KIT exon 17 mutation • PDGFR wild-type

Guardant360® CDx

imatinib • sunitinib • Qinlock (ripretinib)

over1year

Clinicopathological features and prognostic factors of gastric intermediate-risk gastrointestinal stromal tumor after surgical resection: a retrospective study (PubMed, Zhonghua Bing Li Xue Za Zhi)

However, adjuvant imatinib potentially improves DFS of intermediate-risk patients with tumors harboring KIT mutation in the malignant group. Therefore, a comprehensive analysis of gene mutations in benign/malignant GIST will facilitate improvements in therapeutic decision-making.

over 1 year ago

Retrospective data • Journal • Stroma

KIT (KIT proto-oncogene, receptor tyrosine kinase) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha)

KIT mutation • PDGFRA mutation • PDGFR wild-type

imatinib

over1year

Oncogenic Long Non-coding RNA LINC02283 Enhances PDGF Receptor A mediated Signaling and Drives Glioblastoma Tumorigenesis. (PubMed, Neuro Oncol)

Our results provide strong evidence of LINC02283 as a regulator of PDGFRA oncogenic activity and GBM malignancy and support the potential of lncRNAs as possible therapeutic targets.

over 1 year ago

Journal

PDGFRA (Platelet Derived Growth Factor Receptor Alpha)

PDGFRA mutation • PDGFR wild-type

over1year

REGISTRI: Single Agent Regorafenib in First-line for Metastatic/Unresectable KIT/PDGFR Wild Type GIST (clinicaltrials.gov)

P2, N=15, Completed, Grupo Espanol de Investigacion en Sarcomas | Recruiting --> Completed | N=39 --> 15

over 1 year ago

Trial completion • Enrollment change • Metastases

KIT (KIT proto-oncogene, receptor tyrosine kinase)

KIT mutation • KIT exon 11 mutation • KIT exon 13 mutation • KIT exon 17 mutation • KIT wild-type • PDGFR wild-type

Stivarga (regorafenib)

over1year

Clinical response to the PDGFRα inhibitor avapritinib in high-grade glioma patients (AACR 2023)

In summary, we report that avapritinib is a selective, CNS-penetrant small molecule inhibitor of PDGFRA that shows potent activity in preclinical models and produces promising clinical responses with good tolerability in patients with high-grade glioma. This suggests a promising role for avapritinib therapy in this population with previously dismal outcomes.

over 1 year ago

Clinical

PDGFRA (Platelet Derived Growth Factor Receptor Alpha)

PDGFRA mutation • PDGFR wild-type

Ayvakit (avapritinib)

almost2years

Expanded genetic testing of GIST patients identifies high proportion of non-syndromic patients with germline alterations. (PubMed, NPJ Precis Oncol)

P/LP variants in certain genes (e.g., BRCA1/2, SDHB) identified in tumor-only sequencing of GISTs were almost exclusively germline in origin. Our results provide guidance for genetic testing of GIST patients and indicate that germline testing should be offered to all patients with KIT/PDGFRA-wildtype GISTs regardless of their history of syndromic features.

almost 2 years ago

Journal • BRCA Biomarker

BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • KIT (KIT proto-oncogene, receptor tyrosine kinase) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha) • NF1 (Neurofibromin 1) • SDHB (Succinate Dehydrogenase Complex Iron Sulfur Subunit B) • SDHC (Succinate Dehydrogenase Complex Subunit C) • SDHA (Succinate Dehydrogenase Complex Flavoprotein Subunit A)

PDGFR wild-type

almost2years

Expanding Molecular Spectrum of Quadruple Wild-type GIST and GIST-like Tumors: NGS study of a Series of 17 Cases (USCAP 2023)

Our study revealed 6 new cases of quadruple wild-type GIST or GIST-like tumors with possible oncogenic driver alterations (2.4 % of all our archival cases of GIST). While the case with BCOR-CCNB3 fusion rather represents a CD117-positive GIST-like BCOR -rearranged sarcoma, the remaining 5 cases probably belong to the category of true quadruple wild-type GIST. Whereas mutations in MAX and TP53 were already described previously, we are not aware of any study reporting on mutations of ATM , GNAQ and NUP93 in GIST.

almost 2 years ago

Clinical • Next-generation sequencing

EGFR (Epidermal growth factor receptor) • KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • TP53 (Tumor protein P53) • KIT (KIT proto-oncogene, receptor tyrosine kinase) • FGFR1 (Fibroblast growth factor receptor 1) • ARID1A (AT-rich interaction domain 1A) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha) • NF1 (Neurofibromin 1) • GNAQ (G Protein Subunit Alpha Q) • ETV6 (ETS Variant Transcription Factor 6) • BCOR (BCL6 Corepressor) • FGF4 (Fibroblast growth factor 4) • ANO1 (Anoctamin 1) • CHD4 (Chromodomain Helicase DNA Binding Protein 4) • NUP93 (Nucleoporin 93) • MAX (MYC Associated Factor X)

TP53 mutation • KRAS mutation • EGFR mutation • BRAF mutation • ATM mutation • KIT mutation • NF1 mutation • RAS mutation • FGFR1 mutation • CBL mutation • PDGFRA mutation • NUP93 mutation • PDGFR wild-type

TruSight Oncology 500 Assay • Archer® FusionPlex® Sarcoma kit

almost2years

Intestinal LMNA::NTRK1-fused spindle cell neoplasm with S100 and CD34 coexpression: a new case. (PubMed, BMJ Case Rep)

Here, we present a recently encountered intestinal spindle cell neoplasm harbouring an LMNA::NTRK1 gene fusion in a woman in her early 20s, which was initially thought to represent a GIST or a solitary fibrous tumour. Awareness of this emerging tumour type in the gastrointestinal tract is important due to treatment implications.

almost 2 years ago

Journal

BRAF (B-raf proto-oncogene) • KIT (KIT proto-oncogene, receptor tyrosine kinase) • NTRK1 (Neurotrophic tyrosine kinase, receptor, type 1) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha) • RAS (Rat Sarcoma Virus) • CD34 (CD34 molecule) • LMNA (Lamin A/C) • SOX10 (SRY-Box 10) • NTRK (Neurotrophic receptor tyrosine kinase)

NTRK1 fusion • BRAF wild-type • RAS wild-type • LMNA-NTRK1 fusion • PDGFR wild-type

2years

Integrated Antitumor Activities of Cellular Immunotherapy with CIK Lymphocytes and Interferons against KIT/PDGFRA Wild Type GIST. (PubMed, Int J Mol Sci)

Patient-derived CIK were capable of intense killing in vitro against wtGISTc resistant to both imatinib and sunitinib. wtGIST cells that survived IFNα were still sensitive to CIK immunotherapy. Our data support the exploration of CIK immunotherapy in clinical studies for TKI-resistant wtGIST, proposing reevaluation for IFNα within this challenging setting.

2 years ago

Journal • PD(L)-1 Biomarker • IO biomarker

PD-L1 (Programmed death ligand 1) • KIT (KIT proto-oncogene, receptor tyrosine kinase) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha) • IFNG (Interferon, gamma) • GZMB (Granzyme B) • IFNA1 (Interferon Alpha 1)

PD-L1 expression • KIT mutation • PDGFRA mutation • PDGFR wild-type

imatinib • sunitinib

2years

Gastrointestinal stromal tumors caused by novel germline variants in SDHB and KIT: a report of two cases and literature review. (PubMed, Clin J Gastroenterol)

The first case is a 28-year-old female who developed multiple gastric GISTs with widespread abdominal metastases that were resistant to imatinib...Next-generation sequencing revealed a germline KIT exon 17 mutation (NM_000222.3, c.2459A > T, p.D820V). These cases highlight the diverse clinical presentations of patients with germline variants and raise several important points about the diagnosis and management of these patients, in particular: mutation in the SDH family of genes (somatic or germline) should be suspected in KIT and PDGFRA wild-type tumors; germline testing should be considered in patients with multiple GISTs or those who present with disease at a young age; and somatic next-generation sequencing cannot only help identify optimal therapy in all patients with GISTs but also help guide referral to Medical Genetics for appropriate patients.

2 years ago

Review • Journal

PDGFRA (Platelet Derived Growth Factor Receptor Alpha) • SDHB (Succinate Dehydrogenase Complex Iron Sulfur Subunit B)

KIT mutation • KIT exon 17 mutation • PDGFR wild-type

imatinib

2years

PHASE I RESULTS FROM A MULTI-PHASE COMPREHENSIVE GENOMIC SEQUENCING TUMOR STUDY IN GASTROINTESTINAL STROMAL TUMOR PATIENTS (CTOS 2022)

Imatinib, one of the frequently used therapies for GIST, has demonstrated low sensitivity among KIT/PDGFRA wildtype GISTs... Utilizing NGS based CGP is a crucial step in understanding and identifying relevant biomarkers including tumor growth drivers to aid in the treatment decision for optimal patient outcomes. CGP provides relevant data for conducting a more accurate, individualized treatment plan for patients, and prevents patients from undergoing unnecessary therapies that will not work for their respective mutation. Furthermore, this approach accelerates adoption of precision oncology and aids future drug discovery and development programs specifically for GIST patients.

2 years ago

Clinical • P1 data • Tumor Mutational Burden

TMB (Tumor Mutational Burden) • MSI (Microsatellite instability) • KIT (KIT proto-oncogene, receptor tyrosine kinase) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha) • NF1 (Neurofibromin 1) • ETV6 (ETS Variant Transcription Factor 6) • SDHB (Succinate Dehydrogenase Complex Iron Sulfur Subunit B) • NTRK (Neurotrophic receptor tyrosine kinase) • SDHA (Succinate Dehydrogenase Complex Flavoprotein Subunit A)

EGFR mutation • KIT mutation • NF1 mutation • PDGFRA mutation • KIT wild-type • SDHB mutation • SDHB mutation + NF1 mutation • NTRK fusion • PDGFR wild-type

imatinib

2years

Systemic Therapy for Gastrointestinal Stromal Tumor: Current Standards and Emerging Challenges. (PubMed, Curr Treat Options Oncol)

The discovery of imatinib with promising anti-tumor effect and successive tyrosine kinase inhibitors (TKI), including second-line sunitinib and third-line regorafenib, revolutionized the management of advanced and metastatic GIST over the past two decades. Recently, ripretinib and avapritinib were approved for the fourth line setting and for PDGFRA exon 18-mutant GIST in first-line setting, respectively...KIT/PDGFRα wild-type GISTs are generally less sensitive to imatinib and late-line TKIs. Recent studies demonstrated that targeting fibroblast growth factor receptor signaling may be a potential target for the wild-type GISTs.

2 years ago

Review • Journal • PD(L)-1 Biomarker • IO biomarker

PDGFRA (Platelet Derived Growth Factor Receptor Alpha) • FGFR (Fibroblast Growth Factor Receptor) • CTLA4 (Cytotoxic T-Lymphocyte Associated Protein 4)

PDGFRA mutation • PDGFRA exon 18 mutation • PDGFR wild-type

imatinib • sunitinib • Stivarga (regorafenib) • Ayvakit (avapritinib) • Qinlock (ripretinib)

over2years

Correlation of treatment outcome in sanger/RT‑qPCR KIT/PDGFRA wild‑type metastatic gastrointestinal stromal tumors with next‑generation sequencing results: A single‑center report. (PubMed, Oncol Rep)

Their outcome was universally poor. The reliability of RT‑qPCR and direct Sanger sequencing results in this setting is therefore insufficient and it is recommended that NGS becomes a requirement for treatment decision at least in KIT/PDGFRA/BRAF WT GIST as determined by RT‑qPCR and Sanger sequencing.

over 2 years ago

Journal • Next-generation sequencing

BRAF (B-raf proto-oncogene) • KIT (KIT proto-oncogene, receptor tyrosine kinase) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha)

KIT mutation • BRAF wild-type • PDGFRA mutation • PDGFR wild-type

imatinib

over2years

Treatment of Gastrointestinal Stromal Tumors (GISTs): A Focus on Younger Patients. (PubMed, Cancers (Basel))

The optimal treatment strategy should be established by a multidisciplinary team experienced in sarcoma treatment. The impact of treatment on the quality of life and daily activities, including the impact on work, pregnancy, and fertility, in this patient population should be especially taken into consideration.

over 2 years ago

Review • Journal

PDGFRA (Platelet Derived Growth Factor Receptor Alpha)

PDGFRA mutation • PDGFR wild-type

over2years

Our data provide insights into the molecular alterations underpinning KIT/PDGFRA WT GISTs. More effort should be devoted to improve methods to identify this distinct disease subtype within the KIT/PDGFRA WT GIST group.

over 2 years ago

Journal

KIT (KIT proto-oncogene, receptor tyrosine kinase) • NTRK1 (Neurotrophic tyrosine kinase, receptor, type 1) • NTRK3 (Neurotrophic tyrosine kinase, receptor, type 3) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha) • NTRK (Neurotrophic receptor tyrosine kinase)

NTRK1 fusion • NTRK3 fusion • PDGFRA mutation • NTRK expression • NTRK fusion • PDGFR wild-type

over2years

Patient demographics, clinicopathologic features, and outcomes in wild-type gastrointestinal stromal tumor: a national cohort analysis. (PubMed, Sci Rep)

Surgery remains the principal treatment modality. Small intestine primary site and high mitotic count were associated with abbreviated OS.

over 2 years ago

Retrospective data • Journal

PDGFRA (Platelet Derived Growth Factor Receptor Alpha)

KIT wild-type • PDGFR wild-type

almost3years

New Tyrosine Kinase Inhibitors for the Treatment of Gastrointestinal Stromal Tumors. (PubMed, Curr Oncol Rep)

Based on this principle, two new drugs were approved in 2020: ripretinib in GIST patients after progression to all standard treatments and avapritinib, the first agent ever active in the multiresistant PDGFRA D842V-mutant GIST. Additionally, cabozantinib has also shown encouraging activity in imatinib-resistant GIST patients. Finally, novel agents targeting NTRK-driven GIST have emerged as a breakthrough for the treatment of a subset of KIT/PDGFRA wild-type GIST patients. GIST is a paradigmatic tumor model for the rational and successful development of molecularly targeted agents directed against driver mutations in cancer.

almost 3 years ago

Review • Journal

KIT (KIT proto-oncogene, receptor tyrosine kinase) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha) • NTRK (Neurotrophic receptor tyrosine kinase)

PDGFRA D842V • PDGFRA mutation • PDGFR wild-type

imatinib • Cabometyx (cabozantinib tablet) • Ayvakit (avapritinib) • Qinlock (ripretinib)

over3years

Fluorescent In Situ Hybridization Must be Preferred to pan-TRK Immunohistochemistry to Diagnose NTRK3-rearranged Gastrointestinal Stromal Tumors (GIST). (PubMed, Appl Immunohistochem Mol Morphol)

Given the new therapeutic opportunity offered by anti-TRK targeted therapies to treat patients with advanced cancers including GISTs, it is worth to extend molecular analysis to NTRK fusions testing in KIT, PDGFRA, and BRAF wild type GISTs. Pan-TRK IHC appears not relevant in this field but performing a simple NTRK3 fluorescent in situ hybridization test consists in a valuable approach to identify the rare NTRK3-rearranged GISTs treatable using anti-TRK therapies.

over 3 years ago

Journal

BRAF (B-raf proto-oncogene) • KIT (KIT proto-oncogene, receptor tyrosine kinase) • NTRK1 (Neurotrophic tyrosine kinase, receptor, type 1) • NTRK3 (Neurotrophic tyrosine kinase, receptor, type 3) • NTRK2 (Neurotrophic tyrosine kinase, receptor, type 2) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha) • NTRK (Neurotrophic receptor tyrosine kinase)

BRAF V600E • BRAF V600 • KIT mutation • BRAF wild-type • PDGFRA mutation • NTRK positive • NTRK fusion • PDGFR wild-type

VENTANA pan-TRK (EPR17341) Assay