Utility of Circulating Tumor DNA in the Management of Patients With GI Stromal Tumor: Analysis of 243 Patients

Arshad, Junaid; Roberts, Ali; Ahmed, Jibran; Cotta, Jared Addison; Pico, Brian; Kwon, D.; Trent, Jonathan C.

doi:10.1200/po.19.00253

Cited by 32 publications

(31 citation statements)

References 41 publications

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“…However, this will have to be weighed against increased toxicity and financial burden. In the future, as new therapies develop, the role of immunotherapies could be expanded to GIST patients refractory to standard treatments or to a subset of patients harboring specific tumor characteristics after evaluation by next-generation sequencing or circulating tumor DNA [ 40 ].…”

Section: Discussionmentioning

confidence: 99%

Immunotherapy Strategies for Gastrointestinal Stromal Tumor

Arshad

Costa

Barreto-Coelho

et al. 2021

Cancers

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Gastrointestinal stromal tumors (GIST) are the most common mesenchymal soft tissue sarcoma of the gastrointestinal tract. The management of locally advanced or metastatic unresectable GIST involves detecting KIT, PDGFR, or other molecular alterations targeted by imatinib and other tyrosine kinase inhibitors. The role of immunotherapy in soft tissue sarcomas is growing fast due to multiple clinical and pre-clinical studies with no current standard of care. The potential therapies include cytokine-based therapy, immune checkpoint inhibitors, anti-KIT monoclonal antibodies, bi-specific monoclonal antibodies, and cell-based therapies. Here we provide a comprehensive review of the immunotherapeutic strategies for GIST.

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Section: Discussionmentioning

confidence: 99%

Immunotherapy Strategies for Gastrointestinal Stromal Tumor

Arshad

Costa

Barreto-Coelho

et al. 2021

Cancers

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“…The sensitivity of ctDNA is higher in metastatic patients with high disease burden. [11] ctDNA detection is useful in diagnosis, response assessment, and disease progression. [16,17] Presented here is the largest study identifying the genetic makeup of patients with metastatic LMS with the use of ctDNA.…”

Section: Discussionmentioning

confidence: 99%

“…In other tumors, such as GIST, mutations detected on ctDNA analysis, such as KIT/PDGFRA, have been found relevant for diagnostic purposes as well as to predict treatment responses. [11] Meanwhile, there are no available treatment targets in LMS; ctDNA in LMS can be restricted to diagnosis related to the size cutoff 5 cm irrespective of the disease progression, making it a technical sensitivity threshold. This ctDNA detection may help distinguish between leiomyoma and LMS.…”

Section: Discussionmentioning

confidence: 99%

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Identification of Genetic Alterations by Circulating Tumor DNA in Leiomyosarcoma: A Molecular Analysis of 73 Patients

Arshad

Barreto-Coelho

Jonczak

et al. 2020

Journal of Immunotherapy and Precision Oncology

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Background Leiomyosarcoma is a malignant mesenchymal tumor of cells of smooth muscle lineage arising commonly in retroperitoneum, uterus, large veins, and the limbs. The genetics of leiomyosarcomas are complex and there is very limited understanding of common driver mutations. Circulating tumor DNA (ctDNA) offers a rapid and noninvasive method of next-generation sequencing (NGS) that could be used for diagnosis, therapy, and detection of recurrence. Methods ctDNA testing was performed using Guardant360, which detects single nucleotide variants, amplifications, fusions, and specific insertion/deletion mutations in 73 genes using NGS. Results Of 73 patients, 59 were found to have one or more cancer-associated genomic alteration. Forty-five (76%) were female with a median age of 63 (range, 38–87) years. All samples were designated metastatic. The most common alterations were detected in Tp53 (65%), BRAF (13%), CCNE (13%), EGFR (12%), PIK3CA (12%), FGFR1 (10%), RB1(10%), KIT (8%), and PDGFRA (8%). Some of the other alterations included RAF1, ERBB2, MET, PTEN TERT, APC, and NOTCH1. Potentially targetable mutations, by Food and Drug Administration–approved or clinical trials, were found in 24 (40%) of the 73 patients. Four patients (5%) were found to have incidental germline TP53 mutations. Conclusion NGS of ctDNA allows identification of genomic alterations in plasma from patients with leiomyosarcoma. Unfortunately, there is limited activity of current targeted agents in leiomyosarcomas. These results suggest opportunities to develop therapy against TP53, cell cycle, and kinase signaling pathways. Further validation and prospective evaluation is warranted to investigate the clinical utility of ctDNA for patients with leiomyosarcoma.

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“…The majority of liquid biopsy studies in GIST have assessed ctDNA (for a detailed review, see Goḿez-Peregrina et al) (75). Patients with localized disease were less likely to have detectable ctDNA, whereas those with high-burden metastatic disease that was progressing showed the highest rate of ctDNA detection (76). Overall, it is difficult to make direct comparisons between studies, as they have different methodologies.…”

Section: Intra-and Intertumoral Heterogeneity and Clonal Evolution Complicates Treatmentmentioning

confidence: 99%

Early and Next-Generation KIT/PDGFRA Kinase Inhibitors and the Future of Treatment for Advanced Gastrointestinal Stromal Tumor

et al. 2021

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The majority of gastrointestinal stromal tumors (GIST) harbor an activating mutation in either the KIT or PDGFRA receptor tyrosine kinases. Approval of imatinib, a KIT/PDGFRA tyrosine kinase inhibitor (TKI), meaningfully improved the treatment of advanced GIST. Other TKIs subsequently gained approval: sunitinib as a second-line therapy and regorafenib as a third-line therapy. However, resistance to each agent occurs in almost all patients over time, typically due to secondary kinase mutations. A major limitation of these 3 approved therapies is that they target the inactive conformation of KIT/PDGFRA; thus, their efficacy is blunted against secondary mutations in the kinase activation loop. Neither sunitinib nor regorafenib inhibit the full spectrum of KIT resistance mutations, and resistance is further complicated by extensive clonal heterogeneity, even within single patients. To combat these limitations, next-generation TKIs were developed and clinically tested, leading to 2 new USA FDA drug approvals in 2020. Ripretinib, a broad-spectrum KIT/PDGFRA inhibitor, was recently approved for the treatment of adult patients with advanced GIST who have received prior treatment with 3 or more kinase inhibitors, including imatinib. Avapritinib, a type I kinase inhibitor that targets active conformation, was approved for the treatment of adults with unresectable or metastatic GIST harboring a PDGFRA exon 18 mutation, including PDGFRA D842V mutations. In this review, we will discuss how resistance mutations have driven the need for newer treatment options for GIST and compare the original GIST TKIs with the next-generation KIT/PDGFRA kinase inhibitors, ripretinib and avapritinib, with a focus on their mechanisms of action.

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Utility of Circulating Tumor DNA in the Management of Patients With GI Stromal Tumor: Analysis of 243 Patients

Cited by 32 publications

References 41 publications

Immunotherapy Strategies for Gastrointestinal Stromal Tumor

Immunotherapy Strategies for Gastrointestinal Stromal Tumor

Identification of Genetic Alterations by Circulating Tumor DNA in Leiomyosarcoma: A Molecular Analysis of 73 Patients

Early and Next-Generation KIT/PDGFRA Kinase Inhibitors and the Future of Treatment for Advanced Gastrointestinal Stromal Tumor

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