Long-term follow-up results of the multicenter phase II trial of regorafenib in patients with metastatic and/or unresectable GI stromal tumor after failure of standard tyrosine kinase inhibitor therapy

Ben-Ami, Eytan; Barysauskas, Constance M.; Mehren, Margaret von; Heinrich, Michael C.; Corless, C. L.; Butrynski, James E.; Morgan, Jeffrey A.; Wagner, Andrew J.; Choy, Edwin; Yap, Jeffrey T.; Abbeele, Annick D. Van den; Solomon, Sarah; Fletcher, Jonathan A.; Demetri, George D.; George, Suzanne

doi:10.1093/annonc/mdw228

Cited by 93 publications

(86 citation statements)

References 17 publications

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“…This mechanism may account for the efficacy of sunitinib, which has inhibitory effects on both VEGFR and IGF1R, in SDHdeficient GIST, and predicts potential alternative therapeutic angles targeting these receptors or their downstream effectors. 1 A 2016 study by Ben-Ami et al 30 noted potential improvement of progression-free survival with regorafenib among patients with unresectable SDH-deficient GIST after failure of prior therapy with a tyrosine kinase inhibitor.…”

Section: Sdha Mutation-associated Gistsmentioning

confidence: 99%

Succinate Dehydrogenase–Deficient Gastrointestinal Stromal Tumors

Ibrahim

Chopra

2019

Archives of Pathology &Amp; Laboratory Medicine

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Succinate dehydrogenase (SDH)–deficient gastrointestinal stromal tumor (GIST) is a subset of wild-type GIST that constitutes approximately 10% of gastric GISTs. SDH-mutated GISTs lack mutations in the proto-oncogene receptor tyrosine kinase (also known as KIT, c-KIT, or CD117) or platelet-derived growth factor receptor α (PDGFR-α). These tumors have female predilection, affect children and young adults, and have a spectrum of behavior from indolent to progressive. These tumors have characteristic morphologic features including multinodular architecture, multiple tumors, lymphovascular involvement, and occasional lymph node metastasis. They can be seen in patients with Carney triad or Carney-Stratakis syndrome. Although a mutation in any one of the SDH subunits can be pathogenic, deficiency of a single subunit leads to loss of detectable SDH subunit B by immunohistochemistry, enabling a convenient, tissue-based screening method. The prognosis and the clinical course of these tumors is different from that of KIT- or PDGFR-α–mutated GISTs. Surgical management is considered the main line of treatment. SDH-mutated GISTs do not respond well to the common targeted therapy, with no objective tumor response to imatinib. The role of the pathologist in diagnosing these cases is imperative in management and subsequent follow-up.

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Section: Sdha Mutation-associated Gistsmentioning

confidence: 99%

Succinate Dehydrogenase–Deficient Gastrointestinal Stromal Tumors

Ibrahim

Chopra

2019

Archives of Pathology &Amp; Laboratory Medicine

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“…Sunitinib has been approved as second-line treatment for imatinib-resistant GIST and shows efficacy in GIST with imatinib-resistance mutations in the ATP-binding pocket 42 , whereas third-line regorafenib therapy shows predominantly complementary activity by best inhibiting GISTs with imatinib-resistance due to activation loop mutations. 43 However, treatment of metastatic GISTs containing multiple resistant subclones and heterogeneous genomic subpopulations remains a therapeutic challenge. 14 …”

Section: Treatment Of Localized and Advanced Diseasementioning

confidence: 99%

What is New in Gastrointestinal Stromal Tumor?

Schaefer

Mariño-Enríquez

Fletcher

2017

Advances in Anatomic Pathology

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The classification “gastrointestinal stromal tumor” (GIST) became commonplace in the 1990s and since that time various advances have characterized the GIST lineage of origin, tyrosine kinase mutations, and mechanisms of response and resistance to targeted therapies. In addition to tyrosine kinase mutations and their constitutive activation of downstream signaling pathways, GISTs acquire a sequence of chromosomal aberrations. These include deletions of chromosomes 14q, 22q, 1p, and 15q, which harbor putative tumor suppressor genes required for stepwise progression from microscopic, preclinical forms of GIST (“microGIST”) to clinically relevant tumors with malignant potential. Recent advances extend our understanding of GIST biology beyond that of the oncogenic KIT/PDGFRA tyrosine kinases and beyond mechanisms of KIT/PDGFRA-inhibitor treatment response and resistance. These advances have characterized ETV1 as an essential interstitial cell of Cajal-GIST transcription factor in oncogenic KIT signaling pathways, and have characterized the biologically distinct subgroup of SDH-deficient GIST, which are particularly common in young adults. Also, recent discoveries of MAX and dystrophin genomic inactivation have expanded our understanding of GIST development and progression, showing that MAX inactivation is an early event fostering cell cycle activity, whereas dystrophin inactivation promotes invasion and metastasis.

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“…The long-term follow-up results of the multicenter phase II trial of regorafenib in patients with metastatic or unresectable GISTs after failure of imatinib and sunitinib showed benefit in patients with primary KIT exon 11 mutations and SDH-deficient GISTs[28]. …”

Section: Tkis and Biological Therapy In Gistsmentioning

confidence: 99%

Current research and treatment for gastrointestinal stromal tumors

Lim

Tan

2017

WJG

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Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract and have gained considerable research and treatment interest, especially in the last two decades. GISTs are driven by mutations commonly found in the KIT gene and less commonly in the platelet-derived growth factor receptor alpha gene, BRAF gene and succinate dehydrogenase gene. GISTs behave in a spectrum of malignant potential, and both the tumor size and mitotic index are the most commonly used prognostic criteria. Whilst surgical resection can offer the best cure, targeted therapy in the form of tyrosine kinase inhibitors (TKIs) has revolutionized the management options. As the first-line TKI, imatinib offers treatment for advanced and metastatic GISTs, adjuvant therapy in high-risk GISTs and as a neoadjuvant agent to downsize large tumors prior to resection. The emergence of drug resistance has altered some treatment options, including prolonging the first-line TKI from 1 to 3 years, increasing the dose of TKI or switching to second-line TKI. Other newer TKIs, such as sunitinib and regorafenib, may offer some treatment options for imatinib-resistant GISTs. New molecular targeted therapies are being evaluated, such as inhibitors of BRAF, heat shock protein 90, glutamine and mitogen-activated protein kinase signaling, as well as inhibitors of apoptosis proteins antagonist and even immunotherapy. This editorial review summarizes the recent research trials and potential treatment targets that may influence our future patient-specific management of GISTs. The current guidelines in GIST management from Europe, North America and Asia are highlighted.

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Long-term follow-up results of the multicenter phase II trial of regorafenib in patients with metastatic and/or unresectable GI stromal tumor after failure of standard tyrosine kinase inhibitor therapy

Cited by 93 publications

References 17 publications

Succinate Dehydrogenase–Deficient Gastrointestinal Stromal Tumors

Succinate Dehydrogenase–Deficient Gastrointestinal Stromal Tumors

What is New in Gastrointestinal Stromal Tumor?

Current research and treatment for gastrointestinal stromal tumors

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