SDH-deficient gastrointestinal stromal tumours

Gastrointestinal stromal tumours (GIST) comprise a heterogeneous group of the most common mesenchymal neoplasms of the gastrointestinal tract. The majority of GIST are induced by activating, mutually exclusive mutations of two genes – KIT and PDGFRA (platelet-derived growth factor receptor-alpha). However, approximately 10–15% of GISTs lack oncogenic KIT or PDGFRA mutations and these tumours are often called “wild type” (WT) GISTs. The SDH-deficient GISTs form a distinctive subset of tumours accounting for 20–40% of KIT/PDGFRA WT GIST, which results from the loss of function mutations in the genes encoding the SDH enzyme complex. The true frequency of SDH-deficient GISTs was reported to be approximately 7.4 to 7.7%. These tumours usually occur in the stomach (most commonly in the antrum) and have a spectrum of beha­viour from indolent to progressive. In most cases the molecular mechanism behind the SDH-deficient GISTs is connected to germline mutations. SDHA germline mutations occur in approximately 30% of the SDH-deficient GIST, those in SDHB, SDHC, and SDHD appear in 20–30% of patients. The SDH-mutated GISTs do not respond well to the commonly used targeted therapy, with no objective tumour response to imatinib. Taking into account the biological features of SDH-deficient GIST, new therapies of potential in­terest comprise PI3K/AKT/mTOR inhibitors, heat-shock protein inhibitors, HIF1-α targeting agents, epigenetic modifiers and demethylating agents. However, further research is necessary in these fields

SDH-deficient gastrointestinal stromal tumours

Gastrointestinal stromal tumours (GIST) comprise a heterogeneous group of the most common mesenchymal neoplasms of the gastrointestinal tract. The majority of GIST are induced by activating, mutually exclusive mutations of two genes – KIT and PDGFRA (platelet-derived growth factor receptor-alpha). However, approximately 10–15% of GISTs lack oncogenic KIT or PDGFRA mutations and these tumours are often called “wild type” (WT) GISTs. The SDH-deficient GISTs form a distinctive subset of tumours accounting for 20–40% of KIT/PDGFRA WT GIST, which results from the loss of function mutations in the genes encoding the SDH enzyme complex. The true frequency of SDH-deficient GISTs was reported to be approximately 7.4 to 7.7%. These tumours usually occur in the stomach (most commonly in the antrum) and have a spectrum of beha­viour from indolent to progressive. In most cases the molecular mechanism behind the SDH-deficient GISTs is connected to germline mutations. SDHA germline mutations occur in approximately 30% of the SDH-deficient GIST, those in SDHB, SDHC, and SDHD appear in 20–30% of patients. The SDH-mutated GISTs do not respond well to the commonly used targeted therapy, with no objective tumour response to imatinib. Taking into account the biological features of SDH-deficient GIST, new therapies of potential in­terest comprise PI3K/AKT/mTOR inhibitors, heat-shock protein inhibitors, HIF1-α targeting agents, epigenetic modifiers and demethylating agents. However, further research is necessary in these fields

What are the current outcomes of advanced gastrointestinal stromal tumors: who are the long-term survivors treated initially with imatinib?

The introduction of imatinib to clinical practice revolutionized therapy of advanced gastrointestinal stromal tumors (GIST), but its long-term results have been only just collected. We have attempted to identify factors related to the long-term survival. We have analyzed the data of 430 inoperable/metastatic/recurrent GIST patients treated with imatinib in reference centers, assessed the factors influencing the long-term overall survival (OS), and compared the outcomes in three periods of initiation of imatinib therapy during one decade (2001–2003, 2004–2006, 2007–2010). During analyzed time periods, we have found decrease in median largest tumor size at the start of imatinib therapy: 90.5 mm (2001–2003) versus 74 mm (2004–2006) versus 58 mm (2007–2010) (p = 0.002). Median progression-free survival (PFS) on 1st line imatinib was 37.5 months, without differences in PFS between three groups. Median OS was 5.8 years, 8-year OS rate was 43 %, and no difference in OS was demonstrated for patients treated in analyzed time periods. Independent good prognostic factors for longer OS were as follows: surgery of residual disease, initial WHO performance status 0/1, normal baseline albumin level, and the presence of exon 11 KIT mutations. Current median OS in advanced GIST reaches 6 years. The long-term survivors were characterized by smaller maximal tumors at imatinib start, better blood tests results, better performance status, and the surgical removal of residual disease. The latter might reduce the impact of tumor size and equalize the long-term results of therapy during last decade from introduction of imatinib. After introduction of subsequent lines of therapy (as sunitinib), the effect of primary mutational status on the long-term OS is also less visible