Background:
Regorafenib (REG) is an oral multikinase inhibitor used in colorectal cancer, gastrointestinal stromal tumour and hepatocellular carcinoma. Several adverse events (AEs) are commonly ...reported during REG administration, and strategies for managing AEs in everyday clinical practice include supportive care, dose modifications and, when necessary, treatment withdrawal. We performed a systematic review and meta-analysis to assess the schedule treatment modifications of REG associated with AEs across randomized controlled clinical trials (RCTs).
Methods:
Eligible studies included RCTs assessing standard dose REG versus placebo. Outcomes of interest included: AE-related permanent discontinuation, dose interruptions and dose reductions.
Results:
We retrieved all the relevant RCTs through PubMed/Med, Cochrane library and EMBASE: 7 eligible studies involving a total of 2099 patients (Regorafenib: 1362; placebo: 737) were included in our analysis. The use of REG was associated with higher incidence and risk of all outcomes of interest when compared with placebo. The incidences of permanent discontinuation, dose interruptions and dose reductions in patients receiving REG were 9.7%, 57.2% and 47%, respectively, versus 3.3%, 16.7% and 7.7% of placebo group; compared with placebo, the summary relative risks (RRs) of permanent discontinuation, dose interruptions and dose reductions in REG arm were 2.80 (95% CI 1.85–4.22), 3.21 (95% CI 2.59–3.99) and 6.02 (95% CI 3.28–11.03), respectively.
Conclusions:
Treatment with REG at the standard dose of 160 mg is associated with a significant increase in AE-related permanent discontinuation, dose interruptions and dose reductions. Prompt identification and management of AEs seem mandatory to obtain maximal benefit from REG treatment. In the current landscape, dose personalization of REG may have the potential to improve quality of life, minimize treatment discontinuation and maximize patient outcomes.
Recent advances in molecular biology have revolutionized the concept of KIT/PDGFRA wild type (WT) gastrointestinal stromal tumors (GIST) than the past. Indeed, from being defined as GIST without KIT ...or PDGFRA mutations, we are now faced with the opposite scenario, where KIT/PDGFRA WT GIST are "positively" defined according to their specific molecular alterations. In particular, if until recently KIT/PDGFRA GIST without abnormalities of KIT, PDGFRA, SDH, and the RAS signaling pathway were referred as quadruple WT GIST, today also this small subset of GIST is emerging out as a group of heterogeneous distinct entities with multiple different molecular alterations. Therefore, given this still growing and rapidly evolving scenario, the progressive molecular fragmentation may inevitably lead over the time to the disappearance of KIT/PDGFRA WT GIST, destined to be singularly defined by their molecular fingerprint.
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Gastrointestinal stromal tumors (GIST) are rare neoplasms of mesenchymal origin arising in the gastrointestinal tract. The vast majority are characterized by mutually exclusive activating mutations ...in KIT or Platelet-derived growth factor alpha (PDGFRA) receptors, or less frequently by succinate dehydrogenase complex (SDH) or NF1 inactivation, with very rare cases harboring mutant BRAF or RAS alleles. Approximately 5% of GISTs lack any of such mutations and are called
wild-type (WT) GISTs. Recently, deregulated Fibroblast Growth Factor (FGF)/FGF-receptor (FGFR) signaling emerged as a relevant pathway driving oncogenic activity in different molecular subgroups of GISTs. This review summarizes all the current evidences supporting the key role of the FGF/FGFR pathway activation in GISTs, whereby either activating mutations, oncogenic gene fusions, or autocrine/paracrine signaling have been detected in
WT, SDH-
, or KIT-mutant GISTs.
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Targeted therapy in SDH-deficient GIST Nannini, Margherita; Rizzo, Alessandro; Indio, Valentina ...
Therapeutic Advances in Medical Oncology,
2021, Volume:
13
Book Review, Journal Article
Peer reviewed
Open access
The medical management of advanced gastrointestinal stromal tumors (GIST) has improved with the development of tyrosine kinase inhibitors (TKIs) targeting KIT and PDGFRA mutations. However, ...approximately 5–10% of GIST lack KIT and PDGFRA mutations, and about a half are deficient in succinate dehydrogenase (SDH) that promotes carcinogenesis by the cytoplasmic accumulation of succinate. This rare group of GIST primarily occurs in the younger patients than other subtypes, and is frequently associated with hereditary syndromes. The role of TKIs in patients with SDH-deficient GIST is controversial, with conflicting results; thus, there is an urgent need to uncover the disease mechanisms, treatment patterns, and responses to systemic therapy among these patients. Here, based on an extensive literature search, we have provided a rigorous overview of the current evidence on the medical treatment of SDH-deficient GIST.
Summary Nowadays molecular biology represents one of the most interesting topics in medical oncology, because it provides a global and detailed view on the molecular changes involved in tumour ...progression, leading to a better understanding of the carcinogenesis process, to discovering new prognostic markers and novel therapeutic targets. The gene expression profiling analysis with microarray technology has shown a great potential in cancer research and in medical oncology, mapping simultaneously the expression of thousands of genes in a single tumour sample and giving a measurement of articulated genes expression patterns. Colorectal cancer represents a wide and exciting area of research for molecular biology, due to the growing need of a molecular classification as well as prognostic and predictive molecular factors that may guide oncologists in patient’s clinical management. The aim of this review is to analyze the state of art of gene expression profile in colorectal cancer using microarrays technologies and to explore some perspectives in this research field.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Loss of function of the succinate dehydrogenase complex characterizes 20-40% of all
-negative GIST. Approximately half of SDH-deficient GIST patients lack
mutations and are caused by a ...hypermethylation of the
promoter, which causes the repression of
transcription and depletion of SDHC protein levels through a mechanism described as epimutation. The remaining 50% of SDH-deficient GISTs have mutations in one of the SDH subunits and
mutations are the most common (30%), with consequent loss of SDHA and SDHB protein expression immunohistochemically.
,
, and
mutations in GIST occur in only 20-30% of cases and most of these SDH mutations are germline. More recently, germline mutations in
have also been described in several patients with loss of function of the SDH complex.
-mutant patients usually carry two mutational events at the
locus, either the loss of the wild type allele or a second somatic event in compound heterozygosis. This review provides an overview of all data in the literature regarding
-mutated GIST, especially focusing on the prevalence of germline mutations in SDH-deficient GIST populations who harbor
somatic mutations, and offers a view towards understanding the importance of genetic counselling for
-variant carriers and relatives.
The majority of gastrointestinal stromal tumors (GIST) carry a sensitive primary KIT mutation, but approximately 5% to 10% of cases harbor activating mutations of platelet-derived growth factor ...receptor (PDGFRA), mainly involving the A-loop encoded by exon 18 (~5%), or more rarely the JM domain, encoded by exon 12 (~1%), or the ATP binding domain encoded by exon 14 (<1%). The most frequent mutation is the substitution at position 842 in the A-loop of an aspartic acid (D) with a valine (V) in exon 18, widely recognized as D842V. This mutation, as well known, provides primary resistance to imatinib and sunitinib. Thus, until few years ago, no active drugs were available for this subtype of GIST. Conversely, recent years have witnessed the development of a new specific inhibitor-avapritinib-that has been studied in in vitro and clinical setting with promising results. In light of this primary resistance to conventional therapies, the biological background of D842V-mutant GIST has been deeply investigated to better understand what features characterize this peculiar subset of GIST, and some promising insights have emerged. Hereinafter, we present a comprehensive overview on the clinical features and the molecular background of this rare subtype of GIST.
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Mutations of genes encoding the subunits of the succinate dehydrogenase (SDH) complex were described in KIT/PDGFRA wild-type GIST separately in different reports. In this study, we simultaneously ...sequenced the genome of all subunits, SDHA, SDHB, SDHC, and SDHD in a larger series of KIT/PDGFRA wild-type GIST in order to evaluate the frequency of the mutations and explore their biological role. SDHA, SDHB, SDHC, and SDHD were sequenced on the available samples obtained from 34 KIT/PDGFRA wild-type GISTs. Of these, in 10 cases, both tumor and peripheral blood (PB) were available, in 19 cases only tumor, and in 5 cases only PB. Overall, 9 of the 34 patients with KIT/PDGFRA wild-type GIST carried mutations in one of the four subunits of the SDH complex (six patients in SDHA, two in SDHB, one in SDHC). WB and immunohistochemistry analysis showed that patients with KIT/PDGFRA wild-type GIST who harbored SDHA mutations exhibited a significant downregulation of both SDHA and SDHB protein expression, with respect to the other GIST lacking SDH mutations and to KIT/PDGFRA-mutated GIST. Clinically, four out of six patients with SDHA mutations presented with metastatic disease at diagnosis with a very slow, indolent course. Patients with KIT/PDGFRA wild-type GIST may harbor germline and/or de novo mutations of SDH complex with prevalence for mutations within SDHA, which is associated with a downregulation of SDHA and SDHB protein expression. The presence of germline mutations may suggest that these patients should be followed up for the risk of development of other cancers.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Preclinical forms of gastrointestinal stromal tumor (GIST), small asymptomatic lesions, called microGIST, are detected in approximately 30% of the general population. Gastrointestinal stromal tumor ...driver mutation can be already detected in microGISTs, even if they do not progress into malignant cancer; these mutations are necessary, but insufficient events to foster tumor progression. Here we profiled the tissue microbiota of 60 gastrointestinal specimens in three different patient cohorts—micro, low‐risk, and high‐risk or metastatic GIST—exploring the compositional structure, predicted function, and microbial networks, with the aim of providing a complete overview of microbial ecology in GIST and its preclinical form. Comparing microGISTs and GISTs, both weighted and unweighted UniFrac and Bray–Curtis dissimilarities showed significant community‐level separation between them and a pronounced difference in Proteobacteria, Firmicutes, and Bacteroidota was observed. Through the LEfSe tool, potential microbial biomarkers associated with a specific type of lesion were identified. In particular, GIST samples were significantly enriched in the phylum Proteobacteria compared to microGISTs. Several pathways involved in sugar metabolism were also highlighted in GISTs; this was expected as cancer usually displays high aerobic glycolysis in place of oxidative phosphorylation and rise of glucose flux to promote anabolic request. Our results highlight that specific differences do exist in the tissue microbiome community between GIST and benign lesions and that microbiome restructuration can drive the carcinogenesis process.
This is the first work analyzing microbiome community in GIST and microGIST looking for novel players in GIST tumorigenesis. Our results highlight that specific differences do exist in the microbiome community between GISTs and benign lesions and that microbiome restructuration can happens and may drive the carcinogenesis process. Beside molecular alterations taking place over GIST evolution to malignant lesions, a key under‐considered factor can be represented by tumor microenvironment (i.e., microbiome) and further studies should deepen its role. The figure was partially created with Biorender.com.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Visceral sarcomas are a rare malignant subgroup of soft tissue sarcomas (STSs). STSs, accounting for 1% of all adult tumors, are derived from mesenchymal tissues and exhibit a wide heterogeneity. ...Their rarity and the high number of histotypes hinder the understanding of tumor development mechanisms and negatively influence clinical outcomes and treatment approaches. Although some STSs (~20%) have identifiable genetic markers, as specific mutations or translocations, most are characterized by complex genomic profiles. Thus, identification of new therapeutic targets and development of personalized therapies are urgent clinical needs. Although cell lines are useful for preclinical investigations, more reliable preclinical models are required to develop and test new potential therapies. Here, we provide an overview of the available in vitro and in vivo models of visceral sarcomas, whose gene signatures are still not well characterized, to highlight current challenges and provide insights for future studies.
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