Next generation sequencing (NGS) in oncology: lights and shadows:

Advances in tumor genome sequencing using next generation sequencing (NGS) technologies have facilitated a greater understanding of the genetic abnormalities involved in cancer development and progression, dramatically changing oncology research. There are several different types of NGS technologies. Whole genome sequencing (WGS) determines the sequence of the complete genome, providing information on both coding and non-coding regions and structural variants. However, use is limited by the large volume of data generated, and associated time and resource costs. Whole exome sequencing (WES) determines the sequence of coding regions only, making it faster and cheaper than WGS, and the functional consequences of variants are easier to interpret. However, all variations in non-coding regions are missed. WGS and WES are often used together to maximize detection of variants. A less costly approach is the use of targeted sequencing, which focuses on particular regions of interest, based on their biological relevance. NGS technologies can also be used to sequence RNA, referred to as RNA-Seq. All these NGS technologies, individually or in combination, have a number of potential applications, including identification of biomarkers, and development of diagnostic and therapeutic strategies. However, although advances have been made, there are a number of limitations to be overcome before NGS technologies are routinely applied in both research and clinical practice

A multicenter, dose-finding, phase 1b study of imatinib in combination with alpelisib as third-line treatment in patients with advanced gastrointestinal stromal tumor

Alpelisib; Gastrointestinal stromal tumor; ImatinibAlpelisib; Tumor estromal gastrointestinal; ImatinibAlpelisib; Tumor estromal gastrointestinal; ImatinibBackground Acquired resistance to approved tyrosine kinase inhibitors limits their clinical use in patients with gastrointestinal stromal tumor (GIST). This study investigated the safety, tolerability and efficacy of alpelisib, a phosphatidylinositol 3-kinase inhibitor, used in combination with imatinib in patients with advanced GIST who had failed prior therapy with both imatinib and sunitinib. Methods This phase 1b, multicenter, open-label study consisted of 2 phases: dose escalation and dose expansion. Dose escalation involved 200 mg once daily (QD) alpelisib, initially, followed by 250 and 350 mg. These were combined with 400 mg QD imatinib until maximum tolerated dose (MTD) and/or a recommended phase 2 dose (RP2D) of alpelisib in combination with imatinib was determined. This MTD/RP2D dose was tested to evaluate the clinical activity of this combination in dose expansion. Results Fifty-six patients were enrolled, 21 and 35 in the dose escalation and expansion phases, respectively. The MTD of alpelisib given with imatinib was determined as 350 mg QD. Combination treatment showed partial response in 1 (2.9%) and stable disease in 15 (42.9%) patients. Median progression-free survival was 2 months (95% CI 1.8–4.6). Overall, 92.9% patients had adverse events (AEs) while 46.4% had grade 3/4 AEs, hyperglycemia being the most common (23.2%). Conclusions The MTD of alpelisib was estimated as 350 mg QD when used in combination with imatinib 400 mg QD after oral administration in patients with advanced GIST. The safety and tolerability profile of this combination was acceptable; however, the combination did not demonstrate sufficient clinical activity to justify additional clinical testing.The study was funded by the Novartis Pharma AG, Basel, Switzerland

Dose reduction and discontinuation of standard-dose regorafenib associated with adverse drug events in cancer patients: a systematic review and meta-analysis

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

Complete radiological response to first-line regorafenib in a patient with abdominal relapse of BRAF V600E mutated GIST

Up to 13% of KIT and PDGFRA wild-type (WT) gastrointestinal stromal tumours (GIST) harbour a BRAF mutation, mostly involving the exon 15 V600E hot spot. Even if BRAF mutation is recognized as druggable target in other solid tumours, currently advanced BRAF-mutant GIST share the same therapeutical algorithm of KIT/PDGFRA mutants. We report a complete radiological response in a 51-year-old woman with V600E BRAF-mutated metastatic GIST who was treated with regorafenib (REG) as first-line therapy. REG represents the standard third-line therapy for advanced GIST patients progressing on or failing to respond to imatinib and sunitinib. However, according to its wide spectrum of action, with MAPK signalling pathway blockade at different levels, metastatic KIT/PDGFRA WT, including BRAF mutants, may benefit from REG upfront in first line

Successful radiotherapy for local control of progressively increasing metastasis of gastrointestinal stromal tumor

Gastrointestinal stromal tumors (GISTs) are known to be poorly responsive to conventional chemotherapy and historically considered resistant to radiotherapy. In the past the mainstay of GIST treatment was surgery, but the introduction of tyrosine kinase inhibitors (TKIs) imatinib and sunitinib marked the beginning of a new era in the treatment of GIST patients. To date, radiotherapy for GIST has not been administered in clinical practice except for limited palliative settings and there are no clear data on the administration of radiotherapy, alone or in combination with TKIs, with a purely cytoreductive intent. We describe the clinical case of a 48-year-old woman with metastatic GIST treated with external radiotherapy in a critical supraclavicular tumor localization progressively increasing in size with several symptoms and not responsive to systemic TKI therapies. We obtained an initial shrinkage of the mass and subsequent stabilization with an immediate and clear clinical benefit. Although the historical medical literature considered GISTs resistant to radiation therapy, our clinical case suggests this treatment may be appropriate in selected patients

Postsorafenib systemic treatments for hepatocellular carcinoma: questions and opportunities after the regorafenib trial.

The search for systemic therapies for hepatocellular carcinoma has been characterized by difficulties and failures. Despite recent progresses, many issues are still to be settled. In particular, the development of drugs inhibiting different neoplastic pathways remains a priority for patients intolerant or resistant to antiangiogenic drugs. This task may be daunting, as previous failures extensively demonstrated. We aimed to identify the future perspective of postsorafenib trials analyzing the strengths and the critical points of past and currently undergoing studies, in the light of the most recent evidences in the field. We identified various points (including stratification, biomarkers, end points, radiologic criteria of response, treatment beyond radiologic progression) that should be considered by future trials to reduce the risks of failure

Radiomics and artificial intelligence in malignant uterine body cancers: Protocol for a systematic review

IntroductionUterine body cancers (UBC) are represented by endometrial carcinoma (EC) and uterine sarcoma (USa). The clinical management of both is hindered by the complex classification of patients into risk classes. This problem could be simplified through the development of predictive models aimed at treatment tailoring based on tumor and patient characteristics. In this context, radiomics represents a method of extracting quantitative data from images in order to non-invasively acquire tumor biological and genetic information and to predict response to treatments and prognosis. Furthermore, artificial intelligence (AI) methods are an emerging field of translational research, with the aim of managing the amount of data provided by the various -omics, including radiomics, through the process of machine learning, in order to promote precision medicine.ObjectiveThe aim of this protocol for systematic review is to provide an overview of radiomics and AI studies on UBCs.Methods and analysisA systematic review will be conducted using PubMed, Scopus, and the Cochrane Library to collect papers analyzing the impact of radiomics and AI on UBCs diagnosis, prognostic classification, and clinical outcomes. The PICO strategy will be used to formulate the research questions: What is the impact of radiomics and AI on UBCs on diagnosis, prognosis, and clinical results? How could radiomics or AI improve the differential diagnosis between sarcoma and fibroids? Does Radiomics or AI have a predictive role on UBCs response to treatments? Three authors will independently screen articles at title and abstract level based on the eligibility criteria. The risk of bias and quality of the cohort studies, case series, and case reports will be based on the QUADAS 2 quality assessment tools

miRNA Expression May Have Implications for Immunotherapy in PDGFRA Mutant GISTs

Gastrointestinal stromal tumors (GISTs) harboring mutations in the PDGFRA gene occur in only about 5-7% of patients. The most common PDGFRA mutation is exon 18 D842V, which is correlated with specific clinico-pathological features compared to the other PDGFRA mutated GISTs. Herein, we present a miRNA expression profile comparison of PDGFRA D842V mutant GISTs and PDGFRA with mutations other than D842V (non-D842V). miRNA expression profiling was carried out on 10 patients using a TLDA miRNA array. Then, miRNA expression was followed by bioinformatic analysis aimed at evaluating differential expression, pathway enrichment, and miRNA-mRNA networks. We highlighted 24 differentially expressed miRNAs between D842V and non-D842V GIST patients. Pathway enrichment analysis showed that deregulated miRNAs targeted genes that are mainly involved in the immune response pathways. The miRNA-mRNA networks highlighted a signature of miRNAs/mRNA that could explain the indolent behavior of the D842V mutated GIST. The results highlighted a different miRNA fingerprint in PDGFRA D842V GISTs compared to non-D842Vmutated patients, which could explain the different biological behavior of this GIST subset

Genomic Database Analysis of Uterine Leiomyosarcoma Mutational Profile

Uterine Leiomyosarcoma (uLMS) is by far the most common type of uterine sarcoma, characterized by an aggressive clinical course, a heterogeneous genetic profile and a very scarce response to cytotoxic chemotherapy. The genetic make-up of uLMS is an area of active study that could provide essential cues for the development of new therapeutic approaches. A total of 216 patients with uLMS from cBioPortal and AACR-GENIE databases were included in the study. The vast majority of patients (81%) carried at least one mutation in either TP53, RB1, ATRX or PTEN. The most frequently mutated gene was TP53, with 61% of the patients harboring at least one mutation, followed by RB1 at 48%. PTEN alteration was more frequent in metastases than in primary lesions, consistent with a later acquisition during tumor progression. There was a significant trend for TP53 and RB1 mutations to occur together, while both TP53 and RB1 were mutually exclusive with respect to CDKN2A/B inactivation. Overall survival did not show significant correlation with the mutational status, even if RB1 mutation emerged as a favorable prognostic factor in the TP53-mutant subgroup. This comprehensive analysis shows that uLMS is driven almost exclusively by the inactivation of tumor suppressor genes and suggests that future therapeutic strategies should be directed at targeting the main genetic drivers of uLMS oncogenesis

Skull Metastasis From Uterine Leiomyosarcoma, a Rare Presentation for a Rare Tumor: A Case Report and Review of the Literature

Uterine leiomyosarcoma (uLMS) is a rare and aggressive malignancy with poor clinical outcomes. Even when localized, uLMS is associated with high rates of local and distant recurrences that are usually fatal. Common sites of recurrence are lung, liver, pelvic lymph nodes, and vertebral and long bones, though atypical patterns of recurrence have been described. Among them, intracranial recurrence appears as a rare finding, almost exceptional in skull and dura. We describe the case of a solitary skull metastasis from uLMS in a 39-year-old woman, which represents the third reported case of skull recurrence in literature. After multidisciplinary discussion, the patient underwent surgery and received adjuvant radiotherapy. After 4 months, she is currently alive, without evidence of extracranial disease. This case highlights the importance of suspecting and recognizing atypical and extremely rare metastasis to this region. We encourage the need for large case series in order to provide further information about cranial recurrences of uLMS taking into account the paucity of data currently available in literature and the frequently unpredictable behavior of this rare and highly lethal disease