Relationship of radiometabolic biomarkers to KRAS mutation status and ALK rearrangements in cases of lung adenocarcinoma

2019 ◽  
Vol 105 (6) ◽  
pp. 501-508
Author(s):  
Gulfidan Aras ◽  
Zehra Dilek Kanmaz ◽  
Esin Tuncay ◽  
Erdoğan Çetinkaya ◽  
Esin Yentürk ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Fdg Pet ◽  
Kras Mutation ◽  
Kinase Inhibitors ◽  
Meta Analysis ◽  
Diagnostic Value ◽  
Genetic Alterations ◽  
Alk Rearrangement ◽  
Kras Mutations ◽  
Mutational Status

Purpose: Rapid diagnosis of genetic mutations is important for targeted therapies such as EGFR tyrosine kinase inhibitors. KRAS mutation and ALK rearrangement are also important in determining treatment. The purpose of our study was to evaluate the diagnostic value of 18F-FDG PET to predict KRAS mutation and ALK rearrangement in order to determine the frequency of these genetic markers in our lung adenocarcinoma cases and contribute to forthcoming meta-analysis studies. Methods: A total of 218 patients with lung adenocarcinoma (EGFR analyzed) who were seen at our clinic between 2012 and 2014 were included in the study. The results of the 18 F-FDG-PET scans for each patient were retrospectively recorded with the associated medical documents. ALK rearrangements were analyzed in 166 of the 218 patients, while 50 of the 218 patients were analyzed for KRAS mutational status. SPSS 15.0 for Windows was used for statistical analysis. Results: FDG avidity was higher in cases with KRAS mutations and ALK rearrangements than those without, but the difference was not significant. ALK rearrangements were more common in younger, female, and nonsmoking patients with lung adenocarcinoma. Conclusions: The small numbers of KRAS mutations and ALK rearrangements are the limitation of this study for evaluation of diagnostic imaging. The frequency of these genetic alterations was as reported in the literature. We believe that our work will contribute to future meta-analysis.

scholarly journals KRAS Mutations Predict Response and Outcome in Advanced Lung Adenocarcinoma Patients Receiving First-Line Bevacizumab and Platinum-Based Chemotherapy

Cancers ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 1514 ◽  
Author(s):  
Ghimessy ◽  
Gellert ◽  
Schlegl ◽  
Hegedus ◽  
Raso ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Kras Mutation ◽  
Antiangiogenic Therapy ◽  
Hazard Ratio ◽  
Wild Type ◽  
First Line ◽  
Kras Mutations ◽  
Exon 2 ◽  
Mutational Status ◽  
Platinum Based Chemotherapy

Bevacizumab, combined with platinum-based chemotherapy, has been widely used in the treatment of advanced-stage lung adenocarcinoma (LADC). Although KRAS (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) mutation is the most common genetic alteration in human LADC and its role in promoting angiogenesis has been well established, its prognostic and predictive role in the above setting remains unclear. The association between KRAS exon 2 mutational status and clinicopathological variables including progression-free survival and overall survival (PFS and OS, respectively) was retrospectively analyzed in 501 Caucasian stage IIIB-IV LADC patients receiving first-line platinum-based chemotherapy (CHT) with or without bevacizumab (BEV). EGFR (epidermal growth factor receptor)-mutant cases were excluded. Of 247 BEV/CHT and 254 CHT patients, 95 (38.5%) and 75 (29.5%) had mutations in KRAS, respectively. KRAS mutation was associated with smoking (p = 0.008) and female gender (p = 0.002) in the BEV/CHT group. We found no difference in OS between patients with KRAS-mutant versus KRAS wild-type tumors in the CHT-alone group (p = 0.6771). Notably, patients with KRAS-mutant tumors demonstrated significantly shorter PFS (p = 0.0255) and OS (p = 0.0186) in response to BEV/CHT compared to KRAS wild-type patients. KRAS mutation was an independent predictor of shorter PFS (hazard ratio, 0.597; p = 0.011) and OS (hazard ratio, 0.645; p = 0.012) in the BEV/CHT group. G12D KRAS-mutant patients receiving BEV/CHT showed significantly shorter PFS (3.7 months versus 8.27 months in the G12/13x group; p = 0.0032) and OS (7.2 months versus 16.1 months in the G12/13x group; p = 0.0144). In this single-center, retrospective study, KRAS-mutant LADC patients receiving BEV/CHT treatment exhibited inferior PFS and OS compared to those with KRAS wild-type advanced LADC. G12D mutations may define a subset of KRAS-mutant LADC patients unsuitable for antiangiogenic therapy with BEV.

scholarly journals Comprehensive Analysis of SWI/SNF Inactivation in Lung Adenocarcinoma Cell Models

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3712
Author(s):  
Paola Peinado ◽  
Alvaro Andrades ◽  
Marta Cuadros ◽  
Maria Isabel Rodriguez ◽  
Isabel F. Coira ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Cell Line ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cancer Cell Line ◽  
Genetic Alterations ◽  
Cell Models ◽  
Functional Studies ◽  
Cellular Models ◽  
Mutational Status

Mammalian SWI/SNF (SWitch/Sucrose Non-Fermentable) complexes are ATP-dependent chromatin remodelers whose subunits have emerged among the most frequently mutated genes in cancer. Studying SWI/SNF function in cancer cell line models has unveiled vulnerabilities in SWI/SNF-mutant tumors that can lead to the discovery of new therapeutic drugs. However, choosing an appropriate cancer cell line model for SWI/SNF functional studies can be challenging because SWI/SNF subunits are frequently altered in cancer by various mechanisms, including genetic alterations and post-transcriptional mechanisms. In this work, we combined genomic, transcriptomic, and proteomic approaches to study the mutational status and the expression levels of the SWI/SNF subunits in a panel of 38 lung adenocarcinoma (LUAD) cell lines. We found that the SWI/SNF complex was mutated in more than 76% of our LUAD cell lines and there was a high variability in the expression of the different SWI/SNF subunits. These results underline the importance of the SWI/SNF complex as a tumor suppressor in LUAD and the difficulties in defining altered and unaltered cell models for the SWI/SNF complex. These findings will assist researchers in choosing the most suitable cellular models for their studies of SWI/SNF to bring all of its potential to the development of novel therapeutic applications.

scholarly journals EP1.14-47 Lung Adenocarcinoma with Concurrent KRAS Mutation and ALK Rearrangement Responding to Crizotinib

2019 ◽  
Vol 14 (10) ◽  
pp. S1049-S1050
Author(s):  
Y. Zhu ◽  
W. Wang ◽  
C. Xu ◽  
X. Li ◽  
W. Zhuang ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Kras Mutation ◽  
Alk Rearrangement

Diagnostic value of FDG-PET versus magnetic resonance imaging for detecting spondylitis: a systematic review and meta-analysis

2018 ◽  
Vol 18 (12) ◽  
pp. 2323-2332 ◽  
Author(s):  
Yanlin Yin ◽  
Xinwei Liu ◽  
Xinming Yang ◽  
Jie Guo ◽  
Qiang Wang ◽  
...  
Keyword(s):  
Magnetic Resonance Imaging ◽  
Systematic Review ◽  
Magnetic Resonance ◽  
Fdg Pet ◽  
Meta Analysis ◽  
Diagnostic Value ◽  
Resonance Imaging

scholarly journals Allele-Specific PCR for KRAS Mutation Detection Using Phosphoryl Guanidine Modified Primers

Diagnostics ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. 872
Author(s):  
Alexey S. Chubarov ◽  
Igor P. Oscorbin ◽  
Maxim L. Filipenko ◽  
Alexander A. Lomzov ◽  
Dmitrii V. Pyshnyi
Keyword(s):  
Kras Mutation ◽  
Mutation Detection ◽  
Synergetic Effect ◽  
Model Systems ◽  
Wild Type ◽  
Kras Mutations ◽  
Specific Pcr ◽  
Mutational Status ◽  
Allele Specific ◽  
Pcr Method

Establishing the Kirsten rat sarcoma (KRAS) mutational status is essential in terms of managing patients with various types of cancer. Allele-specific real-time polymerase chain reaction (AS-PCR) is a widely used method for somatic mutations detection. To improve the limited sensitivity and specificity, several blocking methods have been introduced in AS-PCR to block the amplification of wild-type templates. Herein, we used a novel modified oligonucleotide with internucleotide phosphates reshaped 1,3-dimethyl-2-imino-imidazolidine moieties (phosphoryl guanidine (PG) groups) as primers and blockers in the AS-PCR method. Four common KRAS mutations were chosen as a model to demonstrate the advantages of the PG primers and blockers utilizing a customized PCR protocol. The methods were evaluated on plasmid model systems providing a KRAS mutation detection limit of 20 copies of mutant DNA in a proportion as low as 0.1% of the total DNA, with excellent specificity. PG-modification can serve as the universal additional mismatch-like disturbance to increase the discrimination between wild-type and mutated DNA. Moreover, PG can serve to increase primer specificity by a synergetic effect with additional mismatch and would greatly facilitate medical research.

scholarly journals Recent advances in the management of anaplastic thyroid cancer

2020 ◽  
Vol 13 (1) ◽  
Author(s):  
Simone De Leo ◽  
Matteo Trevisan ◽  
Laura Fugazzola
Keyword(s):  
Thyroid Cancer ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Treatment Options ◽  
Anaplastic Thyroid Cancer ◽  
Genetic Alterations ◽  
Genetic Profile ◽  
Mutational Status ◽  
Single Target

AbstractAnaplastic thyroid cancer (ATC) is undoubtedly the thyroid cancer histotype with the poorest prognosis. The conventional treatment includes surgery, radiotherapy, and conventional chemotherapy. Surgery should be as complete as possible, securing the airway and ensuring access for nutritional support; the current standard of care of radiotherapy is the intensity-modulated radiation therapy; chemotherapy includes the use of doxorubicin or taxanes (paclitaxel or docetaxel) generally with platin (cisplatin or carboplatin). However, frequently, these treatments are not sufficient and a systemic treatment with kinase inhibitors is necessary. These include multitarget tyrosine kinase inhibitors (Lenvatinib, Sorafenib, Sunitinib, Vandetanib, Axitinib, Pazopanib, Pyrazolo-pyrimidine compounds), single target tyrosine kinase inhibitors (Dabrafenib plus Trametinib and Vemurafenib against BRAF, Gefitinib against EGFR, PPARγ ligands (e.g. Efatutazone), Everolimus against mTOR, vascular disruptors (e.g. Fosbretabulin), and immunotherapy (e.g. Spartalizumab and Pembrolizumab, which are anti PD-1/PD-L1 molecules). Therapy should be tailored to the patients and to the tumor genetic profile. A BRAF mutation analysis is mandatory, but a wider evaluation of tumor mutational status (e.g. by next-generation sequencing) is desirable. When a BRAFV600E mutation is detected, treatment with Dabrafenib and Trametinib should be preferred: this combination has been approved by the Food and Drug Administration for the treatment of patients with locally advanced or metastatic ATC with BRAFV600E mutation and with no satisfactory locoregional treatment options. Alternatively, Lenvatinib, regardless of mutational status, reported good results and was approved in Japan for treating unresectable tumors. Other single target mutation agents with fair results are Everolimus when a mutation involving the PI3K/mTOR pathway is detected, Imatinib in case of PDGF-receptors overexpression, and Spartalizumab in case of PD-L1 positive tumors. Several trials are currently evaluating the possible beneficial role of a combinatorial therapy in ATC. Since in this tumor several genetic alterations are usually found, the aim is to inhibit or disrupt several pathways: these combination strategies use therapy targeting angiogenesis, survival, proliferation, and may act against both MAPK and PI3K pathways. Investigating new treatment options is eagerly awaited since, to date, even the molecules with the best radiological results have not been able to provide a durable disease control.

scholarly journals The Diagnostic Accuracy of Mutant KRAS Detection from Pancreatic Secretions for the Diagnosis of Pancreatic Cancer: A Meta-Analysis

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2353
Author(s):  
Nikhil Patel ◽  
Tatjana Petrinic ◽  
Michael Silva ◽  
Zahir Soonawalla ◽  
Srikanth Reddy ◽  
...  
Keyword(s):  
Chronic Pancreatitis ◽  
Diagnostic Accuracy ◽  
Kras Mutation ◽  
Meta Analysis ◽  
Ductal Adenocarcinoma ◽  
Healthy Individuals ◽  
Kras Mutations ◽  
Cross Sectional ◽  
Specificity And Sensitivity ◽  
Variable Sensitivity

This meta-analysis aims to identify the diagnostic accuracy of mutations in the Kirsten Rat Sarcoma (KRAS) oncogene in the diagnosis of pancreatic ductal adenocarcinoma (PDAC). The survival of PDAC remains poor often due to the fact that disease is advanced at diagnosis. We analysed 22 studies, with a total of 2156 patients, to identify if the detection of KRAS mutations from pancreatic exocrine secretions yields sufficient specificity and sensitivity to detect patients with PDAC amongst healthy individuals. The majority of the studies were retrospective, samples were obtained endoscopically or surgically, and included comparator populations of patients with chronic pancreatitis and pre-malignant pancreatic lesions (PanIN) as well as healthy controls. We performed several analyses to identify the diagnostic accuracy for PDAC among these patient populations. Our results highlighted that the diagnostic accuracy of KRAS mutation for PDAC was of variable sensitivity and specificity when compared with PanINs and chronic pancreatitis, but had a higher specificity among healthy individuals. The sensitivity of this test must be improved to prevent missing early PDAC or PanINs. This could be achieved with rigorous prospective cohort studies, in which high-risk patients with normal cross-sectional imaging undergo surveillance following KRAS mutation testing.

scholarly journals Analysis of Genetic Alterations in Tunisian Patients with Lung Adenocarcinoma

Cells ◽  
2019 ◽  
Vol 8 (6) ◽  
pp. 514 ◽  
Author(s):  
Dhoha Dhieb ◽  
Imen Belguith ◽  
Laura Capelli ◽  
Elisa Chiadini ◽  
Matteo Canale ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Lung Adenocarcinoma ◽  
Genetic Alterations ◽  
Small Sample ◽  
Response To Therapy ◽  
Molecular Profile ◽  
Alk Rearrangement ◽  
P53 Expression ◽  
Anaplastic Lymphoma ◽  
Tunisian Patients

The identification of the mutations that drive lung cancer have furnished new targets for the treatment of non-small cell lung cancer (NSCLC) and led to the development of targeted therapies such as tyrosine kinase inhibitors that are used to combat the molecular changes promoting cancer progression. Furthermore, biomarkers identified from gene analysis can be used to detect early lung cancer, determine patient prognosis, and monitor response to therapy. In the present study we analyzed the molecular profile of seventy-three Tunisian patients with lung adenocarcinoma (LAD). Mutational analyses for EGFR and KRAS were performed using direct sequencing, immunohistochemistry or MassARRAY. Anaplastic lymphoma kinase (ALK) rearrangement was evaluated by immunohistochemistry using the D5F3 clone, and p53 expression was also assessed. The median age of patients at diagnosis was 61 years (range 23–82 years). Using different methodologies, EGFR mutations were found in 5.47% of patients and only exon 19 deletions “E746-A750 del” were detected. KRAS mutations were present in 9.58% of cases, while only one patient was ALK-positive. Moreover, abnormal immunostaining of p53 was detected in 56.16% of patients. In conclusion, the detected rates of EGFR and KRAS mutation and ALK rearrangement were lower than those found in European and Asian countries, whereas, abnormal p53 expression was slightly more frequent. Furthermore, given the small sample size of this study, a more comprehensive analysis of this patient set is warranted.

Molecular changes in epidermal growth factor receptor (EGFR) in non-small cell lung cancer (NSCLC) biopsies at time of progression compared to initial biopsy

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e22066-e22066
Author(s):  
G. Speranza ◽  
V. Cohen ◽  
J. S. Agulnik ◽  
G. Chong ◽  
F. Meilleur ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Progression ◽  
Kinase Inhibitors ◽  
Genetic Alterations ◽  
Egfr Mutations ◽  
Missense Mutations ◽  
Molecular Changes ◽  
Mutational Status ◽  
Exon 19 Deletion ◽  
Exon 19

e22066 Background: EGFR mutations predict sensitivity and clinical outcome to tyrosine kinase inhibitors (TKI) in NSCLC. The two most commonly described mutations are Exon 19 deletion and Exon 21 L858R missense mutations. Genetic alterations over time have been described in other tumour types, but studies assessing EGFR genotypic changes with lung cancer progression are lacking. We sought to compare EGFR mutational status from lung tumors at time of recurrence or progression with the primary tumor. Methods: Using the Jewish General Hospital lung cancer database, of all patients diagnosed with NSCLC since 1999, those with biopsies at two different points in time were identified. All tumour samples were genotyped for EGFR exons 19 and 21 mutations using denaturing high performance liquid chromatography (dHPLC). Results: 29 patients were identified. Data for 12 patients, whose time of recurrence or progression varied between 4 months and 6 years, are available at this time. Of 12 patients, one had EGFR exon 19 mutation at time of diagnosis. One patient who initially displayed no EGFR mutation was found to have an exon 19 deletion at time of recurrence. The one with exon 19 at time of initial diagnosis continued to express exon 19 in the second biopsy. Conclusions: To our knowledge, this is the only study assessing changes in molecular genotype using dHPLC between primary and recurrent or progressive lung cancer biopsy specimens. Although sample size is small, it is evident that changes in EGFR mutational status can occur. Further prospective studies are required to determine how commonly molecular changes occur. No significant financial relationships to disclose.

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