126 research outputs found
Liquid-Biopsy-Based Identification of EGFR T790M Mutation-Mediated Resistance to Afatinib Treatment in Patients with Advanced EGFR Mutation-Positive NSCLC, and Subsequent Response to Osimertinib
No full textArticle full textThe full text of this article can be found here.DisclosuresMaximilian
J. Hochmair has received honoraria from AstraZeneca, Bristol-Myers Squibb,
Boehringer Ingelheim, Merck Sharp & Dohme, Pfizer, Roche and had consulting
or advisory roles with Boehringer Ingelheim, Merck Sharp & Dohme, Novartis
and Roche. Anna Buder has received honoraria from AstraZeneca. Helmut Prosch
has received honoraria from AstraZeneca, Boehringer Ingelheim, Bristol-Myers
Squibb, Merck Sharp & Dohme, Novartis, and Roche, and has received a
research grant from Boehringer Ingelheim. Wolfgang Hilbe has received advisory
board and lecture fees from Boehringer Ingelheim. Agnieszka Cseh and Richard
Fritz are employees of Boehringer Ingelheim. Martin Filipits has received
honoraria from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck Sharp &
Dohme, Novartis, Ratiopharm, and Roche. Sophia Schwab, and Otto C. Burghuber
have no conflicts of interest to declare.
Funding
Medical
writing assistance, supported financially by Boehringer Ingelheim, was provided
by Katharine Williams of GeoMed, an Ashfield company, part of UDG Healthcare
plc, during the development of this manuscript.CopyrightThis video is distributed under the terms of the Creative Commons Attribution Noncommerical Licence which permits any noncommerical use, distribution, and reproduction in any medium, provided the original author(s) and the source is credited.Article full textThe full text of this article can be found here.</p
Biomarkers – the way towards individualized chemotherapy in non-small cell lung cancer (NSCLC)
No full textCancer and Metastasis Reviews / Personalized treatment of advanced non-small-cell lung cancer in routine clinical practice
No full textPersonalized treatment of patients with advanced non-small-cell lung cancer based on clinical and molecular tumor features has entered clinical routine practice. The 2015 pathological classification of lung cancer mandates immunohistochemical and molecular analysis. Therapeutic strategies focused on inhibition of angiogenesis and growth factor receptor signaling. Inhibitors of angiogenesis and monoclonal antibodies directed against the epidermal growth factor receptor have shown efficacy in combination with chemotherapy. Mutations in the epidermal growth factor receptor and anaplastic lymphoma kinase have become clinically relevant therapeutic targets. Immune checkpoint inhibitors are also entering routine clinical practice. Identification of predictive biomarkers is essential and faces several challenges including tumor heterogeneity and dynamic changes of tumor features over time. Liquid biopsies may overcome some of these challenges in the future.(VLID)342650
Osimertinib in advanced EGFR T790M-positive non-small-cell lung cancer: the clinical impact of AURA3
No full textTargeted Oncology / The allele frequency of EGFR mutations predicts survival in advanced EGFR T790M-positive non-small cell lung cancer patients treated with Osimertinib
No full textBackground
The allele frequency of epidermal growth factor receptor (EGFR) mutations could be a potential molecular biomarker for the outcome of osimertinib therapy.
Objective
The purpose of our study was to assess the clinical relevance of the allele frequency of EGFR mutations in plasma-based circulating tumor DNA (ctDNA) before starting osimertinib therapy in patients with advanced EGFR-mutated non-small cell lung cancer (NSCLC) who had progressed under treatment with EGFR tyrosine kinase inhibitors (TKIs).
Patients and Methods
We enrolled 141 patients with advanced EGFR T790M-positive NSCLC who underwent second-line osimertinib treatment. Plasma ctDNA was tested for EGFR-activating mutations (EGFR deletions in exon 19, L858R, L861Q, S768I) and T790M by means of droplet digital polymerase chain reaction (ddPCR).
Results
The allele frequency of EGFR-activating mutations in plasma ctDNA before osimertinib initiation ranged fro
Abstract LB-046: Evaluation of an assay for on-demand and easy assessment of MGMT gene promoter methylation in glioblastoma patients
No full textAbstract
Background: Epigenetic silencing of the O6-methylguanine DNA methyltransferase (MGMT) gene by promoter methylation is observed in 40 to 50% of glioblastomas and is associated with improved overall survival on radiation and/or temozolamide therapy. Currently, pyrosequencing is commonly used to assess the methylation status of the MGMT gene in formalin-fixed, paraffin-embedded (FFPE) samples. We examined the concordance of the recently developed GeneXpert (GX) MGMT Methylation RUO Assay with pyrosequencing in three independent glioblastoma cohorts.
Patients and methods: The GX MGMT Methylation RUO Assay is a research use only, cartridge-based methylation specific PCR assay performed on the GeneXpert® Instrument (Cepheid) that automates DNA purification, bisulfite conversion, and methylation-specific PCR after sample preparation. Cartridge results are reported in less than 4 hours as delta cycle threshold (dCt) measurements (dCt = beta-actin/ACTB Ct - MGMT Ct). The MGMT methylation status was assessed on FFPE tumor blocks from 262 glioblastoma patients obtained from OHSU (n=63), MUV (n=96), and KUL (n=103). Two adjacent sections from each block were prepared, one 4 µm section for H&E staining to determine the % tumor cell content/tumor area and one 4 µm section for lysate preparation and GX testing. Both GX MGMT Methylation testing and pyrosequencing results were correlated with overall survival of the patients in the MUV cohort.
Results: All of the 262 (100%) glioblastoma samples tested yielded valid results for both GX MGMT Methylation testing and pyrosequencing. The cut-offs were set at dCt -6.2 for the GX MGMT Methylation RUO Assay and 8% methylation for pyrosequencing. The concordance rate between GX MGMT Methylation testing and pyrosequencing was 92% (58/63 OHSU samples, 92% (88/96 MUV samples) and 83% (85/103 KUL samples). The overall concordance rate was 88% (231/262 samples). Sensitivity and specificity was 84% (27/32) and 100% (31/31) for OHSU samples, 89% (33/37) and 93% (55/59) for MUV samples, and 70% (31/44/) and 92% (54/59) for KUL samples, respectively. Overall sensitivity was 81% (91/113) and overall specificity was 94% (140/149). Overall survival data were available for 95 MUV patients. Patients with MGMT promoter hypermethylation based on pyrosequencing had a significantly longer overall survival compared to patients without hypermethylation (median 16 vs. 11 months, p = 0.001). Similar results were observed with the GX MGMT Methylation RUO Assay (median 15 vs. 11 months, p = 0.005).
Conclusion: GX MGMT Methylation testing is highly reproducible and shows good concordance with pyrosequencing in three independent cohorts of glioblastoma patients. Our results suggest that standardized, simplified, and on-demand testing of MGMT promoter methylation by the GX MGMT Methylation RUO Assay is feasible.
Citation Format: Martin Filipits, Anita Brandstetter, Matthias Preusser, Johannes Hainfellner, Sabine Spiegl-Kreinecker, Edwin W. Lai, Kriszten Kocmond, Andrew Kohlway, Jodi Weidler, Michael Bates, Christopher Corless. Evaluation of an assay for on-demand and easy assessment of MGMT gene promoter methylation in glioblastoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-046. doi:10.1158/1538-7445.AM2017-LB-046</jats:p
Development of taxane resistance in a panel of human lung cancer cell lines
No full textUsing a selection process designed to reflect clinically relevant conditions, a panel of taxane-selected variants were developed to study further the mechanisms of resistance in lung cancer. Unlike continuous or pulse exposure to high concentrations of chemotherapeutic drugs which yield high resistance and often cross resistance, most variants developed here displayed low level resistance to the selecting drug with slight cross-resistance. Pulsing with taxol resulted in more highly resistant clones (up to 51.4-fold). Analysis of taxol and taxotere in the four major lung cancer cell types showed the taxanes to be more effective against NSCLC (with the exception of SKMES-taxane selected variants) than against the SCLC. Comparison of taxol and taxotere shows that taxol induces higher levels of resistance than taxotere. Further, in taxotere-selected cell lines, the cells are more resistant to taxol than taxotere, suggesting that taxotere may be a superior taxane from a clinical view. Taxol treatment resulted in increased cross-resistance to 5-FU in all classes of lung cancer except DMS-53. The high levels of Pgp in the DMS-53 and selected variant suggests this mechanism is not related to Pgp expression. Analysis of the Pgp and MRP-1 status by combination inhibitory assays and Western blotting showed no consistent relationship between expression of the membrane pumps Pgp or MRP-1 and resistance. However, where high level resistance was seen, the parent cell line expressed Pgp or MRP-1 and was accompanied by increased levels in the variants. Overall we found that the clinically relevant models used here are useful for investigating mechanisms of taxane resistance
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