Prevalence and clinical association of gene mutations through multiplex mutation testing in patients with NSCLC: results from the ETOP Lungscape Project

Kerr, Keith M.; Dafni, Urania; Schulze, Katja; Thunnissen, Erik; Bubendorf, Lukas; Hager, Henrik; Finn, Stephen P.; Biernat, Wojciech; Vliegen, Liesbet; Losa, Javier Hernández; Marchetti, Antonio; Cheney, Richard; Warth, Arne; Speel, Ernst‐Jan M.; Blackhall, Fiona; Monkhorst, Kim; Jantus‐Lewintre, Eloísa; Tischler,; Clark, Caroline; Bertrán-Alamillo, Jordi; Meldgaard, Peter; Gately, Kathy; Wrona, Ania; Vandenberghe, Peter; Felip, Enriqueta; Luca, Graziano De; Savic, Spasenija; Muley, Thomas; Smit, Egbert F.; Dingemans, A-M.C.; Priest, Lynsey; Baas, Paul; Camps, Carlos; Weder, Walter; Polydoropoulou,; Geiger, Thomas; Kammler, Roswitha; Sumiyoshi, Teiko; Molina, Miguel Ángel; Shames, David S.; Stahel, Rolf A.; Peters, Solange

doi:10.1093/annonc/mdx629

Cited by 30 publications

(22 citation statements)

References 34 publications

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“…The patient demographics are in line with what would be expected for such a cohort in terms of stage distribution and postoperative outcomes. As previously discussed, 9 the microfluidic-based polymerase chain reaction platform used for mutation testing was originally developed for testing multiple tumor types, with a corresponding range of clinically relevant genes and mutations. The platform provides an allele-specific range of mutations to be tested.…”

Section: Discussionmentioning

confidence: 99%

“…Central review regarding completeness of mandatory clinical parameters and the seventh TNM staging accuracy was performed. In the frame of Lungscape multiplex substudy, 9 a multigene, multiplex platform was used to generate mutation profiles at the time of resection. Testing was carried out on a highthroughput microfluidic-based polymerase chain reaction platform running an allele-specific multiplex test.…”

Section: Methodsmentioning

confidence: 99%

“…Previously, within the Lungscape project, we have revealed the importance of ALK gene rearrangements as independent prognostic factors 8 and that for other molecular mutations the effect is still unclear with no prognostic associations found for major known drivers. 9 Of these, KRAS mutations are the most frequent gain-offunction alterations found in patients with NSCLC, accounting for up to 25% of all oncogenic mutations. The significance of KRAS mutations has evolved from having uncertain prognostic value and from being "undruggable" to the current status of potential predictive therapeutic target with great promise.…”

Section: Introductionmentioning

confidence: 99%

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Prognostic Impact of KRAS G12C Mutation in Patients With NSCLC: Results From the European Thoracic Oncology Platform Lungscape Project

Finn

Addeo

Dafni

et al. 2021

Journal of Thoracic Oncology

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Introduction: KRAS mutations, the most frequent gain-offunction alterations in NSCLC, are currently emerging as potential predictive therapeutic targets. The role of KRAS-G12C (Kr_G12C) is of special interest after the recent discovery and preclinical analyses of two different Kr_G12C covalent inhibitors (AMG-510, MRTX849).Methods: KRAS mutations were evaluated in formalin-fixed, paraffin-embedded tissue sections by a microfluidic-based multiplex polymerase chain reaction platform as a component of the previously published European Thoracic Oncology Platform Lungscape 003 Multiplex Mutation study, of clinically annotated, resected, stage I to III NSCLC. In this study, -Kr_G12C mutation prevalence and its association with clinicopathologic characteristics, molecular profiles, and postoperative patient outcome (overall survival, relapse-free survival, time-to-relapse) were explored.Results: KRAS gene was tested in 2055 Lungscape cases (adenocarcinomas: 1014 [49%]) with I or II or III stage respective distribution of 53% or 24% or 22% and median follow-up of 57 months. KRAS mutation prevalence in the adenocarcinoma cohort was 38.0% (95% confidence interval (CI): 35.0% to 41.0%), with Kr_G12C mutation representing 17.0% (95% CI: 14.7% to 19.4%). In the "histologicsubtype" cohort, Kr_G12C prevalence was 10.5% (95% CI: 9.2% to 11.9%). When adjusting for clinicopathologic characteristics, a significant negative prognostic effect of Kr_G12C presence versus other KRAS mutations or nonexistence of KRAS mutation was identified in the adenocarcinoma cohort alone and in the "histologic-subtype" cohort. For overall survival in adenocarcinomas, hazard ratio (HR) G12C versus other KRAS is equal to 1.39 (95% CI: 1.03 to 1.89, p ¼ 0.031) and HR G12C versus no KRAS is equal to 1.32 (95% CI: 1.03 to 1.69, p ¼ 0.028) (both also significant in the "histologic-subtype" cohort). For time-to-relapse, HR G12C versus other KRAS is equal to 1.41 (95% CI: 1.03 to 1.92, p ¼ 0.030). In addition, among all patients, for relapsefree survival, HR G12C versus no KRAS is equal to 1.27 (95% CI: 1.04 to 1.54, p ¼ 0.017). Conclusions:In this large, clinically annotated stage I to III NSCLC cohort, the specific Kr_G12C mutation is significantly associated with poorer prognosis (adjusting for clinicopathologic characteristics) among adenocarcinomas and in unselected NSCLCs.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Prognostic Impact of KRAS G12C Mutation in Patients With NSCLC: Results From the European Thoracic Oncology Platform Lungscape Project

Finn

Addeo

Dafni

et al. 2021

Journal of Thoracic Oncology

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“…Presently EGFR mutation testing relies on amplification/sequencing approaches while other actionable abnormalities such as the EML4-ALK translocations are usually detected by fluorescence in situ hybridization or immunohistochemical analysis [ 10 ]. More targets are expected to become relevant as new drugs emerge (PI3K) [ 11 , 12 ] or existing ones expand their initial indications (BRAF, HER2) [ 13 , 14 ]. Considering these developments the need for not only precise and sensitive but also cost effective and scalable detection methods becomes acute as some of these mutations affect less than 1 % from the NSCLC patients.…”

Section: Discussionmentioning

confidence: 99%

Comparison of next generation sequencing, SNaPshot assay and real-time polymerase chain reaction for lung adenocarcinoma EGFR mutation assessment

Cernomaz

Macovei²,

Pavel³

et al. 2016

BMC Pulm Med

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BackgroundThe epidermal growth factor receptor (EGFR) mutation status assessment has become increasingly important given the significant impact of tyrosine kinase inhibitors in lung cancer management.Our aim was to compare real life operational characteristics for three EGFR mutation assays - two targeted approaches and a next generation sequencing (NGS) technique.MethodsEGFR mutation status was assessed for lung adenocarcinoma samples (formalin fixed- paraffin embedded samples) using qPCR, SNaPshot and NGS (Ion Torrent™) techniques.ResultsA total of 15 high clinical significance mutations were identified by at least one technique from the total of 64 samples. All mutations were identified by the TaqMan qPCR technique while SNaPshot in conjunction with fragment analysis identified 11 EGFR mutations. The NGS approach followed by an automatic analysis using the default calling parameters identified 10 mutations from the SNaPshot/qPCR panel and other three insertions, five point mutations and 58 silent variants; manual data review identified all 15 high significance mutations.ConclusionsPerformance was similar for high tumor content samples but careful data analysis and post hoc variant calling filter alterations were necessary in order to obtain robust results from low tumor content samples by NGS. NGS is able to generate a comprehensive mutational profile albeit at a higher cost and workload. Result interpretation should take into account not only general run parameters such as mean read depth but also relative coverage and read distribution; currently there is an acute need to define firm recommendations/standards concerning NGS data interpretation and quality control.

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“…PTEN deletion is also associated with intratumor heterogeneity in prostate cancer [17]. In a large cohort of Non-Small Cell Lung Cancer (NSCLC), PTEN loss was present in half of the squamous cell carcinoma (SCC) and in one-third of adenocarcinoma (AC), and associated with poorer prognosis [18]. In the TCGA melanoma cohort, somatic PTEN alterations were identified in 14% of specimens, consisting of both mutations and focal deletions [19].…”

Section: Background: Tumour Suppressive Functions Of Pten and Prevalementioning

confidence: 99%

Is there a causal link between PTEN deficient tumors and immunosuppressive tumor microenvironment?

Çetintaş

Batada

2020

J Transl Med

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The PTEN tumor suppressor is the second most commonly inactivated gene across cancer types. While it's role in PI3K/AKT and DNA damage pathways are clear, increasing evidences suggest that PTEN may also promote anti-tumor immunity. PTEN-deficient tumors are characterized by (i) reduced levels of cytotoxic T cells, helper T cells and NK cells, (ii) elevated pro-oncogenic inflammatory cytokines like CCL2 and (iii) increased levels of immunosuppressive cells such as MDSCs and Tregs. An intriguing possibility is that link between PTEN and anti-tumor immunity is mediated by the interferon signaling pathway. In this review, we summarize the evidences for the mechanistic link between PTEN deficiency and immunosuppressive tumor microenvironment and the interferon signaling pathway. We further discuss how the link between these pathways can be exploited for development of personalized immunotherapy for patients with PTEN deficient tumors.

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Prevalence and clinical association of gene mutations through multiplex mutation testing in patients with NSCLC: results from the ETOP Lungscape Project

Abstract: Archival FFPE NSCLC material is adequate for multiplex mutation analysis. In this large, predominantly European, clinically annotated stage I-III NSCLC cohort, none of the mutations characterized showed prognostic significance.

Cited by 30 publications

References 34 publications

Prognostic Impact of KRAS G12C Mutation in Patients With NSCLC: Results From the European Thoracic Oncology Platform Lungscape Project

Prognostic Impact of KRAS G12C Mutation in Patients With NSCLC: Results From the European Thoracic Oncology Platform Lungscape Project

Comparison of next generation sequencing, SNaPshot assay and real-time polymerase chain reaction for lung adenocarcinoma EGFR mutation assessment

Is there a causal link between PTEN deficient tumors and immunosuppressive tumor microenvironment?

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