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• W2969883920 abstract "Before initiating treatment of advanced non–small-cell lung cancer with tyrosine kinase inhibitors (eg, erlotinib, gefitinib, osimertinib, and afatinib), which inhibit the catalytic activity of epidermal growth factor receptor (EGFR), clinical guidelines require determining the EGFR mutational status for activating (EGFR exons 18, 19, 20, or 21) and resistance (EGFR exon 20) mutations. The EGFR resistance mutation T790M should be monitored at cancer progression. The Idylla EGFR Mutation Assay, performed on the Idylla molecular diagnostics platform, is a fully automated (<2.5 hours turnaround time) sample-to-result molecular test to qualitatively detect 51 EGFR oncogene point mutations, deletions, or insertions. In a 15-center evaluation, Idylla results on 449 archived formalin-fixed, paraffin-embedded tissue sections, originating from non–small-cell lung cancer biopsies and resection specimens, were compared with data obtained earlier with routine reference methods, including next-generation sequencing, Sanger sequencing, pyrosequencing, mass spectrometry, and PCR-based assays. When results were discordant, a third method of analysis was performed, when possible, to confirm test results. After confirmation testing and excluding invalids/errors and discordant results by design, a concordance of 97.6% was obtained between Idylla and routine test results. Even with <10 mm2 of tissue area, a valid Idylla result was obtained in 98.9% of the cases. The Idylla EGFR Mutation Assay enables sensitive detection of most relevant EGFR mutations in concordance with current guidelines, with minimal molecular expertise or infrastructure. Before initiating treatment of advanced non–small-cell lung cancer with tyrosine kinase inhibitors (eg, erlotinib, gefitinib, osimertinib, and afatinib), which inhibit the catalytic activity of epidermal growth factor receptor (EGFR), clinical guidelines require determining the EGFR mutational status for activating (EGFR exons 18, 19, 20, or 21) and resistance (EGFR exon 20) mutations. The EGFR resistance mutation T790M should be monitored at cancer progression. The Idylla EGFR Mutation Assay, performed on the Idylla molecular diagnostics platform, is a fully automated (<2.5 hours turnaround time) sample-to-result molecular test to qualitatively detect 51 EGFR oncogene point mutations, deletions, or insertions. In a 15-center evaluation, Idylla results on 449 archived formalin-fixed, paraffin-embedded tissue sections, originating from non–small-cell lung cancer biopsies and resection specimens, were compared with data obtained earlier with routine reference methods, including next-generation sequencing, Sanger sequencing, pyrosequencing, mass spectrometry, and PCR-based assays. When results were discordant, a third method of analysis was performed, when possible, to confirm test results. After confirmation testing and excluding invalids/errors and discordant results by design, a concordance of 97.6% was obtained between Idylla and routine test results. Even with <10 mm2 of tissue area, a valid Idylla result was obtained in 98.9% of the cases. The Idylla EGFR Mutation Assay enables sensitive detection of most relevant EGFR mutations in concordance with current guidelines, with minimal molecular expertise or infrastructure. Lung cancer is one of the four most common cancers in Europe and the United States and is undoubtedly one of the deadliest.1Ferlay J. Soerjomataram I. Dikshit R. Eser S. Mathers C. Rebelo M. Parkin D.M. Forman D. Bray F. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012.Int J Cancer. 2015; 136: E359-E386Crossref PubMed Scopus (18715) Google Scholar, 2Ferlay J. Steliarova-Foucher E. Lortet-Tieulent J. Rosso S. Coebergh J.W. Comber H. Forman D. Bray F. Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012.Eur J Cancer. 2013; 49: 1374-1403Abstract Full Text Full Text PDF PubMed Scopus (3813) Google Scholar, 3Siegel R.L. Miller K.D. Jemal A. Cancer statistics, 2017.CA Cancer J Clin. 2017; 67: 7-30Crossref PubMed Scopus (11104) Google Scholar Smoking is the primary risk factor for lung cancer.4Rahal Z. El Nemr S. Sinjab A. Chami H. Tfayli A. Kadara H. Smoking and lung cancer: a geo-regional perspective.Front Oncol. 2017; 7: 194Crossref PubMed Scopus (30) Google Scholar Lung cancer is composed of two main histologic subtypes: non–small-cell lung cancer (NSCLC) and small-cell lung cancer, with NSCLC being the most frequently diagnosed subtype (ie, 85%). Prognosis is poor after advanced NSCLC diagnosis, with the vast majority of patients not surviving, despite treatment.5Heist R.S. Engelman J.A. SnapShot: non-small cell lung cancer.Cancer Cell. 2012; 21: 448.e2Abstract Full Text PDF PubMed Scopus (138) Google Scholar An important improvement in the treatment of metastatic NSCLC was the development of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), such as afatinib, erlotinib, and gefitinib.6Ciardiello F. Tortora G. EGFR antagonists in cancer treatment.N Engl J Med. 2008; 358: 1160-1174Crossref PubMed Scopus (1557) Google Scholar, 7Lee J.K. Hahn S. Kim D.W. Suh K.J. Keam B. Kim T.M. Lee S.H. Heo D.S. Epidermal growth factor receptor tyrosine kinase inhibitors vs conventional chemotherapy in non-small cell lung cancer harboring wild-type epidermal growth factor receptor: a meta-analysis.JAMA. 2014; 311: 1430-1437Crossref PubMed Scopus (117) Google Scholar Those TKIs inhibit the catalytic activity of mutated EGFR, a member of the tyrosine kinase family comprising several isoforms.8Yarden Y. The EGFR family and its ligands in human cancer: signalling mechanisms and therapeutic opportunities.Eur J Cancer. 2001; 37 Suppl 4: S3-S8Abstract Full Text Full Text PDF PubMed Google Scholar, 9Linardou H. Dahabreh I.J. Bafaloukos D. Kosmidis P. Murray S. Somatic EGFR mutations and efficacy of tyrosine kinase inhibitors in NSCLC.Nat Rev Clin Oncol. 2009; 6: 352-366Crossref PubMed Scopus (188) Google Scholar Although TKIs improve overall and progression-free survival, and overall response in NSCLC, resistance to this class of compounds usually develops within 9 to 12 months after initiation of therapy.10Sequist L.V. Waltman B.A. Dias-Santagata D. Digumarthy S. Turke A.B. Fidias P. Bergethon K. Shaw A.T. Gettinger S. Cosper A.K. Akhavanfard S. Heist R.S. Temel J. Christensen J.G. Wain J.C. Lynch T.J. Vernovsky K. Mark E.J. Lanuti M. Iafrate A.J. Mino-Kenudson M. Engelman J.A. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors.Sci Transl Med. 2011; 3: 75ra26Crossref PubMed Scopus (2378) Google Scholar EGFR is the gene that is most frequently mutated in NSCLC in the Asian population (ie, in approximately 50% of the Asian patients) and often in the Western population (ie, in approximately 10% of patients), especially in never smokers.11Hirsch F.R. Bunn Jr., P.A. EGFR testing in lung cancer is ready for prime time.Lancet Oncol. 2009; 10: 432-433Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar At baseline, exon 19 deletions and point mutation L858R in exon 21 account for approximately 85% to 90% of all EGFR-activating mutations.12Fang S. Wang Z. EGFR mutations as a prognostic and predictive marker in non-small-cell lung cancer.Drug Des Devel Ther. 2014; 8: 1595-1611PubMed Google Scholar Less prevalent EGFR mutations, in particular G719A/C/S, T790M, S768I, exon 20 insertions, and L861Q, constitute the remaining 10%.13Li K. Yang M. Liang N. Li S. Determining EGFR-TKI sensitivity of G719X and other uncommon EGFR mutations in non-small cell lung cancer: perplexity and solution (review).Oncol Rep. 2017; 37: 1347-1358Crossref PubMed Scopus (30) Google Scholar The presence of most of these EGFR mutations is predictive for sensitivity to TKIs,14Dahabreh I.J. Linardou H. Siannis F. Kosmidis P. Bafaloukos D. Murray S. Somatic EGFR mutation and gene copy gain as predictive biomarkers for response to tyrosine kinase inhibitors in non-small cell lung cancer.Clin Cancer Res. 2010; 16: 291-303Crossref PubMed Scopus (126) Google Scholar leading to improved progression-free survival but without demonstrable impact on overall survival; they are accordingly referred to as sensitizing or activating EGFR mutations.15Lee C.K. Brown C. Gralla R.J. Hirsh V. Thongprasert S. Tsai C.M. Tan E.H. Ho J.C. Chu da T. Zaatar A. Osorio Sanchez J.A. Vu V.V. Au J.S. Inoue A. Lee S.M. Gebski V. Yang J.C. Impact of EGFR inhibitor in non-small cell lung cancer on progression-free and overall survival: a meta-analysis.J Natl Cancer Inst. 2013; 105: 595-605Crossref PubMed Scopus (410) Google Scholar, 16Laurie S.A. Goss G.D. Role of epidermal growth factor receptor inhibitors in epidermal growth factor receptor wild-type non-small-cell lung cancer.J Clin Oncol. 2013; 31: 1061-1069Crossref PubMed Scopus (78) Google Scholar An exon 20 insertion, on the contrary, may predict resistance.17Yasuda H. Kobayashi S. Costa D.B. EGFR exon 20 insertion mutations in non-small-cell lung cancer: preclinical data and clinical implications.Lancet Oncol. 2012; 13: e23-e31Abstract Full Text Full Text PDF PubMed Scopus (356) Google Scholar Hence, it is required by guidelines to determine the EGFR mutational status in advanced NSCLC for activating or resistance mutations before initiation of TKI therapy.18Novello S. Barlesi F. Califano R. Cufer T. Ekman S. Levra M.G. Kerr K. Popat S. Reck M. Senan S. Simo G.V. Vansteenkiste J. Peters S. ESMO Guidelines Committee: Metastatic non-small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.Ann Oncol. 2016; 27 Suppl 5: v1-v27Abstract Full Text Full Text PDF Scopus (625) Google Scholar, 19Kalemkerian G.P. Narula N. Kennedy E.B. Biermann W.A. Donington J. Leighl N.B. Lew M. Pantelas J. Ramalingam S.S. Reck M. Saqi A. Simoff M. Singh N. Sundaram B. Molecular testing guideline for the selection of patients with lung cancer for treatment with targeted tyrosine kinase inhibitors: American Society of Clinical Oncology Endorsement of the College of American Pathologists/International Association for the Study of Lung Cancer/Association for Molecular Pathology Clinical Practice Guideline Update.J Clin Oncol. 2018; 36: 911-919PubMed Google Scholar, 20Kerr K.M. Bubendorf L. Edelman M.J. Marchetti A. Mok T. Novello S. O'Byrne K. Stahel R. Peters S. Felip E. Panel MembersSecond ESMO consensus conference on lung cancer: pathology and molecular biomarkers for non-small-cell lung cancer.Ann Oncol. 2014; 25: 1681-1690Abstract Full Text Full Text PDF PubMed Scopus (201) Google Scholar, 21NCCN NCCN Guidelines Version 1.2018. Non-Small Cell Lung Cancer. National Comprehensive Cancer Network, Plymouth Meeting, PA2017Google Scholar Appearance of point mutation T790M in exon 20 of EGFR is pivotal in the development of resistance to TKIs10Sequist L.V. Waltman B.A. Dias-Santagata D. Digumarthy S. Turke A.B. Fidias P. Bergethon K. Shaw A.T. Gettinger S. Cosper A.K. Akhavanfard S. Heist R.S. Temel J. Christensen J.G. Wain J.C. Lynch T.J. Vernovsky K. Mark E.J. Lanuti M. Iafrate A.J. Mino-Kenudson M. Engelman J.A. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors.Sci Transl Med. 2011; 3: 75ra26Crossref PubMed Scopus (2378) Google Scholar; and, therefore, T790M should be monitored at least at disease progression. Third-generation TKIs, like osimertinib, have been designed to target the T790M mutation and are used for treatment of patients who have developed this resistance mutation.18Novello S. Barlesi F. Califano R. Cufer T. Ekman S. Levra M.G. Kerr K. Popat S. Reck M. Senan S. Simo G.V. Vansteenkiste J. Peters S. ESMO Guidelines Committee: Metastatic non-small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.Ann Oncol. 2016; 27 Suppl 5: v1-v27Abstract Full Text Full Text PDF Scopus (625) Google Scholar, 22Jänne P.A. Yang J.C. Kim D.W. Planchard D. Ohe Y. Ramalingam S.S. Ahn M.J. Kim S.W. Su W.C. Horn L. Haggstrom D. Felip E. Kim J.H. Frewer P. Cantarini M. Brown K.H. Dickinson P.A. Ghiorghiu S. Ranson M. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer.N Engl J Med. 2015; 372: 1689-1699Crossref PubMed Scopus (1422) Google Scholar Recently, osimertinib has also been approved by the US Food and Drug Administration as a first-line treatment for both sensitizing and T790M-mutated tumors.23Ramalingam S.S. Yang J.C. Lee C.K. Kurata T. Kim D.W. John T. Nogami N. Ohe Y. Mann H. Rukazenkov Y. Ghiorghiu S. Stetson D. Markovets A. Barrett J.C. Thress K.S. Jänne P.A. Osimertinib as first-line treatment of EGFR mutation-positive advanced non-small-cell lung cancer.J Clin Oncol. 2018; 36: 841-849Crossref PubMed Scopus (274) Google Scholar, 24Soria J.C. Ohe Y. Vansteenkiste J. Reungwetwattana T. Chewaskulyong B. Lee K.H. Dechaphunkul A. Imamura F. Nogami N. Kurata T. Okamoto I. Zhou C. Cho B.C. Cheng Y. Cho E.K. Voon P.J. Planchard D. Su W.C. Gray J.E. Lee S.M. Hodge R. Marotti M. Rukazenkov Y. Ramalingam S.S. FLAURA InvestigatorsOsimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer.N Engl J Med. 2018; 378: 113-125Crossref PubMed Scopus (1749) Google Scholar Routinely, EGFR mutation analysis is performed on tumor tissue acquired by surgery or biopsy.25Thunnissen E. Kerr K.M. Herth F.J. Lantuejoul S. Papotti M. Rintoul R.C. Rossi G. Skov B.G. Weynand B. Bubendorf L. Katrien G. Johansson L. López-Ríos F. Ninane V. Olszewski W. Popper H. Jaume S. Schnabel P. Thiberville L. Laenger F. The challenge of NSCLC diagnosis and predictive analysis on small samples: practical approach of a working group.Lung Cancer. 2012; 76: 1-18Abstract Full Text Full Text PDF PubMed Scopus (178) Google Scholar However, tumor tissues are not always satisfactory accessible, and repeated surgery or biopsy to assess treatment resistance is often inappropriate. Moreover, surgery and biopsy might cause clinical complications, with intrathoracic biopsies having a complication rate of 17.1%.26Overman M.J. Modak J. Kopetz S. Murthy R. Yao J.C. Hicks M.E. Abbruzzese J.L. Tam A.L. Use of research biopsies in clinical trials: are risks and benefits adequately discussed?.J Clin Oncol. 2013; 31: 17-22Crossref PubMed Scopus (192) Google Scholar As a result, tissue samples are often small and may have limited tumor content. Several commercially available CE-IVD kits and in-house assays, based on Sanger sequencing, pyrosequencing, next-generation sequencing (NGS), real-time PCR, or mass spectrometry, have been developed to routinely assess the mutational status of formalin-fixed, paraffin-embedded (FFPE) NSCLC tissue samples.27Legras A. Barritault M. Tallet A. Fabre E. Guyard A. Rance B. Digan W. Pecuchet N. Giroux-Leprieur E. Julie C. Jouveshomme S. Duchatelle V. Giraudet V. Gibault L. Cazier A. Pastre J. Le Pimpec-Barthes F. Laurent-Puig P. Blons H. Validity of targeted next-generation sequencing in routine care for identifying clinically relevant molecular profiles in non-small-cell lung cancer: results of a 2-year experience on 1343 samples.J Mol Diagn. 2018; 20: 550-564Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar, 28Leduc C. Merlio J.P. Besse B. Blons H. Debieuvre D. Bringuier P.P. Monnet I. Rouquette I. Fraboulet-Moreau S. Lemoine A. Pouessel D. Mosser J. Vaylet F. Langlais A. Missy P. Morin F. Moro-Sibilot D. Cadranel J. Barlesi F. Beau-Faller M. French Cooperative Thoracic Intergroup (IFCT)Clinical and molecular characteristics of non-small-cell lung cancer (NSCLC) harboring EGFR mutation: results of the nationwide French Cooperative Thoracic Intergroup (IFCT) program.Ann Oncol. 2017; 28: 2715-2724Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar Each of these methods has its sensitivity, specificity, level of automation and multiplexing, turnaround time, cost, and requirement for specialized equipment and trained staff. The Idylla EGFR Mutation Assay (Biocartis, Mechelen, Belgium), performed on the Idylla platform, detects 51 EGFR mutations in FFPE NSCLC tissue samples. Biocartis has since launched a CE-marked IVD (Idylla EGFR Mutation Test) intended to determine the tumor EGFR mutation status of patients with metastatic NSCLC at diagnosis of advanced disease and to facilitate treatment decisions within a multidisciplinary team. The Idylla EGFR Mutation Test is the only fully automated CE-IVD test detecting the mutations in EGFR exons 18, 19, 20, and 21 that are considered clinically relevant, according to current international guidelines.18Novello S. Barlesi F. Califano R. Cufer T. Ekman S. Levra M.G. Kerr K. Popat S. Reck M. Senan S. Simo G.V. Vansteenkiste J. Peters S. ESMO Guidelines Committee: Metastatic non-small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.Ann Oncol. 2016; 27 Suppl 5: v1-v27Abstract Full Text Full Text PDF Scopus (625) Google Scholar, 19Kalemkerian G.P. Narula N. Kennedy E.B. Biermann W.A. Donington J. Leighl N.B. Lew M. Pantelas J. Ramalingam S.S. Reck M. Saqi A. Simoff M. Singh N. Sundaram B. Molecular testing guideline for the selection of patients with lung cancer for treatment with targeted tyrosine kinase inhibitors: American Society of Clinical Oncology Endorsement of the College of American Pathologists/International Association for the Study of Lung Cancer/Association for Molecular Pathology Clinical Practice Guideline Update.J Clin Oncol. 2018; 36: 911-919PubMed Google Scholar, 20Kerr K.M. Bubendorf L. Edelman M.J. Marchetti A. Mok T. Novello S. O'Byrne K. Stahel R. Peters S. Felip E. Panel MembersSecond ESMO consensus conference on lung cancer: pathology and molecular biomarkers for non-small-cell lung cancer.Ann Oncol. 2014; 25: 1681-1690Abstract Full Text Full Text PDF PubMed Scopus (201) Google Scholar, 21NCCN NCCN Guidelines Version 1.2018. Non-Small Cell Lung Cancer. National Comprehensive Cancer Network, Plymouth Meeting, PA2017Google Scholar In the current study, a multicenter evaluation (15 centers) of the performance of the Idylla EGFR Mutation Assay on 449 archived FFPE tissue sections, originating from NSCLC lesions, in comparison with data retrospectively obtained with routine reference methods on matched samples is described. Archived clinical FFPE tissues of 449 NSCLC patients were selected for this study. Samples were obtained from 15 clinical centers: BioPath Innovations S.A./BioMarker Solutions Limited (Athens, Greece; London, UK; n = 28); Klinikum Augsburg (Augsburg, Germany; n = 29); Hospital del Mar (Barcelona, Spain; n = 30); Hospital Universitari de Bellvitge/Catalan Institute of Oncology (Hospitalet, Spain; n = 30); University of Coimbra (Coimbra, Portugal; n = 31); Medizinisches Versorgungszentrum (MVZ) Zentrum für Pathologie und Zytodiagnostik GmbH (ZPZ) Köln (Cologne, Germany; n = 31); Rigshospitalet (Copenhagen, Denmark; n = 30); Royal Cornwall Hospital (Cornwall, UK; n = 29); Canberra Hospital (Garran, ACT, Australia; n = 33); Laboratoriemedicin Gävle (Gävleborg, Sweden; n = 28); University Clinic for Respiratory and Allergic Diseases (Golnik, Slovenia; n = 30); Maastricht UMC+ (Maastricht, the Netherlands; n = 30); Humanitas Research Hospital (Milan, Italy; n = 30); Toulouse Cancer University Institute (IUCT) Oncopole (Toulouse, France; n = 30); and University Hospital Zurich (Zurich, Switzerland; n = 30). The use of these patient samples was approved by the respective local Ethics Committees and was in accordance with the Declaration of Helsinki. Each of the 15 participating clinical centers was asked to select and include at least one NSCLC FFPE sample for each of the seven Idylla EGFR Mutation Assay genotype calls indicated in Table 1.Table 1EGFR Mutations Detected by the Idylla EGFR Mutation AssayExonMutationProtein changeNucleotide changeGenotype call Idylla18G719Ap.Gly719Alac.2156G>CG719A/C/SG719Cp.Gly719Cysc.2155G>Tc.2154_2155delinsTTG719Sp.Gly719Serc.2155G>A19Del 9p.Leu747_Ala750delinsProc.2238_2248delinsGCExon 19 deletionc.2239_2248delinsCp.Leu747_Ala750delinsSerc.2240_2248delp.Leu747_Glu749delc.2239_2247delDel 12p.Leu747_Thr751delinsProc.2239_2251delinsCp.Leu747_Thr751delinsSerc.2240_2251delDel 15p.Glu746_Ala750delc.2235_2249delc.2236_2250delp.Leu747_Thr751delc.2239_2253delc.2240_2254delc.2238_2252delp.Glu746_Thr751delinsAlac.2237_2251delp.Glu746_Thr751delinsIlec.2235_2252delinsAATp.Glu746_Thr751delinsValc.2237_2252delinsTp.Lys745_Ala750delinsThrc.2234_2248delp.Glu746_Thr751delinsLeuc.2236_2253delinsCTAp.Glu746_Thr751delinsValc.2237_2253delinsTAp.Glu746_Thr751delinsAlac.2235_2251delinsAGp.Glu746_Thr751delinsGlnc.2236_2253delinsCAAp.Ile744_Ala750delinsValLysc.2230_2249delinsGTCAADel 18p.Leu747_Pro753delinsSerc.2240_2257delp.Glu746_Ser752delinsValc.2237_2255delinsTp.Leu747_Ser752delc.2239_2256delp.Glu746_Thr751delc.2236_2253delp.Leu747_Pro753delinsGlnc.2239_2258delinsCAp.Glu746_Ser752delinsAlac.2237_2254delp.Glu746_Ser752delinsAspc.2238_2255delp.Glu746_Pro753delinsValSerc.2237_2257delinsTCTp.Glu746_Ser752delinsIlec.2236_2255delinsATc.2236_2256delinsATCp.Glu746_Ser752delinsValc.2237_2256delinsTTc.2237_2256delinsTCc.2235_2255delinsGGTDel 21p.Leu747_Pro753delc.2238_2258delp.Glu746_Ser752delc.2236_2256delDel 24p.Ser752_Ile759delc.2253_2276del20T790Mp.Thr790Metc.2369C>TT790MS768Ip.Ser768Ilec.2303G>TS768IInsGp.Asp770_Asn771insGlyc.2310_2311insGGTExon 20 insertionInsASVp.Val769_Asp770insAlaSerValc.2307_2308insGCCAGCGTGc.2309_2310delinsCCAGCGTGGATInsSVDp.Asp770_Asn771insSerValAspc.2311_2312insGCGTGGACAInsHp.His773_Val774insHisc.2319_2320insCAC21L858Rp.Leu858Argc.2573T>GL858Rc.2573_2574delinsGTc.2573_2574delinsGAL861Qp.Leu861Glnc.2582T>AL861Q Open table in a new tab In this study, Idylla EGFR Mutation Assay cartridges, processed by the Idylla System, were used to analyze the EGFR mutational status of these archival FFPE tissue sections from human NSCLC tissue. Participating centers received proper training to perform the Idylla EGFR Mutation Assay before starting the study. The FFPE tissue sections (mostly one, up to six) had a thickness of 5 or 10 μm and were sampled within the same FFPE block and mostly consecutive to the sections used before to generate the reference result with the routine method. Tumor content and area of the specimen were determined on hematoxylin-eosin–stained slides by a pathologist and, if needed, macrodissection was performed to achieve a neoplastic cell content of at least 10%. The FFPE tissue sections were placed directly into the Idylla cartridge following the assay instructions of the manufacturer (Biocartis). Artificial FFPE samples (ie, FFPE Reference Standards from Horizon Discovery, Cambridge, UK) were included as external controls: all 15 sites tested EGFR L858R and T790M, both at a 20% allelic frequency. The Biocartis Idylla EGFR Mutation Assay, performed on the Idylla System, is an assay intended for the qualitative detection of 51 different EGFR oncogene mutations: exon 18 (G719A/C/S), exon 19 (deletions), exon 20 mutations (T790M, S768I, and insertions), and exon 21 (L858R and L861Q). The detected EGFR mutations and the corresponding Idylla EGFR Mutation Assay genetic calls are presented in Table 1. In this study, the Idylla EGFR Investigational Use Only Assay has been used, as the CE-IVD–labeled Idylla EGFR Mutation Test was not yet on the market. The Idylla EGFR Mutation Assay has, in contrast to the Idylla EGFR Mutation Test (IVD), no performance claims. The Idylla EGFR Mutation Assay uses FFPE tissue sections originating from NSCLC lesions, with a minimum input of one FFPE section (5 μm thick) containing at least 10% of neoplastic cells. The time of completion from FFPE tissue sample to test result (not including macrodissection, if any) is approximately 2.5 hours, with <2 minutes hands-on time. In the cartridge, the entire process from FFPE sample to result, including fully integrated sample preparation, liberation of nucleic acids, and real-time PCR amplification and detection, is covered. Briefly, after insertion of the FFPE tissue section into the cartridge, deparaffinization, disruption of the tissue, and lysis of the cells are induced by a combination of chemical reagents, enzymes, heat, and high-intensity focused ultrasound. The resulting liberated nucleic acids are then analyzed in five parallel multiplex PCRs by means of highly selective target amplification primers and using fluorescently labeled probes to detect target sequences. To this end, the cartridge contains allele-specific primers and probes and all necessary PCR reagents present in a stable formulation. A conserved fragment in the transmembrane region of the EGFR gene is amplified simultaneously and serves as a sample processing control (named EGFR Total) to check for adequate execution of the complete process and as a measure for the amount of amplifiable DNA in the sample. The resulting fluorescence signals are analyzed in the Idylla System by EGFR-specific software and translated into genetic calls. To this end, the fluorescence signals are evaluated for PCR curve validity; and for each valid curve, a cycle of quantification value (Cq) is calculated. The presence of a mutant genotype is determined by calculating the difference between the EGFR Total Cq and the Cq obtained for the mutant signal(s) (ie, the ΔCq). A ΔCq value within a predefined validated range defines a valid mutant signal (mutation detected). Samples with a valid EGFR Total signal but a ΔCq value outside the predefined range for a mutant signal are reported as mutation negative (no mutation detected). In case no EGFR Total signal was detected, no mutant result can be determined and the result for that PCR is considered invalid. Invalid calls might be due to insufficient DNA input, severe DNA fragmentation (potentially caused by extended fixation time), the presence of inhibitors in the sample, incorrect placement of a sample in the cartridge, incorrect storage of the cartridge, use of a cartridge that exceeded its in-use period after removal from the pouch, or cartridge malfunctioning. For the genotype calls that cover several mutations (eg, G719A/C/S, exon 19 deletion, and exon 20 insertion), the genotype call will be reported as positive (mutation detected) if at least one valid mutation signal is detected, regardless of the status (valid/invalid) of the other mutations within the genotype call. For the Idylla EGFR Mutation Assay to be invalid, all seven genotypes must contain an invalid result. A result reporting the presence, absence, or invalidity for each mutation or mutation group in the EGFR gene in the analyzed sample is displayed on the Idylla Console screen, as well as an average of the Cq values of the EGFR Totals (present in each of the five multiplex PCRs). If the Idylla report shows a mix of invalid and valid genotype calls, the robustness for the valid genotype call can be ensured. Each PCR chamber in the EGFR cartridge is individually validated for performance by means of the sample processing control. If a sample processing control signal of a PCR chamber is valid, all results of the PCR chamber are considered valid, independent of the performance of the other chambers. The Idylla Explore application offers visualization of PCR curves and the corresponding Cq values from the Idylla EGFR Mutation Assay results (Figure 1). This is a visualization tool and not intended to be used for data interpretation. The following reference methods were used for routine analysis of the EGFR mutational status: NGS using the Ion Torrent AmpliSeq Colon and Lung Cancer Research Panel version 2 (Thermo Fisher Scientific, Waltham, MA; n = 12 samples), the Oncomine Focus Assay (Thermo Fisher Scientific; n = 25), the HaloPlex Cancer Research Panel (Agilent Technologies, Santa Clara, CA; n = 20), or in-house–developed NGS (n = 3); pyrosequencing using the therascreen EGFR Pyro kit (Qiagen, Venlo, the Netherlands; n = 6) or in-house–developed pyrosequencing (n = 34); PCR-based assays using the cobas EGFR Mutation Test version 2 (Roche Molecular Systems, Pleasanton, CA; n = 130) or the therascreen EGFR RGQ PCR Kit version 1 or 2 (Qiagen; n = 71); mass spectrometric methods using the MassArray Lung Cancer Panel (Diatech, Jesi, Italy; n = 30); and Sanger sequencing using in-house methods (n = 118). Commercial assays were performed according to the manufacturer's instructions. Analytical sensitivities for the commercial assays can be found in the respective manufacturer's instructions. In-house methods were performed by adopting different protocols and equipment at each site. Digital droplet PCR (ddPCR) of DNA retrieved from the Idylla EGFR Mutation Assay cartridge, of DNA used for the reference method, and/or of FFPE tissue sections was performed on a BioRad (Hercules, CA) QX100 system, according to the manufacturer's instructions. Other methods used in further analysis were performed as described above. Agreement between Idylla and the comparator method was evaluated on the basis of point estimates for overall, positive, and negative percentage diagnostic agreement together with 95% one-sided Wilson score CIs. At all 15 sites, the EGFR L858R and T790M (both at a 20% allelic frequency) artificial FFPE samples (ie, FFPE Reference Standards from Horizon Discovery) were included as external controls. The Idylla EGFR Mutation Assay, independently performed at 15 sites, identified each of these two mutations correctly; and, therefore, it can be concluded that interlaboratory reproducibility of the external control samples was 100%. Using the Idylla EGFR Mutation Assay, the EGFR mutational status of archived clinical FFPE tissue sections, originating from NSCLC lesions from 449 patients, was determined at 15 centers (Supplemental Table S1). The Idylla results were compared with the original resul" @default.
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• W2969883920 date "2019-11-01" @default.
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• W2969883920 title "Multicenter Evaluation of the Fully Automated PCR-Based Idylla EGFR Mutation Assay on Formalin-Fixed, Paraffin-Embedded Tissue of Human Lung Cancer" @default.
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• W2969883920 doi "https://doi.org/10.1016/j.jmoldx.2019.06.010" @default.
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