Biomarker analysis has become routine practice in the treatment of non-small cell lung cancer (NSCLC). To ensure high quality testing, participation to external quality assessment (EQA) schemes is essential. This article provides a longitudinal overview of the EQA performance for EGFR, ALK, and ROS1 analyses in NSCLC between 2012 and 2015. The four scheme years were organized by the European Society of Pathology according to the ISO 17043 standard. Participants were asked to analyze the provided tissue using their routine procedures. Analysis scores improved for individual laboratories upon participation to more EQA schemes, except for ROS1 immunohistochemistry (IHC). For EGFR analysis, scheme error rates were 18.8%, 14.1% and 7.5% in 2013, 2014 and 2015 respectively. For ALK testing, error rates decreased between 2012 and 2015 by 5.2%, 3.2% and 11.8% for the fluorescence in situ hybridization (FISH), FISH digital, and IHC subschemes, respectively. In contrast, for ROS1 error rates increased between 2014 and 2015 for FISH and IHC by 3.2% and 9.3%. Technical failures decreased over the years for all three markers. Results show that EQA contributes to an ameliorated performance for most predictive biomarkers in NSCLC. Room for improvement is still present, especially for ROS1 analysis.

Center for Oncologic Research University of Antwerp Antwerp Belgium

Charles University Medical Faculty and University Hospital Department of Pathology Hradec Kralove Czech Republic

Cytogenetics and Cellular Biology Department CHU de Rennes Rennes France

GILAB AG Allschwil Switzerland

INSERM INRA Université Rennes 1 Université Bretagne Loire Nutrition Metabolisms and Cancer Rennes France

Technical University Munich Munich Germany

University Hospital Antwerp Department of Pathology Edegem Belgium

University Hospital Heidelberg Heidelberg Germany

University Medical Center Groningen Department of Pathology Groningen The Netherlands

University of Basel Basel Switzerland

University of Leuven Department of Public Health and Primary Care Biomedical Quality Assurance Research Unit Leuven Belgium

Zobrazit více v PubMed

Saijo N. Critical comments for roles of biomarkers in the diagnosis and treatment of cancer. Cancer Treat Rev. 2012;38:63–67. https://doi.org/10.1016/j.ctrv.2011.02.004. PubMed DOI

Thunnissen E, van der Oord K, den Bakker M. Prognostic and predictive biomarkers in lung cancer. A review. Virchows Arch. 2014;464:347–58. https://doi.org/10.1007/s00428-014-1535-4. PubMed DOI

Lindeman NI, Cagle PT, Beasley MB, Chitale DA, Dacic S, Giaccone G, Jenkins RB, Kwiatkowski DJ, Saldivar JS, Squire J, Thunnissen E, Ladanyi M. Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. J Thorac Oncol. 2013;8:823–59. https://doi.org/10.1097/JTO.0b013e318290868f. PubMed DOI PMC

Shaw AT, Ou SH, Bang YJ, Camidge DR, Solomon BJ, Salgia R, Riely GJ, Varella-Garcia M, Shapiro GI, Costa DB, Doebele RC, Le LP, Zheng Z, et al. Crizotinib in ROS1-rearranged non-small-cell lung cancer. N Engl J Med. 2014;371:1963–71. https://doi.org/10.1056/NEJMoa1406766. PubMed DOI PMC

Xalkori: EPAR summary for the public, European Medicine Agency (EMA), 2012 [cited 27 July 2017]. Availabe from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/002489/WC500134762.pdf.

Xalkori prescribing information, Food and Drug Administration (FDA), 2013 [cited 28 July 2017]; Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/202570s002lbl.pdf.

Stuart BW, Wild CP. World Cancer Report, World Health Organization (WHO), 2014 [cited 28 July 2017]. Available from: http://publications.iarc.fr/Non-Series-Publications/World-Cancer-Reports/World-Cancer-Report-2014.

Tembuyser L, Dequeker EM. Endorsing good quality assurance practices in molecular pathology: risks and recommendations for diagnostic laboratories and external quality assessment providers. Virchows Arch. 2016;468:31–41. https://doi.org/10.1007/s00428-015-1839-z. PubMed DOI

Cagle PT, Allen TC, Olsen RJ. Lung cancer biomarkers: present status and future developments. Arch Pathol Lab Med. 2013;137:1191–98. https://doi.org/10.5858/arpa.2013-0319-CR. PubMed DOI

O’Brien CP, Taylor SE, O’Leary JJ, Finn SP. Molecular testing in oncology: problems, pitfalls and progress. Lung Cancer. 2014;83:309–15. https://doi.org/10.1016/j.lungcan.2013.12.010. PubMed DOI

Dubbink HJ, Deans ZC, Tops BB, van Kemenade FJ, Koljenović S, van Krieken HJ, Blokx WA, Dinjens WN, Groenen PJ. Next generation diagnostic molecular pathology: critical appraisal of quality assurance in Europe. Mol Oncol. 2014;8:830–39. https://doi.org/10.1016/j.molonc.2014.03.004. PubMed DOI PMC

Salto-Tellez M, Gonzalez de Castro D. Next-generation sequencing: a change of paradigm in molecular diagnostic validation. J Pathol. 2014;234:5–10. https://doi.org/10.1002/path.4365. PubMed DOI

Tack V, Ligtenberg MJ, Tembuyser L, Normanno N, Vander Borght S, Han van Krieken J, Dequeker EM. External quality assessment unravels interlaboratory differences in quality of RAS testing for anti-EGFR therapy in colorectal cancer. Oncologist. 2015;20:257–62. https://doi.org/10.1634/theoncologist.2014-0382. PubMed DOI PMC

van Krieken JH, Normanno N, Blackhall F, Boone E, Botti G, Carneiro F, Celik I, Ciardiello F, Cree IA, Deans ZC, Edsjö A, Groenen PJ, Kamarainen O, et al. Guideline on the requirements of external quality assessment programs in molecular pathology. Virchows Arch. 2013;462:27–37. https://doi.org/10.1007/s00428-012-1354-4. PubMed DOI

International Organization for Standardization . ISO 15189:2012 Medical laboratories - Particular requirements for quality and competence. Geneva: ISO; 2012.

Clinical Laboratory Improvement Amendments of. 1988, 42 U.S.C. 263a PL100-578, 1988. Laboratory Requirements, 2003, 42 C.F.R. Chapter IV, Part 493.

Tembuyser L, Tack V, Zwaenepoel K, Pauwels P, Miller K, Bubendorf L, Kerr K, Schuuring E, Thunnissen E, Dequeker EM. The relevance of external quality assessment for molecular testing for ALK positive non-small cell lung cancer: results from two pilot rounds show room for optimization. PLoS One. 2014;9:e112159. https://doi.org/10.1371/journal.pone.0112159. PubMed DOI PMC

Thunnissen E, Bubendorf L, Dietel M, Elmberger G, Kerr K, Lopez-Rios F, Moch H, Olszewski W, Pauwels P, Penault-Llorca F, Rossi G. EML4-ALK testing in non-small cell carcinomas of the lung: a review with recommendations. Virchows Arch. 2012;461:245–57. https://doi.org/10.1007/s00428-012-1281-4. PubMed DOI PMC

Camidge DR, Kono SA, Flacco A, Tan AC, Doebele RC, Zhou Q, Crino L, Franklin WA, Varella-Garcia M. Optimizing the detection of lung cancer patients harboring anaplastic lymphoma kinase (ALK) gene rearrangements potentially suitable for ALK inhibitor treatment. Clin Cancer Res. 2010;16:5581–90. https://doi.org/10.1158/1078-0432.CCR-10-0851. PubMed DOI PMC

Vysis ALK Break Apart FISH Probe Kit, Abbott, [cited 18 January 2017]. Available from: https://www.molecular.abbott/sal/en-us/staticAssets/Vysis_ALK_Evaluation_Guide_Final.pdf.

Patton S, Normanno N, Blackhall F, Murray S, Kerr KM, Dietel M, Filipits M, Benlloch S, Popat S, Stahel R, Thunnissen E. Assessing standardization of molecular testing for non-small-cell lung cancer: results of a worldwide external quality assessment (EQA) scheme for EGFR mutation testing. Br J Cancer. 2014;111:413–20. https://doi.org/10.1038/bjc.2014.353. PubMed DOI PMC

Deans ZC, Bilbe N, O’Sullivan B, Lazarou LP, de Castro DG, Parry S, Dodson A, Taniere P, Clark C, Butler R. Improvement in the quality of molecular analysis of EGFR in non-small-cell lung cancer detected by three rounds of external quality assessment. J Clin Pathol. 2013;66:319–25. https://doi.org/10.1136/jclinpath-2012-201227. PubMed DOI

Normanno N, Pinto C, Taddei G, Gambacorta M, Castiglione F, Barberis M, Clemente C, Marchetti A. Results of the First Italian External Quality Assurance Scheme for somatic EGFR mutation testing in non-small-cell lung cancer. J Thorac Oncol. 2013;8:773–8. https://doi.org/10.1097/JTO.0b013e31828c2b08. PubMed DOI

Dequeker EM, Keppens C, Egele C, Delen S, Lamy A, Lemoine A, Sabourin JC, Andrieu C, Ligtenberg M, Fetique D, Tops B, Descarpentries C, Blons H, et al. Three Rounds of External Quality Assessment in France to Evaluate the Performance of 28 Platforms for Multiparametric Molecular Testing in Metastatic Colorectal and Non-Small Cell Lung Cancer. J Mol Diagn. 2016;18:205–14. https://doi.org/10.1016/j.jmoldx.2015.09.004. PubMed DOI

V Laffert M, Warth A, Penzel R, Schirmacher P, Jonigk D, Kreipe H, Schildhaus HU, Merkelbach-Bruse S, Büttner R, Reu S, Kerler R, Jung A, Kirchner T, et al. Anaplastic lymphoma kinase (ALK) gene rearrangement in non-small cell lung cancer (NSCLC): results of a multi-centre ALK-testing. Lung Cancer. 2013;81:200–06. https://doi.org/10.1016/j.lungcan.2013.04.015. PubMed DOI

International Organization for Standardization . ISO 17043:2010 Conformity assessment - General requirements for proficiency testing. Geneva: ISO; 2010.

Cree IA, Deans Z, Ligtenberg MJ, Normanno N, Edsjö A, Rouleau E, Solé F, Thunnissen E, Timens W, Schuuring E, Dequeker E, Murray S, Dietel M, et al. European Society of Pathology Task Force on Quality Assurance in Molecular Pathology, and Royal College of Pathologists Guidance for laboratories performing molecular pathology for cancer patients. J Clin Pathol. 2014;67:923–31. https://doi.org/10.1136/jclinpath-2014-202404. PubMed DOI PMC

Pao W, Miller VA, Politi KA, Riely GJ, Somwar R, Zakowski MF, Kris MG, Varmus H. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med. 2005;2:e73. https://doi.org/10.1371/journal.pmed.0020073. PubMed DOI PMC

Osimertinib (TAGRISSO), Food and Drug Administration (FDA), [cited 18 January 2017]. Available from: https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm549683.htm.

Tagrisso: EPAR summary for the public, European Medicines Agency (EMA), 2015 [cited 18 January 2017]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/004124/WC500202025.pdf.

Tsao MS, Hirsch F, Yatabe Y. IASLC atlas of ALK and ROS1 testing in lung cancer. 2nd edition. Editorial Rx Press; 2016.

Conklin CM, Craddock KJ, Have C, Laskin J, Couture C, Ionescu DN. Immunohistochemistry is a reliable screening tool for identification of ALK rearrangement in non-small-cell lung carcinoma and is antibody dependent. J Thorac Oncol. 2013;8:45–51. https://doi.org/10.1097/JTO.0b013e318274a83e. PubMed DOI

Zwaenepoel K, Van Dongen A, Lambin S, Weyn C, Pauwels P. Detection of ALK expression in non-small-cell lung cancer with ALK gene rearrangements—comparison of multiple immunohistochemical methods. Histopathology. 2014;65:539–48. https://doi.org/10.1111/his.12414. PubMed DOI

Wang Q, Zhao L, Yang X, Wei S, Zeng Y, Mao C, Lin L, Fu P, Lyu L, Li Z, Xiao H. Antibody 1A4 with routine immunohistochemistry demonstrates high sensitivity for ALK rearrangement screening of Chinese lung adenocarcinoma patients: A single-center large-scale study. Lung Cancer. 2016;95:39–43. https://doi.org/10.1016/j.lungcan.2016.02.014. PubMed DOI

Ibrahim M, Parry S, Wilkinson D, Bilbe N, Allen D, Forrest S, Maxwell P, O’Grady A, Starczynski J, Tanier P, Gosney J, Kerr K, Miller K, Thunnissen E. ALK Immunohistochemistry in NSCLC: Discordant Staining Can Impact Patient Treatment Regimen. J Thorac Oncol. 2016;11:2241–47. https://doi.org/10.1016/j.jtho.2016.07.012. PubMed DOI

Bubendorf L, Büttner R, Al-Dayel F, Dietel M, Elmberger G, Kerr K, López-Ríos F, Marchetti A, Öz B, Pauwels P, Penault-Llorca F, Rossi G, Ryška A, Thunnissen E. Testing for ROS1 in non-small cell lung cancer: a review with recommendations. Virchows Arch. 2016;469:489–503. https://doi.org/10.1007/s00428-016-2000-3. PubMed DOI PMC

Mescam-Mancini L, Lantuéjoul S, Moro-Sibilot D, Rouquette I, Souquet PJ, Audigier-Valette C, Sabourin JC, Decroisette C, Sakhri L, Brambilla E, McLeer-Florin A. On the relevance of a testing algorithm for the detection of ROS1-rearranged lung adenocarcinomas. Lung Cancer. 2014;83:168–73. https://doi.org/10.1016/j.lungcan.2013.11.019. PubMed DOI

Expert opinion on NSCLC small specimen biomarker testing - Part 2: Analysis, reporting, and quality assessment

PD-L1 immunohistochemistry in non-small-cell lung cancer: unraveling differences in staining concordance and interpretation

Lung cancer biomarker testing: perspective from Europe

Sensitive detection methods are key to identify secondary EGFR c.2369C>T p.(Thr790Met) in non-small cell lung cancer tissue samples