BACKGROUND: The introduction of targeted treatments for subsets of non-small cell lung cancer (NSCLC) has highlighted the importance of accurate molecular diagnosis to determine if an actionable genetic alteration is present. Few data are available for Central and Eastern Europe (CEE) on mutation rates, testing rates, and compliance with testing guidelines. METHODS: A questionnaire about molecular testing and NSCLC management was distributed to relevant specialists in nine CEE countries, and pathologists were asked to provide the results of EGFR and ALK testing over a 1-year period. RESULTS: A very high proportion of lung cancer cases are confirmed histologically/cytologically (75-100%), and molecular testing of NSCLC samples has been established in all evaluated CEE countries in 2014. Most countries follow national or international guidelines on which patients to test for EGFR mutations and ALK rearrangements. In most centers at that time, testing was undertaken on request of the clinician rather than on the preferred reflex basis. Immunohistochemistry, followed by fluorescent in situ hybridization confirmation of positive cases, has been widely adopted for ALK testing in the region. Limited reimbursement is a significant barrier to molecular testing in the region and a disincentive to reflex testing. Multidisciplinary tumor boards are established in most of the countries and centers, with 75-100% of cases being discussed at a multidisciplinary tumor board at specialized centers. CONCLUSIONS: Molecular testing is established throughout the CEE region, but improved and unbiased reimbursement remains a major challenge for the future. Increasing the number of patients reviewed by multidisciplinary boards outside of major centers and access to targeted therapy based on the result of molecular testing are other major challenges.

1st Institute of Pathology and Experimental Cancer Research Semmelweis University Budapest Hungary

Cerrahpasa Medical Faculty Istanbul Turkey

Department of Oncology Specialised Hospital of St Zoerardus Zobor Nitra Slovakia

Department of Pathology Comenius University Jessenius Medical Faculty and University Hospital Martin Slovakia

Institute of Oncology Warsaw Poland

Institute of Pathology Medical University of Graz Graz Austria

Institute of Pathology University of Zagreb School of Medicine Zagreb Croatia

Medical Faculty Ljubljana University Clinic Golnik Golnik Slovenia

Medical University of Gdansk Gdansk Poland

Meir Medical Center Kfar Saba Israel

The Fingerland Department of Pathology Charles University Faculty of Medicine and University Hospital Hradec Králové Czech Republic

Zobrazit více v PubMed

GLOBOCAN . 2012 v1.0, cancer incidence and mortality worldwide: IARC CancerBase no. 11. Lyon: International Agency for Research on Cancer; 2013.

Kerr KM, Bubendorf L, Edelman MJ, Marchetti A, Mok T, Novello S, O'Byrne K, Stahel R, Peters S, Felip E. Second ESMO consensus conference on lung cancer: pathology and molecular biomarkers for non-small-cell lung cancer. Ann Oncol. 2014;25(9):1681–1690. doi: 10.1093/annonc/mdu145. PubMed DOI

Travis WD, Brambilla E, Noguchi M, Nicholson AG, Geisinger KR, Yatabe Y, Beer DG, Powell CA, Riely GJ, Van Schil PE, et al. International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society international multidisciplinary classification of lung Adenocarcinoma. J Thorac Oncol. 2011;6(2n):244–285. doi: 10.1097/JTO.0b013e318206a221. PubMed DOI PMC

Couraud S, Zalcman G, Milleron B, Morin F, Souquet PJ. Lung cancer in never smokers – a review. Eur J Cancer. 2012;48(9):1299–1311. doi: 10.1016/j.ejca.2012.03.007. PubMed DOI

Black RC, Khurshid H. NSCLC: an update of driver mutations, their role in pathogenesis and clinical significance. R I Med J (2013) 2015;98(10):25–28. PubMed

Dacic S. Molecular genetic testing for lung adenocarcinomas: a practical approach to clinically relevant mutations and translocations. J Clin Pathol. 2013;66(10):870–874. doi: 10.1136/jclinpath-2012-201336. PubMed DOI

Popper HH, Ryska A, Timar J, Olszewski W. Molecular testing in lung cancer in the era of precision medicine. Transl Lung Cancer Res. 2014;3(5):291–300. PubMed PMC

Kris MG, Johnson BE, Berry LD, Kwiatkowski DJ, Iafrate AJ, Wistuba II, Varella-Garcia M, Franklin WA, Aronson SL, Su PF, et al. Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs. JAMA. 2014;311(19):1998–2006. doi: 10.1001/jama.2014.3741. PubMed DOI PMC

Besse B, Adjei A, Baas P, Meldgaard P, Nicolson M, Paz-Ares L, Reck M, Smit EF, Syrigos K, Stahel R, et al. 2nd ESMO consensus conference on lung cancer: non-small-cell lung cancer first-line/second and further lines of treatment in advanced disease. Ann Oncol. 2014;25(8):1475–1484. doi: 10.1093/annonc/mdu123. PubMed DOI

Zhang WQ, Li T, Li H. Efficacy of EGFR tyrosine kinase inhibitors in non-small-cell lung cancer patients with/without EGFR-mutation: evidence based on recent phase III randomized trials. Med Sci Monit. 2014;20:2666–2676. doi: 10.12659/MSM.892476. PubMed DOI PMC

Solomon BJ, Mok T, Kim DW, Wu YL, Nakagawa K, Mekhail T, Felip E, Cappuzzo F, Paolini J, Usari T, et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med. 2014;371(23):2167–2177. doi: 10.1056/NEJMoa1408440. PubMed DOI

Lindeman NI, Cagle PT, Beasley MB, Chitale DA, Dacic S, Giaccone G, Jenkins RB, Kwiatkowski DJ, Saldivar JS, Squire J, et al. 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 Mol Diagn. 2013;15(4):415–453. doi: 10.1016/j.jmoldx.2013.03.001. PubMed DOI

Ramlau R, Cufer T, Berzinec P, Dziadziuszko R, Olszewski W, Popper H, Bajcic P, Dusek L, Zbozinkova Z, Pirker R. Epidermal growth factor receptor mutation-positive non-small-cell lung cancer in the real-world setting in Central Europe: the INSIGHT study. J Thorac Oncol. 2015;10(9):1370–1374. doi: 10.1097/JTO.0000000000000621. PubMed DOI

Wahbah M, Boroumand N, Castro C, El-Zeky F, Eltorky M. Changing trends in the distribution of the histologic types of lung cancer: a review of 4,439 cases. Ann Diagn Pathol. 2007;11(2):89–96. doi: 10.1016/j.anndiagpath.2006.04.006. PubMed DOI

van Dorn A. Bulgaria lags behind Europe in pollution and smoking targets. Lancet Respir Med. 2014;2(3):182–183. doi: 10.1016/S2213-2600(14)70056-6. PubMed DOI

Lim C, Tsao MS, Le LW, Shepherd FA, Feld R, Burkes RL, Liu G, Kamel-Reid S, Hwang D, Tanguay J, et al. Biomarker testing and time to treatment decision in patients with advanced nonsmall-cell lung cancer. Ann Oncol. 2015;26(7):1415–1421. doi: 10.1093/annonc/mdv208. PubMed DOI

Li AR, Chitale D, Riely GJ, Pao W, Miller VA, Zakowski MF, Rusch V, Kris MG, Ladanyi M. EGFR mutations in lung adenocarcinomas: clinical testing experience and relationship to EGFR gene copy number and immunohistochemical expression. J Mol Diagn. 2008;10(3):242–248. doi: 10.2353/jmoldx.2008.070178. PubMed DOI PMC

Shikhrakab H, Elamin YY, O'Brien C, Gately K, Finn S, O'Byrne K, Osman N. Epidermal growth factor receptor (EGFR) mutation testing, from bench to practice: a single institute experience. Ir Med J. 2014;107(7):201–204. PubMed

Lohinai Z, Klikovits T, Moldvay J, Ostoros G, Raso E, Timar J, Fabian K, Kovalszky I, Kenessey I, Aigner C, et al. KRAS-mutation incidence and prognostic value are metastatic site-specific in lung adenocarcinoma: poor prognosis in patients with KRAS mutation and bone metastasis. Sci Rep. 2017;7:39721. doi: 10.1038/srep39721. PubMed DOI PMC

Pekar-Zlotin M, Hirsch FR, Soussan-Gutman L, Ilouze M, Dvir A, Boyle T, Wynes M, Miller VA, Lipson D, Palmer GA, et al. Fluorescence in situ hybridization, immunohistochemistry, and next-generation sequencing for detection of EML4-ALK rearrangement in lung cancer. Oncologist. 2015;20(3):316–322. doi: 10.1634/theoncologist.2014-0389. PubMed DOI PMC

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(4):539–548. doi: 10.1111/his.12414. PubMed DOI

Savic S, Bode B, Diebold J, Tosoni I, Barascud A, Baschiera B, Grilli B, Herzog M, Obermann E, Bubendorf L. Detection of ALK-positive non-small-cell lung cancers on cytological specimens: high accuracy of immunocytochemistry with the 5A4 clone. J Thorac Oncol. 2013;8(8):1004–1011. doi: 10.1097/JTO.0b013e3182936ca9. PubMed DOI

Savic S, Diebold J, Zimmermann AK, Jochum W, Baschiera B, Grieshaber S, Tornillo L, Bisig B, Kerr K, Bubendorf L. Screening for ALK in non-small cell lung carcinomas: 5A4 and D5F3 antibodies perform equally well, but combined use with FISH is recommended. Lung Cancer. 2015;89(2):104–109. doi: 10.1016/j.lungcan.2015.05.012. PubMed DOI

von Laffert M, Warth A, Penzel R, Schirmacher P, Kerr KM, Elmberger G, Schildhaus HU, Buttner R, Lopez-Rios F, Reu S, et al. Multicenter immunohistochemical ALK-testing of non-small-cell lung cancer shows high concordance after harmonization of techniques and interpretation criteria. J Thorac Oncol. 2014;9(11):1685–1692. doi: 10.1097/JTO.0000000000000332. PubMed DOI

Park HS, Lee JK, Kim DW, Kulig K, Kim TM, Lee SH, Jeon YK, Chung DH, Heo DS. Immunohistochemical screening for anaplastic lymphoma kinase (ALK) rearrangement in advanced non-small cell lung cancer patients. Lung Cancer. 2012;77(2):288–292. doi: 10.1016/j.lungcan.2012.03.004. PubMed DOI

Houang M, Toon CW, Clarkson A, Sioson L, Watson N, Farzin M, Selinger CI, Chou A, Morey AL, Cooper WA, et al. Reflex ALK immunohistochemistry is feasible and highly specific for ALK gene rearrangements in lung cancer. Pathology. 2014;46(5):383–388. doi: 10.1097/PAT.0000000000000114. PubMed DOI

Wang W, Tang Y, Li J, Jiang L, Jiang Y, Su X. Detection of ALK rearrangements in malignant pleural effusion cell blocks from patients with advanced non-small cell lung cancer: a comparison of Ventana immunohistochemistry and fluorescence in situ hybridization. Cancer Cytopathol. 2015;123(2):117–122. doi: 10.1002/cncy.21510. PubMed DOI

von Laffert M, Stenzinger A, Hummel M, Weichert W, Lenze D, Warth A, Penzel R, Herbst H, Kellner U, Jurmeister P, et al. ALK-FISH borderline cases in non-small cell lung cancer: implications for diagnostics and clinical decision making. Lung Cancer. 2015;90(3):465–471. doi: 10.1016/j.lungcan.2015.09.022. PubMed DOI

VENTANA ALK (D5F3) CDx Assay - P140025. https://www.accessdata.fda.gov/cdrh_docs/pdf14/p140025b.pdf. Accessed 25 Jan 2018.

Dietel M, Bubendorf L, Dingemans AM, Dooms C, Elmberger G, Garcia RC, Kerr KM, Lim E, Lopez-Rios F, Thunnissen E, et al. Diagnostic procedures for non-small-cell lung cancer (NSCLC): recommendations of the European expert group. Thorax. 2016;71(2):177–184. doi: 10.1136/thoraxjnl-2014-206677. PubMed DOI PMC

Atherly AJ, Camidge DR. The cost-effectiveness of screening lung cancer patients for targeted drug sensitivity markers. Br J Cancer. 2012;106(6):1100–1106. doi: 10.1038/bjc.2012.60. PubMed DOI PMC

Dietel M, Johrens K, Laffert MV, Hummel M, Blaker H, Pfitzner BM, Lehmann A, Denkert C, Darb-Esfahani S, Lenze D, et al. A 2015 update on predictive molecular pathology and its role in targeted cancer therapy: a review focussing on clinical relevance. Cancer Gene Ther. 2015;22(9):417–430. doi: 10.1038/cgt.2015.39. PubMed DOI

von Laffert M, Penzel R, Schirmacher P, Warth A, Lenze D, Hummel M, Dietel M. Multicenter ALK testing in non-small-cell lung cancer: results of a round robin test. J Thorac Oncol. 2014;9(10):1464–1469. doi: 10.1097/JTO.0000000000000307. PubMed DOI

Patton S, Normanno N, Blackhall F, Murray S, Kerr KM, Dietel M, Filipits M, Benlloch S, Popat S, Stahel R, et al. 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(2):413–420. doi: 10.1038/bjc.2014.353. PubMed DOI PMC

van Krieken JH, Siebers AG, Normanno N. European consensus conference for external quality assessment in molecular pathology. Ann Oncol. 2013;24(8):1958–1963. doi: 10.1093/annonc/mdt153. PubMed DOI

Developments in predictive biomarker testing and targeted therapy in advanced stage non-small cell lung cancer and their application across European countries

Lung cancer biomarker testing: perspective from Europe

The leading role of pathology in assessing the somatic molecular alterations of cancer: Position Paper of the European Society of Pathology

Non-Small Cell Lung Cancer in Countries of Central and Southeastern Europe: Diagnostic Procedures and Treatment Reimbursement Surveyed by the Central European Cooperative Oncology Group