Predictors of EGFR mutation and factors associated with clinical tumor stage at diagnosis: Experience of the INSIGHT study in Poland

Ramlau,Rodryg; Krawczyk,Paweł; Dziadziuszko,Rafał; Chmielewska,Izabela; Milanowski,Janusz; Olszewski,Włodzimierz; Stencel,Katarzyna; Ramlau‑Piątek,Katarzyna; Segiet,Agnieszka; Skroński,Michał; Grudny,Jacek; Chorostowska‑Wynimko,Joanna

doi:10.3892/ol.2017.6907

Predictors of EGFR mutation and factors associated with clinical tumor stage at diagnosis: Experience of the INSIGHT study in Poland

Authors:
- Rodryg Ramlau
- Paweł Krawczyk
- Rafał Dziadziuszko
- Izabela Chmielewska
- Janusz Milanowski
- Włodzimierz Olszewski
- Katarzyna Stencel
- Katarzyna Ramlau‑Piątek
- Agnieszka Segiet
- Michał Skroński
- Jacek Grudny
- Joanna Chorostowska‑Wynimko
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Affiliations: Department of Oncology, Poznan University of Medical Sciences, 60‑569 Poznan, Poland, Department of Pneumology, Oncology and Allergology, Medical University of Lublin, 20‑954 Lublin, Poland, Department of Oncology and Radiotherapy, Medical University of Gdansk, 80‑211 Gdansk, Poland, The Maria Sklodowska‑Curie Institute of Oncology, 02‑781 Warsaw, Poland, Department of Chemotherapy, Poznan University of Medical Sciences, 60‑569 Poznan, Poland, Departament of Radiology, Poznan University of Medical Sciences, 61‑848 Poznan, Poland, First Faculty of Medicine, Medical University of Warsaw, 02‑091 Warsaw, Poland, Department of Genetics and Clinical Immunology, National Institute of Tuberculosis and Lung Diseases, 01‑138 Warsaw, Poland, III Department of Lung Diseases, National Institute of Tuberculosis and Lung Diseases, 01‑138 Warsaw, Poland
Published online on: September 7, 2017 https://doi.org/10.3892/ol.2017.6907
Pages: 5611-5618

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Abstract

Targeted therapy of non‑small cell lung cancer (NSCLC) patients with mutations in the epidermal growth factor receptor (EGFR) gene has been associated with improved prognosis. However, there is a shortage on data from real‑world clinical practice in management of EGFR‑positive NSCLC patients in Poland. The present study retrospectively analyzed data from the INSIGHT study to evaluate the incidence and clinical management of EGFR‑positive NSCLC in Poland. The authors additionally aimed to identify predictors of the EGFR mutation and factors associated with clinical stage of the tumor at diagnosis. Incidence of EGFR mutations was 11.8% and the most common mutations were a deletion on exon 19 and an L858R substitution on exon 21. Mutations were strongly associated with female gender [male vs. female odds ratio (OR): 0.51; P=0.004] and never having smoked (current/past smoker vs. never smoked OR: 0.16; P<0.001), and advanced clinical stage (stage IV vs. stage I/II OR: 2.89; P=0.029). Patients with EGFR mutation were also observed to have a greater propensity to develop bone metastasis (OR: 11.62; P=0.008). Multivariate regression analysis demonstrated that patients with past or current smoking history or a poor performance on the Eastern Cooperative Oncology Group (ECOG) scale were less likely to have the EGFR mutation. Furthermore, EGFR‑positive patients with greater ECOG scores and a tumor other than adenocarcinoma or squamous cell carcinoma were more likely to present advanced tumors. Early screening for EGFR mutation and the use of EGFR‑targeting therapies as first‑line agents may lead to better prognosis and successful clinical management of EGFR‑positive NSCLC patients.

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1	Coate LE, John T, Tsao MS and Shepherd FA: Molecular predictive and prognostic markers in non-small-cell lung cancer. Lancet Oncol. 10:1001–1010. 2009. View Article : Google Scholar : PubMed/NCBI
2	Kerr KM, Bubendorf L, Edelman MJ, Marchetti A, Mok T, Novello S, O'Byrne K, Stahel R, Peters S, Felip E, et al: Second ESMO consensus conference on lung cancer: Pathology and molecular biomarkers for non-small-cell lung cancer. Ann Oncol. 25:1681–1690. 2014. View Article : Google Scholar : PubMed/NCBI
3	O'Byrne KJ, Gatzemeier U, Bondarenko I, Barrios C, Eschbach C, Martens UM, Hotko Y, Kortsik C, Paz-Ares L, Pereira JR, et al: Molecular biomarkers in non-small-cell lung cancer: A retrospective analysis of data from the phase 3 FLEX study. Lancet Oncol. 12:795–805. 2011. View Article : Google Scholar : PubMed/NCBI
4	Chatziandreou I, Tsioli P, Sakellariou S, Mourkioti I, Giannopoulou I, Levidou G, Korkolopoulou P, Patsouris E and Saetta AA: Comprehensive molecular analysis of NSCLC; Clinicopathological Associations. PLoS One. 10:e01338592015. View Article : Google Scholar : PubMed/NCBI
5	Dearden S, Stevens J, Wu YL and Blowers D: Mutation incidence and coincidence in non small-cell lung cancer: Meta-analyses by ethnicity and histology (mutMap). Ann Oncol. 24:2371–2376. 2013. View Article : Google Scholar : PubMed/NCBI
6	D'Arcangelo M and Cappuzzo F: K-Ras mutations in non-small-cell lung cancer: Prognostic and predictive value. ISRN Mol Biol. 2012:8373062012.PubMed/NCBI
7	Aisner DL and Marshall CB: Molecular pathology of non-small cell lung cancer: A practical guide. Am J Clin Pathol. 138:332–346. 2012. View Article : Google Scholar : PubMed/NCBI
8	Boch C, Kollmeier J, Roth A, Stephan-Falkenau S, Misch D, Grüning W, Bauer TT and Mairinger T: The frequency of EGFR and KRAS mutations in non-small cell lung cancer (NSCLC): Routine screening data for central Europe from a cohort study. BMJ Open. 3:pii:e0025602013. View Article : Google Scholar
9	Eberhard DA, Giaccone G and Johnson BE: Non-Small-Cell lung Cancer Working Group: Biomarkers of response to epidermal growth factor receptor inhibitors in Non-Small-Cell Lung Cancer Working Group: Standardization for use in the clinical trial setting. J Clin Oncol. 26:983–994. 2008. View Article : Google Scholar : PubMed/NCBI
10	Gahr S, Stoehr R, Geissinger E, Ficker JH, Brueckl WM, Gschwendtner A, Gattenloehner S, Fuchs FS, Schulz C, Rieker RJ, et al: EGFR mutational status in a large series of Caucasian European NSCLC patients: Data from daily practice. Br J Cancer. 109:1821–1828. 2013. View Article : Google Scholar : PubMed/NCBI
11	Kosaka T, Yatabe Y, Endoh H, Kuwano H, Takahashi T and Mitsudomi T: Mutations of the epidermal growth factor receptor gene in lung cancer: Biological and clinical implications. Cancer Res. 64:8919–8923. 2004. View Article : Google Scholar : PubMed/NCBI
12	Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, Harris PL, Haserlat SM, Supko JG, Haluska FG, et al: Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Eng J Med. 350:2129–2139. 2004. View Article : Google Scholar
13	Paez JG, Jänne PA, Lee JC, Tracy S, Greulich H, Gabriel S, Herman P, Kaye FJ, Lindeman N, Boggon TJ, et al: EGFR mutations in lung cancer: Correlation with clinical response to gefitinib therapy. Science. 304:1497–1500. 2004. View Article : Google Scholar : PubMed/NCBI
14	Pao W, Miller V, Zakowski M, Doherty J, Politi K, Sarkaria I, Singh B, Heelan R, Rusch V, Fulton L, et al: EGF receptor gene mutations are common in lung cancers from ‘never smokers’ and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci USA. 101:13306–13311. 2004. View Article : Google Scholar : PubMed/NCBI
15	Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, Palmero R, Garcia-Gomez R, Pallares C, Sanchez JM, et al: Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): A multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 13:239–246. 2012. View Article : Google Scholar : PubMed/NCBI
16	Shigematsu H, Lin L, Takahashi T, Nomura M, Suzuki M, Wistuba II, Fong KM, Lee H, Toyooka S, Shimizu N, et al: Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. J Natl Cancer Inst. 97:339–346. 2005. View Article : Google Scholar : PubMed/NCBI
17	Souglakos J: Customizing chemotherapy in non-small cell lung cancer: The promise is still unmet. Trans Lung Cancer Res. 4:653–655. 2015.
18	Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H, Gemma A, Harada M, Yoshizawa H, Kinoshita I, et al: Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Eng J Med. 362:2380–2388. 2010. View Article : Google Scholar
19	Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I, Tsurutani J, Seto T, Satouchi M, Tada H, Hirashima T, et al: Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): An open label, randomised phase 3 trial. Lancet Oncol. 11:121–128. 2010. View Article : Google Scholar : PubMed/NCBI
20	Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, Sunpaweravong P, Han B, Margono B, Ichinose Y, et al: Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Eng J Med. 361:947–957. 2009. View Article : Google Scholar
21	Sequist LV, Yang JC, Yamamoto N, O'Byrne K, Hirsh V, Mok T, Geater SL, Orlov S, Tsai CM, Boyer M, et al: Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. 31:3327–3334. 2013. View Article : Google Scholar : PubMed/NCBI
22	Wu YL, Zhou C, Hu CP, Feng J, Lu S, Huang Y, Li W, Hou M, Shi JH, Lee KY, et al: Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): An open-label, randomised phase 3 trial. Lancet Oncol. 15:213–222. 2014. View Article : Google Scholar : PubMed/NCBI
23	Yang JC, Wu YL, Schuler M, Sebastian M, Popat S, Yamamoto N, Zhou C, Hu CP, O'Byrne K, Feng J, et al: Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): Analysis of overall survival data from two randomised, phase 3 trials. Lancet Oncol. 16:141–151. 2015. View Article : Google Scholar : PubMed/NCBI
24	Zhou C, Wu YL, Chen G, Feng J, Liu XQ, Wang C, Zhang S, Wang J, Zhou S, Ren S, et al: Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): A multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 12:735–742. 2011. View Article : Google Scholar : PubMed/NCBI
25	Ettinger DS, Akerley W, Bepler G, Blum MG, Chang A, Cheney RT, Chirieac LR, D'Amico TA, Demmy TL, Ganti AK, et al: Non-small cell lung cancer. J Natl Compr Canc Netw. 8:740–801. 2010. View Article : Google Scholar : PubMed/NCBI
26	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. Arch Pathol Lab Med. 137:828–860. 2013. View Article : Google Scholar : PubMed/NCBI
27	Marchetti A, Normanno N AIOM-SIAPEC-IAP, Pinto C, Taddei GL, Adamo V, Ardizzoni A, Botti G, Bardelli A, Comin C, et al: Recommendations for mutational analysis of EGFR in lung carcinoma. Pathologica. 102:119–126. 2010.(In English, Italian). PubMed/NCBI
28	Pirker R, Herth FJ, Kerr KM, Filipits M, Taron M, Gandara D, Hirsch FR, Grunenwald D, Popper H, Smit E, et al: Consensus for EGFR mutation testing in non-small cell lung cancer: Results from a European workshop. J Thorac Oncol. 5:1706–1713. 2010. View Article : Google Scholar : PubMed/NCBI
29	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. 6:244–285. 2011. View Article : Google Scholar : PubMed/NCBI
30	Westwood M, Joore M, Whiting P, van Asselt T, Ramaekers B, Armstrong N, Misso K, Severens J and Kleijnen J: Epidermal growth factor receptor tyrosine kinase (EGFR-TK) mutation testing in adults with locally advanced or metastatic non-small cell lung cancer: A systematic review and cost-effectiveness analysis. Health Technol Assess. 18:1–166. 2014. View Article : Google Scholar
31	Keedy VL, Temin S, Somerfield MR, Beasley MB, Johnson DH, McShane LM, Milton DT, Strawn JR, Wakelee HA and Giaccone G: American Society of Clinical Oncology provisional clinical opinion: Epidermal growth factor receptor (EGFR) Mutation testing for patients with advanced non-small-cell lung cancer considering first-line EGFR tyrosine kinase inhibitor therapy. J Clin Oncol. 29:2121–2127. 2011. View Article : Google Scholar : PubMed/NCBI
32	Krawczyk P, Chorostowska-Wynimko J, Dziadziuszko R, Jassem J, Krzakowski M, Langfort R, Puacz E, Wasąg B and Wojas-Krawczyk K: Methodological recommendations for the diagnostics of EGFR gene mutations and ALK gene rearrangement in the selection of non-small-cell lung cancer patients to molecularly targeted therapies. Pneumonol Alergol Pol. 82:437–444. 2014. View Article : Google Scholar : PubMed/NCBI
33	Krawczyk P, Ramlau R, Chorostowska-Wynimko J, Powrózek T, Lewandowska MA, Limon J, Wasąg B, Pankowski J, Kozielski J, Kalinka-Warzocha E, et al: The efficacy of EGFR gene mutation testing in various samples from non-small cell lung cancer patients: A multicenter retrospective study. J Cancer Res Clin Oncol. 141:61–68. 2015. View Article : Google Scholar : PubMed/NCBI
34	Ramlau R, Cufer T, Berzinec P, Dziadziuszko R, Olszewski W, Popper H, Bajcic P, Dušek L, Zbozinkova Z and Pirker R: INSIGHT study team: 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. 10:1370–1374. 2015. View Article : Google Scholar : PubMed/NCBI
35	Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET and Carbone PP: Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 5:649–655. 1982. View Article : Google Scholar : PubMed/NCBI
36	R Development Core Team: R: A language and environment for statistical computingR Foundation for Statistical Computing. Vienna: 2014
37	Santini D, Barni S, Intagliata S, Falcone A, Ferraù F, Galetta D, Moscetti L, La Verde N, Ibrahim T, Petrelli F, et al: Natural history of non-small-cell lung cancer with bone metastases. Sci Rep. 5:186702015. View Article : Google Scholar : PubMed/NCBI
38	Petrelli F, Borgonovo K, Cabiddu M and Barni S: Efficacy of EGFR tyrosine kinase inhibitors in patients with EGFR-mutated non-small-cell lung cancer: A meta-analysis of 13 randomized trials. Clin Lung Cancer. 13:107–114. 2012. View Article : Google Scholar : PubMed/NCBI
39	Barlesi F, Mazieres J, Merlio JP, Debieuvre D, Mosser J, Lena H, Ouafik L, Besse B, Rouquette I, Westeel V, et al: Routine molecular profiling of patients with advanced non-small-cell lung cancer: Results of a 1-year nationwide programme of the French Cooperative Thoracic Intergroup (IFCT). Lancet. 387:1415–1426. 2016. View Article : Google Scholar : PubMed/NCBI
40	Beau-Faller M, Prim N, Ruppert AM, Nanni-Metéllus I, Lacave R, Lacroix L, Escande F, Lizard S, Pretet JL, Rouquette I, et al: Rare EGFR exon 18 and exon 20 mutations in non-small-cell lung cancer on 10 117 patients: A multicentre observational study by the French ERMETIC-IFCT network. Ann Oncol. 25:126–131. 2014. View Article : Google Scholar : PubMed/NCBI
41	Powrózek T, Krawczyk P, Ramlau R, Sura S, Wojas-Krawczyk K, Kucharczyk T, Walczyna B, Szumiło J, Szyszka-Barth K, Milecki P, et al: EGFR gene mutations in patients with adenosquamous lung carcinoma. Asia Pac J Clin Oncol. 10:340–345. 2014. View Article : Google Scholar : PubMed/NCBI
42	Krawczyk P, Nicoś M, Ramlau R, Powrózek T, Wojas-Krawczyk K, Sura S, Jarosz B, Szumiło J, Warda E, Mazurkiewicz T, et al: The incidence of EGFR-activating mutations in bone metastases of lung adenocarcinoma. Pathol Oncol Res. 20:107–112. 2014. View Article : Google Scholar : PubMed/NCBI
43	Lee CK, Brown C, Gralla RJ, Hirsh V, Thongprasert S, Tsai CM, Tan EH, Ho JC, da Chu T, Zaatar A, et al: Impact of EGFR inhibitor in non-small cell lung cancer on progression-free and overall survival: A meta-analysis. J Natl Cancer Inst. 105:595–605. 2013. View Article : Google Scholar : PubMed/NCBI
44	Girard N, Sima CS, Jackman DM, Sequist LV, Chen H, Yang JC, Ji H, Waltman B, Rosell R, Taron M, et al: Nomogram to predict the presence of EGFR activating mutation in lung adenocarcinoma. Eur Respir J. 39:366–372. 2012. View Article : Google Scholar : PubMed/NCBI