Genetic alterations in epidermal growth factor receptor‑tyrosine kinase inhibitor‑naïve non‑small cell lung carcinoma

Yamaura,Takumi; Muto,Satoshi; Mine,Hayato; Takagi,Hironori; Watanabe,Masayuki; Ozaki,Yuki; Inoue,Takuya; Fukuhara,Mitsuro; Okabe,Naoyuki; Matsumura,Yuki; Hasegawa,Takeo; Osugi,Jun; Hoshino,Mika; Higuchi,Mitsunori; Shio,Yutaka; Suzuki,Hiroyuki

doi:10.3892/ol.2020.11524

Genetic alterations in epidermal growth factor receptor‑tyrosine kinase inhibitor‑naïve non‑small cell lung carcinoma

Authors:
- Takumi Yamaura
- Satoshi Muto
- Hayato Mine
- Hironori Takagi
- Masayuki Watanabe
- Yuki Ozaki
- Takuya Inoue
- Mitsuro Fukuhara
- Naoyuki Okabe
- Yuki Matsumura
- Takeo Hasegawa
- Jun Osugi
- Mika Hoshino
- Mitsunori Higuchi
- Yutaka Shio
- Hiroyuki Suzuki
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Affiliations: Department of Chest Surgery, Fukushima Medical University School of Medicine, Fukushima City, Fukushima 960‑1295, Japan
Published online on: April 8, 2020 https://doi.org/10.3892/ol.2020.11524
Pages: 4169-4176

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Abstract

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are an approved first-line therapy against unresectable or advanced non‑small cell lung cancer (NSCLC) harboring EGFR gene activating mutations. However, the majority of tumors develop acquired resistance against EGFR‑TKIs and some tumors exhibit natural resistance. A number of resistance mechanisms against the latest third‑generation EGFR‑TKIs have been reported, including tertiary EGFR C797S mutation and several gene alterations activating EGFR or other signaling pathways. The current study aimed to identify the frequency of natural EGFR‑TKI resistance in pretreatment NSCLC and to predict the therapeutic effect of EGFR‑TKIs. A total of 246 EGFR‑TKI‑naïve NSCLC patients harboring known EGFR gene mutations were identified. The presence of EGFR C797S and T790M mutations were determined using the peptide nucleic acid‑locked nucleic acid PCR clamp method. ERBB2, MET, EGFR, ALK, BRAF, FGFR1, MYC, RET, CCND1, CCND2, CDK4, CDK6, MDM2 and MDM4 gene amplification, which can lead to resistance against any generation EGFR‑TKIs, was determined using the multiplex ligation‑dependent probe amplification assay. No concurrent C797S mutation with known EGFR mutations were identified. T790M mutation was identified in 12 patients (4.9%). ERBB2 or MET gene amplification was found in some patients (0.0‑0.4%). MDM2 gene amplification was associated with tumor recurrence and shorter progression‑free survival (PFS) for first‑ or second‑generation EGFR‑TKIs. De novo EGFR C797S mutation was not identified. Other resistance mechanisms against EGFR‑TKIs were indicated in some patients with EGFR‑TKI‑naïve NSCLC. MDM2 gene amplification, which can lead to altered cell cycle, was associated with tumor recurrence and shorter PFS in EGFR‑TKI therapy.

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1	Yang JC, Ahn MJ, Kim DW, Ramalingam SS, Sequist LV, Su WC, Kim SW, Kim JH, Planchard D, Felip E, et al: Osimertinib in pretreated T790M-Positive advanced non-small-cell lung cancer: AURA study phase II extension component. J Clin Oncol. 35:1288–1296. 2017. View Article : Google Scholar : PubMed/NCBI
2	Lin CC, Shih JY, Yu CJ, Ho CC, Liao WY, Lee JH, Tsai TH, Su KY, Hsieh MS, Chang YL, et al: Outcomes in patients with non-small-cell lung cancer and acquired Thr790Met mutation treated with osimertinib: A genomic study. Lancet Respir Med. 6:107–116. 2018. View Article : Google Scholar : PubMed/NCBI
3	Ramalingam SS, Yang JC, Lee CK, Kurata T, Kim DW, John T, Nogami N, Ohe Y, Mann H, Rukazenkov Y, et al: Osimertinib as first-line treatment of EGFR mutation-positive advanced non-small-cell lung cancer. J Clin Oncol. 36:841–849. 2018. View Article : Google Scholar : PubMed/NCBI
4	Soria JC, Ohe Y, Vansteenkiste J, Reungwetwattana T, Chewaskulyong B, Lee KH, Dechaphunkul A, Imamura F, Nogami N, Kurata T, et al: Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med. 378:113–125. 2018. View Article : Google Scholar : PubMed/NCBI
5	Kobayashi S, Boggon TJ, Dayaram T, Jänne PA, Kocher O, Meyerson M, Johnson BE, Eck MJ, Tenen DG and Halmos B: EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med. 352:786–792. 2005. View Article : Google Scholar : PubMed/NCBI
6	Thress KS, Paweletz CP, Felip E, Cho BC, Stetson D, Dougherty B, Lai Z, Markovets A, Vivancos A, Kuang Y, et al: Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M. Nat Med. 21:560–562. 2015. View Article : Google Scholar : PubMed/NCBI
7	Su KY, Chen HY, Li KC, Kuo ML, Yang JC, Chan WK, Ho BC, Chang GC, Shih JY, Yu SL and Yang PC: Pretreatment epidermal growth factor receptor (EGFR) T790M mutation predicts shorter EGFR tyrosine kinase inhibitor response duration in patients with non-small-cell lung cancer. J Clin Oncol. 30:433–440. 2012. View Article : Google Scholar : PubMed/NCBI
8	Lee JS, Hur JY, Kim HJ, Lee KY and Kim WS: A case of concurrent de novo C797S and L858R EGFR mutation detected in stage IA non-small cell lung cancer patient. J Thorac Oncol. 12:e179–e181. 2017. View Article : Google Scholar : PubMed/NCBI
9	Zheng D, Hu M, Bai Y, Zhu X, Lu X, Wu C, Wang J, Liu L, Wang Z, Ni J, et al: EGFR G796D mutation mediates resistance to osimertinib. Oncotarget. 8:49671–49679. 2017.PubMed/NCBI
10	Ercan D, Choi HG, Yun CH, Capelletti M, Xie T, Eck MJ, Gray NS and Jänne PA: EGFR mutations and resistance to irreversible pyrimidine-based EGFR inhibitors. Clin Cancer Res. 21:3913–3923. 2015. View Article : Google Scholar : PubMed/NCBI
11	Le X, Puri S, Negrao MV, Nilsson MB, Robichaux J, Boyle T, Hicks JK, Lovinger KL, Roarty E, Rinsurongkawong W, et al: Landscape of EGFR-Dependent and -independent resistance mechanisms to osimertinib and continuation therapy beyond progression in EGFR-Mutant NSCLC. Clin Cancer Res. 24:6195–6203. 2018. View Article : Google Scholar : PubMed/NCBI
12	Takezawa K, Pirazzoli V, Arcila ME, Nebhan CA, Song X, de Stanchina E, Ohashi K, Janjigian YY, Spitzler PJ, Melnick MA, et al: HER2 amplification: A potential mechanism of acquired resistance to EGFR inhibition in EGFR-mutant lung cancers that lack the second-site EGFRT790M mutation. Cancer Discov. 2:922–933. 2012. View Article : Google Scholar : PubMed/NCBI
13	Ou SI, Agarwal N and Ali SM: High MET amplification level as a resistance mechanism to osimertinib (AZD9291) in a patient that symptomatically responded to crizotinib treatment post-osimertinib progression. Lung Cancer. 98:59–61. 2016. View Article : Google Scholar : PubMed/NCBI
14	Blakely CM, Watkins TBK, Wu W, Gini B, Chabon JJ, McCoach CE, McGranahan N, Wilson GA, Birkbak NJ, Olivas VR, et al: Evolution and clinical impact of co-occurring genetic alterations in advanced-stage EGFR-mutant lung cancers. Nat Genet. 49:1693–1704. 2017. View Article : Google Scholar : PubMed/NCBI
15	Yu HA, Suzawa K, Jordan E, Zehir A, Ni A, Kim R, Kris MG, Hellmann MD, Li BT, Somwar R, et al: Concurrent alterations in EGFR-Mutant lung cancers associated with resistance to EGFR kinase inhibitors and characterization of MTOR as a mediator of resistance. Clin Cancer Res. 24:3108–3118. 2018. View Article : Google Scholar : PubMed/NCBI
16	Sequist LV, Waltman BA, Dias-Santagata D, Digumarthy S, Turke AB, Fidias P, Bergethon K, Shaw AT, Gettinger S, Cosper AK, et al: Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med. 3:75ra262011. View Article : Google Scholar : PubMed/NCBI
17	Okabe N, Takagi H, Mine H, Fukai S, Minemura H and Suzuki H: Osimertinib for epidermal growth factor receptor mutation-positive lung adenocarcinoma that transformed to T790M-Positive squamous cell carcinoma. J Thorac Oncol. 12:e167–e169. 2017. View Article : Google Scholar : PubMed/NCBI
18	Watanabe K, Fukuhara T, Tsukita Y, Morita M, Suzuki A, Tanaka N, Terasaki H, Nukiwa T and Maemondo M: EGFR mutation analysis of circulating tumor DNA using an improved PNA-LNA PCR clamp method. Can Respir J. 2016:52973292016. View Article : Google Scholar : PubMed/NCBI
19	Schouten JP, McElgunn CJ, Waaijer R, Zwijnenburg D, Diepvens F and Pals G: Relative quantification of 40 nucleic acid sequences by multiplex ligation-dependent probe amplification. Nucleic Acids Res. 30:e572002. View Article : Google Scholar : PubMed/NCBI
20	Oxnard GR, Hu Y, Mileham KF, Husain H, Costa DB, Tracy P, Feeney N, Sholl LM, Dahlberg SE, Redig AJ, et al: Assessment of resistance mechanisms and clinical implications in patients with EGFR T790M-Positive lung cancer and acquired resistance to osimertinib. JAMA Oncol. 4:1527–1534. 2018. View Article : Google Scholar : PubMed/NCBI
21	Niederst MJ, Hu H, Mulvey HE, Lockerman EL, Garcia AR, Piotrowska Z, Sequist LV and Engelman JA: The allelic context of the C797S mutation acquired upon treatment with third-generation EGFR inhibitors impacts sensitivity to subsequent treatment strategies. Clin Cancer Res. 21:3924–3933. 2015. View Article : Google Scholar : PubMed/NCBI
22	Yatabe Y, Takahashi T and Mitsudomi T: Epidermal growth factor receptor gene amplification is acquired in association with tumor progression of EGFR-mutated lung cancer. Cancer Res. 68:2106–2111. 2008. View Article : Google Scholar : PubMed/NCBI
23	Zhao J, Zou M, Lv J, Han Y and Wang G and Wang G: Effective treatment of pulmonary adenocarcinoma harboring triple EGFR mutations of L858R, T790M, and cis-C797S by osimertinib, bevacizumab, and brigatinib combination therapy: A case report. Onco Targets Ther. 11:5545–5550. 2018. View Article : Google Scholar : PubMed/NCBI
24	Jia Y, Yun CH, Park E, Ercan D, Manuia M, Juarez J, Xu C, Rhee K, Chen T, Zhang H, et al: Overcoming EGFR(T790M) and EGFR(C797S) resistance with mutant-selective allosteric inhibitors. Nature. 534:129–132. 2016. View Article : Google Scholar : PubMed/NCBI
25	Sholl LM, Yeap BY, Iafrate AJ, Holmes-Tisch AJ, Chou YP, Wu MT, Goan YG, Su L, Benedettini E, Yu J, et al: Lung adenocarcinoma with EGFR amplification has distinct clinicopathologic and molecular features in never-smokers. Cancer Res. 69:8341–8348. 2009. View Article : Google Scholar : PubMed/NCBI
26	Dworakowska D, Jassem E, Jassem J, Peters B, Dziadziuszko R, Zylicz M, Jakóbkiewicz-Banecka J, Kobierska-Gulida G, Szymanowska A, Skokowski J, et al: MDM2 gene amplification: A new independent factor of adverse prognosis in non-small cell lung cancer (NSCLC). Lung Cancer. 43:285–295. 2004. View Article : Google Scholar : PubMed/NCBI
27	Turke AB, Zejnullahu K, Wu YL, Song Y, Dias-Santagata D, Lifshits E, Toschi L, Rogers A, Mok T, Sequist L, et al: Preexistence and clonal selection of MET amplification in EGFR mutant NSCLC. Cancer Cell. 17:77–88. 2010. View Article : Google Scholar : PubMed/NCBI
28	Planchard D, Loriot Y, André F, Gobert A, Auger N, Lacroix L and Soria JC: EGFR-independent mechanisms of acquired resistance to AZD9291 in EGFR T790M-positive NSCLC patients. Ann Oncol. 26:2073–2078. 2015. View Article : Google Scholar : PubMed/NCBI
29	Dei Tos AP, Doglioni C, Piccinin S, Sciot R, Furlanetto A, Boiocchi M, Dal Cin P, Maestro R, Fletcher CD and Tallini G: Coordinated expression and amplification of the MDM2, CDK4, and HMGI-C genes in atypical lipomatous tumours. J Pathol. 190:531–536. 2000. View Article : Google Scholar : PubMed/NCBI
30	Deben C, Deschoolmeester V, Lardon F, Rolfo C and Pauwels P: TP53 and MDM2 genetic alterations in non-small cell lung cancer: Evaluating their prognostic and predictive value. Crit Rev Oncol Hematol. 99:63–73. 2016. View Article : Google Scholar : PubMed/NCBI