Abstract
Purpose
This study aimed to determine the molecular features and clinical outcomes of young patients with non-small cell lung cancer (NSCLC) harboring ALK fusion genes.
Methods
We interrogated the genomic profile of 1652 patients with lung cancer who underwent targeted next-generation sequencing to screen for candidate oncogenic drivers using histological specimens acquired from January 2016 to December 2018.
Results
ALK fusions were identified in 101 NSCLC patients, and 52 of them were diagnosed before the age of 50 years (52/367, 14.2%). Of the 52 patients with early-onset disease, 22 (42.3%) were male and 43 (82.7%) never smoked; the median patient age was 44 years (range 28–50 years). The most frequently occurring ALK fusion partner was EML4, which was identified in 80.8% (42/52) of young patients. Compared to the older patients, patients with early-onset disease were more likely to harbor EML4-ALK variant 1 (38.5% vs. 14.3%; P = 0.007). We also identified rare ALK fusions, including CHRNA7-ALK, TACR1-ALK, HIP1-ALK, DYSF-ALK and ITGAV-ALK, in patients with early-onset disease, and patients with these fusions responded well to crizotinib treatment. A statistically significant difference was observed in progression-free survival (PFS) between the young patients and older patients who received crizotinib as the first-line therapy (17.5 months vs 9.0 months, P = 0.048). However, the median PFS of young patients harboring concurrent TP53 mutations was only 6.2 months.
Conclusion
Unique genetic characteristics were found in ALK-rearranged NSCLC patients with early disease onset, and these patients responded better to crizotinib and had longer PFS compared to patients with later disease onset. However, patients with concomitant TP53 mutations may not have a significant response to treatment.
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Abbreviations
- ALK:
-
Anaplastic lymphoma kinase
- EML4:
-
Echinoderm microtubule-associated protein-like 4
- NSCLC:
-
Non-small cell lung cancer
- PD:
-
Progressive disease
- PFS:
-
Progression-free survival
- TKI:
-
Tyrosine kinase inhibitor
References
Camidge DR, Otterson GA, Clark JW, Ou SHI, Weiss J, Ades S (2018) Crizotinib in patients (pts) with met-amplified non-small cell lung cancer (NSCLC): updated safety and efficacy findings from a phase 1 trial. J Clin Oncol 36(15):9062. https://doi.org/10.1200/Jco.2018.36.15_Suppl.9062
Canale M, Petracci E, Delmonte A, Chiadini E, Dazzi C, Papi M, Ulivi P (2017) Impact of TP53 mutations on outcome in EGFR-mutated patients treated with first-line tyrosine kinase inhibitors. Clin Cancer Res 23(9):2195–2202. https://doi.org/10.1158/1078-0432.CCR-16-0966
Chen RL, Zhao J, Zhang XC, Lou NN, Chen HJ, Yang X, Yang JJ (2018) Crizotinib in advanced non-small-cell lung cancer with concomitant ALK rearrangement and c-Met overexpression. BMC Cancer 18:89. https://doi.org/10.1186/S12885-018-5078-Y
Chen L, Hu X, Wu H, Liu J, Mu X, Wu H, Zhao Y (2019) Unique profiles of targetable genomic alterations and prognosis in young Chinese patients with lung adenocarcinoma. Pathol Res Pract 215(6):152407. https://doi.org/10.1016/j.prp.2019.03.035
Childress MA, Himmelberg SM, Chen H, Deng W, Davies MA, Lovly CM (2018) ALK fusion partners impact response to ALK inhibition: differential effects on sensitivity, cellular phenotypes, and biochemical properties. Mol Cancer Res 16(11):1724–1736. https://doi.org/10.1158/1541-7786.MCR-18-0171
Christopoulos P, Dietz S, Kirchner M, Volckmar AL, Endris V, Neumann O, Stenzinger A (2019) Detection of TP53 mutations in tissue or liquid rebiopsies at progression identifies ALK+ lung cancer patients with poor survival. Cancers (Basel) 11(1):124. https://doi.org/10.3390/cancers11010124
Cui JJ, Tran-Dube M, Shen H, Nambu M, Kung PP, Pairish M, Edwards MP (2011) Structure based drug design of crizotinib (PF-02341066), a potent and selective dual inhibitor of mesenchymal–epithelial transition factor (c-MET) kinase and anaplastic lymphoma kinase (ALK). J Med Chem 54(18):6342–6363. https://doi.org/10.1021/jm2007613
Du X, Shao Y, Gao H, Zhang X, Zhang H, Ban Y, Tai Y (2018a) CMTR1-ALK: an ALK fusion in a patient with no response to ALK inhibitor crizotinib. Cancer Biol Ther 19(11):962–966. https://doi.org/10.1080/15384047.2018.1480282
Du X, Shao Y, Qin HF, Tai YH, Gao HJ (2018b) ALK-rearrangement in non-small-cell lung cancer (NSCLC). Thorac Cancer 9(4):423–430. https://doi.org/10.1111/1759-7714.12613
Fu S, Wang HY, Wang F, Huang MY, Deng L, Zhang X, Shao JY (2015) Clinicopathologic characteristics and therapeutic responses of Chinese patients with non-small cell lung cancer who harbor an anaplastic lymphoma kinase rearrangement. Chin J Cancer 34(9):404–412. https://doi.org/10.1186/s40880-015-0032-8
Gitlitz BJ, Morosini D, Sable-Hunt AL, Addario BJ, Mach SL, Jennings MB, Oxnard GR (2016) The genomics of young lung cancer. J Clin Oncol 34(15):9083. https://doi.org/10.1200/Jco.2016.34.15_Suppl.9083
Goldstraw P, Chansky K, Crowley J, Rami-Porta R, Asamura H, Eberhardt WE, Nicholson AG, Groome P, Mitchell A, Bolejack V, International Association for the Study of Lung Cancer Staging and Prognostic Factors Committee, Advisory Boards, and Participating Institutions, International Association for the Study of Lung Cancer Staging and Prognostic Factors Committee Advisory Boards and Participating Institutions (2016) The IASLC Lung Cancer staging project: proposals for revision of the tnm stage groupings in the forthcoming (eighth) edition of the tnm classification for Lung Cancer. J Thor Oncol 11(1):39–51
Hasty P, Montagna C (2014) Chromosomal rearrangements in cancer: detection and potential causal mechanisms. Mol Cell Oncol 1(1):e29904. https://doi.org/10.4161/mco.29904
Jorge SE, Schulman S, Freed JA, VanderLaan PA, Rangachari D, Kobayashi SS, Costa DB (2015) Responses to the multitargeted MET/ALK/ROS1 inhibitor crizotinib and co-occurring mutations in lung adenocarcinomas with MET amplification or MET exon 14 skipping mutation. Lung Cancer 90(3):369–374. https://doi.org/10.1016/j.lungcan.2015.10.028
Kayaniyil S, Hurry M, Wilson J, Wheatley-Price P, Melosky B, Rothenstein J, Liu G (2016) Treatment patterns and survival in patients with ALK-positive non-small-cell lung cancer: a Canadian retrospective study. Curr Oncol 23(6):e589–e597. https://doi.org/10.3747/co.23.3273
Kron A, Alidousty C, Scheffler M, Merkelbach-Bruse S, Seidel D, Riedel R, Wolf J (2018) Impact of TP53 mutation status on systemic treatment outcome in ALK-rearranged non-small-cell lung cancer. Ann Oncol 29(10):2068–2075. https://doi.org/10.1093/annonc/mdy333
Kwak EL, Bang YJ, Camidge DR, Shaw AT, Solomon B, Maki RG, Iafrate AJ (2010) Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 363(18):1693–1703. https://doi.org/10.1056/NEJMoa1006448
Lei YY, Yang JJ, Zhang XC, Zhong WZ, Zhou Q, Tu HY, Wu YL (2016) Anaplastic lymphoma kinase variants and the percentage of ALK-positive tumor cells and the efficacy of crizotinib in advanced NSCLC. Clin Lung Cancer 17(3):223–231. https://doi.org/10.1016/j.cllc.2015.09.002
Mao Y, Wu S (2017) ALK and ROS1 concurrent with egfr mutation in patients with lung adenocarcinoma. OncoTargets Ther 10:3399–3404. https://doi.org/10.2147/OTT.S133349
Pan X, Lv T, Zhang F, Fan H, Liu H, Song Y (2018) Frequent genomic alterations and better prognosis among young patients with non-small-cell lung cancer aged 40 years or younger. Clin Transl Oncol 20(9):1168–1174. https://doi.org/10.1007/s12094-018-1838-z
Sacher AG, Dahlberg SE, Heng J, Mach S, Janne PA, Oxnard GR (2016) Association between younger age and targetable genomic alterations and prognosis in non-small-cell lung cancer. JAMA Oncol 2(3):313–320. https://doi.org/10.1001/jamaoncol.2015.4482
Sato S, Nagahashi M, Koike T, Ichikawa H, Shimada Y, Watanabe S, Tsuchida M (2018) Impact of concurrent genomic alterations detected by comprehensive genomic sequencing on clinical outcomes in east-asian patients with EGFR-mutated lung adenocarcinoma. Sci Rep 8:1005. https://doi.org/10.1038/S41598-017-18560-Y
Schmid S, Gautschi O, Rothschild S, Mark M, Froesch P, Klingbiel D, Fruh M (2017) Clinical outcome of ALK-positive non-small cell lung cancer (NSCLC) patients with de novo EGFR or KRAS co-mutations receiving tyrosine kinase inhibitors (TKIS). J Thorac Oncol 12(4):681–688. https://doi.org/10.1016/j.jtho.2016.12.003
Schwartz LH, Litiere S, de Vries E, Ford R, Gwyther S, Mandrekar S, Seymour L (2016) RECIST 1.1—update and clarification: from the RECIST committee. Eur J Cancer 62:132–137. https://doi.org/10.1016/j.ejca.2016.03.081
Soda M, Choi YL, Enomoto M, Takada S, Yamashita Y, Ishikawa S, Mano H (2007) Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 448(7153):561–566. https://doi.org/10.1038/nature05945
Song P, Zhang F, Li Y, Yang G, Li W, Ying J, Gao S (2019) Concomitant TP53 mutations with response to crizotinib treatment in patients with ALK-rearranged non-small-cell lung cancer. Cancer Med 8(4):1551–1557. https://doi.org/10.1002/cam4.2043
Su Y, Long X, Song Y, Chen P, Li S, Yang H, Liang N (2019) Distribution of ALK fusion variants and correlation with clinical outcomes in Chinese patients with non-small cell lung cancer treated with crizotinib. Target Oncol 14(2):159–168. https://doi.org/10.1007/s11523-019-00631-x
Subramanian J, Morgensztern D, Goodgame B, Baggstrom MQ, Gao F, Piccirillo J, Govindan R (2010) Distinctive characteristics of non-small cell lung cancer (NSCLC) in the young: a surveillance, epidemiology, and end results (SEER) analysis. J Thorac Oncol 5(1):23–28. https://doi.org/10.1097/JTO.0b013e3181c41e8d
Suidan AM, Roisman L, Belilovski Rozenblum A, Ilouze M, Dudnik E, Zer A, Peled N (2019) Lung cancer in young patients: Higher rate of driver mutations and brain involvement, but better survival. J Glob Oncol 5:1–8. https://doi.org/10.1200/JGO.18.00216
Tanaka K, Hida T, Oya Y, Yoshida T, Shimizu J, Mizuno T, Yatabe Y (2017) Unique prevalence of oncogenic genetic alterations in young patients with lung adenocarcinoma. Cancer 123(10):1731–1740. https://doi.org/10.1002/cncr.30539
Thomas A, Chen Y, Yu T, Jakopovic M, Giaccone G (2015) Trends and characteristics of young non-small cell lung cancer patients in the United States. Front Oncol 5:113. https://doi.org/10.3389/fonc.2015.00113
Tian HX, Zhang XC, Yang JJ, Guo WB, Chen ZH, Wang Z, Wu YL (2017) Clinical characteristics and sequence complexity of anaplastic lymphoma kinase gene fusions in Chinese lung cancer patients. Lung Cancer 114:90–95. https://doi.org/10.1016/j.lungcan.2017.11.001
Togashi Y, Soda M, Sakata S, Sugawara E, Hatano S, Asaka R, Takeuchi K (2012) KLC1-ALK: a novel fusion in lung cancer identified using a formalin-fixed paraffin-embedded tissue only. PLoS ONE 7(2):e31323. https://doi.org/10.1371/journal.pone.0031323
Wong DW, Leung EL, So KK, Tam IY, Sihoe AD, Cheng LC, University of Hong Kong Lung Cancer Study, G (2009) The EML4-ALK fusion gene is involved in various histologic types of lung cancers from nonsmokers with wild-type EGFR and KRAS. Cancer 115(8):1723–1733. https://doi.org/10.1002/cncr.24181
Wong DW, Leung EL, Wong SK, Tin VP, Sihoe AD, Cheng LC, Wong MP (2011) A novel KIF5B-ALK variant in nonsmall cell lung cancer. Cancer 117(12):2709–2718. https://doi.org/10.1002/cncr.25843
Woo CG, Seo S, Kim SW, Jang SJ, Park KS, Song JY, Choi J (2017) Differential protein stability and clinical responses of EML4-ALK fusion variants to various ALK inhibitors in advanced ALK-rearranged non-small cell lung cancer. Ann Oncol 28(4):791–797. https://doi.org/10.1093/annonc/mdw693
Yoshida T, Oya Y, Tanaka K, Shimizu J, Horio Y, Kuroda H, Yatabe Y (2016) Differential crizotinib response duration among ALK fusion variants in ALK-positive non-small-cell lung cancer. J Clin Oncol 34(28):3383–3389. https://doi.org/10.1200/JCO.2015.65.8732
Zhao R, Zhang J, Han Y, Shao J, Zhu L, Xiang C, Ding W (2019) Clinicopathological features of ALK expression in 9889 cases of non-small-cell lung cancer and genomic rearrangements identified by capture-based next-generation sequencing: a Chinese retrospective analysis. Mol Diagn Ther 23(3):395–405. https://doi.org/10.1007/s40291-019-00389-y
Zhou X, Shou J, Sheng J, Xu C, Ren S, Cai X, Fang Y (2019) Molecular and clinical analysis of chinese patients with anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer. Cancer Sci 110(10):3382–3390. https://doi.org/10.1111/cas.14177
Acknowledgements
This work was supported by the National Key Development Plan for Precision Medicine Research of China (2017YFC0910004), the National Major Sci-Tech Project of China (2017ZX10103004-012) and the National Science Foundation of China (81871890, 91859203).
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432_2019_3116_MOESM1_ESM.tiff
EML4 and non-EML4 ALK fusions detected in the cohorts. Illustration of the breakpoint for ALK fusions. Gene names on the left indicate the fusion partner. Numbers in parenthesis indicates detection frequency. Specific breakpoint position of the fusion is depicted on the right; Ex | Ex represents exon number/position of gene fusion partner on the left of the vertical bar, exon number of ALK on the right of the vertical bar. (TIFF 4006 kb)
432_2019_3116_MOESM2_ESM.tif
Concurrent TP53 mutations were more frequent in patients 50 years older than younger group. X-axis denotes the age stratification. Y-axis denotes the TP53 mutation detection rate. (TIF 220 kb)
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Tian, P., Liu, Y., Zeng, H. et al. Unique molecular features and clinical outcomes in young patients with non-small cell lung cancer harboring ALK fusion genes. J Cancer Res Clin Oncol 146, 935–944 (2020). https://doi.org/10.1007/s00432-019-03116-6
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DOI: https://doi.org/10.1007/s00432-019-03116-6