Abstract
Background
ALK-rearranged non-small cell lung cancer (NSCLC) represents a molecular subgroup with high sensitivity to ALK inhibitors. Crizotinib, a US Food and Drug Administration (FDA)-approved tyrosine kinase inhibitor for treating ALK-rearranged NSCLC, has shown remarkable response in ALK-positive NSCLC. However, heterogeneity of clinical responses exists among different ALK fusion partners. Several small studies have investigated the correlation between fusion partners and efficacy, but not yielded consistent results.
Objective
We investigated the prevalence of ALK rearrangements in a Chinese NSCLC population, and correlated clinical outcomes of crizotinib with different ALK partners/variants.
Patients and methods
We retrospectively reviewed genomic profiling and clinical data of 110 ALK-rearranged NSCLC patients from five centers. The clinical response to crizotinib and survival data in ALK-positive patients was retrospectively analyzed.
Results
A total of 134 ALK rearrangements with 39 partners were identified in 110 patients (5.6%) among a cohort of 1971 NSCLC patients. The most frequently occurring ALK fusion partner was EML4, which was identified in 71.6% (96/134) of all of the rearrangements in 87.3% (96/110) patients, and with variant 3 (41/96, 42.7%) as the main variant type. No statistically significant differences in terms of progression-free survival (PFS) and overall survival (OS) were found between EML4-ALK and non-EML4-ALK NSCLC patients in our cohort (PFS, p = 0.207; OS, p = 0.678). Outcomes did not differ significantly between patients above and below 40 years of age (PFS, p = 0.427; OS, p = 0.686), nor between patients treated with crizotinib in different lines of therapy (PFS, p = 0.171; OS, p = 0.922). For EML4-ALK-positive NSCLC (n = 96), patients harboring variant 3 or variant 5 displayed significantly lower PFS and OS than those with other variants (PFS, 8.6 vs. 11.3 months, p = 0.046; OS, 31.0 vs. 37.6 months, p = 0.026). In addition, patients with a single EML4-ALK rearrangement event displayed favorable PFS (10.0 vs. 7.2 months, p = 0.040) and OS (36.0 vs. 20.0 months, p = 0.029) compared to those harboring multiple ALK rearrangements.
Conclusions
This study illustrates the patterns of ALK fusion variants present in Chinese NSCLC patients and might help explain heterogeneous clinical outcomes to crizotinib treatment according to different ALK fusion variants.
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References
Li T, Kung HJ, Mack PC, Gandara DR. Genotyping and genomic profiling of non-small-cell lung cancer: implications for current and future therapies. J Clin Oncol. 2013;31(8):1039–49. https://doi.org/10.1200/JCO.2012.45.3753.
Buettner R, Wolf J, Thomas RK. Lessons learned from lung cancer genomics: the emerging concept of individualized diagnostics and treatment. J Clin Oncol. 2013;31(15):1858–65. https://doi.org/10.1200/JCO.2012.45.9867.
McLeer-Florin A, Duruisseaux M, Pinsolle J, Dubourd S, Mondet J, Phillips Houlbracq M, et al. ALK fusion variants detection by targeted RNA-next generation sequencing and clinical responses to crizotinib in ALK-positive non-small cell lung cancer. Lung Cancer. 2018;116:15–24. https://doi.org/10.1016/j.lungcan.2017.12.004.
Soda M, Choi YL, Enomoto M, Takada S, Yamashita Y, Ishikawa S, et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature. 2007;448(7153):561–6. https://doi.org/10.1038/nature05945.
Horn L, Pao W. EML4-ALK: honing in on a new target in non-small-cell lung cancer. J Clin Oncol. 2009;27(26):4232–5. https://doi.org/10.1200/JCO.2009.23.6661.
Sasaki T, Rodig SJ, Chirieac LR, Janne PA. The biology and treatment of EML4-ALK non-small cell lung cancer. Eur J Cancer. 2010;46(10):1773–80. https://doi.org/10.1016/j.ejca.2010.04.002.
Sabir SR, Yeoh S, Jackson G, Bayliss R. EML4-ALK variants: biological and molecular properties, and the implications for patients. Cancers. 2017. https://doi.org/10.3390/cancers9090118.
Sanders HR, Li HR, Bruey JM, Scheerle JA, Meloni-Ehrig AM, Kelly JC, et al. Exon scanning by reverse transcriptase-polymerase chain reaction for detection of known and novel EML4-ALK fusion variants in non-small cell lung cancer. Cancer Genet. 2011;204(1):45–52. https://doi.org/10.1016/j.cancergencyto.2010.08.024.
Choi YL, Takeuchi K, Soda M, Inamura K, Togashi Y, Hatano S, et al. Identification of novel isoforms of the EML4-ALK transforming gene in non-small cell lung cancer. Cancer Res. 2008;68(13):4971–6. https://doi.org/10.1158/0008-5472.CAN-07-6158.
Takeuchi K, Choi YL, Soda M, Inamura K, Togashi Y, Hatano S, et al. Multiplex reverse transcription-PCR screening for EML4-ALK fusion transcripts. Clin Cancer Res. 2008;14(20):6618–24. https://doi.org/10.1158/1078-0432.CCR-08-1018.
Aguado C, Gil MD, Yeste Z, Gimenez-Capitan A, Teixido C, Karachaliou N, et al. Response to crizotinib in a non-small-cell lung cancer patient harboring an EML4-ALK fusion with an atypical LTBP1 insertion. Onco Targets Ther. 2018;11:1117–20. https://doi.org/10.2147/OTT.S148363.
Togashi Y, Soda M, Sakata S, Sugawara E, Hatano S, Asaka R, et al. KLC1-ALK: a novel fusion in lung cancer identified using a formalin-fixed paraffin-embedded tissue only. PLoS One. 2012;7(2):e31323. https://doi.org/10.1371/journal.pone.0031323.
Choi YL, Lira ME, Hong M, Kim RN, Choi SJ, Song JY, et al. A novel fusion of TPR and ALK in lung adenocarcinoma. J Thorac Oncol. 2014;9(4):563–6. https://doi.org/10.1097/JTO.0000000000000093.
Shan L, Jiang P, Xu F, Zhang W, Guo L, Wu J, et al. BIRC6-ALK, a novel fusion gene in ALK break-apart FISH-negative lung adenocarcinoma, responds to crizotinib. J Thorac Oncol. 2015;10(6):e37–9. https://doi.org/10.1097/JTO.0000000000000467.
Yeap BY, Engelman JA, Awad MM, Shaw AT, Varghese AM, Riely GJ, et al. Pemetrexed-based chemotherapy in patients with advanced, ALK-positive non-small cell lung cancer. Ann Oncol. 2012;24(1):59–66. https://doi.org/10.1093/annonc/mds242.
Solomon BJ, Mok T, Kim DW, Wu YL, Nakagawa K, Mekhail T, et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med. 2014;371(23):2167–77. https://doi.org/10.1056/NEJMoa1408440.
Lu S, Mok T, Lu Y, Zhou J, Shi Y, Sriuranpong V, et al. Phase 3 study of first-line crizotinib vs. pemetrexed − cisplatin/carboplatin (PCC) in East Asian patients (pts) with ALK + advanced non-squamous non-small cell lung cancer (NSCLC). J Clin Oncol. 2016;34(15_suppl):9058. https://doi.org/10.1200/jco.2016.34.15_suppl.9058.
Yoshida T, Oya Y, Tanaka K, Shimizu J, Horio Y, Kuroda H, et al. Differential crizotinib response duration among ALK fusion variants in ALK-positive non-small-cell lung cancer. J Clin Oncol. 2016;34(28):3383–9. https://doi.org/10.1200/JCO.2015.65.8732.
Li Y, Zhang T, Zhang J, Li W, Yuan P, Xing P, et al. Response to crizotinib in advanced ALK-rearranged non-small cell lung cancers with different ALK-fusion variants. Lung Cancer. 2018;118:128–33. https://doi.org/10.1016/j.lungcan.2018.01.026.
Woo CG, Seo S, Kim SW, Jang SJ, Park KS, Song JY, et al. 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. 2017;28(4):791–7. https://doi.org/10.1093/annonc/mdw693.
Lin JJ, Zhu VW, Yoda S, Yeap BY, Schrock AB, Dagogo-Jack I, et al. Impact of EML4-ALK variant on resistance mechanisms and clinical outcomes in ALK-positive lung cancer. J Clin Oncol. 2018;36(12):1199–206. https://doi.org/10.1200/JCO.2017.76.2294.
Travis WD, Brambilla E, Nicholson AG, Yatabe Y, Austin JHM, Beasley MB, et al. The 2015 World Health Organization classification of lung tumors: impact of genetic, clinical and radiologic advances since the 2004 classification. J Thorac Oncol. 2015;10(9):1243–60. https://doi.org/10.1097/JTO.0000000000000630.
Mao X, Zhang Z, Zheng X, Xie F, Duan F, Jiang L, et al. Capture-based targeted ultradeep sequencing in paired tissue and plasma samples demonstrates differential subclonal ctDNA-releasing capability in advanced lung cancer. J Thorac Oncol. 2017;12(4):663–72. https://doi.org/10.1016/j.jtho.2016.11.2235.
Li H, Durbin R. Fast and accurate short read alignment with Burrows–Wheeler transform. Bioinformatics. 2009;25(14):1754–60. https://doi.org/10.1093/bioinformatics/btp324.
McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A, et al. the genome analysis toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 2010;20(9):1297–303. https://doi.org/10.1101/gr.107524.110.
Koboldt DC, Zhang Q, Larson DE, Shen D, McLellan MD, Lin L, et al. VarScan 2: somatic mutation and copy number alteration discovery in cancer by exome sequencing. Genome Res. 2012;22(3):568–76. https://doi.org/10.1101/gr.129684.111.
Newman AM, Bratman SV, Stehr H, Lee LJ, Liu CL, Diehn M, et al. FACTERA: a practical method for the discovery of genomic rearrangements at breakpoint resolution. Bioinformatics. 2014;30(23):3390–3. https://doi.org/10.1093/bioinformatics/btu549.
Wang K, Li M, Hakonarson H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res. 2010;38(16):e164. https://doi.org/10.1093/nar/gkq603.
Cingolani P, Platts A, le Wang L, Coon M, Nguyen T, Wang L, et al. A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3. Fly. 2012;6(2):80–92. https://doi.org/10.4161/fly.19695.
Tanaka K, Hida T, Oya Y, Yoshida T, Shimizu J, Mizuno T, et al. Unique prevalence of oncogenic genetic alterations in young patients with lung adenocarcinoma. Cancer. 2017;123(10):1731–40. https://doi.org/10.1002/cncr.30539.
Shaw AT, Kim DW, Nakagawa K, Seto T, Crino L, Ahn MJ, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med. 2013;368(25):2385–94. https://doi.org/10.1056/NEJMoa1214886.
Lei YY, Yang JJ, Zhang XC, Zhong WZ, Zhou Q, Tu HY, et al. Anaplastic lymphoma kinase variants and the percentage of ALK-positive tumor cells and the efficacy of crizotinib in advanced NSCLC. Clin Lung Cancer. 2016;17(3):223–31. https://doi.org/10.1016/j.cllc.2015.09.002.
Hrustanovic G, Olivas V, Pazarentzos E, Tulpule A, Asthana S, Blakely CM, et al. RAS-MAPK dependence underlies a rational polytherapy strategy in EML4-ALK-positive lung cancer. Nat Med. 2015;21(9):1038–47. https://doi.org/10.1038/nm.3930.
Heuckmann JM, Balke-Want H, Malchers F, Peifer M, Sos ML, Koker M, et al. Differential protein stability and ALK inhibitor sensitivity of EML4-ALK fusion variants. Clin Cancer Res. 2012;18(17):4682–90. https://doi.org/10.1158/1078-0432.CCR-11-3260.
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We would like to acknowledge all of the patients and their families for their contributions to this study.
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Funding
This study was funded by Beijing Natural Science Foundation (7182132), Major projects of the Beijing Municipal Science and Technology Commission (Z171100002017013), Capital Special Project for Featured Clinical Application (Z151100004015157), The Peking Union Medical College Hospital Youth Fund (PUMCH-2016-2.25, HI626500), PUMC Special Youth Teacher Project (2014zlgc0717), PUMC Special Youth Teacher Project (2014zlgc0135), Science and Technique Foundation of Tianjin Public Health Bureau (No.2015KZ085), and The Clinical Trial Foundation of Tianjin Tumor Hospital (No.C1712).
Conflict of interest
Yudong Su, Xiang Long, Yang Song, Peng Chen, Shanqing Li, Huaxia Yang, Pancheng Wu, Yanyu Wang, Zhongxing Bing, Zhili Cao, Lei Cao, Yijun Wu, Zhe Zhang, Jing Liu, Bing Li, Jianxing Xiang, Ke Ma, Tengfei Zhang, Lu Zhang, Xinru Mao, Hao Liu, Puyuan Xing and Naixin Liang declare that they have no conflicts of interest that might be relevant to the contents of this article.
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Su, Y., Long, X., Song, Y. et al. Distribution of ALK Fusion Variants and Correlation with Clinical Outcomes in Chinese Patients with Non-Small Cell Lung Cancer Treated with Crizotinib. Targ Oncol 14, 159–168 (2019). https://doi.org/10.1007/s11523-019-00631-x
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DOI: https://doi.org/10.1007/s11523-019-00631-x