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Efficacy of EGFR tyrosine kinase inhibitors in patients having EGFR-activating mutations with or without BIM polymorphisms

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Abstract

Purpose

Patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer with BIM deletion polymorphism may have a limited response to EGFR tyrosine kinase inhibitors (EGFR-TKIs). However, some results of previous reports are discordant. It is necessary to evaluate the relationship between BIM polymorphism and the efficacy of EGFR-TKIs.

Methods

We retrospectively analyzed patients treated with EGFR-TKIs. We collected serum samples from patients before EGFR-TKI administration. We analyzed BIM deletion polymorphism and BIM single nucleotide polymorphism in exon 5 c465C > T by the Invader® assay.

Results

BIM deletion polymorphism was identified in 27 of 194 patients (13.9%). BIM single nucleotide polymorphism was identified in 29 of 194 patients (14.9%). The overall response ratio was 81.5% in patients with BIM deletion polymorphism, 89.7% with BIM single nucleotide polymorphism, and 83.6% with BIM wild type. Median progression-free survival was 10.3 months with BIM deletion polymorphism, 8.5 months with BIM single nucleotide polymorphism, and 10.4 months with BIM wild type. Overall survival was 38.4 months with BIM deletion polymorphism, 29.1 months with BIM single nucleotide polymorphism, and 31.6 months with BIM wild type. There were no significant differences between the groups in overall response ratio, progression-free survival, and overall survival.

Conclusions

BIM polymorphism does not affect EGFR-TKI efficacy.

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References

  1. Shigematsu H, Lin L, Takahashi T et al (2005) Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. J Natl Cancer Inst 97:339–346. https://doi.org/10.1093/jnci/dji055

    Article  PubMed  CAS  Google Scholar 

  2. Maemondo M, Inoue A, Kobayashi K et al (2010) Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med 362:2380–2388. https://doi.org/10.1056/NEJMoa0909530

    Article  PubMed  CAS  Google Scholar 

  3. Mitsudomi T, Morita S, Yatabe Y et al (2010) 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. https://doi.org/10.1016/S1470-2045(09)70364-X

    Article  PubMed  CAS  Google Scholar 

  4. Zhou C, Wu Y-L, Chen G et al (2011) 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. https://doi.org/10.1016/S1470-2045(11)70184-X

    Article  PubMed  CAS  Google Scholar 

  5. Wu Y-L, Zhou C, Hu C-P et al (2014) 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. https://doi.org/10.1016/S1470-2045(13)70604-1

    Article  PubMed  CAS  Google Scholar 

  6. Inoue A, Yoshida K, Morita S et al (2016) Characteristics and overall survival of EGFR mutation-positive non-small cell lung cancer treated with EGFR tyrosine kinase inhibitors: a retrospective analysis for 1660 Japanese patients. Jpn J Clin Oncol 46:462–467. https://doi.org/10.1093/jjco/hyw014

    Article  PubMed  PubMed Central  Google Scholar 

  7. Morgillo F, Della Corte CM, Fasano M, Ciardiello F (2016) Mechanisms of resistance to EGFR-targeted drugs: lung cancer. ESMO Open 1:e000060. https://doi.org/10.1136/esmoopen-2016-000060

    Article  PubMed  PubMed Central  Google Scholar 

  8. Cross DAE, Ashton SE, Ghiorghiu S et al (2014) AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov 4:1046–1061. https://doi.org/10.1158/2159-8290.CD-14-0337

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Mok TS, Wu Y-L, Ahn M-J et al (2017) Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N Engl J Med 376:629–640. https://doi.org/10.1056/NEJMoa1612674

    Article  PubMed  CAS  Google Scholar 

  10. Santoni-Rugiu E, Melchior LC, Urbanska EM et al (2019) Intrinsic resistance to EGFR-tyrosine kinase inhibitors in EGFR-mutant non-small cell lung cancer: differences and similarities with acquired resistance. Cancers (Basel). https://doi.org/10.3390/cancers11070923

    Article  Google Scholar 

  11. Youle RJ, Strasser A (2008) The BCL-2 protein family: opposing activities that mediate cell death. Nat Rev Mol Cell Biol 9:47–59. https://doi.org/10.1038/nrm2308

    Article  PubMed  CAS  Google Scholar 

  12. Gong Y, Somwar R, Politi K et al (2007) Induction of BIM is essential for apoptosis triggered by EGFR kinase inhibitors in mutant EGFR-dependent lung adenocarcinomas. PLoS Med 4:e294. https://doi.org/10.1371/journal.pmed.0040294

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Ng KP, Hillmer AM, Chuah CTH et al (2012) A common BIM deletion polymorphism mediates intrinsic resistance and inferior responses to tyrosine kinase inhibitors in cancer. Nat Med 18:521–528. https://doi.org/10.1038/nm.2713

    Article  PubMed  CAS  Google Scholar 

  14. Lee JK, Shin J-Y, Kim S et al (2013) Primary resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in patients with non-small-cell lung cancer harboring TKI-sensitive EGFR mutations: an exploratory study. Ann Oncol 24:2080–2087. https://doi.org/10.1093/annonc/mdt127

    Article  PubMed  CAS  Google Scholar 

  15. Nakagawa T, Takeuchi S, Yamada T et al (2013) EGFR-TKI resistance due to BIM polymorphism can be circumvented in combination with HDAC inhibition. Can Res 73:2428–2434. https://doi.org/10.1158/0008-5472.CAN-12-3479

    Article  CAS  Google Scholar 

  16. Isobe K, Hata Y, Tochigi N et al (2014) Clinical significance of BIM deletion polymorphism in non-small-cell lung cancer with epidermal growth factor receptor mutation. J Thorac Oncol 9:483–487. https://doi.org/10.1097/JTO.0000000000000125

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Lee J-H, Lin Y-L, Hsu W-H et al (2014) Bcl-2-like protein 11 deletion polymorphism predicts survival in advanced non-small-cell lung cancer. J Thorac Oncol 9:1385–1392. https://doi.org/10.1097/JTO.0000000000000238

    Article  PubMed  CAS  Google Scholar 

  18. Zhao M, Zhang Y, Cai W et al (2014) The Bim deletion polymorphism clinical profile and its relation with tyrosine kinase inhibitor resistance in Chinese patients with non–small cell lung cancer. Cancer 120:2299–2307. https://doi.org/10.1002/cncr.28725

    Article  PubMed  CAS  Google Scholar 

  19. Cardona AF, Rojas L, Wills B et al (2016) BIM deletion polymorphisms in Hispanic patients with non-small cell lung cancer carriers of EGFR mutations. Oncotarget 7:68933–68942. https://doi.org/10.18632/oncotarget.12112

    Article  PubMed  PubMed Central  Google Scholar 

  20. Yuan J, Li B, Zhang N et al (2018) Clinical implications of the bim deletion polymorphism in advanced lung adenocarcinoma treated with gefitinib. Clin Lung Cancer 19:e431–e438. https://doi.org/10.1016/j.cllc.2018.02.007

    Article  PubMed  CAS  Google Scholar 

  21. Lee JY, Ku BM, Lim SH et al (2015) The BIM deletion polymorphism and its clinical implication in patients with EGFR-mutant non-small-cell lung cancer treated with EGFR tyrosine kinase inhibitors. J Thorac Oncol 10:903–909. https://doi.org/10.1097/JTO.0000000000000535

    Article  PubMed  CAS  Google Scholar 

  22. Wu S-G, Liu Y-N, Yu C-J et al (2016) Association of BIM deletion polymorphism with intrinsic resistance to EGFR tyrosine kinase inhibitors in patients with lung adenocarcinoma. JAMA Oncol 2:826–828. https://doi.org/10.1001/jamaoncol.2016.0016

    Article  PubMed  Google Scholar 

  23. Sun S, Yu H, Wang H et al (2017) Exploratory cohort study and meta-analysis of BIM deletion polymorphism in patients with epidermal growth factor receptor-mutant non-small-cell lung cancer treated with epidermal growth factor receptor tyrosine kinase inhibitors. Onco Targets Ther 10:1955–1967. https://doi.org/10.2147/OTT.S126075

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Soh SX, Siddiqui FJ, Allen JC et al (2017) A systematic review and meta-analysis of individual patient data on the impact of the BIM deletion polymorphism on treatment outcomes in epidermal growth factor receptor mutant lung cancer. Oncotarget. https://doi.org/10.1832/oncotarget.17102

    Article  PubMed  PubMed Central  Google Scholar 

  25. Augis V, Airiau K, Josselin M et al (2013) A single nucleotide polymorphism in cBIM is associated with a slower achievement of major molecular response in chronic myeloid leukaemia treated with imatinib. PLoS ONE 8:e78582. https://doi.org/10.1371/journal.pone.0078582

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Olivier M (2005) The Invader® assay for SNP genotyping. Mutat Res 573:103–110. https://doi.org/10.1016/j.mrfmmm.2004.08.016

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Eisenhauer EA, Therasse P, Bogaerts J et al (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45:228–247. —https://doi.org/10.1016/j.ejca.2008.10.026

    Article  PubMed  CAS  Google Scholar 

  28. Ito Y, Umezu T, Tadokoro K et al (2019) BIM deletion polymorphism accounts for lack of favorable outcome in Japanese females with follicular lymphoma. Leuk Lymphoma 60:1283–1288. https://doi.org/10.1080/10428194.2018.1529310

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

We thank Dr. H. Yamamoto (Health Policy and Management, School of Medicine, Keio University) for advice about statistical analysis.

Funding

This study was supported in part by the grant from MEXT/JSPS KAKENHI grant number 17H06327 (to N. Fujita) and 19H03524 (to R. Katayama), and the grant from the AMED grant number JP20cm0106203h0005 (to R. Katayama), and the grant from the Nippon Foundation (to N. Fujita).

Author information

Author notes

  1. Ryo Ariyasu and Noriko Yanagitani contributed equally to this work.

Authors and Affiliations

  1. Department of Thoracic Medical Oncology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3-8-31, Ariake, Koto-ku, Tokyo, 135-8550, Japan

    Ryo Ariyasu, Noriko Yanagitani, Ken Uchibori, Satoru Kitazono & Makoto Nishio

  2. BML, INC, 1361-1, Matoba, Kawagoe-shi, Saitama, 350-1101, Japan

    Kenichi Tadokoro & Toshikazu Yamaguchi

  3. Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-8-31, Ariake, Koto-ku, Tokyo, 135-8550, Japan

    Naoya Fujita & Ryohei Katayama

Authors
  1. Ryo Ariyasu
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Contributions

NY, RK, NM planned the study. RA, RK, NM drafted the manuscript. KT and TY performed the experiments. RA and NY analyzed clinical data. KT, TY, KU, SK and NF advised on results interpretation and revised manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Ryohei Katayama or Makoto Nishio.

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Conflict of interest

KT and TY are employees of BML, INC. NF reports grants and non-financial support from Api Corporation, grants from Toppan Printing Corporation, grants from Japan Agency for Medical Research and Development, personal fees from Pfizer, outside the submitted work. MN reports grants and non-financial support from F. Hoffmann-La Roche, during the conduct of the study; grants and personal fees from Ono Pharmaceutical, grants and personal fees from Bristol Myers Squibb, grants and personal fees from Pfizer, grants and personal fees from Chugai Pharmaceutical, grants and personal fees from Eli Lilly, grants and personal fees from Taiho Pharmaceutical, grants and personal fees from AstraZeneca, personal fees from Boehringer-Ingelheim, grants and personal fees from MSD, grants and personal fees from Novartis, personal fees from Sankyo Healthcare, personal fees from Taiho Pharmaceutical, personal fees from Merck Serono, grants from Astellas, outside the submitted work. The remaining authors declare no competing interests.

Ethical approval

This study was approved by the Institutional Review Board and Bioethics Committee for Human Genome and Gene Analysis of the Cancer Institute Hospital of Japanese Foundation for Cancer Research. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent

All patients signed an informed consent for comprehensive agreement for research using serum samples and opt out of this study was done on the website of our hospital.

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Ariyasu, R., Yanagitani, N., Tadokoro, K. et al. Efficacy of EGFR tyrosine kinase inhibitors in patients having EGFR-activating mutations with or without BIM polymorphisms. Cancer Chemother Pharmacol 86, 517–525 (2020). https://doi.org/10.1007/s00280-020-04136-7

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  • DOI: https://doi.org/10.1007/s00280-020-04136-7

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