Skip to main content

Advertisement

SpringerLink
Log in

MET overexpression correlated with prognosis of EGFR-mutant treatment‑naïve advanced lung adenocarcinoma: a real‑world retrospective study

  • RESEARCH ARTICLE
  • Published:
Clinical and Translational Oncology Aims and scope Submit manuscript

Abstract

Background

About 50–60% treatment-naïve advanced non-small-cell lung cancers were coexistence of epidermal growth factor receptor (EGFR) and mesenchymal epithelial transition (MET) overexpression. However, few studies demonstrated the prognostic value of MET protein expression in untreated EGFR-mutant lung adenocarcinoma (LUAD).

Methods

A total of 235 EGFR-mutant untreated advanced LUAD patients were retrospectively enrolled. MET expression was determined using immunohistochemistry, and MET positivity was defined as 2 + or 3 + using the METmab scoring algorithm. Progression-free survival (PFS) and overall survival (OS) were analysed according to MET expression status. Independent factors predicting prognosis were identified using multivariate Cox regression analyses.

Results

Of the 235 patients, 113 (48.1%) harboured exon 19 deletion (19_del), 103 (43.8%) had exon 21 L858R mutations, and 19 (8.1%) had other mutation types, including exon 21 L861Q, exon 18 G719A/C, exon 20 S768I, and L858R/19_del double mutations. MET-positive expression was observed in 192 (81.7%) cases. There was no significant difference in baseline clinicopathological characteristics between MET positivity and MET negativity groups. Patients were stratified by different EGFR mutation subtypes. MET-positive patients in the L858R mutation subgroup had markedly shorter PFS and OS than MET-negative patients (median PFS: 13 versus 27.5 months, p < 0.001; median OS: 29 versus not reached, p = 0.008), but no significant difference was observed in the 19_del subgroup. Multivariate Cox regression analyses indicated that MET positivity was an independent predictor for poor PFS and OS in L858R subgroup (PFS: HR = 3.059, 95% CI 1.552–6.029, p = 0.001; OS: HR = 3.511, 95% CI 1.346–9.160, p = 0.010). Additionally, an inferior survival outcome of MET positivity was observed in the L858R mutation subgroup when treated with EGFR–tyrosine kinase inhibitor (TKI) monotherapy as the first-line regimen (median PFS: 13 versus 36.5 months, p < 0.001; median OS: 29 versus not reached, p = 0.012) but not with EGFR–TKI plus platinum doublet chemotherapy.

Conclusions

MET positive expression was an independent predictor of poor outcomes in untreated EGFR L858R mutation advanced LUAD patients treated with first-line EGFR–TKI monotherapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

References

  1. Ettinger DS, Wood DE, Aisner DL, Akerley W, Bauman JR, Bharat A, et al. Non-Small Cell Lung Cancer, Version 3.2022, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2022;20(5):497–530.

    Article  PubMed  Google Scholar 

  2. Miller KD, Nogueira L, Devasia T, Mariotto AB, Yabroff KR, Jemal A, et al. Cancer treatment and survivorship statistics, 2022. CA Cancer J Clin. 2022. https://doi.org/10.3322/caac.21731.

    Article  PubMed  Google Scholar 

  3. Liu Q, Yu S, Zhao W, Qin S, Chu Q, Wu K. EGFR-TKIs resistance via EGFR-independent signaling pathways. Mol Cancer. 2018;17(1):53. https://doi.org/10.1186/s12943-018-0793-1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Nagano T, Tachihara M, Nishimura Y. Mechanism of Resistance to Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors and a Potential Treatment Strategy. Cells. 2018. https://doi.org/10.3390/cells7110212.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Passaro A, Janne PA, Mok T, Peters S. Overcoming therapy resistance in EGFR-mutant lung cancer. Nat Cancer. 2021;2(4):377–91. https://doi.org/10.1038/s43018-021-00195-8.

    Article  CAS  PubMed  Google Scholar 

  6. Engelman JA, Zejnullahu K, Mitsudomi T, Song Y, Hyland C, Park JO, et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science. 2007;316(5827):1039–43. https://doi.org/10.1126/science.1141478.

    Article  ADS  CAS  PubMed  Google Scholar 

  7. Guo A, Villen J, Kornhauser J, Lee KA, Stokes MP, Rikova K, et al. Signaling networks assembled by oncogenic EGFR and c-Met. Proc Natl Acad Sci U S A. 2008;105(2):692–7. https://doi.org/10.1073/pnas.0707270105.

    Article  ADS  PubMed  PubMed Central  Google Scholar 

  8. Hong S, Gao F, Fu S, Wang Y, Fang W, Huang Y, et al. Concomitant Genetic Alterations With Response to Treatment and Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Patients With EGFR-Mutant Advanced Non-Small Cell Lung Cancer. JAMA Oncol. 2018;4(5):739–42. https://doi.org/10.1001/jamaoncol.2018.0049.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Liang H, Li C, Zhao Y, Zhao S, Huang J, Cai X, et al. Concomitant Mutations in EGFR 19Del/L858R Mutation and Their Association with Response to EGFR-TKIs in NSCLC Patients. Cancer Manag Res. 2020;12:8653–62. https://doi.org/10.2147/CMAR.S255967.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Guo R, Berry LD, Aisner DL, Sheren J, Boyle T, Bunn PA Jr, et al. MET IHC Is a Poor Screen for MET Amplification or MET Exon 14 Mutations in Lung Adenocarcinomas: Data from a Tri-Institutional Cohort of the Lung Cancer Mutation Consortium. J Thorac Oncol. 2019;14(9):1666–71. https://doi.org/10.1016/j.jtho.2019.06.009.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Li A, Niu FY, Han JF, Lou NN, Yang JJ, Zhang XC, et al. Predictive and prognostic value of de novo MET expression in patients with advanced non-small-cell lung cancer. Lung Cancer. 2015;90(3):375–80. https://doi.org/10.1016/j.lungcan.2015.10.021.

    Article  PubMed  Google Scholar 

  12. Tsakonas G, Botling J, Micke P, Rivard C, LaFleur L, Mattsson J, et al. c-MET as a biomarker in patients with surgically resected non-small cell lung cancer. Lung Cancer. 2019;133:69–74. https://doi.org/10.1016/j.lungcan.2019.04.028.

    Article  PubMed  Google Scholar 

  13. Huang L, An SJ, Chen ZH, Su J, Yan HH, Wu YL. MET expression plays differing roles in non-small-cell lung cancer patients with or without EGFR mutation. J Thorac Oncol. 2014;9(5):725–8. https://doi.org/10.1097/JTO.0000000000000105.

    Article  CAS  PubMed  Google Scholar 

  14. Raghav K, Bailey AM, Loree JM, Kopetz S, Holla V, Yap TA, et al. Untying the gordion knot of targeting MET in cancer. Cancer Treat Rev. 2018;66:95–103. https://doi.org/10.1016/j.ctrv.2018.04.008.

    Article  CAS  PubMed  Google Scholar 

  15. Drilon A, Cappuzzo F, Ou SI, Camidge DR. Targeting MET in Lung Cancer: Will Expectations Finally Be MET? J Thorac Oncol. 2017;12(1):15–26. https://doi.org/10.1016/j.jtho.2016.10.014.

    Article  PubMed  Google Scholar 

  16. Scagliotti G, Moro-Sibilot D, Kollmeier J, Favaretto A, Cho EK, Grosch H, et al. A Randomized-Controlled Phase 2 Study of the MET Antibody Emibetuzumab in Combination with Erlotinib as First-Line Treatment for EGFR Mutation-Positive NSCLC Patients. J Thorac Oncol. 2020;15(1):80–90. https://doi.org/10.1016/j.jtho.2019.10.003.

    Article  CAS  PubMed  Google Scholar 

  17. Koeppen H, Yu W, Zha J, Pandita A, Penuel E, Rangell L, et al. Biomarker analyses from a placebo-controlled phase II study evaluating erlotinib+/-onartuzumab in advanced non-small cell lung cancer: MET expression levels are predictive of patient benefit. Clin Cancer Res. 2014;20(17):4488–98. https://doi.org/10.1158/1078-0432.CCR-13-1836.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Kang SJ, Cho YR, Park GM, Ahn JM, Han SB, Lee JY, et al. Predictors for functionally significant in-stent restenosis: an integrated analysis using coronary angiography, IVUS, and myocardial perfusion imaging. JACC Cardiovasc Imaging. 2013;6(11):1183–90. https://doi.org/10.1016/j.jcmg.2013.09.006.

    Article  PubMed  Google Scholar 

  19. Spigel DR, Edelman MJ, O’Byrne K, Paz-Ares L, Mocci S, Phan S, et al. Results From the Phase III Randomized Trial of Onartuzumab Plus Erlotinib Versus Erlotinib in Previously Treated Stage IIIB or IV Non-Small-Cell Lung Cancer: METLung. J Clin Oncol. 2017;35(4):412–20. https://doi.org/10.1200/JCO.2016.69.2160.

    Article  CAS  PubMed  Google Scholar 

  20. Wu YL, Zhang L, Kim DW, Liu X, Lee DH, Yang JC, et al. Phase Ib/II Study of Capmatinib (INC280) Plus Gefitinib After Failure of Epidermal Growth Factor Receptor (EGFR) Inhibitor Therapy in Patients With EGFR-Mutated, MET Factor-Dysregulated Non-Small-Cell Lung Cancer. J Clin Oncol. 2018;36(31):3101–9. https://doi.org/10.1200/JCO.2018.77.7326.

    Article  CAS  PubMed  Google Scholar 

  21. Bauml J, Cho BC, Park K, Lee KH, Cho EK, Kim DW, et al. Amivantamab in combination with lazertinib for the treatment of osimertinib-relapsed, chemotherapy-naive EGFR mutant (EGFRm) non-small cell lung cancer (NSCLC) and potential biomarkers for response. J Clin Oncol. 2021. https://doi.org/10.1200/JCO.2021.39.15_suppl.9006.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Oxnard GR, Yang JC, Yu H, Kim SW, Saka H, Horn L, et al. TATTON: a multi-arm, phase Ib trial of osimertinib combined with selumetinib, savolitinib, or durvalumab in EGFR-mutant lung cancer. Ann Oncol. 2020;31(4):507–16. https://doi.org/10.1016/j.annonc.2020.01.013.

    Article  CAS  PubMed  Google Scholar 

  23. Wu YL, Cheng Y, Zhou J, Lu S, Zhang Y, Zhao J, et al. Tepotinib plus gefitinib in patients with EGFR-mutant non-small-cell lung cancer with MET overexpression or MET amplification and acquired resistance to previous EGFR inhibitor (INSIGHT study): an open-label, phase 1b/2, multicentre, randomised trial. Lancet Respir Med. 2020;8(11):1132–43. https://doi.org/10.1016/S2213-2600(20)30154-5.

    Article  CAS  PubMed  Google Scholar 

  24. Wang N, Zhu Y, Wu Y, Huang B, Wu J, Zhang R, et al. MET overexpression in EGFR L858R mutant treatment-naive advanced lung adenocarcinoma correlated with poor prognosis: a real-world retrospective study. J Cancer Res Clin Oncol. 2022. https://doi.org/10.1007/s00432-022-04225-5.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Kumar A, Petri ET, Halmos B, Boggon TJ. Structure and clinical relevance of the epidermal growth factor receptor in human cancer. J Clin Oncol. 2008;26(10):1742–51. https://doi.org/10.1200/JCO.2007.12.1178.

    Article  CAS  PubMed  Google Scholar 

  26. Paik PK, Felip E, Veillon R, Sakai H, Cortot AB, Garassino MC, et al. Tepotinib in Non-Small-Cell Lung Cancer with MET Exon 14 Skipping Mutations. N Engl J Med. 2020;383(10):931–43. https://doi.org/10.1056/NEJMoa2004407.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Wolf J, Seto T, Han JY, Reguart N, Garon EB, Groen HJM, et al. Capmatinib in MET Exon 14-Mutated or MET-Amplified Non-Small-Cell Lung Cancer. N Engl J Med. 2020;383(10):944–57. https://doi.org/10.1056/NEJMoa2002787.

    Article  CAS  PubMed  Google Scholar 

  28. Spigel DR, Ervin TJ, Ramlau RA, Daniel DB, Goldschmidt JH Jr, Blumenschein GR Jr, et al. Randomized phase II trial of Onartuzumab in combination with erlotinib in patients with advanced non-small-cell lung cancer. J Clin Oncol. 2013;31(32):4105–14. https://doi.org/10.1200/JCO.2012.47.4189.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Hartmaier R, Han JY, Cho BC, Markovets A, Kurian N, Cantarini M, et al. Tumor response and MET-detection methods exploratory biomarker analysis of Part B of the Ph 1b TATTON study. Cancer Res. 2021;81(13):2.

    Google Scholar 

Download references

Acknowledgements

Not applicable.

Funding

This work was supported by the National Natural Science Foundation of China [Grant number 82072333]; and the Natural Science Foundation of Hubei Province [Grant number 2023AFB986]; and the National Key Research and Development Program of China [Grant number 2022YFF1203300].

Author information

Author notes

  1. Na Wang, Yuan Zhang, and Junhua Wu contributed equally to this work.

Authors and Affiliations

  1. Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, Hubei, China

    Na Wang, Junhua Wu, Bo Huang, Jun Fan & Xiu Nie

  2. Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, China

    Yuan Zhang

  3. Department of Pathology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China

    Yili Zhu

  4. Department of Pathology, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, 441000, Hubei, China

    Ying Wu

  5. Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, China

    Ruiguang Zhang

Authors
  1. Na Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yuan Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Junhua Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yili Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ying Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Bo Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ruiguang Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jun Fan
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Xiu Nie
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

NW: methodology, writing—original draft, formal analysis. YZ: methodology, conceptualization. JW: formal analysis, resources. YZ: investigation, data curation. YW: investigation. BH: resources, project administration. RZ: resources. JF: conceptualization, supervision, project administration. XN: conceptualization, supervision, funding acquisition.

Corresponding authors

Correspondence to Jun Fan or Xiu Nie.

Ethics declarations

Conflict of interest

The authors declare no competing interest.

Ethics approval and consent to participate

Approval was obtained from the ethics committee of Tongji Medical College of Huazhong University of Science and Technology, and all patients signed informed consent forms. The procedures used in this study adhere to the tenets of the Declaration of Helsinki.

Consent for publication

Not applicable.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, N., Zhang, Y., Wu, J. et al. MET overexpression correlated with prognosis of EGFR-mutant treatment‑naïve advanced lung adenocarcinoma: a real‑world retrospective study. Clin Transl Oncol (2024). https://doi.org/10.1007/s12094-024-03391-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12094-024-03391-x

Keywords

Search

Navigation