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Clinical significance of serum EGFR gene mutation and serum tumor markers in predicting tyrosine kinase inhibitor efficacy in lung adenocarcinoma

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Abstract

Objective

To study the clinical significance of serum epidermal growth factor receptor (EGFR) gene mutation and serum tumor markers in the prediction of tyrosine kinase inhibitor (TKI) efficacy in patients with lung adenocarcinoma.

Methods

Ninety patients with pathologically diagnosed lung adenocarcinoma were enrolled. Further, 51 out of 90 patients received the EGFR-TKI therapy, oral gefitinib. The correlations among serum EGFR gene mutations in exons 18–21, serum tumor markers such as carcinoembryonic antigen (CEA), carbohydrate antigen 24-2 (CA24-2), carbohydrate antigen 125, carbohydrate antigen 15-3 as well as carbohydrate antigen 19-9 (CA19-9) levels, and EGFR-TKI efficacy were determined.

Results

There was a high consistency of EGFR gene mutation rate between serum and tissue samples. The serum EGFR gene mutation rate in female patients or non-smokers was significantly higher than that in male patients or smokers, respectively. Serum CA19-9, CA24-2, and CEA levels were significantly correlated with serum EGFR mutation. After receiving gefitinib, the progression-free survivals (PFSs) of patients with high serum CEA level, high serum CA19-9 level, or serum EGFR gene mutation were significantly higher than those of normal patients, respectively. The PFSs were significantly prolonged in patients with EGFR gene mutation and high serum CEA level or patients with EGFR gene mutation and high serum CA19-9 level compared with those in patients with one abnormal biomarker and normal patients.

Conclusion

Combined detection of EGFR gene mutations as well as CA19-9 and CEA levels in peripheral blood can predict the efficacy of EGFR-TKI in the treatment of patients with lung adenocarcinoma.

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References

  1. Blandin Knight S, et al. Progress and prospects of early detection in lung cancer. Open Biol. 2017;7(9):170070. https://doi.org/10.1098/rsob.170070.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Vergnenegre A, Chouaid C. Review of economic analyses of treatment for non-small-cell lung cancer (NSCLC). Expert Rev Pharmacoecon Outcomes Res. 2018;18(5):519–28.

    Article  Google Scholar 

  3. Bai Y, et al. Differential diagnosis and cancer staging of a unique case with multiple nodules in the lung–lung adenocarcinoma, metastasis of colon adenocarcinoma, and colon adenocarcinoma metastasizing to lung adenocarcinoma. Thorac Cancer. 2015;6(3):363–7.

    Article  Google Scholar 

  4. Cha YK, et al. Survival outcome assessed according to tumor burden and progression patterns in patients with epidermal growth factor receptor mutant lung adenocarcinoma undergoing epidermal growth factor receptor tyrosine kinase inhibitor therapy. Clin Lung Cancer. 2015;16(3):228–36.

    Article  CAS  Google Scholar 

  5. Yatabe Y, Takahashi T, Mitsudomi T. Epidermal growth factor receptor gene amplification is acquired in association with tumor progression of EGFR-mutated lung cancer. Cancer Res. 2008;68(7):2106–11.

    Article  CAS  Google Scholar 

  6. Komura N, et al. Tyrosine kinase inhibitor, methyl 2,5-dihydromethylcinnimate, induces PML nuclear body formation and apoptosis in tumor cells. Exp Cell Res. 2007;313(13):2753–65.

    Article  CAS  Google Scholar 

  7. Dorsey J, et al. Discovery of a novel abl tyrosine kinase inhibitor that selectively induces apoptosis of bcr-abl-positive leukemic cells. Exp Hematol. 2000;28(7):49.

    Article  Google Scholar 

  8. Ma C, Wei S, Song Y. T790 M and acquired resistance of EGFR TKI: a literature review of clinical reports. J Thorac Dis. 2011;3(1):10–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Zhong J, et al. Potential resistance mechanisms revealed by targeted sequencing from lung adenocarcinoma patients with primary resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). J Thorac Oncol. 2017;12(12):1766–78.

    Article  Google Scholar 

  10. Generali D, et al. EGFR mutations in exons 18–21 in sporadic breast cancer. Ann Oncol. 2007;18(1):203–5.

    Article  CAS  Google Scholar 

  11. Chabot-Richards D, Buehler K, Vasef MA. Detection of epidermal growth factor receptor (EGFR) exon 19 E746-A750 deletion and EGFR exon 21 point mutations in lung adenocarcinoma by immunohistochemistry: a comparative study to EGFR exons 19 and 21 mutations analysis using PCR followed by high-resolution melting and pyrosequencing. J Histotechnol. 2015;38(2):56–62.

    Article  CAS  Google Scholar 

  12. Hyun MH, et al. Quantification of circulating cell-free DNA to predict patient survival in non-small-cell lung cancer. Oncotarget. 2017;8(55):94417–30.

    Article  Google Scholar 

  13. Ning S, et al. Clinical significance and diagnostic capacity of serum TK1, CEA, CA 19-9 and CA 72-4 levels in gastric and colorectal cancer patients. J Cancer. 2018;9(3):494–501.

    Article  Google Scholar 

  14. Gao Y, et al. Evaluation of serum CEA, CA19-9, CA72-4, CA125 and ferritin as diagnostic markers and factors of clinical parameters for colorectal cancer. Sci Rep. 2018;8(1):2732.

    Article  Google Scholar 

  15. Cui S, et al. Use of superarms EGFR mutation detection kit to detect EGFR in plasma cell-free DNA of patients with lung adenocarcinoma. Clin Lung Cancer. 2018;19(3):e313–22.

    Article  CAS  Google Scholar 

  16. Zhong W, et al. Association of serum levels of CEA, CA199, CA125, CYFRA21-1 and CA72-4 and disease characteristics in colorectal cancer. Pathol Oncol Res. 2015;21(1):83–95.

    Article  CAS  Google Scholar 

  17. Wu TH, et al. Best response according to RECIST during first-line EGFR-TKI treatment predicts survival in EGFR mutation-positive non-small-cell lung cancer patients. Clin Lung Cancer. 2018;19(3):e361–72.

    Article  CAS  Google Scholar 

  18. McHugh ML. Interrater reliability: the kappa statistic. Biochem Med (Zagreb). 2012;22(3):276–82.

    Article  Google Scholar 

  19. Wang K, Li D, Sun L. High levels of EGFR expression in tumor stroma are associated with aggressive clinical features in epithelial ovarian cancer. Onco Targets Ther. 2016;9:377–86.

    Article  CAS  Google Scholar 

  20. Krawczyk P, et al. Comparison of the effectiveness of erlotinib, gefitinib, and afatinib for treatment of non-small cell lung cancer in patients with common and rare EGFR gene mutations. Oncol Lett. 2017;13(6):4433–44.

    Article  CAS  Google Scholar 

  21. Lopes GL, Vattimo EF, Castro Junior G. Identifying activating mutations in the EGFR gene: prognostic and therapeutic implications in non-small cell lung cancer. J Bras Pneumol. 2015;41(4):365–75.

    Article  Google Scholar 

  22. Normanno N, et al. Guide to detecting epidermal growth factor receptor (EGFR) mutations in ctDNA of patients with advanced non-small-cell lung cancer. Oncotarget. 2017;8(7):12501–16.

    Article  Google Scholar 

  23. Guo K, et al. Detection of epidermal growth factor receptor mutation in plasma as a biomarker in Chinese patients with early-stage non-small cell lung cancer. Onco Targets Ther. 2015;8:3289–96.

    Article  Google Scholar 

  24. He W, et al. Correlation between epidermal growth factor receptor tyrosine kinase inhibitor efficacy and circulating tumor cell levels in patients with advanced non-small cell lung cancer. Onco Targets Ther. 2016;9:7515–20.

    Article  CAS  Google Scholar 

  25. Robert C, et al. Three-year overall survival for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001. J Clin Oncol. 2016;34((15_suppl)):9503–9503.

    Article  Google Scholar 

  26. Mao C, et al. Blood as a substitute for tumor tissue in detecting EGFR mutations for guiding EGFR TKIs treatment of nonsmall cell lung cancer: a systematic review and meta-analysis. Med (Baltim). 2015;94(21):e775.

    Article  CAS  Google Scholar 

  27. Teng YH, et al. Mutations in the epidermal growth factor receptor (EGFR) gene in triple negative breast cancer: possible implications for targeted therapy. Breast Cancer Res. 2011;13(2):R35.

    Article  CAS  Google Scholar 

  28. Kobayashi Y, Mitsudomi T. Not all epidermal growth factor receptor mutations in lung cancer are created equal: perspectives for individualized treatment strategy. Cancer Sci. 2016;107(9):1179–86.

    Article  CAS  Google Scholar 

  29. Rossi S, et al. Different EGFR gene mutations in exon 18, 19 and 21 as prognostic and predictive markers in NSCLC: a single institution analysis. Mol Diagn Ther. 2016;20(1):55–63.

    Article  CAS  Google Scholar 

  30. Ma G, et al. Epidermal growth factor receptor T790 M mutation as a prognostic factor in EGFR-mutant non-small cell lung cancer patients that acquired resistance to EGFR tyrosine kinase inhibitors. Oncotarget. 2017;8(59):99429–37.

    PubMed  PubMed Central  Google Scholar 

  31. Wei H, et al. Concomitance of P-gp/LRP expression with EGFR mutations in exons 19 and 21 in non-small cell lung cancers. Yonsei Med J. 2016;57(1):50–7.

    Article  CAS  Google Scholar 

  32. Masago K, et al. Epidermal growth factor receptor (EGFR) double-activating somatic mutations in exons 19 and 21 in Japanese non-small cell lung cancer patients. Cancer Genet Cytogenet. 2009;195(2):179–82.

    Article  CAS  Google Scholar 

  33. Unal OU, et al. Relationship between epidermal growth factor receptor gene mutations and clinicopathological features in patients with non-small cell lung cancer in western Turkey. Asian Pac J Cancer Prev. 2013;14(6):3705–9.

    Article  Google Scholar 

  34. Fan MJ, et al. Relationship of epidermal growth factor receptor gene mutations, clinicopathologic features and prognosis in patients with non-small cell lung cancer. Zhonghua Bing Li Xue Za Zhi. 2011;40(10):679–82.

    CAS  PubMed  Google Scholar 

  35. Rodriguez-Lara V, Hernandez-Martinez JM, Arrieta O. Influence of estrogen in non-small cell lung cancer and its clinical implications. J Thorac Dis. 2018;10(1):482–97.

    Article  Google Scholar 

  36. Chakraborty S, et al. Lung cancer in women: role of estrogens. Expert Rev Respir Med. 2010;4(4):509–18.

    Article  CAS  Google Scholar 

  37. Cortinovis D, et al. A new race against lung cancer. J Vis Surg. 2017;3:110.

    Article  Google Scholar 

  38. Williams CD, et al. Impact of race on treatment and survival among US veterans with early-stage lung cancer. J Thorac Oncol. 2016;11(10):1672–81.

    Article  Google Scholar 

  39. Huang Z, et al. The detection of EGFR mutation status in plasma is reproducible and can dynamically predict the efficacy of EGFR-TKI. Thorac Cancer. 2012;3(4):334–40.

    Article  Google Scholar 

  40. Wang Y, et al. Association between advanced NSCLC T790 M EGFR-TKI secondary resistance and prognosis: a observational study. Med (Baltim). 2018;97(28):e11346.

    Article  Google Scholar 

  41. Wang Z, et al. Quantification and dynamic monitoring of EGFR T790 M in plasma cell-free DNA by digital PCR for prognosis of EGFR-TKI treatment in advanced NSCLC. PLoS One. 2014;9(11):e110780.

    Article  Google Scholar 

  42. Kimura T, et al. Phase II study of carboplatin and pemetrexed in advanced EGFR-wild-type non-squamous non-small cell lung cancer: the central japan lung study group trial 0906. Anticancer Res. 2016;36(4):1767–71.

    CAS  PubMed  Google Scholar 

  43. Kimura H, et al. Plasma MIP-1beta levels and skin toxicity in Japanese non-small cell lung cancer patients treated with the EGFR-targeted tyrosine kinase inhibitor, gefitinib. Lung Cancer. 2005;50(3):393–9.

    Article  Google Scholar 

  44. Okamura K, et al. Diagnostic value of CEA and CYFRA 21-1 tumor markers in primary lung cancer. Lung Cancer. 2013;80(1):45–9.

    Article  Google Scholar 

  45. Chen F, et al. Diagnostic value of CYFRA 21-1 and CEA for predicting lymph node metastasis in operable lung cancer. Int J Clin Exp Med. 2015;8(6):9820–4.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Takeuchi A, et al. Predictive and prognostic value of CYFRA 21-1 for advanced non-small cell lung cancer treated with EGFR-TKIs. Anticancer Res. 2017;37(10):5771–6.

    CAS  PubMed  Google Scholar 

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Author notes

  1. L. X. Feng and J. Wang contributed equally to this work.

Authors and Affiliations

  1. Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao, 266003, Shandong, People’s Republic of China

    L. X. Feng, J. Wang, Z. Yu, S. A. Song, W. X. Zhai, S. H. Dong & H. S. Yu

  2. Department of Ultrasound, The Affiliated Hospital of Qingdao University, Qingdao, 266003, Shandong, People’s Republic of China

    Y. Zhang

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  1. L. X. Feng
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This study was approved by the Ethics Committee of The Affiliated Hospital of Qingdao University.

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Feng, L.X., Wang, J., Yu, Z. et al. Clinical significance of serum EGFR gene mutation and serum tumor markers in predicting tyrosine kinase inhibitor efficacy in lung adenocarcinoma. Clin Transl Oncol 21, 1005–1013 (2019). https://doi.org/10.1007/s12094-018-02014-6

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  • DOI: https://doi.org/10.1007/s12094-018-02014-6

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