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Journal of Cancer Research and Clinical Oncology

, Volume 144, Issue 8, pp 1601–1611 | Cite as

Survival analysis and pathological features of advanced non-small cell lung cancer with miliary pulmonary metastases in patients harboring epidermal growth factor receptor mutations

  • Yusuke Okuma
  • Jumpei Kashima
  • Kageaki Watanabe
  • Sadamu Homma
Original Article – Clinical Oncology
  • 119 Downloads

Abstract

Purpose

Metastasis of non-small cell lung cancer (NSCLC), indicating hematogenous dissemination, is more frequent in patients harboring epidermal growth factor receptor (EGFR) mutations, who respond dramatically to EGFR–tyrosine kinase inhibitors (TKIs).

Methods

Based on the proposed association of miliary pulmonary metastasis and EGFR mutations in the previous studies, we conducted a retrospective study to assess survival of NSCLC with miliary pulmonary metastases in 223 patients harboring EGFR mutations who were treated with single agent EGFR–TKIs.

Results

Progression-free survival (PFS) and overall survival (OS) with single agent EGFR–TKIs were 11.7 months [95% confidence interval (CI) 9.6–13.7] and 23.7 months (95% CI 20.3–26.9), respectively. Patients with and without miliary pulmonary metastases were matched using propensity scores (n = 29 per group) based on clinical characteristics. After matching, the PFS were 8.2 months (95% CI 5.2–15.0) and 14.3 months (95% CI 9.6–30.0) (p = 0.02) in patients with and without miliary pulmonary metastases, respectively. Conversely, the OS were 15.3 months (95% CI 10.6–19.4) and 27.9 months (95% CI 22.0–33.0) (p = 0.003) in patients with and without miliary pulmonary metastases, respectively. By multivariate analysis, miliary pulmonary metastasis was associated with poor prognosis (p = 0.0035).

Conclusion

The prognosis of patients with advanced NSCLC harboring EGFR mutations with miliary pulmonary metastasis demonstrated significantly worse outcomes compared to those without miliary pulmonary metastasis.

Keywords

Epidermal growth factor receptor mutation Lung cancer Miliary pulmonary metastasis Prognosis Tyrosine kinase inhibitor 

Abbreviations

CEA

Carcinoembryonic antigen

CT

Computed tomography

CI

Confidence interval

ECOG-PS

Eastern Cooperative Oncology Group performance status

EGFR

Epidermal growth factor receptor

TKI

Tyrosine kinase inhibitor

HR

Hazard ratio

NSCLC

Non-small cell lung cancer

OS

Overall survival

PFS

Progression-free survival

PCR

Polymerase chain reaction

PD-1

Programmed death-1

PD-L1

Programmed death-ligand 1

TIL

Tumor-infiltrating lymphocyte

Notes

Acknowledgements

The authors thank Makoto Saito, the Senior Biostatistician at the Office for Clinical Research Support in Tokyo Metropolitan Cancer and Infectious diseases Center Komagome Hospital for statistical advice. The authors would like to thank Enago (http://www.enago.jp) for the English language review.

Funding

This report did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Compliance with ethical standards

Conflict of interest

There are no conflicts of interest.

Ethical approval

The study protocol was approved by the Ethics Committee of the Tokyo Metropolitan Cancer and Infectious diseases Center Komagome Hospital and was conducted according to the Declaration of Helsinki.

Informed consent

The Ethics Committee of the Tokyo Metropolitan Cancer and Infectious diseases Center Komagome Hospital waive the requirement for the investigator to obtain a signed consent form for participants.

Research involving human participants and/or animals

Not applicable.

References

  1. Austin PC (2008) A critical appraisal of propensity-score matching in the medical literature between 1996 and 2003. Stat Med 27:2037–2049.  https://doi.org/10.1002/sim.3150 CrossRefPubMedGoogle Scholar
  2. Borghaei H et al (2015) Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med 373:1627–1639.  https://doi.org/10.1056/NEJMoa1507643 CrossRefPubMedPubMedCentralGoogle Scholar
  3. Brahmer J et al (2015) Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 373:123–135.  https://doi.org/10.1056/NEJMoa1504627 CrossRefPubMedPubMedCentralGoogle Scholar
  4. Chang A et al (2006) Gefitinib (IRESSA) in patients of Asian origin with refractory advanced non-small cell lung cancer: subset analysis from the ISEL study. J Thorac Oncol 1:847–855CrossRefPubMedGoogle Scholar
  5. Connors AF Jr et al (1996) The effectiveness of right heart catheterization in the initial care of critically ill patients. JAMA 276:889–897 (support investigators) CrossRefPubMedGoogle Scholar
  6. Fukuoka M et al (2003) Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer (The IDEAL 1 Trial) (corrected). J Clin Oncol 21:2237–2246.  https://doi.org/10.1200/JCO.2003.10.038 CrossRefPubMedGoogle Scholar
  7. Hansell DM, Bankier AA, MacMahon H, McLoud TC, Muller NL, Remy J (2008) Fleischner Society: glossary of terms for thoracic imaging. Radiology 246:697–722.  https://doi.org/10.1148/radiol.2462070712 CrossRefPubMedGoogle Scholar
  8. Herbst RS et al (2016) Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet 387:1540–1550.  https://doi.org/10.1016/S0140-6736(15)01281-7 CrossRefPubMedGoogle Scholar
  9. Herold CJ, Bankier AA, Fleischmann D (1996) Lung metastases. Eur Radiol 6:596–606CrossRefPubMedGoogle Scholar
  10. Kim ES et al (2008) Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial. Lancet 372:1809–1818.  https://doi.org/10.1016/S0140-6736(08)61758-4 CrossRefPubMedGoogle Scholar
  11. Kobayashi S et al (2005) EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med 352:786–792.  https://doi.org/10.1056/NEJMoa044238 CrossRefPubMedGoogle Scholar
  12. Lee VH et al (2013) Association of exon 19 and 21 EGFR mutation patterns with treatment outcome after first-line tyrosine kinase inhibitor in metastatic non-small-cell lung cancer. J Thorac Oncol 8:1148–1155.  https://doi.org/10.1097/JTO.0b013e31829f684a CrossRefPubMedGoogle Scholar
  13. Lee CK et al (2015) Impact of specific epidermal growth factor receptor (EGFR) mutations and clinical characteristics on outcomes after treatment with EGFR tyrosine kinase inhibitors versus chemotherapy in EGFR-mutant lung cancer: a meta-analysis. J Clin Oncol 33:1958–1965.  https://doi.org/10.1200/JCO.2014.58.1736 CrossRefPubMedGoogle Scholar
  14. Lin C et al (2015) Programmed death-ligand 1 expression predicts tyrosine kinase inhibitor response and better prognosis in a cohort of patients with epidermal growth factor receptor mutation-positive lung adenocarcinoma. Clin Lung Cancer 16:e25–e35.  https://doi.org/10.1016/j.cllc.2015.02.002 CrossRefPubMedGoogle Scholar
  15. Lyamichev V et al (1999) Polymorphism identification and quantitative detection of genomic DNA by invasive cleavage of oligonucleotide probes. Nat Biotechnol 17:292–296.  https://doi.org/10.1038/7044 CrossRefPubMedGoogle Scholar
  16. Lynch TJ et al (2004) Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350:2129–2139.  https://doi.org/10.1056/NEJMoa040938 CrossRefPubMedGoogle Scholar
  17. Maemondo M 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 CrossRefPubMedGoogle Scholar
  18. Masago K et al (2009) Epidermal growth factor receptor gene mutations in papillary thyroid carcinoma. Int J Cancer 124:2744–2749.  https://doi.org/10.1002/ijc.24250 CrossRefPubMedGoogle Scholar
  19. Mitsudomi T 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 CrossRefPubMedGoogle Scholar
  20. Nagai Y et al (2005) Genetic heterogeneity of the epidermal growth factor receptor in non-small cell lung cancer cell lines revealed by a rapid and sensitive detection system, the peptide nucleic acid-locked nucleic acid PCR clamp. Cancer Res 65:7276–7282.  https://doi.org/10.1158/0008-5472.CAN-05-0331 CrossRefPubMedGoogle Scholar
  21. Paez JG et al (2004) EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304:1497–1500.  https://doi.org/10.1126/science.1099314 CrossRefPubMedGoogle Scholar
  22. Pardoll DM (2012) The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 12:252–264.  https://doi.org/10.1038/nrc3239 CrossRefPubMedPubMedCentralGoogle Scholar
  23. Park K, Goto K (2006) A review of the benefit-risk profile of gefitinib in Asian patients with advanced non-small-cell lung cancer. Curr Med Res Opin 22:561–573.  https://doi.org/10.1185/030079906X89847 CrossRefPubMedGoogle Scholar
  24. Reck M et al (2016) Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med 375:1823–1833.  https://doi.org/10.1056/NEJMoa1606774 CrossRefPubMedGoogle Scholar
  25. Rittmeyer A et al (2017) Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label multicentre randomised controlled trial. Lancet 389:255–265.  https://doi.org/10.1016/S0140-6736(16)32517-X CrossRefPubMedGoogle Scholar
  26. Rosell R et al (2009) Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med 361:958–967.  https://doi.org/10.1056/NEJMoa0904554 CrossRefPubMedGoogle Scholar
  27. Rosell R et al (2012) Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol 13:239–246  https://doi.org/10.1016/S1470-2045(11)70393-X CrossRefPubMedGoogle Scholar
  28. Rosenbaum PR, Rubin DB (1983) The central role of the propensity score in observational studies for causal effects. Biometrika 1983:41–55CrossRefGoogle Scholar
  29. Sequist LV, Bell DW, Lynch TJ, Haber DA (2007) Molecular predictors of response to epidermal growth factor receptor antagonists in non-small-cell lung cancer. J Clin Oncol 25:587–595.  https://doi.org/10.1200/JCO.2006.07.3585 CrossRefPubMedGoogle Scholar
  30. Sharma SK, Mohan A, Sharma A, Mitra DK (2005) Miliary tuberculosis: new insights into an old disease. Lancet Infect Dis 5:415–430.  https://doi.org/10.1016/S1473-3099(05)70163-8 CrossRefPubMedGoogle Scholar
  31. Sharma SV, Bell DW, Settleman J, Haber DA (2007) Epidermal growth factor receptor mutations in lung cancer. Nat Rev Cancer 7:169–181.  https://doi.org/10.1038/nrc2088 CrossRefPubMedGoogle Scholar
  32. Shigematsu H 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 CrossRefPubMedGoogle Scholar
  33. Shim HS, Lee da H, Park EJ, Kim SH (2011) Histopathologic characteristics of lung adenocarcinomas with epidermal growth factor receptor mutations in the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society lung adenocarcinoma classification. Arch Pathol Lab Med 135:1329–1334.  https://doi.org/10.5858/arpa.2010-0493-OA CrossRefPubMedGoogle Scholar
  34. Siegel RL, Miller KD, Jemal A (2015) Cancer statistics, 2015. CA Cancer J Clin 65:5–29.  https://doi.org/10.3322/caac.21254 CrossRefPubMedGoogle Scholar
  35. Streicher K et al (2017) Increased CD73 and reduced IFNG signature expression in relation to response rates to anti-PD-1(L1) therapies in EGFR-mutant NSCLC. J Clin Oncol 35:11505–11505.  https://doi.org/10.1200/JCO.2017.35.15_suppl.11505 Google Scholar
  36. Sznol M, Chen L (2013) Antagonist antibodies to PD-1 and B7-H1 (PD-L1) in the treatment of advanced human cancer. Clin Cancer Res 19:1021–1034.  https://doi.org/10.1158/1078-0432.CCR-12-2063 CrossRefPubMedPubMedCentralGoogle Scholar
  37. Togashi Y et al (2011) Association of diffuse, random pulmonary metastases, including miliary metastases, with epidermal growth factor receptor mutations in lung adenocarcinoma. Cancer 117:819–825.  https://doi.org/10.1002/cncr.25618 CrossRefPubMedGoogle Scholar
  38. Wu SG et al (2013) Frequent EGFR mutations in nonsmall cell lung cancer presenting with miliary intrapulmonary carcinomatosis. Eur Respir J 41:417–424.  https://doi.org/10.1183/09031936.00006912 CrossRefPubMedGoogle Scholar
  39. Zompatori M et al (2004) Diagnostic imaging of diffuse infiltrative disease of the lung. Respiration 71:4–19.  https://doi.org/10.1159/000075642 CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Thoracic Oncology and Respiratory MedicineTokyo Metropolitan Cancer and Infectious diseases Center Komagome HospitalTokyoJapan
  2. 2.Division of Oncology, Research Center for Medical SciencesJikei University School of MedicineTokyoJapan
  3. 3.Department of PathologyTokyo Metropolitan Cancer and Infectious diseases Center Komagome HospitalTokyoJapan

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