Cancer Chemotherapy and Pharmacology

, Volume 73, Issue 1, pp 131–137 | Cite as

Changes in epidermal growth factor receptor expression during chemotherapy in non-small cell lung cancer

  • Jan Nyrop Jakobsen
  • Eric Santoni-Rugiu
  • Jens Benn Sørensen
Original Article

Abstract

Background

Antibodies targeting epidermal growth factor receptor (EGFR), such as cetuximab, may potentially improve outcome in non-small cell lung cancer (NSCLC) patients with high EGFR expression. The EGFR expression may be heterogeneously distributed within tumors, and small biopsies may thus not accurately reveal the EGFR expression. In addition, EGFR expression may also change during chemotherapy. The current study investigates the magnitude of these two issues.

Materials and methods

EGFR expression in diagnostic biopsies and resection specimen was compared in 53 NSCLC patients stage T1-4N0-1M0 treated with surgery without preceding chemotherapy (OP group), and 65 NSCLC patients stage T1-3N0-2M0 (NAC group) treated with preoperative carboplatin and paclitaxel in order to evaluate the discordance of EGFR expression between samples.

Results

Discordance between tumors dichotomized according to EGFR expression (high: H-score ≥200; low: H-score <200) in diagnostic biopsies and immediate resection specimens was 25 % in the OP group and 33 % in the NAC group (p = 0.628). Five (9 %) of primary tumors in the OP group and 4 (13 %) in the NAC group had increased EGFR expression in the resection specimens as compared to the diagnostic biopsies (p = 0.583). A decrease in EGFR expression was observed in 6 (11 %) in the OP group and 7 (23 %) in the NAC group (p = 0.148).

Conclusion

EGFR expression in 25 % of diagnostic biopsies may potentially not be accurate compared to the prevailing pattern in the whole tumor based on the larger resection specimens. This may potentially be an obstacle for proper use of antibodies targeting the EGFR in NSCLC. EGFR expression does, however, not change significantly during paclitaxel and carboplatin and rebiopsies in order to decide on anti-EGFR antibody therapy following chemotherapy do not seem warranted.

Keywords

NSCLC Chemotherapy Biomarker EGFR Heterogeneity 

Notes

Acknowledgments

We thank Camilla Cordua Mortensen, Heidi Ugleholdt, and Lone Svendstrup for expert technical assistance. This study was supported by the Danish Cancer Research Foundation, Arvid Nillsons Foundation, Torben and Alice Frimodts Foundation, Aase and Ejnar Danielsens Foundation, Eva and Henry Fraenkels Foundation, The Danish Research Foundation, Snedkermester Sophus Jacobsen and Hustru Astrid Jacobsens Foundation, The Foundation for the Promotion of Medical Cancer Treatment, and The Research Foundation of the Department of Oncology, Rigshospitalet.

Conflict of interest

The authors Jan Nyrop Jakobsen and Eric Santoni-Rugiu did not declare any conflicts of interest, and Jens Benn Sørensen received speaker’s fee from Roche.

References

  1. 1.
    Burgess AW, Cho HS, Eigenbrot C, Ferguson KM, Garrett TPJ, Leahy DJ et al (2003) An open-and-shut case? Recent insights into the activation of EGF/ErbB receptors. Mol Cell 12(3):541–552PubMedCrossRefGoogle Scholar
  2. 2.
    Pérez-Soler R (2004) HER1/EGFR targeting: refining the strategy. Oncologist 9(1):58–67PubMedCrossRefGoogle Scholar
  3. 3.
    Yarden Y (2001) The EGFR family and its ligands in human cancer. signalling mechanisms and therapeutic opportunities. Eur J Cancer 37(Suppl 4):S3–S8PubMedCrossRefGoogle Scholar
  4. 4.
    Wolff AC, Hammond MEH, Schwartz JN, Hagerty KL, Allred DC, Cote RJ et al (2007) American society of clinical oncology/college of American pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol 25(1):118–145PubMedCrossRefGoogle Scholar
  5. 5.
    Nicholson RI, Gee JM, Harper ME (2001) EGFR and cancer prognosis. Eur J Cancer 37(Suppl 4):S9–15PubMedCrossRefGoogle Scholar
  6. 6.
    Jonker DJ, O’Callaghan CJ, Karapetis CS, Zalcberg JR, Tu D, Au HJ et al (2007) Cetuximab for the treatment of colorectal cancer. N Engl J Med 357(20):2040–2048PubMedCrossRefGoogle Scholar
  7. 7.
    Amado RG, Wolf M, Peeters M, Van Cutsem E, Siena S, Freeman DJ et al (2008) Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol 26(10):1626–1634PubMedCrossRefGoogle Scholar
  8. 8.
    Pirker R, Pereira JR, von Pawel J, Krzakowski M, Ramlau R, Park K et al (2012) EGFR expression as a predictor of survival for first-line chemotherapy plus cetuximab in patients with advanced non-small-cell lung cancer: analysis of data from the phase 3 FLEX study. Lancet Oncol 13(1):33–42PubMedCrossRefGoogle Scholar
  9. 9.
    Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N et al (2009) Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 361(10):947–957PubMedCrossRefGoogle Scholar
  10. 10.
    Jakobsen J, Santoni-Rugiu E, Ravn J, Sorensen J (2013) Intratumor variation of biomarker expression by immunohistochemistry in resectable non-small cell lung cancer. Eur J Cancer. doi: 10.1016/j.ejca.2013.04.003
  11. 11.
    Meert AP, Martin B, Verdebout JM, Paesmans M, Berghmans T, Ninane V et al (2004) Correlation of different markers (p53, EGF-R, c-erbB-2, Ki-67) expression in the diagnostic biopsies and the corresponding resected tumors in non-small cell lung cancer. Lung Cancer 44(3):295–301PubMedCrossRefGoogle Scholar
  12. 12.
    Taillade L, Penault-Llorca F, Boulet T, Fouret P, Michiels S, Taranchon E et al (2007) Immunohistochemical expression of biomarkers: a comparative study between diagnostic bronchial biopsies and surgical specimens of non-small-cell lung cancer. Ann Oncol 18(6):1043–1050PubMedCrossRefGoogle Scholar
  13. 13.
    Grob TJ, Hoenig T, Clauditz TS, Atanackovic D, Koenig AM, Vashist YK et al (2013) Frequent intratumoral heterogeneity of EGFR gene copy gain in non-small cell lung cancer. Lung Cancer 79(3):221–227PubMedCrossRefGoogle Scholar
  14. 14.
    Pápay J, Sápi Z, Egri G, Gyulai M, Szende B, Losonczy G et al (2009) Platinum-based chemotherapy in lung cancer affects the expression of certain biomarkers including ERCC1. Pathol Oncol Res 15(3):445–450PubMedCrossRefGoogle Scholar
  15. 15.
    Junker K, Stachetzki U, Rademacher D, Linder A, Macha HN, Heinecke A et al (2005) HER2/neu expression and amplification in non-small cell lung cancer prior to and after neoadjuvant therapy. Lung Cancer 48(1):59–67PubMedCrossRefGoogle Scholar
  16. 16.
    Bai H, Wang Z, Chen K, Zhao J, Lee JJ, Wang S et al (2012) Influence of chemotherapy on EGFR mutation status among patients with non-small-cell lung cancer. J Clin Oncol 30(25):3077–3083PubMedCrossRefGoogle Scholar
  17. 17.
    Taniguchi K, Okami J, Kodama K, Higashiyama M, Kato K (2008) Intratumor heterogeneity of epidermal growth factor receptor mutations in lung cancer and its correlation to the response to gefitinib. Cancer Sci 99(5):929–935PubMedCrossRefGoogle Scholar
  18. 18.
    Kalikaki A, Koutsopoulos A, Trypaki M, Souglakos J, Stathopoulos E, Georgoulias V et al (2008) Comparison of EGFR and K-RAS gene status between primary tumours and corresponding metastases in NSCLC. Br J Cancer 99(6):923–929PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Gomez-Roca C, Raynaud CM, Penault-Llorca F, Mercier O, Commo F, Morat L et al (2009) Differential expression of biomarkers in primary non-small cell lung cancer and metastatic sites. J Thorac Oncol 4(10):1212–1220PubMedCrossRefGoogle Scholar
  20. 20.
    Chang YL, Wu CT, Shih JY, Lee YC (2011) Comparison of p53 and epidermal growth factor receptor gene status between primary tumors and lymph node metastases in non-small cell lung cancers. Ann Surg Oncol 18(2):543–550Google Scholar
  21. 21.
    Italiano A, Vandenbos FB, Otto J, Mouroux J, Fontaine D, Marcy PY et al (2006) Comparison of the epidermal growth factor receptor gene and protein in primary non-small-cell-lung cancer and metastatic sites: implications for treatment with EGFR-inhibitors. Ann Oncol 17(6):981–985PubMedCrossRefGoogle Scholar
  22. 22.
    Rao C, Hu Q, Ma J, Li J, Zhang C, Shen L et al (2010) Comparison of the epidermal growth factor receptor protein expression between primary non-small cell lung cancer and paired lymph node metastases: implications for targeted nuclide radiotherapy. J Exp Clin Cancer Res 29:7PubMedCrossRefGoogle Scholar
  23. 23.
    Felip E, Rojo F, Reck M, Heller A, Klughammer B, Sala G et al (2008) A phase II pharmacodynamic study of erlotinib in patients with advanced non-small cell lung cancer previously treated with platinum-based chemotherapy. Clin Cancer Res 14(12):3867–3874PubMedCrossRefGoogle Scholar
  24. 24.
    De Pas T, Pelosi G, de Braud F, Veronesi G, Curigliano G, Leon ME et al (2004) Modulation of epidermal growth factor receptor status by chemotherapy in patients with locally advanced non-small-cell lung cancer is rare. J Clin Oncol 22(24):4966–4970PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Jan Nyrop Jakobsen
    • 1
  • Eric Santoni-Rugiu
    • 2
  • Jens Benn Sørensen
    • 1
  1. 1.Department of OncologyRigshospitaletCopenhagenDenmark
  2. 2.Department of PathologyRigshospitaletCopenhagenDenmark

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