Annals of Surgical Oncology

, Volume 14, Issue 7, pp 2150–2158 | Cite as

Pancreatic Cancer Epidermal Growth Factor Receptor (EGFR) Intron 1 Polymorphism Influences Postoperative Patient Survival and in vitro Erlotinib Response

  • Ching-Wei D. Tzeng
  • Andrey Frolov
  • Natalya Frolova
  • Nirag C. Jhala
  • J. Harrison Howard
  • Selwyn M. Vickers
  • Donald J. Buchsbaum
  • Martin J. Heslin
  • J. Pablo Arnoletti
Laboratory Research

Abstract

Background

Epidermal growth factor receptor (EGFR) has a highly polymorphic CA repeat region that affects transcription efficiency and anti-EGFR drug sensitivity in carcinomas. Erlotinib is an EGFR tyrosine kinase inhibitor approved for pancreatic cancer treatment. We analyzed the impact of EGFR intron 1 CA repeat lengths in pancreatic cancer clinical outcome and in vitro response to erlotinib.

Methods

Allele-specific EGFR intron 1 lengths were analyzed in 30 microdissected pancreatic cancer surgical specimens, matched peripheral blood samples, and 9 pancreatic cancer cell lines treated with erlotinib. CA repeat lengths were correlated with survival, tumor parameters, molecular markers of EGFR pathway activation, and in vitro antiproliferative effects of erlotinib.

Results

Both patient samples and cell lines displayed the full spectrum of EGFR CA repeat lengths (14–22 per allele). Patients with shorter sum of total CA repeats (<36) had worse median survival than patients with ≥36 repeats (13.7 vs 30.6 months, P = .002). Shorter patient EGFR intron 1 length correlated with EGFR expression (P = .026). Tumor intron 1 length was identical to that of matched peripheral blood specimens. There was no correlation between EGFR intron 1 length and pancreatic cancer stage, nodal status, grade, or expression of p-EGFR, p-ERK and p-Akt. Shorter EGFR intron 1 length was associated with in vitro response to erlotinib treatment (P = .02).

Conclusions

Shorter EGFR intron 1 CA repeat length is associated with worse pancreatic cancer clinical prognosis and in vitro response to erlotinib. EGFR intron 1 length can be reliably measured in peripheral blood and may translate into a quantitative predictive marker of both pancreatic cancer aggressiveness and erlotinib sensitivity.

Keywords

EGFR Epidermal growth factor receptor Pancreatic cancer Intron 1 Polymorphism Erlotinib 

References

  1. 1.
    Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2006. CA Cancer J Clin 2006; 56(2):106–30PubMedGoogle Scholar
  2. 2.
    Friess H, Wang L, Zhu Z, et al. Growth factor receptors are differentially expressed in cancers of the papilla of vater and pancreas. Ann Surg 1999;230(6):767–74; discussion 74–5PubMedCrossRefGoogle Scholar
  3. 3.
    Moore M, Goldstein D, Hamm J, et al. Erlotinib plus gemcitabine compared to gemcitabine alone in patients with advanced pancreatic cancer. A Phase III trial of the National Cancer Institute of Canada Clinical Trials Group (NCIC-CTG). Proc Am Soc Clin Oncol 2005 2005; p. 24Google Scholar
  4. 4.
    Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004;350(21):2129–39PubMedCrossRefGoogle Scholar
  5. 5.
    Kwak EL, Jankowski J, Thayer SP, et al. Epidermal growth factor receptor kinase domain mutations in esophageal and pancreatic adenocarcinomas. Clin Cancer Res 2006;12(14 Pt 1):4283–7PubMedCrossRefGoogle Scholar
  6. 6.
    Immervoll H, Hoem D, Kugarajh K, Steine SJ, Molven A. Molecular analysis of the EGFR-RAS-RAF pathway in pancreatic ductal adenocarcinomas: lack of mutations in the BRAF and EGFR genes. Virchows Arch 2006;448(6):788–96PubMedCrossRefGoogle Scholar
  7. 7.
    Tzeng C, Frolov A, Frolova N, et al. Epidermal growth factor receptor (EGFR) is highly conserved in pancreatic cancer. Surgery 2007;141(4):464–9PubMedCrossRefGoogle Scholar
  8. 8.
    Amador ML, Oppenheimer D, Perea S, et al. An epidermal growth factor receptor intron 1 polymorphism mediates response to epidermal growth factor receptor inhibitors. Cancer Res 2004;64(24):9139–43PubMedCrossRefGoogle Scholar
  9. 9.
    Etienne-Grimaldi MC, Pereira S, Magne N, et al. Analysis of the dinucleotide repeat polymorphism in the epidermal growth factor receptor (EGFR) gene in head and neck cancer patients. Ann Oncol 2005;16(6):934–41PubMedCrossRefGoogle Scholar
  10. 10.
    Buerger H, Gebhardt F, Schmidt H, et al. Length and loss of heterozygosity of an intron 1 polymorphic sequence of egfr is related to cytogenetic alterations and epithelial growth factor receptor expression. Cancer Res 2000;60(4):854–7PubMedGoogle Scholar
  11. 11.
    Gebhardt F, Zanker KS, Brandt B. Modulation of epidermal growth factor receptor gene transcription by a polymorphic dinucleotide repeat in intron 1. J Biol Chem 1999;274(19):13176–80PubMedCrossRefGoogle Scholar
  12. 12.
    Iwamura T, Katsuki T, Ide K. Establishment and characterization of a human pancreatic cancer cell line (SUIT-2) producing carcinoembryonic antigen and carbohydrate antigen 19-9. Jpn J Cancer Res 1987;78(1):54–62PubMedGoogle Scholar
  13. 13.
    Simone NL, Remaley AT, Charboneau L, et al. Sensitive immunoassay of tissue cell proteins procured by laser capture microdissection. Am J Pathol 2000;156(2):445–52PubMedGoogle Scholar
  14. 14.
    Frolov A, Chahwan S, Ochs M, et al. Response markers and the molecular mechanisms of action of Gleevec in gastrointestinal stromal tumors. Mol Cancer Ther 2003;2(8):699–709PubMedGoogle Scholar
  15. 15.
    Bor MV, Sorensen BS, Rammer P, Nexo E. Calibrated user-friendly reverse transcriptase-PCR assay: quantitation of epidermal growth factor receptor mRNA. Clin Chem 1998;44(6 Pt 1):1154–60PubMedGoogle Scholar
  16. 16.
    Cameron JL, Riall TS, Coleman J, Belcher KA. One thousand consecutive pancreaticoduodenectomies. Ann Surg 2006;244(1):10–5PubMedCrossRefGoogle Scholar
  17. 17.
    Liu W, Innocenti F, Chen P, Das S, Cook EH Jr, Ratain MJ. Interethnic difference in the allelic distribution of human epidermal growth factor receptor intron 1 polymorphism. Clin Cancer Res 2003;9(3):1009–12PubMedGoogle Scholar
  18. 18.
    Mendelsohn J, Baselga J. Epidermal growth factor receptor targeting in cancer. Semin Oncol 2006;33(4):369–85PubMedCrossRefGoogle Scholar
  19. 19.
    Ono M, Kuwano M. Molecular mechanisms of epidermal growth factor receptor (EGFR) activation and response to gefitinib and other EGFR-targeting drugs. Clin Cancer Res 2006;12(24):7242–51PubMedCrossRefGoogle Scholar
  20. 20.
    Meric-Bernstam F, Hung MC. Advances in targeting human epidermal growth factor receptor-2 signaling for cancer therapy. Clin Cancer Res 2006;12(21):6326–30PubMedCrossRefGoogle Scholar
  21. 21.
    Richter M, Zhang H. Receptor-targeted cancer therapy. DNA Cell Biol 2005;24(5):271–82PubMedCrossRefGoogle Scholar
  22. 22.
    Hirsch FR, Varella-Garcia M, Bunn PA Jr, et al. Molecular predictors of outcome with gefitinib in a phase III placebo-controlled study in advanced non-small-cell lung cancer. J Clin Oncol 2006;24(31):5034–42PubMedCrossRefGoogle Scholar
  23. 23.
    Galizia G, Lieto E, Ferraraccio F, et al. Prognostic significance of epidermal growth factor receptor expression in colon cancer patients undergoing curative surgery. Ann Surg Oncol 2006;13(6):823–35PubMedCrossRefGoogle Scholar
  24. 24.
    Hitt R, Ciruelos E, Amador ML, et al. Prognostic value of the epidermal growth factor receptor (EGRF) and p53 in advanced head and neck squamous cell carcinoma patients treated with induction chemotherapy. Eur J Cancer 2005;41(3):453–60PubMedCrossRefGoogle Scholar
  25. 25.
    Baselga J, Arteaga CL. Critical update and emerging trends in epidermal growth factor receptor targeting in cancer. J Clin Oncol 2005;23(11):2445–59PubMedCrossRefGoogle Scholar
  26. 26.
    Haley J, Whittle N, Bennet P, Kinchington D, Ullrich A, Waterfield M. The human EGF receptor gene: structure of the 110 kb locus and identification of sequences regulating its transcription. Oncogene Res 1987;1(4):375–96PubMedGoogle Scholar
  27. 27.
    Haley JD, Waterfield MD. Contributory effects of de novo transcription and premature transcript termination in the regulation of human epidermal growth factor receptor proto-oncogene RNA synthesis. J Biol Chem 1991;266(3):1746–53PubMedGoogle Scholar
  28. 28.
    Gebhardt F, Burger H, Brandt B. Modulation of EGFR gene transcription by a polymorphic repetitive sequence—a link between genetics and epigenetics. Int J Biol Markers 2000;15(1):105–10PubMedGoogle Scholar
  29. 29.
    Zhang W, Gordon M, Press OA, et al. Cyclin D1 and epidermal growth factor polymorphisms associated with survival in patients with advanced colorectal cancer treated with Cetuximab. Pharmacogenet Genomics 2006;16(7):475–83PubMedCrossRefGoogle Scholar
  30. 30.
    Zhang W, Stoehlmacher J, Park DJ, et al. Gene polymorphisms of epidermal growth factor receptor and its downstream effector, interleukin-8, predict oxaliplatin efficacy in patients with advanced colorectal cancer. Clin Colorectal Cancer 2005;5(2):124–31PubMedCrossRefGoogle Scholar
  31. 31.
    Zhang W, Park DJ, Lu B, et al. Epidermal growth factor receptor gene polymorphisms predict pelvic recurrence in patients with rectal cancer treated with chemoradiation. Clin Cancer Res 2005;11(2 Pt 1):600–5PubMedGoogle Scholar
  32. 32.
    Longnecker DS, Karagas MR, Tosteson TD, Mott LA. Racial differences in pancreatic cancer: comparison of survival and histologic types of pancreatic carcinoma in Asians, blacks, and whites in the United States. Pancreas 2000;21(4):338–43PubMedCrossRefGoogle Scholar
  33. 33.
    Weinstein I. Cancer Cell Addiction to oncogenes—the Achilles heal of cancer. Science 2002;297(5578):63–4PubMedCrossRefGoogle Scholar

Copyright information

© Society of Surgical Oncology 2007

Authors and Affiliations

  • Ching-Wei D. Tzeng
    • 1
  • Andrey Frolov
    • 1
  • Natalya Frolova
    • 2
  • Nirag C. Jhala
    • 2
  • J. Harrison Howard
    • 1
  • Selwyn M. Vickers
    • 3
  • Donald J. Buchsbaum
    • 4
  • Martin J. Heslin
    • 1
  • J. Pablo Arnoletti
    • 1
  1. 1.Department of SurgeryUniversity of Alabama at BirminghamBirminghamUSA
  2. 2.Department of PathologyUniversity of Alabama of BirminghamBirminghamUSA
  3. 3.Department of SurgeryUniversity of MinnesotaMinneapolisUSA
  4. 4.Department of Radiation OncologyUniversity of Alabama at BirminghamBirminghamUSA

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