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

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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.

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Acknowledgment

We would like to thank Maria Salazar in the UAB Core Sequencing Facility for her assistance with EGFR intron 1 polymorphism length analysis and Dr. Andra Frost for her guidance in the UAB Laser Microdissection Facility. This study was supported by the John W. Kirklin Research and Education Fellowship Award (J.P.A.), the James Ewing Oncology Fellowship Award for Basic Research (J.P.A.), and UAB’s P20 Pancreatic S.P.O.R.E. (CA10195-01).

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Authors and Affiliations

  1. Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, USA

    Ching-Wei D. Tzeng MD, Andrey Frolov MD, PhD, J. Harrison Howard MD, Martin J. Heslin MD & J. Pablo Arnoletti MD

  2. Department of Pathology, University of Alabama of Birmingham, Birmingham, AL, USA

    Natalya Frolova MD & Nirag C. Jhala MD

  3. Department of Surgery, University of Minnesota, Minneapolis, MN, USA

    Selwyn M. Vickers MD

  4. Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, AL, USA

    Donald J. Buchsbaum PhD

Authors
  1. Ching-Wei D. Tzeng MD
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  2. Andrey Frolov MD, PhD
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  3. Natalya Frolova MD
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  4. Nirag C. Jhala MD
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  8. Martin J. Heslin MD
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  9. J. Pablo Arnoletti MD
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Correspondence to J. Pablo Arnoletti MD.

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Tzeng, CW.D., Frolov, A., Frolova, N. et al. Pancreatic Cancer Epidermal Growth Factor Receptor (EGFR) Intron 1 Polymorphism Influences Postoperative Patient Survival and in vitro Erlotinib Response. Ann Surg Oncol 14, 2150–2158 (2007). https://doi.org/10.1245/s10434-007-9409-5

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  • DOI: https://doi.org/10.1245/s10434-007-9409-5

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