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

¹ Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, USA
² Department of Pathology, University of Alabama of Birmingham, Birmingham, AL, USA
³ Department of Surgery, University of Minnesota, Minneapolis, MN, USA
⁴ Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, AL, USA

Correspondence: Address correspondence and reprint requests to: J. Pablo Arnoletti, MD; E-mail: pablo.arnoletti{at}ccc.uab.edu

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.

Key Words: EGFR • Epidermal growth factor receptor • Pancreatic cancer • Intron 1 • Polymorphism • Erlotinib

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