Laboratory Research

Annals of Surgical Oncology

, Volume 14, Issue 7, pp 2150-2158

First online:

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

  • Ching-Wei D. TzengAffiliated withDepartment of Surgery, University of Alabama at Birmingham
  • , Andrey FrolovAffiliated withDepartment of Surgery, University of Alabama at Birmingham
  • , Natalya FrolovaAffiliated withDepartment of Pathology, University of Alabama of Birmingham
  • , Nirag C. JhalaAffiliated withDepartment of Pathology, University of Alabama of Birmingham
  • , J. Harrison HowardAffiliated withDepartment of Surgery, University of Alabama at Birmingham
  • , Selwyn M. VickersAffiliated withDepartment of Surgery, University of Minnesota
  • , Donald J. BuchsbaumAffiliated withDepartment of Radiation Oncology, University of Alabama at Birmingham
  • , Martin J. HeslinAffiliated withDepartment of Surgery, University of Alabama at Birmingham
  • , J. Pablo ArnolettiAffiliated withDepartment of Surgery, University of Alabama at Birmingham Email author 

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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.

Keywords

EGFR Epidermal growth factor receptor Pancreatic cancer Intron 1 Polymorphism Erlotinib