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Int J Cancer. 2016 Feb 1;138(3):739-46. doi: 10.1002/ijc.29807. Epub 2015 Sep 18.

Influence of mRNA expression of epiregulin and amphiregulin on outcome of patients with metastatic colorectal cancer treated with 5-FU/LV plus irinotecan or irinotecan plus oxaliplatin as first-line treatment (FIRE 1-trial).

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Department of Medicine III And Comprehensive Cancer Centre, University Hospital Grosshadern, University of Munich, Germany.
Institute of Pathology, University of Munich, Germany.
DKTK, German Cancer Consortium, German Cancer Research Centre (DKFZ), Heidelberg, Germany.
Institute of Medical Informatics, Biometry, and Epidemiology, University of Munich, Germany.
Klinikum St. Marien, Oncology, Amberg, Germany.
Onkologische Praxis, Landshut, Germany.
Onkologische Schwerpunktpraxis in Kronach, Ambulantes Zentrum Für Hämatologie Und Onkologie, Kronach, Germany.
Klinikum Chemnitz, Chemnitz, Germany.
ClinAssess GmbH, Leverkusen, Germany.


Our aim was to investigate the impact of EREG and AREG mRNA expression (by RT-qPCR) in patients with metastatic colorectal cancer (mCRC). In addition, epidermal growth factor receptor (EGFR) expression (by immunohistochemistry) as well as RAS-and PIK3CA-mutations (by pyrosequencing) were assessed. Tumors of 208 mCRC patients receiving 5-fluorouracil/leucovorin plus irinotecan (FUFIRI) or irinotecan plus oxaliplatin (mIROX) within the FIRE-1 trial were analyzed for mutations. Molecular characteristics were correlated with response, progression-free survival (PFS), overall survival (OS). mRNA expression was evaluated using ROC-analysis in 192 tumors (AREG high n = 31 vs. low n = 161; EREG high n = 89 vs. low n = 103). High versus low AREG expression was associated with PFS of 10.0 versus 8.0 months (HR = 0.62, 95% CI: 0.402-0.940, p = 0.03) and OS of 24.6 versus 18.7 months (HR = 0.72, 95% CI: 0.476-1.078, p = 0.11). High versus low EREG expression correlated with prolonged PFS (9.4 vs. 6.8 months, HR = 0.62, 95% CI: 0.460-0.846, p = 0.002) and OS (25.8 vs. 15.5 months, HR = 0.48, 95% CI: 0.351-0.657, p < 0.001). The positive prognostic effect of high EREG expression was confirmed in a multivariate analysis and was neither affected by EGFR expression nor by mutations of RAS- and PIK3CA-genes. EREG expression appears as an independent prognostic marker in patients with mCRC receiving first-line irinotecan-based chemotherapy.


AREG; EREG; RAS; metastatic colorectal cancer

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