Amphiregulin (AREG) and Epiregulin (EREG) Gene Expression as Predictor for Overall Survival (OS) in Oxaliplatin/Fluoropyrimidine Plus Bevacizumab Treated mCRC Patients-Analysis of the Phase III AIO KRK-0207 Trial.

Sebastian Stintzing,Andrea Tannapfel,Ingrid Ricard,Andreas Jung,Hendrik Juette,Thomas Kirchner,Susanna Hegewisch-Becker,Boryana Ivanova,Dirk Arnold,Anke Reinacher-Schick

doi:10.3389/fonc.2018.00474

Abstract

Background: The EGFR (epithelial growth factor receptor) ligands amphiregulin (AREG) and epiregulin (EREG) have been considered as predictors for EGFR-antibody efficacy. The effect of AREG and EREG expression levels in primary tumor samples on the outcome of bevacizumab-treated patients is unknown.Patients and Methods: Formalin-fixed paraffin-embedded (FFPE) tumor samples from surgically removed primaries of the AIO KRK-0207 trial have been tested for AREG and EREG expression. The AIO KRK-0207 trial was a randomized phase-3 study to investigate the best maintenance strategy after oxaliplatin/fluoropyrimidine plus bevacizumab induction treatment in patients with mCRC. Association of AREG and EREG levels with outcome parameters were investigated, taking into account RAS and BRAF mutations.Results: A total of 331 tumor samples had measurable AREG and EREG tissue levels. In the total cohort using continuous expression levels, higher logAREG and logEREG levels were associated with a significant longer overall survival (OS) (HR 0.80; p = 0.003 and HR 0.78; p = 0.001, respectively). The subgroup of BRAF mutant tumors displayed significantly lower AREG and EREG levels compared to wild-type tumors. The prognostic effect of AREG and EREG expression was limited to the double wild-type subpopulation, whereas in the RAS mutant and BRAF mutant subgroups no prognostic effect was detected.Conclusion: Low logAREG and logEREG levels are associated with a shorter OS in oxaliplatin/fluoropyrimidine plus bevacizumab treated patients. As low AREG and EREG level are associated with BRAF mutations, the prognostic value of EREG and AREG levels is limited to the RAS and BRAF wild-type subpopulation.

Highlights

According to current guidelines, testing for RAS and BRAF (V600E) mutations [1, 2] is recommended before initiating treatment in metastatic colorectal cancer
Using log-transformed AREG and EREG levels, we first analyzed their association with BRAF V600E and RAS mutations with the use of an ANOVA
We found significantly lower AREG and EREG levels in BRAF V600E mutant samples compared to BRAF wild-type tumors and RAS mutant tumors

Summary

Introduction

According to current guidelines, testing for RAS and BRAF (V600E) mutations [1, 2] is recommended before initiating treatment in metastatic colorectal cancer (mCRC). EGFR (epithelial growth factor receptor) antibodies are not efficient in RAS (rat sarcoma) mutant tumors [3] and may even have a detrimental effect on overall survival (OS) if used in combination with oxaliplatin [4, 5]. The use of the anti-EGFR-antibodies cetuximab and panitumumab is restricted to patients with tumors not carrying a RAS mutation. Besides this negative predictive value of RAS mutations for anti-EGFR strategies both RAS and BRAF mutations have been found to be prognostic for OS [6]. The EGFR (epithelial growth factor receptor) ligands amphiregulin (AREG) and epiregulin (EREG) have been considered as predictors for EGFR-antibody efficacy. The effect of AREG and EREG expression levels in primary tumor samples on the outcome of bevacizumab-treated patients is unknown

Results

Discussion

Conclusion