Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2020 Dec 15;26(24):6559-6567.
doi: 10.1158/1078-0432.CCR-20-2748. Epub 2020 Sep 17.

Amphiregulin Expression Is a Predictive Biomarker for EGFR Inhibition in Metastatic Colorectal Cancer: Combined Analysis of Three Randomized Trials

Arndt Stahler  1 , Sebastian Stintzing  2   3 , Dominik P Modest  3   4 , Ingrid Ricard  5 , Clemens Giessen-Jung  5 , Christine Kapaun  6 , Boryana Ivanova  6 , Florian Kaiser  7 , Ludwig Fischer von Weikersthal  8 , Nicolas Moosmann  9 , Andreas Schalhorn  5 , Martina Stauch  10 , Alexander Kiani  11 , Swantje Held  12 , Thomas Decker  13 , Markus Moehler  14 , Jens Neumann  3   6 , Thomas Kirchner  3   6 , Andreas Jung  3   6 , Volker Heinemann  5   3
Affiliations

Amphiregulin Expression Is a Predictive Biomarker for EGFR Inhibition in Metastatic Colorectal Cancer: Combined Analysis of Three Randomized Trials

Arndt Stahler et al. Clin Cancer Res. .

Abstract

Purpose: Amphiregulin (AREG) and epiregulin (EREG) are ligands of EGFR. Predictive information for anti-EGFR treatment in metastatic colorectal cancer (mCRC) was observed, but data for other agents is limited.

Experimental design: Ligand mRNA expression; RAS, BRAF, PIK3CA mutations; and EGFR expression were assessed by qRT-PCR, pyrosequencing, and IHC, respectively, in mCRC tumor tissue of patients participating in the randomized controlled trials FIRE-1, CIOX, and FIRE-3. Normalized mRNA expression was dichotomized using median and third quartile. Overall (OS) and progression-free survival (PFS) were estimated by Kaplan-Meier method including univariate and multivariate Cox regression analyses. Penalized spline regression analysis tested interaction of mRNA expression and outcome.

Results: Of 688 patients with available material, high AREG expression was detected in 343 (>median) and 172 (>3rd quartile) patients. High AREG expression was associated with significantly higher OS [26.2 vs. 21.5 months, HR = 0.80; 95% confidence interval (CI), 0.68-0.94; P = 0.007], PFS (10.0 vs. 8.1 months, HR = 0.74; 95% CI, 0.63-0.86; P = 0.001), and objective response rate (63.1% vs. 51.6%, P = 0.004) compared to low expression at both threshold values. This effect remained significant in multivariate Cox regression analysis (OS: P = 0.01, PFS: P = 0.002). High AREG mRNA expression interacted significantly with the efficacy of cetuximab compared with bevacizumab (OS: P = 0.02, PFS: P = 0.04) in RAS WT mCRC.

Conclusions: High AREG mRNA expression is a favorable prognostic biomarker for mCRC which interacted significantly with efficacy of anti-EGFR treatment.

PubMed Disclaimer

References

    1. Holch JW, Ricard I, Stintzing S, Modest DP, Heinemann V. The relevance of primary tumour location in patients with metastatic colorectal cancer: a meta-analysis of first-line clinical trials. Eur J Cancer. 2017;70:87–98.
    1. Arnold D, Lueza B, Douillard JY, Peeters M, Lenz HJ, Venook A, et al. Prognostic and predictive value of primary tumour side in patients with RAS wild-type metastatic colorectal cancer treated with chemotherapy and EGFR directed antibodies in six randomized trials. Ann Oncol. 2017;28:1713–29.
    1. Carpenter BL, Chen M, Knifley T, Davis KA, Harrison SM, Stewart RL, et al. Integrin alpha6beta4 promotes autocrine epidermal growth factor receptor (EGFR) signaling to stimulate migration and invasion toward hepatocyte growth factor (HGF). J Biol Chem. 2015;290:27228–38.
    1. Carpenter BL, Liu J, Qi L, Wang C, O'Connor KL. Integrin alpha6beta4 upregulates amphiregulin and epiregulin through base excision repair-mediated DNA demethylation and promotes genome-wide DNA hypomethylation. Sci Rep. 2017;7:6174.
    1. Lee MS, McGuffey EJ, Morris JS, Manyam G, Baladandayuthapani V, Wei W, et al. Association of CpG island methylator phenotype and EREG/AREG methylation and expression in colorectal cancer. Br J Cancer. 2016;114:1352–61.

Publication types

MeSH terms