Clinical impact of amphiregulin expression in patients with epidermal growth factor receptor (EGFR) wild‐type nonsmall cell lung cancer treated with EGFR‐tyrosine kinase inhibitors

Chang, Myung Hee; Ahn, Hee Kyung; Lee, Jeeyun; Jung, Chan Kwon; Choi, Yoon–La; Park, Yeon Hee; Ahn, Jin Seok; Park, Keunchil; Ahn, Myung‐Ju

doi:10.1002/cncr.25560

Cited by 35 publications

(41 citation statements)

References 44 publications

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“…Our study showed for the first time that high AREG expression in SCCHN tumors is an independent prognosticator of poor outcome on cetuximab-docetaxel treatment. This is in clear contrast to the results from clinical studies of mCRC (14,15) and NSCLC (26), in which the clinical activity of treatment with the EGFR targeting agents cetuximab, gefitinib, or erlotinib was positively associated with AREG expression. Technical differences in the AREG immunostaining methods as a possible reason for differences in the prognostic value of AREG expression levels are rather unlikely because the same antibody was used in the NSCLC (26) and our study.…”

Section: Discussioncontrasting

confidence: 98%

Expression of Amphiregulin and EGFRvIII Affect Outcome of Patients with Squamous Cell Carcinoma of the Head and Neck Receiving Cetuximab–Docetaxel Treatment

Tinhofer

Klinghammer

Weichert

et al. 2011

Clinical Cancer Research

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Purpose: Constitutive activation of epidermal growth factor receptor (EGFR) as a result of gene amplification, mutation, or overexpression of its ligands has been associated with response to EGFR targeting strategies. The role of these molecular mechanisms for the responsiveness of squamous cell carcinoma of the head and neck (SCCHN) to cetuximab-containing regimens remains unknown.Experimental Design: Tumor biopsies from 47 patients, enrolled in a single-arm phase II multicenter study for second-line treatment of recurrent or metastatic SCCHN with cetuximab and docetaxel, were analyzed by immunohistochemistry for expression of EGFR, its deletion variant III (EGFRvIII) and its ligand amphiregulin (AREG). The relation between expression levels and disease control rate (DCR) was evaluated by logistic regression. Association between expression levels, progression-free survival (PFS), and overall survival (OS) was determined by Kaplan-Meier analysis, log-rank test, and uni-and multivariate Cox regression analysis.Results: High expression of EGFR, EGFRvIII, and AREG was detected in 73%, 17%, and 45% of SCCHN cases, respectively. Expression levels of EGFR had no impact on PFS or OS. High expression levels of EGFRvIII were significantly associated with reduced DCR and shortened PFS (HR: 3.3, P ¼ 0.005) but not with OS. Patients with high AREG expression in tumor cells had significantly shortened OS (HR: 2.2, P ¼ 0.002) and PFS (HR 2.2, P ¼ 0.019) compared with patients with low expression score. Multivariate Cox analysis revealed an independent association of AREG and EGFRvIII with PFS but only AREG was an independent prognosticator of OS.Conclusions: High EGFRvIII and AREG expression levels identify SCCHN patients who are less likely to benefit from combination treatment with cetuximab and docetaxel.

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Section: Discussioncontrasting

confidence: 98%

Expression of Amphiregulin and EGFRvIII Affect Outcome of Patients with Squamous Cell Carcinoma of the Head and Neck Receiving Cetuximab–Docetaxel Treatment

Tinhofer

Klinghammer

Weichert

et al. 2011

Clinical Cancer Research

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“…Interestingly, it was recently reported that high amphiregulin expression could be coupled to shortened overall and progression-free survival during treatment for HNSCC with a combination of cetuximab and docetaxel (Tinhofer et al 2011), thus being a negative predictor of cetuximab response. It was suggested that tissue-specific functions of amphiregulin might explain the contradictory findings in mCRC (Jacobs et al 2009;Khambata-Ford et al 2007), NSCLC (Chang et al 2011;Yonesaka et al 2008) and HNSCC. An observation from our work is that several of the cell lines that release amphiregulin under ordinary growth conditions do not release more growth factor when treated with ligand-binding competitor.…”

Section: Discussionmentioning

confidence: 97%

Autocrine epidermal growth factor receptor ligand production and cetuximab response in head and neck squamous cell carcinoma cell lines

Oshima

Wennerberg

Yamatodani

et al. 2011

J Cancer Res Clin Oncol

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“…Recently, Chang et al [28] analyzed the expression of amphiregulin, a novel molecular biomarker, in patients with EGFR wild-type NSCLC who were treated with EGFR-TKIs. They reported that, although the relationship with DCR was not statistically significant, positive amphiregulin status using immunohistochemical staining was associated with prolonged PFS and OS.…”

Section: Discussionmentioning

confidence: 99%

A phase II trial of erlotinib in patients with EGFR wild-type advanced non-small-cell lung cancer

Kobayashi

Koizumi

Agatsuma

et al. 2012

Cancer Chemother Pharmacol

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Clinical impact of amphiregulin expression in patients with epidermal growth factor receptor (EGFR) wild‐type nonsmall cell lung cancer treated with EGFR‐tyrosine kinase inhibitors

Cited by 35 publications

References 44 publications

Expression of Amphiregulin and EGFRvIII Affect Outcome of Patients with Squamous Cell Carcinoma of the Head and Neck Receiving Cetuximab–Docetaxel Treatment

Expression of Amphiregulin and EGFRvIII Affect Outcome of Patients with Squamous Cell Carcinoma of the Head and Neck Receiving Cetuximab–Docetaxel Treatment

Autocrine epidermal growth factor receptor ligand production and cetuximab response in head and neck squamous cell carcinoma cell lines

A phase II trial of erlotinib in patients with EGFR wild-type advanced non-small-cell lung cancer

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