Increases of Amphiregulin and Transforming Growth Factor-α in Serum as Predictors of Poor Response to Gefitinib among Patients with Advanced Non–Small Cell Lung Cancers

Abstract

Serum levels of amphiregulin and transforming growth factor-A (TGF-A), which were identified previously to be expressed at high levels in non-small cell lung cancer (NSCLC) with poor response to gefitinib, were examined by ELISA using blood samples taken from 50 patients with advanced NSCLCs. Of 14 cases that revealed above the cutoff line for amphiregulin in serum, 12 responded poorly to gefitinib, whereas 18 of the 36 cases showing below the cutoff revealed partial response (PR) or stable disease (SD; P = 0.026). Thirteen of 15 patients who were positive for TGF-A responded poorly to gefitinib, whereas 18 of the 35 patients with negative TGF-A levels turned out to be relatively good responders (P = 0.014). Of 22 patients with positive values for either or both markers, 19 were poor responders. On the other hand, among 28 patients negative for both markers, 17 were classified into the PR or SD groups (P = 0.001). Gefitinib-treated NSCLC patients whose serum amphiregulin or TGF-A was positive showed a poorer tumor-specific survival (P = 0.037 and 0.002, respectively, by univariate analysis) compared with those whose serum amphiregulin or TGF-A concentrations were negative. Multivariate analysis showed an independent association between positivity for TGF-A and shorter survival times among NSCLC patients treated with gefitinib (P = 0.034). Amphiregulin or TGF-A positivity in NSCLC tissues was significantly higher in male, nonadenocarcinomas, and smokers. Our data suggest that the status of amphiregulin and TGF-A in serum can be an important predictor of the resistance to gefitinib among patients with advanced NSCLC. (Cancer Res 2005; 65(20): 9176-84)

Alteration of the serum levels of the epidermal growth factor receptor and its ligands in patients with non-small cell lung cancer and head and neck carcinoma

“…For AR, we found a significant decrease in HNC, whereas in NSCLC patients only a trend to impairment was detected. To our knowledge, there is only one report on serum AR and TGF-a in advanced NSCLC (healthy donors not measured) studying the relationship of their serum levels with the response of patients to gefitinib (Ishikawa et al, 2005). In that work, AR and TGF-a levels were detected with the same commercial antibodies used here and were quite similar to the ones shown by us.…”

“…Our data also agree with their observation of a high-value dispersion. Interestingly, those authors proposed that the value of AR correlates with the distinct response of the patients to the drug (Ishikawa et al, 2005). Therefore, further studies to establish if the serum levels of AR during treatment are useful for predicting chemosensitivity of patients, will be of great aid.…”

The increasing role of amphiregulin in non-small cell lung cancer

“…These data are confirmed by RT-PCR, immunohistochemistry, and serologic ELISA assays : AREG is indeed significantly overexpressed in gefitinib non-responders but undetectable in responders. Moreover, NSCLC patients with the worst prognosis and a shorter survival time present high levels of seric AREG, which is correlated with gefitinib resistance [4]. This subset of gefitinib non responders patients contains principally males, smokers with non-adenocarcinomas NSCLC.…”

A Monoclonal Antibody to ADAM17 Inhibits Tumor Growth by Inhibiting EGFR and Non–EGFR-Mediated Pathways

“…High expression of both ADAM17 and TGFa correlate with reduced survival in breast cancer as well as in other indications (7). Amphiregulin and TGFa are both elevated in progressing gefitinib-treated patients relative to those patients with partial clinical responses or stable disease (8). Furthermore,ADAM17 has been implicated in the shedding of HER pathway-independent cytokines, growth factors, receptors, and adhesion molecules (reviewed in ref.…”