Clinical significance of pretreatment serum amphiregulin and transforming growth factor‐α, and an epidermal growth factor receptor somatic mutation in patients with advanced non‐squamous, non‐small cell lung cancer

Abstract

Circulating amphiregulin and transforming growth factor-a (TGF-a) have been found to be correlated with an unfavorable response to gefitinib based on the identification of patients with a higher probability of resistance to the drug. However, the association between an epidermal growth factor receptor (EGFR) somatic mutation and the overexpression of its ligands has not been determined. To verify the clinical significance of the two serum markers and EGFR mutation status, we determined serum amphiregulin and TGF-a levels by enzyme-linked immunosorbent assay in 93 patients with advanced non-squamous, non-small cell lung cancer and EGFR somatic mutation status using the peptic nucleic acid-locked nucleic acid clamp method in 46 cases. The relationship between each independent clinicopathological variable and the response to gefitinib therapy was examined. We also evaluated the risk factors associated with prognosis. Fourteen (41.0%) of 34 progressive disease cases were positive for amphiregulin (P = 0.007). Eleven (32.4%) of 34 progressive disease cases were positive for TGF-a (P = 0.005). The median survival time of patients with the EGFR somatic mutation was significantly longer (P = 0.01). The same was true of amphiregulin-(P = 0.046) and TGF-a-negative patients (P < 0.01). In multivariate analysis, serum TGF-a positivity (hazard ratio, 2.558; P = 0.005) and the wild type EGFR gene (hazard ratio, 1.894; P = 0.003) were significant independent prognostic factors. Our study demonstrates that the status of the serum EGFR ligand, in addition to EGFR activating mutation, is a predictive factor for response to gefitinib therapy. (Cancer Sci 2008; 99: 2295-2301)

Amphiregulin and Epiregulin Expression in Colorectal Carcinoma and the Correlation with Clinicopathological Characteristics

“…Several other studies have reported thatAREGup-regulationisoneofthebiomarkerspredicting gefitinibnon-responsivenessandmighthencebeapredictor of response to gefitinib therapy [9,10,24]. In the future, research on AREG and EREG may involve other malignancies.…”

“…AREG induces tyrosine phosphorylation of the EGFR, and downstream activation of the extra-cellular regulated kinase signalingcascade [3].EREGhasbeencharacterizedtobean autocrine growth factor in keratinocytes in vitro [4]. Both AREG and EREG show bifunctional regulatory activity: stimulating the proliferation of fibroblasts, hepatocytes, smooth muscle cells, and keratinocytes but inhibiting the growthofseveraltumor-derivedcelllines [5][6][7][8].Somestudies have confirmed clinical roles of AREG and EREG, such as acting as predictive markers for some anti-tumor agents, as prognosticfactorsfornon-smallcelllungcancer(NSCLC) [9,10], as prognostic markers for liver metastases of colorectal carcinoma (CRC) [11], and as ligands for testing specific HER1 tyrosine kinase inhibitors in clinical trails of human prostatecancer [12].SerumAREGlevelhasbeenexamined in NSCLC, but has never been reported in CRC. As for EREG,itsserumlevelhasnotbeenreportedinanycancer.…”

Hypertension and Circulating Cytokines and Angiogenic Factors in Patients With Advanced Non-Clear Cell Renal Cell Carcinoma Treated With Sunitinib: Results From a Phase II Trial

“…Similarly, TGF-a has been associated with prognosis or a poor response to treatment in a number of cancers, but no data were previously available for RCC [36][37][38]. A member of the epidermal growth factor (EGF) family and a ligand of the EGF receptor, TGF-a is upregulated by hypoxia-inducible factor in RCC and was found sufficient to promote the growth of ccRCC tumor cells [39].…”

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

“…18 In contrast, increased levels of AR in serum were correlated with a poor response to gefitinib in patients with advanced NSCLC. 20,29 Other investigators have reported that AR overexpression promotes resistance rather than sensitivity to gefitinib in patients with NSCLC through inhibition of the Bcl2-associated X protein BAX. 30 These discrepancies may be explained by the heterogeneous methods that were used to detect AR expression, different cancer types, and differences in AR distribution between local tumors and systemic circulation.…”