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There is growing evidence that estrogen receptors (ER) are expressed in lung cancer cells, and are able to interact with the epidermal growth factor receptor (EGFR) signaling pathway. However, data on the association between cytoplasmic ER expression and the response to EGFR-tyrosine kinase inhibitors (TKI) treatment are limited. The aim of the present study was to investigate the associations between ERα/ERβ expression and EGFR mutational status and response to TKI treatment in metastatic lung adenocarcinoma. A retrospective study of 126 consecutive patients with lung adenocarcinoma who were diagnosed with stage IV disease and had received EGFR-TKI treatment was conducted. ER expression was detected by immunohistochemistry. EGFR and GTPase KRas (KRAS) mutational statuses were evaluated by denaturing high performance liquid chromatography and PCR-restriction fragment length polymorphism, respectively. In the overall cohort of 126 lung adenocarcinoma samples analyzed, ERα expression in the nucleus of tumor cells was identified in 17 (18.9%) patients, whereas ERβ expression was identified in the nucleus (22/126, 17.5%) and cytoplasm (17/126, 13.5%). The nuclear expression of ERβ was positively associated with the degree of tumor differentiation (P=0.010). EGFR-sensitizing mutations were significantly associated with improved objective response rates (ORR), disease control rates (DCR), median progression-free survival (mPFS) and median overall survival (mOS) (P&lt;0.001; P&lt;0.001; P=0.003; and P=0.026, respectively). Patients with cytoplasmic ERβ expression exhibited non-significant poorer ORR, DCR, mPFS and mOS compared with patients without cytoplasmic ERβ expression (P=0.082; P=0.106; P=0.084; and P=0.119, respectively). However, the significant decrease of ORR, DCR and mPFS was observed in patients with coexisting cytoplasmic ERβ expression and EGFR-sensitizing mutations (P=0.030; P=0.009; and P=0.018, respectively) in comparison with the subgroup with EGFR sensitizing mutations but negative expression of cytoplasmic ERβ. A trend towards shorter mOS was also observed in patients with coexisting cytoplasmic ERβ expression and EGFR-sensitizing mutations (P=0.071). No KRAS mutations were identified in patients with cytoplasmic ERβ expression. Subsequent to adjusting for sex, smoking status and EGFR mutation status, the Cox repression analysis indicated that cytoplasmic expression of ERβ was a negative independent predictor for mPFS in the whole patient cohort (HR=1.870; 95% confidence interval 1.058-3.305; P=0.031). Cytoplasmic ERβ expression was negatively correlated with the efficacy of EGFR-TKI treatment for metastatic lung adenocarcinoma, particularly for patients with coexisting cytoplasmic ERβ expression and EGFR-sensitizing mutations. Cytoplasmic ERβ may be a promising marker to predict the outcome of EGFR-TKI treatment.

Cytoplasmic expression of estrogen receptor β may predict poor outcome of EGFR‑TKI therapy in metastatic lung adenocarcinoma