Background: Targeted therapy with epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) for lung adenocarcinoma still inevitably leads to drug resistance. The estrogen pathway interacts with the epidermal growth factor receptor (EGFR) signaling pathway, which is a potential combined therapeutic approach. However, findings from some previous preclinical studies evaluating the combination of EGFR-TKI with estrogen receptor antagonists have been inconsistent. The failure to stratify tumors based on the expression status of estrogen receptors may partly explain the inconsistency in the reported results. This study aims to explore the correlation between the expression status of G protein-coupled estrogen receptor (GPER), estrogen receptor α (ERα), and estrogen receptor β (ERβ) in lung adenocarcinoma with malignant pleural effusion (MPE) and the treatment outcomes of patients receiving EGFR-TKI.

Methods: The clinical data of 106 lung cancer patients with MPE at the initial diagnosis were retrospectively analyzed. The expression of GPER, ERα and ERβ in the malignant pleural effusion cell blocks of the patients was detected using immunohistochemistry, and the expression correlation among GPER, ERα and ERβ was analyzed using Spearman method. The Kaplan-Meier method and log-rank test were used to compare the effects of different expression levels of GPER, ERα, and ERβ on the progression-free survival (PFS) of patients. The Cox proportional hazards model was used to analyze the independent risk factors influencing the PFS rate of patients.

Results: Among these 106 cases, a total of 68 cases (64.2%) tested positive for GPER, 56 cases (52.8%) tested positive for ERα, and 60 cases (56.6%) tested positive for ERβ. The expression levels of GPER, ERα and ERβ were significantly correlated. Specifically, for ERα and GPER, r_s = 0.515, p < 0.001; ERβ and GPER, r_s = 0.497, p < 0.001; ERα and ERβ, r_s = 0.469, p < 0.001. The objective response rate (ORR) of GPER-positive patients was lower than that of GPER-negative patients (48.5% vs 73.7%, p = 0.012). The 12-month PFS rates of the GPER positive group and the GPER negative group were 41.0% and 57.9%, respectively, and the median PFS of the GPER positive group and the GPER negative group were 10.6 months and 13.2 months, respectively (p = 0.035). Cox multivariate analysis confirmed that positive GPER was significantly and independently associated with a shorter PFS (hazard ratio [HR] 2.003, 95% CI 1.231–3.259, p = 0.005).

Conclusion: High expression of GPER in advanced lung adenocarcinoma with malignant pleural effusion is a negative predictor of the efficacy of EGFR-TKI in these patients. Further prospective studies based on the stratification of GPER expression are warranted to understand the differences in the therapeutic effects of anti-estrogen treatment among patients with different levels of GPER expression.