Prognostic value of the estrogen receptor alpha, ESR1, and aromatase expression in non-small cell lung cancer: A meta-analysis.
Authors: Omar A. Borges-Sosa, Yenny Viviana Pinzón, Arantza Lizbeth Garcia Loera, Natalia Michel Carrillo, Nuria Caravajal Noh, Abril Carrillo, Patricia Silveyra
Journal: Journal of Clinical Oncology (2025)

e20529 Background: Despite the significant advancements in recent decades, lung cancer remains the leading cause of cancer-related mortality. A potential link between estrogen and lung cancer outcomes has been suggested, particularly concerning the roles of estrogen receptor alpha (ER alpha) and aromatase. A meta-analysis was conducted to evaluate the prognostic value of the ER alpha and aromatase protein expression, as well as the ESR1 gene expression in tumor samples. These expressions were categorized as negative versus positive or low versus high. To our knowledge, this is the first meta-analysis that focuses on the protein expression of ER alpha and aromatase in non-small cell lung cancer (NSCLC) patients. Methods: A systematic search was conducted across the PubMed, Embase, and ScienceDirect databases for all articles available until January 2025. The primary outcome evaluated was overall survival (OS). Hazard ratios (HR) for OS were pooled using the Inverse Variance Method, while risk ratios (RR) for OS at three and five years were analyzed using the Mantel-Haenszel method, along with 95% confidence intervals (CI). Mortality rates were estimated based on Kaplan-Meier curves. Statistical analyses were performed using R software version 4.4.2, employing a random effects model. Only pan-protein expression was analyzed; isoforms and mutations were excluded. Results: A total of 17 studies met the eligibility criteria and were included in the analysis. The univariate analysis for OS indicated no significant difference (HR 1.23, IC95% 0.40-3.76) between patients with negative versus positive ER alpha protein expression. Mortality rates at three years (RR 1.20, 95%CI 0.80-1.82) and five years (RR 1.26, 95%CI 0.90-1.77) did not show significant differences in patients with ER alpha. Additionally, the univariate analysis for OS in patients expressing high versus low ESR1 demonstrated no significance (HR 0.84, 95% CI 0.51-1.38). However, the multivariate analysis showed significant differences in patients with high versus low ESR1 gene expression (HR 0.33, IC95% 0.19-0.55, I 2 0%), with a prediction interval (PI) between 0.10 and 1.02. Patients with high protein expression of aromatase showed increased mortality at five years (RR 1.50, 95% CI 1.11-2.02, I 2 0%) compared to those with low expression, with a PI ranging from 0.97 to 2.31. Conclusions: This meta-analysis suggests that high aromatase protein expression is associated with increased mortality at five years, while high ESR1 gene expression is associated with better survival in patients with NSCLC. These findings warrant further investigation to determine their validity as prognostic markers in NSCLC patients, including the development of refined cut-off values. More research is needed to explore survival outcomes in NSCLC patients expressing these estrogen-related proteins and genes.