The Impact of Estrogen Receptor Expression on Mutational Status in the Evolution of Non-Small Cell Lung Cancer

Background: The role of estrogen receptor (ER) status in the carcinogenesis of lung cancer and its impact on prognosis remain unclear.

Materials and methods: We previously reported a prospective, multicenter, molecular epidemiology study (Japan Molecular Epidemiology for Lung Cancer Study [JME]). We examined the relationship of ER status with reproductive and hormonal factors, mutational profile, and survival using JME study data. Patients were enrolled between July 2012 and December 2013, with follow-up until November, 2017.

Results: Among 441 ever- and 435 never-smokers, ER expression was observed in 46.4% and 53.5%, respectively (P = .022). Hormone use and reproductive history of female patients were not associated with ER status. Mutations in EGFR (P = .003), TP53 (P = .007), and CTNNB1 (P = .027) were significantly associated with ER expression. Multivariate analysis showed that mutations in EGFR (P = .032) and CTNNB1 (P = .026) were significantly associated with ER expression, whereas TP53 mutations exhibited a trend toward significance (P = .059). Relapse-free survival (RFS) was longer in all the patients with ER-positive tumors than those with ER-negative tumors (P = .021). RFS and overall survival were longer (P = .024, P = .011, respectively) in the stage I patients with ER-positive tumors than those with ER-negative tumors.

Conclusion: ERβ expression is positively associated with EGFR mutations and negatively with TP53 and CTNNB1 mutations. ER-positive tumors can be associated with better prognosis of the patients, suggesting that ER expression with coexisting EGFR mutations and wild-type TP53 contribute to the biology of non-small cell lung cancer.