Menopausal Hormone Therapy, Hormone Receptor Status, and Lung Cancer in Women

Gender differences in lung cancer incidence and outcome suggest a potential role for reproductive hormones. However, observational studies regarding menopausal hormone therapy use and lung cancer have given mixed results. Some have associated hormone therapy use with increased lung cancer risk, while others have shown no effect or found lower lung cancer risk in hormone therapy users. Against this background the Women's Health Initiative (WHI) randomized controlled trial evaluating conjugated equine estrogen (CEE) and medroxyprogesterone acetate (MPA) in postmenopausal women identified an increase in malignancies in the hormone therapy group during the post intervention period. Post hoc analyses identified a statistically significant increase in deaths from lung cancer for women in the hormone group largely related to effects on non-small cell lung cancer (NSCLC). The NSCLCs were more commonly poorly differentiated and were diagnosed at a metastatic stage, suggesting a hormone effect on already established lung cancer growth. Ongoing preclinical and clinical analyses have identified estrogen receptors in the nucleus and cytoplasm of lung tissue and lung cancers. More recently, intriguing associations among estrogen receptor expression, lung cancer histology, clinical prognosis, and epidermal growth factor receptor (EGFR) mutations have been reported. The WHI clinical findings should be integrated into risk-benefit discussion with women considering combined hormone therapy use. In addition, the findings, together with ongoing studies evaluating estrogen receptor status and function, support further efforts to develop lung cancer intervention strategies targeting estrogen receptor expression.