Background: The incidence of lung cancer is increasing dramatically in women and displays some specific epidemiological, radiological, clinical and pathological characteristics. Two main mechanisms emerged from recent findings in the field of lung carcinogenesis in women: the preferential involvement of the EGFR pathway and the potential impact of hormonal factors. The interaction of estrogen receptors with growth factor receptor signalling has also been shown. Preclinical data have shown that the combination of an EGFR-Tyrosine Kinase Inhibitor (TKI) with an anti-estrogen could overcome resistance to EGFR-TKI by postponing the reactivation of the PI3K-AKT pathway through the estrogen-mediated non-genomic pathway. Methods: We launched an open-label phase II randomized trial dedicated to women with advanced stage adenocarcinoma. Patients are treated by gefitinib (250 mg/d) vs. gefitinib + fulvestrant 500 mg MI / month (with a supplementary dose at day 15) in the EGFR mutated group (EGFR +) in first or second line setting and by erlotinib (150 mg/d, according to marketing authorization at trial initiation) vs. erlotinib + fulvestrant in the EGFR wild-type group (EGFR WT) in second or third line setting. Treatments are given until progression or unacceptable toxicity. Follow-up is performed in both arms every month to minimize the potential bias due to monthly fulvestrant injection. Primary objective is progression-free survival (PFS) at 3 and 9 months for EGFR WT and EGFR + patients, respectively. Secondary objectives are safety, overall survival and quality of life. Exploratory objective is biomarkers analysis. The main inclusion criteria are histologically-confirmed non-squamous NSCLC, available tumor tissue for EGFR mutation analysis, post-menopausal women, PS 0-2. The study has been approved by all ethical committees. First patients have been enrolled in May 2012. To date, 223 patients (89 EGFR+, 134 EGFR WT) have been enrolled and 394 (204 EGFR +, 190 EGFR WT) are expected. Clinical trial registry number NCT01556191. Clinical trial information: NCT01556191