Background: CALGB 40503 testedwhether therapy with B prolongs PFS when added to first-line L as treatment of hormone receptor-positive (HR+) MBC. We aimed to identify germline variants associated with clinical outcome. Methods: Postmenopausal women with HR+ MBC were randomized 1:1 in a multicenter, open-label, phase III trial of L (2.5 mg orally/day) with or without B (15 mg/kg IV every 3 weeks). 343 patients received treatment. The primary endpoint of the study was PFS. The addition of B resulted in a significant reduction in the hazard of progression (hazard ratio [HR] = 0.75, 95% CI = 0.59-0.96; p = 0.016) and a prolongation in median PFS from 15.6 to 20.2 months with L and L+B, respectively (Dickler MN et al., ASCO 2015). DNA was extracted from peripheral blood and genotyped on the Illumina OmniExpress Exome chip for ~700,000 single-nucleotide polymorphisms (SNPs). The association between SNPs and PFS in 210 patients of estimated European genetic ancestry was tested by a Cox proportional hazards model using B as a stratification factor. Results: Median PFS in genotyped patients was 17.9 months. The top ranked SNP was rs9916211 (HR 2.15, 1.58-2.92, p < 1.04x10^-6). rs9916211 (C to T) is a common germline variant (16% frequency) located in close proximity (~4 Kb) of TMEM132E gene. Median PFS for patients with the CC, CT or TT genotypes of rs9916211 was 20.70 (17.7-24.4), 12.71 (10.9-18.2) or 2.33 (2.2-4.6) months, respectively. TMEM132E codes for transmembrane protein 132E. Germline variants in TMEM132E have been reported as genetic modifiers of the risk of breast cancer in menopausal women taking hormone replacement therapy (Rudolph A et al., 2013). Conclusions: To our knowledge, this is the first GWAS ever reported in HR+ MBC patients treated with L. The top hit is a common variant in TMEM132E and confers worse PFS. This study selects TMEM132E as a new putative determinant of MBC progression in HR+ patients treated with endocrine therapy. This result may point towards a role of gene modifiers of breast cancer risk as determinants of clinical outcome. Further replication in additional patients is required.