biostudies-literatureHoppe RBundesministerium für Bildung und Forschung (Federal Ministry of Education and Research)Canadian Cancer Society Research Institute (Société Canadienne du Cancer)Cancer Research UKBreast Cancer NowDeutsche Forschungsgemeinschaft (German Research Foundation)EC | EC Seventh Framework Programm | FP7 Health (FP7-HEALTH - Specific Programme "Cooperation": Health)MOH | National Medical Research Council (NMRC)National Institute for Health Research (NIHR)NCI NIH HHSNIGMS NIH HHSDeutsche Krebshilfe (German Cancer Aid)18https://www.ebi.ac.uk/biostudies/studies/S-EPMC11840073biostudies-literatureUnknown11(1)The role of germline genetics in adjuvant aromatase inhibitor (AI) treatment efficacy in ER-positive breast cancer is poorly understood. We employed a two-stage candidate gene approach to examine associations between survival endpoints and common germline variants in 753 endocrine resistance-related genes. For a discovery cohort, we screened the Breast Cancer Association Consortium database (n ≥ 90,000 cases) and retrieved 2789 AI-treated patients. Cox model-based analysis revealed 125 variants associated with overall, distant relapse-free, and relapse-free survival (p-value ≤ 1E-04). In validation analysis using five independent cohorts (n = 8857), none of the six selected candidates representing major linkage blocks at CELA2B/CASP9, NR1I2/GSK3B, LRP1B, and MIR143HG (CARMN) were validatedNPJ breast cancerLessons learned from a candidate gene study investigating aromatase inhibitor treatment outcome in breast cancer.PMC11840073C5047/A10692NIHR20331201KW9976/8U19 CA148537110828110826C12292/A11174C1287/A10118C1281/A12014C1287/A10710R01 CA1289782010PR62U19 CA148065R35 CA253187108419106332C1275/C22524R01 CA176785DFG Do761/15-1C1275/A11699MOH-000984P50 CA116201EXC 2180-39090067701KW01142013PR044SCHR 1323/2-1HEALTH-F2-2009-223175C1275/A19187BMBF 01ZP050201KH04001KW9975/5U19 GM061388PPRPGM-Nov20\100002C1287/A16563C8197/A16565MOH-000377R01 CA196648R01 CA11616701KW9977/0U01 CA164920NMRC/CIRG/1423/2015C1275/A15956108253U10 CA077202CCS 015469R01 CA19239370-2892-BR IC5047/A8384U19 CA148112C5047/A15007Mavroudis DDork TObi NCairns JKristensen VNAntoniou ACPharoah PDPWang LWang QKeeman REaston DFHoppe RKalari KRSimard JCouch FJTapper WJLo WYBolla MKChang-Claude JWeinshilboum RWendt CAbubakar MGundert MFasching PAHooning MJHall PSchwab MSchmidt MKNevanlinna HNeven PMichailidou KHe WWinqvist RLinn SLush MHaberle LSaloustros ESchroth WPylkas KBrauch HFigueroa JDGarcia-Saenz JAHan STomlinson IChen BENbcs CollaboratorsHuebner HIngle JNShepherd LBeckmann MWKhor CCJohn EMPark-Simon TWWinter SCzene KMargolin SGago-Dominguez MEccles DMRomero ARuebner MDennis JAbctb InvestigatorsSawyer EJArmasu SMKo YDChowbay BHack CCCastelao JEHamann UDunning AMGoetz MPLarson NLBruning TRashid MUfalseLessons learned from a candidate gene study investigating aromatase inhibitor treatment outcome in breast cancer.The role of germline genetics in adjuvant aromatase inhibitor (AI) treatment efficacy in ER-positive breast cancer is poorly understood. We employed a two-stage candidate gene approach to examine associations between survival endpoints and common germline variants in 753 endocrine resistance-related genes. For a discovery cohort, we screened the Breast Cancer Association Consortium database (n ≥ 90,000 cases) and retrieved 2789 AI-treated patients. Cox model-based analysis revealed 125 variants associated with overall, distant relapse-free, and relapse-free survival (p-value ≤ 1E-04). In validation analysis using five independent cohorts (n = 8857), none of the six selected candidates representing major linkage blocks at CELA2B/CASP9, NR1I2/GSK3B, LRP1B, and MIR143HG (CARMN) were validated2025-01-01T00:00:00Z2025 Feb2026-06-02T04:11:50.446Z2025-04-19T21:13:24.016ZS-EPMC118400733997196510.1038/s41523-025-00733-y