Lessons learned from a candidate gene study investigating aromatase inhibitor treatment outcome in breast cancer.
Hoppe R., Winter S., Lo W-Y., Michailidou K., Bolla MK., Keeman R., Wang Q., Dennis J., Lush M., Kalari KR., Goetz MP., Wang L., Cairns J., Weinshilboum R., Shepherd L., Chen BE., Häberle L., Ruebner M., Beckmann MW., He W., Larson NL., Armasu SM., Schroth W., Chowbay B., Khor CC., Abubakar M., Antoniou AC., Brüning T., Castelao JE., Chang-Claude J., Nbcs Collaborators None., Dörk T., Eccles DM., Figueroa JD., Gago-Dominguez M., García-Sáenz JA., Gündert M., Hack CC., Hamann U., Han S., Hooning MJ., Huebner H., Abctb Investigators None., John EM., Ko Y-D., Kristensen VN., Linn S., Margolin S., Mavroudis D., Nevanlinna H., Neven P., Obi N., Park-Simon T-W., Pylkäs K., Rashid MU., Romero A., Saloustros E., Sawyer EJ., Tapper WJ., Tomlinson I., Wendt C., Winqvist R., Dunning AM., Simard J., Hall P., Pharoah PDP., Schwab M., Couch FJ., Czene K., Fasching PA., Easton DF., Schmidt MK., Ingle JN., Brauch H.
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 validated. We discuss potential reasons for the failed validation and replication of published findings, including study/treatment heterogeneity and other limitations inherent to genomic treatment outcome studies. For the future, we envision prospective longitudinal studies with sufficiently long follow-up and endpoints that reflect the dynamic nature of endocrine resistance.