| Title: |
Lessons learned from a candidate gene study investigating aromatase inhibitor treatment outcome in breast cancer |
| Authors: |
Hoppe,Reiner; Winter,Stefan; Lo,Wing Yee; Michailidou,Kyriaki; Bolla,Manjeet K.; Keeman,Renske; Wang,Qin; Dennis,Joe; Lush,Michael; Kalari,Krishna R.; Goetz,Matthew P.; Wang,Liewei; Cairns,Junmei; Weinshilboum,Richard; Shepherd,Lois; Chen,Bingshu E.; Häberle,Lothar; Ruebner,Matthias; Beckmann,Matthias W.; He,Wei; Larson,Nicole L.; Armasu,Sebastian M.; Schroth,Werner; Chowbay,Balram; Khor,Chiea Chuen; Abubakar,Mustapha; Antoniou,Antonis C.; Brüning,Thomas; Castelao,Jose E.; Chang-Claude,Jenny; NBCS Collaborators,Collaborators; Dörk,Thilo; Eccles,Diana M.; Figueroa,Jonine D.; Gago-Dominguez,Manuela; García-Sáenz,José A.; Gündert,Melanie; Hack,Carolin C.; Hamann,Ute; Han,Sileny; Hooning,Maartje J.; Huebner,Hanna; ABCTB Investigators,Investigators; John,Esther M.; Ko,Yon Dschun; Kristensen,Vessela N.; Linn, Sabine; Margolin,Sara; Mavroudis,Dimitrios; Nevanlinna,Heli; Neven,Patrick; Obi,Nadia; Park-Simon,Tjoung Won; Pylkäs,Katri; Rashid,Muhammad U.; Romero,Atocha; Saloustros,Emmanouil; Sawyer,Elinor J.; Tapper,William J.; Tomlinson,Ian; Wendt,Camilla; Winqvist,Robert; Dunning,Alison M.; Simard,Jacques; Hall,Per; Pharoah,Paul D.P.; Schwab,Matthias; Couch,Fergus J.; Czene,Kamila; Fasching,Peter A.; Easton,Douglas F.; Schmidt,Marjanka K.; Ingle,James N.; Brauch,Hiltrud; Cancer; Pathologie |
| Publication Year: |
2025 |
| Subject Terms: |
Oncology; Radiology Nuclear Medicine and imaging; Pharmacology (medical) |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| File Description: |
text/plain |
| Language: |
English |
| ISSN: |
2374-4677 |
| Relation: |
https://dspace.library.uu.nl/handle/1874/460767 |
| Availability: |
https://dspace.library.uu.nl/handle/1874/460767 |
| Rights: |
info:eu-repo/semantics/OpenAccess |
| Accession Number: |
edsbas.7B78BD62 |
| Database: |
BASE |