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<p>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 (<i>n</i> ≥ 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 (<i>p-</i>value ≤ 1E-04). In validation analysis using five independent cohorts (<i>n</i> = 8857), none of the six selected candidates representing major linkage blocks at <i>CELA2B/CASP9</i>, <i>NR1I2/GSK3B, LRP1B</i>, and <i>MIR143HG</i> (<i>CARMN</i>) 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.</p>

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Lessons learned from a candidate gene study investigating aromatase inhibitor treatment outcome in breast cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年2月19日

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  • Reiner Hoppe,
  • Stefan Winter,
  • Wing-Yee Lo,
  • Kyriaki Michailidou,
  • Manjeet K. Bolla,
  • Renske Keeman,
  • Qin Wang,
  • Joe Dennis,
  • Michael Lush,
  • Krishna R. Kalari,
  • Matthew P. Goetz,
  • Liewei Wang,
  • Junmei Cairns,
  • Richard Weinshilboum,
  • Lois Shepherd,
  • Bingshu E. Chen,
  • Lothar Häberle,
  • Matthias Ruebner,
  • Matthias W. Beckmann,
  • Wei He,
  • Nicole L. Larson,
  • Sebastian M. Armasu,
  • Werner Schroth,
  • Balram Chowbay,
  • Chiea Chuen Khor,
  • Mustapha Abubakar,
  • Antonis C. Antoniou,
  • Thomas Brüning,
  • Jose E. Castelao,
  • Jenny Chang-Claude,
  • NBCS Collaborators,
  • Thilo Dörk,
  • Diana M. Eccles,
  • Jonine D. Figueroa,
  • Manuela Gago-Dominguez,
  • José A. García-Sáenz,
  • Melanie Gündert,
  • Carolin C. Hack,
  • Ute Hamann,
  • Sileny Han,
  • Maartje J. Hooning,
  • Hanna Huebner,
  • ABCTB Investigators,
  • Esther M. John,
  • Yon-Dschun Ko,
  • Vessela N. Kristensen,
  • Sabine Linn,
  • Sara Margolin,
  • Dimitrios Mavroudis,
  • Heli Nevanlinna,
  • Patrick Neven,
  • Nadia Obi,
  • Tjoung-Won Park-Simon,
  • Katri Pylkäs,
  • Muhammad U. Rashid,
  • Atocha Romero,
  • Emmanouil Saloustros,
  • Elinor J. Sawyer,
  • William J. Tapper,
  • Ian Tomlinson,
  • Camilla Wendt,
  • Robert Winqvist,
  • Alison M. Dunning,
  • Jacques Simard,
  • Per Hall,
  • Paul D. P. Pharoah,
  • Matthias Schwab,
  • Fergus J. Couch,
  • Kamila Czene,
  • Peter A. Fasching,
  • Douglas F. Easton,
  • Marjanka K. Schmidt,
  • James N. Ingle,
  • Hiltrud Brauch

摘要

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.