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

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; Collaborators 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; Investigators 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

doi:10.1038/s41523-025-00733-y

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

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, Collaborators 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, Investigators 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

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

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.

Original language	English
Article number	18
Journal	NPJ breast cancer
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41523-025-00733-y
Publication status	Published - 19 Feb 2025

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s41523-025-00733-yFinal published version, 2.08 MBLicence: CC BY-NC-ND

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Hoppe, R., Winter, S., Lo, W. Y., Michailidou, K., Bolla, M. K., Keeman, R., Wang, Q., Dennis, J., Lush, M., Kalari, K. R., Goetz, M. P., Wang, L., Cairns, J., Weinshilboum, R., Shepherd, L., Chen, B. E., Häberle, L., Ruebner, M., Beckmann, M. W., ... Brauch, H. (2025). Lessons learned from a candidate gene study investigating aromatase inhibitor treatment outcome in breast cancer. NPJ breast cancer, 11(1), Article 18. https://doi.org/10.1038/s41523-025-00733-y

@article{8e9bafa04b28440ca0ad070a12cf44a6,

title = "Lessons learned from a candidate gene study investigating aromatase inhibitor treatment outcome in breast cancer",

abstract = "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.",

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

note = "Publisher Copyright: {\textcopyright} The Author(s) 2025.",

year = "2025",

month = feb,

day = "19",

doi = "10.1038/s41523-025-00733-y",

language = "English",

volume = "11",

journal = "NPJ breast cancer",

issn = "2374-4677",

publisher = "Springer Nature",

number = "1",

}

Hoppe, R, Winter, S, Lo, WY, 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, C, 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, I, John, EM, Ko, YD, Kristensen, VN, Linn, S, Margolin, S, Mavroudis, D, Nevanlinna, H, Neven, P, Obi, N, Park-Simon, TW, 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 2025, 'Lessons learned from a candidate gene study investigating aromatase inhibitor treatment outcome in breast cancer', NPJ breast cancer, vol. 11, no. 1, 18. https://doi.org/10.1038/s41523-025-00733-y

TY - JOUR

T1 - Lessons learned from a candidate gene study investigating aromatase inhibitor treatment outcome in breast cancer

AU - Hoppe, Reiner

AU - Winter, Stefan

AU - Lo, Wing Yee

AU - Michailidou, Kyriaki

AU - Bolla, Manjeet K.

AU - Keeman, Renske

AU - Wang, Qin

AU - Dennis, Joe

AU - Lush, Michael

AU - Kalari, Krishna R.

AU - Goetz, Matthew P.

AU - Wang, Liewei

AU - Cairns, Junmei

AU - Weinshilboum, Richard

AU - Shepherd, Lois

AU - Chen, Bingshu E.

AU - Häberle, Lothar

AU - Ruebner, Matthias

AU - Beckmann, Matthias W.

AU - He, Wei

AU - Larson, Nicole L.

AU - Armasu, Sebastian M.

AU - Schroth, Werner

AU - Chowbay, Balram

AU - Khor, Chiea Chuen

AU - Abubakar, Mustapha

AU - Antoniou, Antonis C.

AU - Brüning, Thomas

AU - Castelao, Jose E.

AU - Chang-Claude, Jenny

AU - NBCS Collaborators, Collaborators

AU - Dörk, Thilo

AU - Eccles, Diana M.

AU - Figueroa, Jonine D.

AU - Gago-Dominguez, Manuela

AU - García-Sáenz, José A.

AU - Gündert, Melanie

AU - Hack, Carolin C.

AU - Hamann, Ute

AU - Han, Sileny

AU - Hooning, Maartje J.

AU - Huebner, Hanna

AU - ABCTB Investigators, Investigators

AU - John, Esther M.

AU - Ko, Yon Dschun

AU - Kristensen, Vessela N.

AU - Linn, Sabine

AU - Margolin, Sara

AU - Mavroudis, Dimitrios

AU - Nevanlinna, Heli

AU - Neven, Patrick

AU - Obi, Nadia

AU - Park-Simon, Tjoung Won

AU - Pylkäs, Katri

AU - Rashid, Muhammad U.

AU - Romero, Atocha

AU - Saloustros, Emmanouil

AU - Sawyer, Elinor J.

AU - Tapper, William J.

AU - Tomlinson, Ian

AU - Wendt, Camilla

AU - Winqvist, Robert

AU - Dunning, Alison M.

AU - Simard, Jacques

AU - Hall, Per

AU - Pharoah, Paul D.P.

AU - Schwab, Matthias

AU - Couch, Fergus J.

AU - Czene, Kamila

AU - Fasching, Peter A.

AU - Easton, Douglas F.

AU - Schmidt, Marjanka K.

AU - Ingle, James N.

AU - Brauch, Hiltrud

PY - 2025/2/19

Y1 - 2025/2/19

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85218491572

U2 - 10.1038/s41523-025-00733-y

DO - 10.1038/s41523-025-00733-y

M3 - Article

AN - SCOPUS:85218491572

SN - 2374-4677

VL - 11

JO - NPJ breast cancer

JF - NPJ breast cancer

IS - 1

M1 - 18

ER -

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

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