Predictive Biomarkers for Endocrine Therapy: Retrospective Study in Tamoxifen and Exemestane Adjuvant Multinational (TEAM) Trial

Antonia K Roseweir; Lindsay Bennett; Ashley Dickson; Kelvin Cheng; Mary-Anne Quintayo; Jane Bayani; Donald C McMillan; Paul G Horgan; Cornelis J H van de Velde; Caroline Seynaeve; Annette Hasenburg; Dirk G Kieback; Christos Markopoulos; Luc Y Dirix; Daniel Rea; Elizabeth A Mallon; John M S Bartlett; Joanne Edwards

doi:10.1093/jnci/djx255

Predictive Biomarkers for Endocrine Therapy: Retrospective Study in Tamoxifen and Exemestane Adjuvant Multinational (TEAM) Trial

Antonia K Roseweir, Lindsay Bennett, Ashley Dickson, Kelvin Cheng, Mary-Anne Quintayo, Jane Bayani, Donald C McMillan, Paul G Horgan, Cornelis J H van de Velde, Caroline Seynaeve, Annette Hasenburg, Dirk G Kieback, Christos Markopoulos, Luc Y Dirix, Daniel Rea, Elizabeth A Mallon, John M S Bartlett, Joanne Edwards

Cancer Clinical Trials Unit

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Abstract

Background: Aromatase inhibitors improve disease-free survival compared with tamoxifen in postmenopausal women with hormone receptor-positive breast cancer. The Tamoxifen and Exemestane Adjuvant Multinational (TEAM) trial compared exemestane monotherapy with sequential therapy of tamoxifen followed by exemestane. The trial failed to show a statistically significant difference between treatment arms. A robust translational program was established to investigate predictive biomarkers.

Methods: A tissue microarray was retrospectively constructed using a subset of patient tissues (n = 4631) from the TEAM trial (n = 9766). Immunohistochemistry was performed for biomarkers, classed into three groups: MAPK pathway, NF-kappa B pathway, and estrogen receptor (ER) phosphorylation. Expression was analyzed for association with relapse-free survival (RFS) at 2.5 and 10 years and treatment regimen using Kaplan-Meier curves and log-rank analysis. All statistical tests were two-sided.

Results: In univariate analysis, ER167 (hazard ratio [HR] = 0.71, 95% confidence interval [CI] = 0.59 to 0.85, P < .001), IKKα (HR = 0.74, 95% CI = 0.60 to 0.92, P = .005), Raf-1338 (HR = 0.64, 95% CI = 0.52 to 0.80, P < .001), and p44/42 MAPK202/204 (HR = 0.77, 95% CI = 0.64 to 0.92, P = .004) were statistically significantly associated with improved RFS at 10 years in patients receiving sequential therapy. Associations were strengthened when IKKα, Raf-1338, and ER167 were combined into a cumulative prognostic score (HR = 0.64, 95% CI = 0.52 to 0.77, P < .001). Patients with an all negative IKKα, Raf-1338, and ER167 score favored exemestane monotherapy (odds ratio = 0.56, 95% CI = 0.35 to 0.90). In multivariable analysis, the IKKα, Raf-1338, and ER167 score (P = .001) was an independent prognostic factor for RFS at 10 years in patients receiving sequential therapy.

Conclusions: The IKKα, Raf-1338, and ER167 score is an independent predictive biomarker for lower recurrence on sequential therapy. Negative expression may further offer predictive value for exemestane monotherapy.

Original language	English
Pages (from-to)	616-627
Number of pages	12
Journal	Journal of the National Cancer Institute
Volume	110
Issue number	6
DOIs	https://doi.org/10.1093/jnci/djx255
Publication status	Published - 1 Jun 2018

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Antonia_K_Roseweir_et_al_Predictive_biomarkers_for_endocrine_therapy_JNCI_2018
Checked for eligibility: 28/06/2018 This is a pre-copyedited, author-produced version of an article accepted for publication in JNCI: Journal of the National Cancer Institute following peer review. The version of record: Antonia K Roseweir, Lindsay Bennett, Ashley Dickson, Kelvin Cheng, Mary-Anne Quintayo, Jane Bayani, Donald C McMillan, Paul G Horgan, Cornelis J H van de Velde, Caroline Seynaeve, Annette Hasenburg, Dirk G Kieback, Christos Markopoulos, Luc Y Dirix, Daniel W Rea, Elizabeth A Mallon, John M S Bartlett, Joanne Edwards; Predictive Biomarkers for Endocrine Therapy: Retrospective Study in Tamoxifen and Exemestane Adjuvant Multinational (TEAM) Trial, JNCI: Journal of the National Cancer Institute, Volume 110, Issue 6, 1 June 2018, Pages 616–627 is available online at: https://doi.org/10.1093/jnci/djx255
Accepted author manuscript, 397 KBLicence: Other (please specify with Rights Statement)
Antonia_K_Roseweir_et_al_Predictive_biomarkers_for_endocrine_therapy_JNCI_2018_Supplementary_data
Checked for eligibility: 28/06/2018 This is a pre-copyedited, author-produced version of an article accepted for publication in JNCI: Journal of the National Cancer Institute following peer review. The version of record: Antonia K Roseweir, Lindsay Bennett, Ashley Dickson, Kelvin Cheng, Mary-Anne Quintayo, Jane Bayani, Donald C McMillan, Paul G Horgan, Cornelis J H van de Velde, Caroline Seynaeve, Annette Hasenburg, Dirk G Kieback, Christos Markopoulos, Luc Y Dirix, Daniel W Rea, Elizabeth A Mallon, John M S Bartlett, Joanne Edwards; Predictive Biomarkers for Endocrine Therapy: Retrospective Study in Tamoxifen and Exemestane Adjuvant Multinational (TEAM) Trial, JNCI: Journal of the National Cancer Institute, Volume 110, Issue 6, 1 June 2018, Pages 616–627 is available online at: https://doi.org/10.1093/jnci/djx255
Accepted author manuscript, 292 KBLicence: Other (please specify with Rights Statement)
Antonia_K_Roseweir_et_al_Predictive_biomarkers_for_endocrine_therapy_JNCI_2018_Figures
Checked for eligibility: 28/06/2018 This is a pre-copyedited, author-produced version of an article accepted for publication in JNCI: Journal of the National Cancer Institute following peer review. The version of record: Antonia K Roseweir, Lindsay Bennett, Ashley Dickson, Kelvin Cheng, Mary-Anne Quintayo, Jane Bayani, Donald C McMillan, Paul G Horgan, Cornelis J H van de Velde, Caroline Seynaeve, Annette Hasenburg, Dirk G Kieback, Christos Markopoulos, Luc Y Dirix, Daniel W Rea, Elizabeth A Mallon, John M S Bartlett, Joanne Edwards; Predictive Biomarkers for Endocrine Therapy: Retrospective Study in Tamoxifen and Exemestane Adjuvant Multinational (TEAM) Trial, JNCI: Journal of the National Cancer Institute, Volume 110, Issue 6, 1 June 2018, Pages 616–627 is available online at: https://doi.org/10.1093/jnci/djx255
Accepted author manuscript, 1.02 MBLicence: Other (please specify with Rights Statement)

https://academic.oup.com/jnci/article/110/6/616/4780394Licence: None: All rights reserved

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Roseweir, A. K., Bennett, L., Dickson, A., Cheng, K., Quintayo, M.-A., Bayani, J., McMillan, D. C., Horgan, P. G., van de Velde, C. J. H., Seynaeve, C., Hasenburg, A., Kieback, D. G., Markopoulos, C., Dirix, L. Y., Rea, D., Mallon, E. A., Bartlett, J. M. S., & Edwards, J. (2018). Predictive Biomarkers for Endocrine Therapy: Retrospective Study in Tamoxifen and Exemestane Adjuvant Multinational (TEAM) Trial. Journal of the National Cancer Institute, 110(6), 616-627. https://doi.org/10.1093/jnci/djx255

@article{6f03ee7a3a9f4bc38eeebb9b8022f274,

title = "Predictive Biomarkers for Endocrine Therapy: Retrospective Study in Tamoxifen and Exemestane Adjuvant Multinational (TEAM) Trial",

abstract = "Background: Aromatase inhibitors improve disease-free survival compared with tamoxifen in postmenopausal women with hormone receptor-positive breast cancer. The Tamoxifen and Exemestane Adjuvant Multinational (TEAM) trial compared exemestane monotherapy with sequential therapy of tamoxifen followed by exemestane. The trial failed to show a statistically significant difference between treatment arms. A robust translational program was established to investigate predictive biomarkers.Methods: A tissue microarray was retrospectively constructed using a subset of patient tissues (n = 4631) from the TEAM trial (n = 9766). Immunohistochemistry was performed for biomarkers, classed into three groups: MAPK pathway, NF-kappa B pathway, and estrogen receptor (ER) phosphorylation. Expression was analyzed for association with relapse-free survival (RFS) at 2.5 and 10 years and treatment regimen using Kaplan-Meier curves and log-rank analysis. All statistical tests were two-sided.Results: In univariate analysis, ER167 (hazard ratio [HR] = 0.71, 95% confidence interval [CI] = 0.59 to 0.85, P < .001), IKKα (HR = 0.74, 95% CI = 0.60 to 0.92, P = .005), Raf-1338 (HR = 0.64, 95% CI = 0.52 to 0.80, P < .001), and p44/42 MAPK202/204 (HR = 0.77, 95% CI = 0.64 to 0.92, P = .004) were statistically significantly associated with improved RFS at 10 years in patients receiving sequential therapy. Associations were strengthened when IKKα, Raf-1338, and ER167 were combined into a cumulative prognostic score (HR = 0.64, 95% CI = 0.52 to 0.77, P < .001). Patients with an all negative IKKα, Raf-1338, and ER167 score favored exemestane monotherapy (odds ratio = 0.56, 95% CI = 0.35 to 0.90). In multivariable analysis, the IKKα, Raf-1338, and ER167 score (P = .001) was an independent prognostic factor for RFS at 10 years in patients receiving sequential therapy.Conclusions: The IKKα, Raf-1338, and ER167 score is an independent predictive biomarker for lower recurrence on sequential therapy. Negative expression may further offer predictive value for exemestane monotherapy.",

author = "Roseweir, {Antonia K} and Lindsay Bennett and Ashley Dickson and Kelvin Cheng and Mary-Anne Quintayo and Jane Bayani and McMillan, {Donald C} and Horgan, {Paul G} and {van de Velde}, {Cornelis J H} and Caroline Seynaeve and Annette Hasenburg and Kieback, {Dirk G} and Christos Markopoulos and Dirix, {Luc Y} and Daniel Rea and Mallon, {Elizabeth A} and Bartlett, {John M S} and Joanne Edwards",

year = "2018",

month = jun,

day = "1",

doi = "10.1093/jnci/djx255",

language = "English",

volume = "110",

pages = "616--627",

journal = "Journal of the National Cancer Institute",

issn = "0027-8874",

publisher = "Oxford University Press",

number = "6",

}

Roseweir, AK, Bennett, L, Dickson, A, Cheng, K, Quintayo, M-A, Bayani, J, McMillan, DC, Horgan, PG, van de Velde, CJH, Seynaeve, C, Hasenburg, A, Kieback, DG, Markopoulos, C, Dirix, LY, Rea, D, Mallon, EA, Bartlett, JMS & Edwards, J 2018, 'Predictive Biomarkers for Endocrine Therapy: Retrospective Study in Tamoxifen and Exemestane Adjuvant Multinational (TEAM) Trial', Journal of the National Cancer Institute, vol. 110, no. 6, pp. 616-627. https://doi.org/10.1093/jnci/djx255

TY - JOUR

T1 - Predictive Biomarkers for Endocrine Therapy

T2 - Retrospective Study in Tamoxifen and Exemestane Adjuvant Multinational (TEAM) Trial

AU - Roseweir, Antonia K

AU - Bennett, Lindsay

AU - Dickson, Ashley

AU - Cheng, Kelvin

AU - Quintayo, Mary-Anne

AU - Bayani, Jane

AU - McMillan, Donald C

AU - Horgan, Paul G

AU - van de Velde, Cornelis J H

AU - Seynaeve, Caroline

AU - Hasenburg, Annette

AU - Kieback, Dirk G

AU - Markopoulos, Christos

AU - Dirix, Luc Y

AU - Rea, Daniel

AU - Mallon, Elizabeth A

AU - Bartlett, John M S

AU - Edwards, Joanne

PY - 2018/6/1

Y1 - 2018/6/1

N2 - Background: Aromatase inhibitors improve disease-free survival compared with tamoxifen in postmenopausal women with hormone receptor-positive breast cancer. The Tamoxifen and Exemestane Adjuvant Multinational (TEAM) trial compared exemestane monotherapy with sequential therapy of tamoxifen followed by exemestane. The trial failed to show a statistically significant difference between treatment arms. A robust translational program was established to investigate predictive biomarkers.Methods: A tissue microarray was retrospectively constructed using a subset of patient tissues (n = 4631) from the TEAM trial (n = 9766). Immunohistochemistry was performed for biomarkers, classed into three groups: MAPK pathway, NF-kappa B pathway, and estrogen receptor (ER) phosphorylation. Expression was analyzed for association with relapse-free survival (RFS) at 2.5 and 10 years and treatment regimen using Kaplan-Meier curves and log-rank analysis. All statistical tests were two-sided.Results: In univariate analysis, ER167 (hazard ratio [HR] = 0.71, 95% confidence interval [CI] = 0.59 to 0.85, P < .001), IKKα (HR = 0.74, 95% CI = 0.60 to 0.92, P = .005), Raf-1338 (HR = 0.64, 95% CI = 0.52 to 0.80, P < .001), and p44/42 MAPK202/204 (HR = 0.77, 95% CI = 0.64 to 0.92, P = .004) were statistically significantly associated with improved RFS at 10 years in patients receiving sequential therapy. Associations were strengthened when IKKα, Raf-1338, and ER167 were combined into a cumulative prognostic score (HR = 0.64, 95% CI = 0.52 to 0.77, P < .001). Patients with an all negative IKKα, Raf-1338, and ER167 score favored exemestane monotherapy (odds ratio = 0.56, 95% CI = 0.35 to 0.90). In multivariable analysis, the IKKα, Raf-1338, and ER167 score (P = .001) was an independent prognostic factor for RFS at 10 years in patients receiving sequential therapy.Conclusions: The IKKα, Raf-1338, and ER167 score is an independent predictive biomarker for lower recurrence on sequential therapy. Negative expression may further offer predictive value for exemestane monotherapy.

AB - Background: Aromatase inhibitors improve disease-free survival compared with tamoxifen in postmenopausal women with hormone receptor-positive breast cancer. The Tamoxifen and Exemestane Adjuvant Multinational (TEAM) trial compared exemestane monotherapy with sequential therapy of tamoxifen followed by exemestane. The trial failed to show a statistically significant difference between treatment arms. A robust translational program was established to investigate predictive biomarkers.Methods: A tissue microarray was retrospectively constructed using a subset of patient tissues (n = 4631) from the TEAM trial (n = 9766). Immunohistochemistry was performed for biomarkers, classed into three groups: MAPK pathway, NF-kappa B pathway, and estrogen receptor (ER) phosphorylation. Expression was analyzed for association with relapse-free survival (RFS) at 2.5 and 10 years and treatment regimen using Kaplan-Meier curves and log-rank analysis. All statistical tests were two-sided.Results: In univariate analysis, ER167 (hazard ratio [HR] = 0.71, 95% confidence interval [CI] = 0.59 to 0.85, P < .001), IKKα (HR = 0.74, 95% CI = 0.60 to 0.92, P = .005), Raf-1338 (HR = 0.64, 95% CI = 0.52 to 0.80, P < .001), and p44/42 MAPK202/204 (HR = 0.77, 95% CI = 0.64 to 0.92, P = .004) were statistically significantly associated with improved RFS at 10 years in patients receiving sequential therapy. Associations were strengthened when IKKα, Raf-1338, and ER167 were combined into a cumulative prognostic score (HR = 0.64, 95% CI = 0.52 to 0.77, P < .001). Patients with an all negative IKKα, Raf-1338, and ER167 score favored exemestane monotherapy (odds ratio = 0.56, 95% CI = 0.35 to 0.90). In multivariable analysis, the IKKα, Raf-1338, and ER167 score (P = .001) was an independent prognostic factor for RFS at 10 years in patients receiving sequential therapy.Conclusions: The IKKα, Raf-1338, and ER167 score is an independent predictive biomarker for lower recurrence on sequential therapy. Negative expression may further offer predictive value for exemestane monotherapy.

U2 - 10.1093/jnci/djx255

DO - 10.1093/jnci/djx255

M3 - Article

C2 - 29917140

SN - 0027-8874

VL - 110

SP - 616

EP - 627

JO - Journal of the National Cancer Institute

JF - Journal of the National Cancer Institute

IS - 6

ER -

Predictive Biomarkers for Endocrine Therapy: Retrospective Study in Tamoxifen and Exemestane Adjuvant Multinational (TEAM) Trial

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