17β-Hydroxysteroid dehydrogenases 1 and 2: potential markers for breast cancer recurrence and tamoxifen resistance among premenopausal women diagnosed with breast cancer in Denmark

Lindsay J. Collin; Kirsten M. Woolpert; Anders Kjaersgaard; Thomas P. Ahern; Michael Goodman; Lauren E. McCullough; Lance A. Waller; Kristina B. Christensen; Per Damkier; Stephen J. Hamilton-Dutoit; Kristina L. Lauridsen; Peer M. Christiansen; Bent Ejlertsen; Henrik T. Sørensen; Deirdre P. Cronin-Fenton; Timothy L. Lash

doi:10.1186/s13058-025-02196-2

17β-Hydroxysteroid dehydrogenases 1 and 2: potential markers for breast cancer recurrence and tamoxifen resistance among premenopausal women diagnosed with breast cancer in Denmark

Lindsay J. Collin^*
, Kirsten M. Woolpert
, Anders Kjaersgaard
, Thomas P. Ahern
, Michael Goodman
, Lauren E. McCullough
, Lance A. Waller
, Kristina B. Christensen
, Per Damkier
, Stephen J. Hamilton-Dutoit
, Kristina L. Lauridsen
, Peer M. Christiansen
, Bent Ejlertsen
, Henrik T. Sørensen
, Deirdre P. Cronin-Fenton
, Timothy L. Lash

^*Kontaktforfatter

Aarhus Universitetshospital
Emory University
The University of Vermont
Regionshospitalet Randers
Københavns Universitet
Rigshospitalet

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Abstract

BACKGROUND: Premenopausal women diagnosed with estrogen receptor (ER)-positive breast cancer are prescribed 5-10 years of tamoxifen therapy to prevent or delay a recurrence. The enzymes 17β-hydroxysteroid dehydrogenase 1 and 2 (HSD17B1 and HSD17B2, respectively) regulate the relative concentrations of estrogen metabolites and may modify tamoxifen effectiveness. We evaluated the prognostic and predictive value of HSD17B1 and HSD17B2 expression in breast tumors.

METHODS: We identified a cohort of premenopausal breast cancer patients from the Danish Breast Cancer Group database (2002-2011) and stratified on ER status and receipt of tamoxifen (4600 ER+/TAM + and 1359 ER-/TAM-). Biomarkers HSD17B1 and HSD17B2 were assayed by immunohistochemistry. We used Cox proportional hazards regression to compute the hazard ratios (HRs) and 95% simulation intervals (SIs) associating each biomarker with recurrence, with bias adjustment to account for mismeasurement of biomarker expression and baseline selection bias from tumor sample availability.

RESULTS: Among ER+/TAM + breast cancers, 24% had any HSD17B1 expression compared with 13% of ER-/TAM - breast cancers. In the bias-adjusted analyses, women diagnosed with tumors positive for HSD17B1 expression had a slight increased rate of recurrence: HR = 1.13 (95% SI 0.90, 1.43) in the ER+/TAM + stratum and HR = 1.15 (95% SI 0.77, 1.79) in the ER-/TAM - stratum. A 10-unit increase in HSD17B2 expression corresponded with a decrease in the estimated rate of recurrence among ER+/TAM + patients (HR = 0.85, 95% SI 0.69, 1.05), but not among ER-/TAM - patients (HR = 1.07, 95% SI 0.82, 1.42).

CONCLUSIONS: HSD17B1 may be a prognostic marker for recurrence and HSD17B2 may be predictive of response to tamoxifen therapy in breast cancer.

Originalsprog	Engelsk
Artikelnummer	28
Tidsskrift	Breast Cancer Research
Vol/bind	28
Udgave nummer	1
Antal sider	12
ISSN	1465-542X
DOI	https://doi.org/10.1186/s13058-025-02196-2
Status	Udgivet - 2026

Finansiering

The results reported in this paper correspond to the Specific Aims of R01 CA166825 from the US National Cancer Institute awarded to Timothy L. Lash. Lindsay J. Collin was supported by the US National Cancer Institute (F31CA239566, R00CA277580). This project was also supported by the Danish Cancer Society (DP06117) awarded to Stephen Hamilton-Dutoit and the Danish Medical Research Council (DOK 1158869) awarded to Timothy L. Lash. Thomas P. Ahern was supported in part by funding from the National Institute of General Medical Sciences (P20GM103644). The content of this paper is solely the responsibility of the authors and does not necessarily represent the official views of the US National Institutes of Health or other sources of funding support.

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Collin, L. J., Woolpert, K. M., Kjaersgaard, A., Ahern, T. P., Goodman, M., McCullough, L. E., Waller, L. A., Christensen, K. B., Damkier, P., Hamilton-Dutoit, S. J., Lauridsen, K. L., Christiansen, P. M., Ejlertsen, B., Sørensen, H. T., Cronin-Fenton, D. P., & Lash, T. L. (2026). 17β-Hydroxysteroid dehydrogenases 1 and 2: potential markers for breast cancer recurrence and tamoxifen resistance among premenopausal women diagnosed with breast cancer in Denmark. Breast Cancer Research, 28(1), Artikel 28. https://doi.org/10.1186/s13058-025-02196-2

@article{5a0d77e33f9d4706a495fed088e1a958,

title = "17β-Hydroxysteroid dehydrogenases 1 and 2: potential markers for breast cancer recurrence and tamoxifen resistance among premenopausal women diagnosed with breast cancer in Denmark",

abstract = "BACKGROUND: Premenopausal women diagnosed with estrogen receptor (ER)-positive breast cancer are prescribed 5-10 years of tamoxifen therapy to prevent or delay a recurrence. The enzymes 17β-hydroxysteroid dehydrogenase 1 and 2 (HSD17B1 and HSD17B2, respectively) regulate the relative concentrations of estrogen metabolites and may modify tamoxifen effectiveness. We evaluated the prognostic and predictive value of HSD17B1 and HSD17B2 expression in breast tumors.METHODS: We identified a cohort of premenopausal breast cancer patients from the Danish Breast Cancer Group database (2002-2011) and stratified on ER status and receipt of tamoxifen (4600 ER+/TAM + and 1359 ER-/TAM-). Biomarkers HSD17B1 and HSD17B2 were assayed by immunohistochemistry. We used Cox proportional hazards regression to compute the hazard ratios (HRs) and 95\% simulation intervals (SIs) associating each biomarker with recurrence, with bias adjustment to account for mismeasurement of biomarker expression and baseline selection bias from tumor sample availability.RESULTS: Among ER+/TAM + breast cancers, 24\% had any HSD17B1 expression compared with 13\% of ER-/TAM - breast cancers. In the bias-adjusted analyses, women diagnosed with tumors positive for HSD17B1 expression had a slight increased rate of recurrence: HR = 1.13 (95\% SI 0.90, 1.43) in the ER+/TAM + stratum and HR = 1.15 (95\% SI 0.77, 1.79) in the ER-/TAM - stratum. A 10-unit increase in HSD17B2 expression corresponded with a decrease in the estimated rate of recurrence among ER+/TAM + patients (HR = 0.85, 95\% SI 0.69, 1.05), but not among ER-/TAM - patients (HR = 1.07, 95\% SI 0.82, 1.42).CONCLUSIONS: HSD17B1 may be a prognostic marker for recurrence and HSD17B2 may be predictive of response to tamoxifen therapy in breast cancer.",

author = "Collin, \{Lindsay J.\} and Woolpert, \{Kirsten M.\} and Anders Kjaersgaard and Ahern, \{Thomas P.\} and Michael Goodman and McCullough, \{Lauren E.\} and Waller, \{Lance A.\} and Christensen, \{Kristina B.\} and Per Damkier and Hamilton-Dutoit, \{Stephen J.\} and Lauridsen, \{Kristina L.\} and Christiansen, \{Peer M.\} and Bent Ejlertsen and S{\o}rensen, \{Henrik T.\} and Cronin-Fenton, \{Deirdre P.\} and Lash, \{Timothy L.\}",

year = "2026",

doi = "10.1186/s13058-025-02196-2",

language = "English",

volume = "28",

journal = "Breast Cancer Research",

issn = "1465-542X",

publisher = "BioMed Central",

number = "1",

}

Collin, LJ, Woolpert, KM, Kjaersgaard, A, Ahern, TP, Goodman, M, McCullough, LE, Waller, LA, Christensen, KB, Damkier, P, Hamilton-Dutoit, SJ, Lauridsen, KL, Christiansen, PM, Ejlertsen, B, Sørensen, HT, Cronin-Fenton, DP & Lash, TL 2026, '17β-Hydroxysteroid dehydrogenases 1 and 2: potential markers for breast cancer recurrence and tamoxifen resistance among premenopausal women diagnosed with breast cancer in Denmark', Breast Cancer Research, bind 28, nr. 1, 28. https://doi.org/10.1186/s13058-025-02196-2

17β-Hydroxysteroid dehydrogenases 1 and 2: potential markers for breast cancer recurrence and tamoxifen resistance among premenopausal women diagnosed with breast cancer in Denmark. / Collin, Lindsay J.; Woolpert, Kirsten M.; Kjaersgaard, Anders et al.
I: Breast Cancer Research, Bind 28, Nr. 1, 28, 2026.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

TY - JOUR

T1 - 17β-Hydroxysteroid dehydrogenases 1 and 2

T2 - potential markers for breast cancer recurrence and tamoxifen resistance among premenopausal women diagnosed with breast cancer in Denmark

AU - Collin, Lindsay J.

AU - Woolpert, Kirsten M.

AU - Kjaersgaard, Anders

AU - Ahern, Thomas P.

AU - Goodman, Michael

AU - McCullough, Lauren E.

AU - Waller, Lance A.

AU - Christensen, Kristina B.

AU - Damkier, Per

AU - Hamilton-Dutoit, Stephen J.

AU - Lauridsen, Kristina L.

AU - Christiansen, Peer M.

AU - Ejlertsen, Bent

AU - Sørensen, Henrik T.

AU - Cronin-Fenton, Deirdre P.

AU - Lash, Timothy L.

PY - 2026

Y1 - 2026

N2 - BACKGROUND: Premenopausal women diagnosed with estrogen receptor (ER)-positive breast cancer are prescribed 5-10 years of tamoxifen therapy to prevent or delay a recurrence. The enzymes 17β-hydroxysteroid dehydrogenase 1 and 2 (HSD17B1 and HSD17B2, respectively) regulate the relative concentrations of estrogen metabolites and may modify tamoxifen effectiveness. We evaluated the prognostic and predictive value of HSD17B1 and HSD17B2 expression in breast tumors.METHODS: We identified a cohort of premenopausal breast cancer patients from the Danish Breast Cancer Group database (2002-2011) and stratified on ER status and receipt of tamoxifen (4600 ER+/TAM + and 1359 ER-/TAM-). Biomarkers HSD17B1 and HSD17B2 were assayed by immunohistochemistry. We used Cox proportional hazards regression to compute the hazard ratios (HRs) and 95% simulation intervals (SIs) associating each biomarker with recurrence, with bias adjustment to account for mismeasurement of biomarker expression and baseline selection bias from tumor sample availability.RESULTS: Among ER+/TAM + breast cancers, 24% had any HSD17B1 expression compared with 13% of ER-/TAM - breast cancers. In the bias-adjusted analyses, women diagnosed with tumors positive for HSD17B1 expression had a slight increased rate of recurrence: HR = 1.13 (95% SI 0.90, 1.43) in the ER+/TAM + stratum and HR = 1.15 (95% SI 0.77, 1.79) in the ER-/TAM - stratum. A 10-unit increase in HSD17B2 expression corresponded with a decrease in the estimated rate of recurrence among ER+/TAM + patients (HR = 0.85, 95% SI 0.69, 1.05), but not among ER-/TAM - patients (HR = 1.07, 95% SI 0.82, 1.42).CONCLUSIONS: HSD17B1 may be a prognostic marker for recurrence and HSD17B2 may be predictive of response to tamoxifen therapy in breast cancer.

AB - BACKGROUND: Premenopausal women diagnosed with estrogen receptor (ER)-positive breast cancer are prescribed 5-10 years of tamoxifen therapy to prevent or delay a recurrence. The enzymes 17β-hydroxysteroid dehydrogenase 1 and 2 (HSD17B1 and HSD17B2, respectively) regulate the relative concentrations of estrogen metabolites and may modify tamoxifen effectiveness. We evaluated the prognostic and predictive value of HSD17B1 and HSD17B2 expression in breast tumors.METHODS: We identified a cohort of premenopausal breast cancer patients from the Danish Breast Cancer Group database (2002-2011) and stratified on ER status and receipt of tamoxifen (4600 ER+/TAM + and 1359 ER-/TAM-). Biomarkers HSD17B1 and HSD17B2 were assayed by immunohistochemistry. We used Cox proportional hazards regression to compute the hazard ratios (HRs) and 95% simulation intervals (SIs) associating each biomarker with recurrence, with bias adjustment to account for mismeasurement of biomarker expression and baseline selection bias from tumor sample availability.RESULTS: Among ER+/TAM + breast cancers, 24% had any HSD17B1 expression compared with 13% of ER-/TAM - breast cancers. In the bias-adjusted analyses, women diagnosed with tumors positive for HSD17B1 expression had a slight increased rate of recurrence: HR = 1.13 (95% SI 0.90, 1.43) in the ER+/TAM + stratum and HR = 1.15 (95% SI 0.77, 1.79) in the ER-/TAM - stratum. A 10-unit increase in HSD17B2 expression corresponded with a decrease in the estimated rate of recurrence among ER+/TAM + patients (HR = 0.85, 95% SI 0.69, 1.05), but not among ER-/TAM - patients (HR = 1.07, 95% SI 0.82, 1.42).CONCLUSIONS: HSD17B1 may be a prognostic marker for recurrence and HSD17B2 may be predictive of response to tamoxifen therapy in breast cancer.

U2 - 10.1186/s13058-025-02196-2

DO - 10.1186/s13058-025-02196-2

M3 - Journal article

C2 - 41469704

AN - SCOPUS:105028807486

SN - 1465-542X

VL - 28

JO - Breast Cancer Research

JF - Breast Cancer Research

IS - 1

M1 - 28

ER -

17β-Hydroxysteroid dehydrogenases 1 and 2: potential markers for breast cancer recurrence and tamoxifen resistance among premenopausal women diagnosed with breast cancer in Denmark

Abstract

Finansiering

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