Immunohistochemical biomarkers to predict adjuvant chemotherapy response in patients with early breast cancer in the MATADOR trial (BOOG 2005-02)

Mark Opdam; Nigel Ultee; Jill J.J. Geenen; Annelot G.J. van Rossum; Ingrid A.M. Mandjes; Sara Balduzzi; Ingrid Hofland; Jelle Wesseling; Renee X. Menezes; Hendrika M. Oosterkamp; Sabine C. Linn

doi:10.1016/j.breast.2026.104749

Immunohistochemical biomarkers to predict adjuvant chemotherapy response in patients with early breast cancer in the MATADOR trial (BOOG 2005-02)

Mark Opdam
, Nigel Ultee
, Jill J.J. Geenen
, Annelot G.J. van Rossum
, Ingrid A.M. Mandjes
, Sara Balduzzi
, Ingrid Hofland
, Jelle Wesseling
, Renee X. Menezes
, Hendrika M. Oosterkamp
, Sabine C. Linn^*
,

^*Corresponding author for this work

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

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Abstract

Background: Intensified anthracycline-based regimens are as effective as standard anthracycline-based chemotherapy with taxanes in unselected high-risk patients with early breast cancer and come with their own toxicity profiles. Many biomarkers linked to taxane resistance have been identified, but none are used clinically. A predictive biomarker for taxane resistance or sensitivity would help personalise treatment. Methods: In the randomised controlled trial MATADOR (ISRCTN61893718), 664 patients with pT1-3, pN0-3 breast cancer were treated with either docetaxel, doxorubicin, and cyclophosphamide (TAC) or dose-dense schedule of doxorubicin and cyclophosphamide (ddAC). IHC protocols for 13 previously proposed biomarkers (ABCB1, AR, BCL2, CyclinD1, EZH2, GSTP1, pH2AX, Ki67, MAPT, P53, Thioredoxin, TUBB, and TUBB3) were tested in all 577 clinical high-risk patients. The prognostic and predictive value was assessed in the total group, and in the hormone receptor-positive HER2-negative and in the triple-negative (TN) subgroup. Results: Patients with TN EZH2_high tumours have improved RFS after TAC treatment (n = 83 adjusted hazard ratio [adjHR] 0.35 [0.14–0.83]), while with EZH2_low RFS improved after ddAC (n = 16 adjHR 6.31 [0.79–50.5]; P_interaction0.01). Similar findings are observed for TUBB when stromal tumour-infiltrating lymphocytes (sTILs) are included in the model. TUBB_high have improved outcome after TAC treatment (n = 48 adjHR 0.26 [0.08–0.80]), while for TUBB_low improved with ddAC (n = 47 adjHR 1.94 [0.58–6.50]; P_interaction0.03). Conclusions: Patients with TN EZH2_low tumours benefit more from ddAC, while EZH2_high have a better outcome after TAC. High tubulin expression may predict docetaxel benefit if adjusted for sTILs. Further research with more patients is needed to find the best use of these biomarkers. Clinical trial identification: MATADOR, ISRCTN61893718, BOOG 2005-02, CKTO 2004-04.

Original language	English
Article number	104749
Journal	Breast
Volume	87
DOIs	https://doi.org/10.1016/j.breast.2026.104749
Publication status	Published - Jun 2026

Keywords

Early breast cancers
EZH2
Prognostic and predictive biomarkers
Taxanes
Tubulins

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Immunohistochemical biomarkers to predict adjuvant chemotherapy response in patients with early breast cancer in the MATADOR trial (BOOG 2005-02)Final published version, 10.3 MBLicence: CC BY-NC

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Opdam, M., Ultee, N., Geenen, J. J. J., van Rossum, A. G. J., Mandjes, I. A. M., Balduzzi, S., Hofland, I., Wesseling, J., Menezes, R. X., Oosterkamp, H. M., Linn, S. C. (2026). Immunohistochemical biomarkers to predict adjuvant chemotherapy response in patients with early breast cancer in the MATADOR trial (BOOG 2005-02). Breast, 87, Article 104749. https://doi.org/10.1016/j.breast.2026.104749

@article{340f05ae15b0409fbce9df7530d8ceb5,

title = "Immunohistochemical biomarkers to predict adjuvant chemotherapy response in patients with early breast cancer in the MATADOR trial (BOOG 2005-02)",

abstract = "Background: Intensified anthracycline-based regimens are as effective as standard anthracycline-based chemotherapy with taxanes in unselected high-risk patients with early breast cancer and come with their own toxicity profiles. Many biomarkers linked to taxane resistance have been identified, but none are used clinically. A predictive biomarker for taxane resistance or sensitivity would help personalise treatment. Methods: In the randomised controlled trial MATADOR (ISRCTN61893718), 664 patients with pT1-3, pN0-3 breast cancer were treated with either docetaxel, doxorubicin, and cyclophosphamide (TAC) or dose-dense schedule of doxorubicin and cyclophosphamide (ddAC). IHC protocols for 13 previously proposed biomarkers (ABCB1, AR, BCL2, CyclinD1, EZH2, GSTP1, pH2AX, Ki67, MAPT, P53, Thioredoxin, TUBB, and TUBB3) were tested in all 577 clinical high-risk patients. The prognostic and predictive value was assessed in the total group, and in the hormone receptor-positive HER2-negative and in the triple-negative (TN) subgroup. Results: Patients with TN EZH2high tumours have improved RFS after TAC treatment (n = 83 adjusted hazard ratio [adjHR] 0.35 [0.14–0.83]), while with EZH2low RFS improved after ddAC (n = 16 adjHR 6.31 [0.79–50.5]; Pinteraction0.01). Similar findings are observed for TUBB when stromal tumour-infiltrating lymphocytes (sTILs) are included in the model. TUBBhigh have improved outcome after TAC treatment (n = 48 adjHR 0.26 [0.08–0.80]), while for TUBBlow improved with ddAC (n = 47 adjHR 1.94 [0.58–6.50]; Pinteraction0.03). Conclusions: Patients with TN EZH2low tumours benefit more from ddAC, while EZH2high have a better outcome after TAC. High tubulin expression may predict docetaxel benefit if adjusted for sTILs. Further research with more patients is needed to find the best use of these biomarkers. Clinical trial identification: MATADOR, ISRCTN61893718, BOOG 2005-02, CKTO 2004-04.",

keywords = "Early breast cancers, EZH2, Prognostic and predictive biomarkers, Taxanes, Tubulins",

author = "Mark Opdam and Nigel Ultee and Geenen, \{Jill J.J.\} and \{van Rossum\}, \{Annelot G.J.\} and Mandjes, \{Ingrid A.M.\} and Sara Balduzzi and Ingrid Hofland and Jelle Wesseling and Menezes, \{Renee X.\} and Oosterkamp, \{Hendrika M.\} and Linn, \{Sabine C.\}",

note = "Publisher Copyright: {\textcopyright} 2026 The Authors",

year = "2026",

month = jun,

doi = "10.1016/j.breast.2026.104749",

language = "English",

volume = "87",

journal = "Breast",

issn = "0960-9776",

publisher = "Churchill Livingstone",

}

TY - JOUR

T1 - Immunohistochemical biomarkers to predict adjuvant chemotherapy response in patients with early breast cancer in the MATADOR trial (BOOG 2005-02)

AU - Opdam, Mark

AU - Ultee, Nigel

AU - Geenen, Jill J.J.

AU - van Rossum, Annelot G.J.

AU - Mandjes, Ingrid A.M.

AU - Balduzzi, Sara

AU - Hofland, Ingrid

AU - Wesseling, Jelle

AU - Menezes, Renee X.

AU - Oosterkamp, Hendrika M.

AU - Linn, Sabine C.

PY - 2026/6

Y1 - 2026/6

N2 - Background: Intensified anthracycline-based regimens are as effective as standard anthracycline-based chemotherapy with taxanes in unselected high-risk patients with early breast cancer and come with their own toxicity profiles. Many biomarkers linked to taxane resistance have been identified, but none are used clinically. A predictive biomarker for taxane resistance or sensitivity would help personalise treatment. Methods: In the randomised controlled trial MATADOR (ISRCTN61893718), 664 patients with pT1-3, pN0-3 breast cancer were treated with either docetaxel, doxorubicin, and cyclophosphamide (TAC) or dose-dense schedule of doxorubicin and cyclophosphamide (ddAC). IHC protocols for 13 previously proposed biomarkers (ABCB1, AR, BCL2, CyclinD1, EZH2, GSTP1, pH2AX, Ki67, MAPT, P53, Thioredoxin, TUBB, and TUBB3) were tested in all 577 clinical high-risk patients. The prognostic and predictive value was assessed in the total group, and in the hormone receptor-positive HER2-negative and in the triple-negative (TN) subgroup. Results: Patients with TN EZH2high tumours have improved RFS after TAC treatment (n = 83 adjusted hazard ratio [adjHR] 0.35 [0.14–0.83]), while with EZH2low RFS improved after ddAC (n = 16 adjHR 6.31 [0.79–50.5]; Pinteraction0.01). Similar findings are observed for TUBB when stromal tumour-infiltrating lymphocytes (sTILs) are included in the model. TUBBhigh have improved outcome after TAC treatment (n = 48 adjHR 0.26 [0.08–0.80]), while for TUBBlow improved with ddAC (n = 47 adjHR 1.94 [0.58–6.50]; Pinteraction0.03). Conclusions: Patients with TN EZH2low tumours benefit more from ddAC, while EZH2high have a better outcome after TAC. High tubulin expression may predict docetaxel benefit if adjusted for sTILs. Further research with more patients is needed to find the best use of these biomarkers. Clinical trial identification: MATADOR, ISRCTN61893718, BOOG 2005-02, CKTO 2004-04.

AB - Background: Intensified anthracycline-based regimens are as effective as standard anthracycline-based chemotherapy with taxanes in unselected high-risk patients with early breast cancer and come with their own toxicity profiles. Many biomarkers linked to taxane resistance have been identified, but none are used clinically. A predictive biomarker for taxane resistance or sensitivity would help personalise treatment. Methods: In the randomised controlled trial MATADOR (ISRCTN61893718), 664 patients with pT1-3, pN0-3 breast cancer were treated with either docetaxel, doxorubicin, and cyclophosphamide (TAC) or dose-dense schedule of doxorubicin and cyclophosphamide (ddAC). IHC protocols for 13 previously proposed biomarkers (ABCB1, AR, BCL2, CyclinD1, EZH2, GSTP1, pH2AX, Ki67, MAPT, P53, Thioredoxin, TUBB, and TUBB3) were tested in all 577 clinical high-risk patients. The prognostic and predictive value was assessed in the total group, and in the hormone receptor-positive HER2-negative and in the triple-negative (TN) subgroup. Results: Patients with TN EZH2high tumours have improved RFS after TAC treatment (n = 83 adjusted hazard ratio [adjHR] 0.35 [0.14–0.83]), while with EZH2low RFS improved after ddAC (n = 16 adjHR 6.31 [0.79–50.5]; Pinteraction0.01). Similar findings are observed for TUBB when stromal tumour-infiltrating lymphocytes (sTILs) are included in the model. TUBBhigh have improved outcome after TAC treatment (n = 48 adjHR 0.26 [0.08–0.80]), while for TUBBlow improved with ddAC (n = 47 adjHR 1.94 [0.58–6.50]; Pinteraction0.03). Conclusions: Patients with TN EZH2low tumours benefit more from ddAC, while EZH2high have a better outcome after TAC. High tubulin expression may predict docetaxel benefit if adjusted for sTILs. Further research with more patients is needed to find the best use of these biomarkers. Clinical trial identification: MATADOR, ISRCTN61893718, BOOG 2005-02, CKTO 2004-04.

KW - Early breast cancers

KW - EZH2

KW - Prognostic and predictive biomarkers

KW - Taxanes

KW - Tubulins

UR - https://www.scopus.com/pages/publications/105033474675

U2 - 10.1016/j.breast.2026.104749

DO - 10.1016/j.breast.2026.104749

M3 - Article

AN - SCOPUS:105033474675

SN - 0960-9776

VL - 87

JO - Breast

JF - Breast

M1 - 104749

ER -

Immunohistochemical biomarkers to predict adjuvant chemotherapy response in patients with early breast cancer in the MATADOR trial (BOOG 2005-02)

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Keywords

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