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.