Neither targeted therapies nor predictors for chemotherapy sensitivity are available for triple-negative breast cancer (TNBC). Our study included 187 patients with TNBC, 164 of whom were treated with anthracycline-based adjuvant chemotherapy. Eleven molecular biomarkers were analyzed. BCL2, epidermal growth factor receptor (EGFR), MYC, TOP2A, and Ki-67 protein expression was evaluated by immunohistochemistry. The status of the EGFR, MYC, and TOP2A genes and chromosomes 7, 8, and 17 was assessed using fluorescence in situ hybridization. High BCL2 expression predicted poor relapse-free survival (RFS) in patients treated with anthracycline-based adjuvant chemotherapy (p = 0.035), poor breast cancer-specific survival (BCSS) (p = 0.048), and a trend to poor overall survival (OS) (p = 0.085). High levels of BCL2 expression predicted poor OS in basal-like (BL) TNBC patients treated with adjuvant anthracycline-based regimens (log-rank p = 0.033, hazard ratio (HR) 3.04, 95 % confidence interval (CI) 1.04–8.91) and a trend to poor RFS (log-rank p = 0.079) and poor BCSS (log-rank p = 0.056). Multivariate analysis showed that BCL2 status, tumor size, and nodal status all had independent predictive significance for RFS (p = 0.005, p = 0.091, p = 0.003, respectively; likelihood ratio test for the whole model, p = 0.003), BCSS (p = 0.012, p = 0.077, p = 0.01, respectively; likelihood ratio test for the whole model, p = 0.016), and OS (p = 0.008, p = 0.004, p = 0.004, respectively; likelihood ratio test for the whole model, p = 0.0006). Similarly, multivariate analysis for BL TNBC showed BCL2, tumor size, and nodal status all had independent predictive significance for RFS (likelihood ratio test for the whole model, p = 0.00125), BCSS (p = 0.00035), and OS (p = 0.00063). High EGFR expression was associated with poor BCSS (p = 0.039) in patients treated with anthracycline-based adjuvant chemotherapy. Patients who underwent anthracycline-based adjuvant chemotherapy and exhibited CMYC amplification had a trend to worse BCSS (p = 0.066). In conclusion, high BCL2 expression is a significant independent predictor of poor outcome in TNBC patients treated with anthracycline-based adjuvant chemotherapy, and this is the first study showing the BCL2 prediction in BL TNBC. BCL2 expression analysis could facilitate decision making on adjuvant treatment in TNBC patients.
Adjuvant chemotherapy Anthracycline BCL2 EGFR Predictive marker Triple-negative breast cancer
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We thank Jiri Bartek and Alice Hlobilkova for many helpful comments. We also thank Dana Knoflickova, Sona Mlcochova, and Eva Sedlakova for excellent technical assistance.
This work was supported by the Czech Ministry of Health (IGA NS10286-3, IGA NS10357-3, IGA NT14599-32013). The infrastructural part of the project (Institute of Molecular and Translational Medicine, Biomedreg) was supported under the Operational Programme Research and Development for Innovations (CZ.1.05/2.1.00/01.0030), National Sustainability Programme (LO1304), and Czech Technology Agency (Center of Competence for Molecular Diagnostics and Personalized Medicine) (TE02000058).
Conflicts of interest
MH and RT are owners of Intellmed stock.
KB conceived, designed, and directed the study; analyzed the data; and wrote the manuscript. MS obtained clinical data. GK performed IHC (BCL2, TOP2A, EGFR, CMYC), and JV and LR performed the statistical analyses. JB had oversight of the study’s progression and contributed to the data analysis and the writing of the manuscript. RT and VK performed the FISH experiments. KC and MH contributed to the editing of the manuscript. ZK contributed to the writing of the manuscript. All authors approved the manuscript.
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