Serum copper, zinc and copper/zinc ratio in relation to survival after breast cancer diagnosis: A prospective multicenter cohort study

Ylva Bengtsson, Kamil Demircan, Johan Vallon-Christersson, Martin Malmberg, Lao H Saal, Lisa Rydén, Åke Borg, Lutz Schomburg, Malte Sandsveden, Jonas Manjer, Ylva Bengtsson, Kamil Demircan, Johan Vallon-Christersson, Martin Malmberg, Lao H Saal, Lisa Rydén, Åke Borg, Lutz Schomburg, Malte Sandsveden, Jonas Manjer

Abstract

Background: The essential trace elements copper and zinc, and their ratio (copper/zinc), are important for maintaining redox homeostasis. Previous studies suggest that these elements may impact breast cancer survival. However, no epidemiological study has so far been conducted on the potential association between copper and copper/zinc levels and survival after breast cancer diagnosis. In this study, we aimed to examine the relationship between serum copper, zinc and copper/zinc levels and survival following breast cancer diagnosis.

Patients and methods: The Sweden Cancerome Analysis Network - Breast Initiative (SCAN-B) is a population-based cohort study including multiple participating hospitals in Sweden. A total of 1998 patients diagnosed with primary invasive breast cancer were followed for approximately nine years. Serum levels of copper and zinc and their ratio at the time of diagnosis was analyzed in relation to breast cancer survival using multivariate Cox regression, yielding hazard ratios (HR) with 95% confidence intervals.

Results: A higher copper/zinc ratio was associated with lower overall survival after breast cancer diagnosis. Comparing patients with a copper/zinc ratio in quartile 4 vs 1, the crude HR was 2.29 (1.65-3.19) (Ptrend <0.01) and the fully adjusted HR was 1.58 (1.11-2.25) (Ptrend = 0.01). No overall associations were seen between serum copper or zinc levels on their own and survival after breast cancer diagnosis, although a tendency toward lower breast cancer survival was seen for higher copper levels and lower zinc levels.

Conclusion: There is evidence that the serum copper/zinc ratio provides an independent predictive value for overall survival following breast cancer diagnosis.

Keywords: Biomarkers; Breast cancer; Copper; Copper/zinc ratio; Survival; Zinc.

Conflict of interest statement

Declaration of competing interest The authors declare that they have no conflicts of interest with respect to the research, authorship and/or publication of this article in Redox Biology.

Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.

Figures

Graphical abstract
Graphical abstract
Fig. 1
Fig. 1
Flowchart of inclusion and exclusion criteria. Of the total 9313 patients with invasive breast cancer included in the registry, 1998 cases were eligible for analysis and ultimately included in the study. The flowchart is adapted from Demircan K, Bengtsson Y, Sun Q, Brange A, Vallon-Christersson J, Rijntjes E, et al. Serum selenium, selenoprotein P and glutathione peroxidase 3 as predictors of mortality and recurrence following breast cancer diagnosis: A multicentre cohort study. Redox Biol. 2021; 47:102145.
Fig. 2
Fig. 2
Kaplan Meier plots for overall survival by quartiles of serum copper (A), zinc (B) and copper/zinc (C). Log-Rank-Test was used to evaluate differences. The visualization was enhanced by setting the Y-axis-limits to 0.4 and 1.0, and all points are included.
Fig. 3
Fig. 3
Predictive value of quartiles of copper, zinc and copper/zinc ratio for overall mortality. The first panel compares each trace element individually, the second panel compares tumor characteristics and age individually and the third panel comparers the predictors in combined models. AUCt (y-axis) was computed at each time of death, marked with the symbol ○. An AUC of 1.0 represents a prediction model with 100% specificity and 100% sensitivity. iAUC = Integrated area under the curve.

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