Prediagnostic Levels of Copper and Zinc and Breast Cancer Risk in the ORDET Cohort

Background: Case–control studies show that copper (Cu) is high and zinc (Zn) low in blood and urine of women with breast cancer compared with controls. Methods: To assess whether prediagnostic Cu and Zn are associated with breast cancer risk, OR of breast cancer according to Cu, Zn, and Cu/Zn ratio in plasma and urine was estimated in a nested case–control study within the ORDET cohort, using conditional logistic regression adjusted for multiple variables: First 496 breast cancer cases and matched controls, diagnosed ≥2 years after recruitment (to eliminate reverse causation) were analyzed. Then all eligible cases/controls were analyzed with stratification into years from recruitment to diagnosis. Results: For women diagnosed ≥2 years, compared with lowest tertiles, breast cancer risk was higher in the highest tertile of plasma Cu/Zn ratio (OR, 1.75; 95% CI, 1.21–2.54) and the highest tertile of both plasma and urine Cu/Zn ratio (OR, 2.37; 95% CI, 1.32–4.25). Risk did not vary with ER/PR/HER2 status. For women diagnosed <2 years, high Cu/Zn ratio was strongly associated with breast cancer risk. Conclusions: Our prospective findings suggest that increased Cu/Zn ratio in plasma and urine may be both an early marker of, and a risk factor for, breast cancer development. Further studies are justified to confirm or otherwise our results and to investigate mechanisms. Impact: Our finding that prediagnostic Cu/Zn ratio is a strong risk factor for breast cancer development deserves further investigation and, if confirmed, might open the way to interventions to reduce breast cancer risk in women with disrupted Cu/Zn homeostasis.