Copper isotope ratios in serum do not track cancerous tumor evolution, but organ failure

Relative to healthy controls, lighter copper isotopic compositions have been observed in the serum of breast cancer and end-stage liver disease patients, raising the possibility that Cu isotope ratios could be used as a tracer for disease progression. Here, we assess the potential of natural Cu isotopic variations (expressed as delta 65Cu) as diagnostic tools for cancer progression and/or liver failure by performing a first-order analysis of Cu isotopic cycling in the human body. Using a box model, we simulate the kinetics of Cu mass transfer throughout significant reservoirs in the body, allowing isotopic fractionation to occur during Cu uptake/release from these reservoirs. With this model, we determine under which conditions the serum delta 65Cu values would reflect perturbation related to cancer growth and/or liver failure at a level resolvable with modern mass spectrometry. We find that tumor growth alone is unable to explain the light isotopic signature observed in serum. Instead, we find that metabolic changes to the liver function resulting in a similar to 1 parts per thousand isotope fractionation during Cu uptake from the blood into the liver can readily explain the long-term serum isotopic shift of similar to 0.2 parts per thousand observed in cancer patients. A similar fractionation (similar to 1.3 parts per thousand) during Cu uptake into the liver also readily explains the -1.2 parts per thousand shift observed in the serum of cirrhosis patients with ascites, suggesting a potentially common driver of isotopic fractionation in both cases. Using this model, we then test hypotheses put forward by previous studies and begin to probe the mechanisms behind the measured isotopic compositions. Graphical Abstract Copper (Cu) isotopic compositions have been observed to be lighter in the serum of individuals with certain cancers and liver disease relative to those of healthy controls. We utilize box modeling of the human body to quantitatively assess the conditions under which serum copper isotopic ratios would reflect disease-related perturbations. Using several test cases, we provide recommendations on the potential for Cu isotope ratios to act as a diagnostic tool.