Figure 1.

Causes of treatment-related changes in the circulating metabolome in individuals who have received antineoplastic agents. Pharmacologic effects are independent of therapeutic benefit. Antineoplastic effects are associated with benefit. Such antineoplastic effects include changes in the metabolome that are secondary to cell death, reduced cell proliferation, or a loss of “tumor signal” (which is a product of the effects on the metabolome by the tumor and by the host response to the tumor). The experimental design for discovery of a response biomarker (which signifies therapeutic benefit) will require effective linkage of metabolomic changes with objective effects on tumor progression. If treatment-related changes in the metabolome (from pre-treatment baseline) are linked to objective measures of response, then the non-specific pharmacologic effects of the drug will be effectively excluded, yielding a response biomarker.