Circulating tumor DNA as a novel tool to shape clinical trial designs with the potential to impact outcomes: a focus on PI3K inhibitors

Tumor heterogeneity is a major challenge for drug development, and changes in heterogeneity are thought to contribute to anticancer treatment resistance. However, the standard diagnostic approach in clinical trials relies on analysis of a single (usually archival) sample from the primary tumor [1]. This provides limited characterization of a single tumor at initial diagnosis that is not necessarily representative of current disease status [1]. Recent studies have also highlighted challenges with intratumoral heterogeneity in advanced cancers [2, 3]. The success of targeted therapies is closely associated with identification of the target within a tumor sample. However, most tumors develop resistance due to intratumoral heterogeneity, clonal evolution, and selection pressure [1–4].