Tumor clone dynamics in lethal prostate cancer
A partir d'échantillons de tissu tumoral et de plasma prélevés sur 16 patients à plusieurs étapes de la progression d'un cancer avancé de la prostate ERG+, cette étude met en évidence l'intérêt d'une telle stratégie de biopsies séquentielles pour détecter l'apparition de mécanismes de résistance thérapeutique et améliorer la prise en charge des patients
It is unclear whether a single clone metastasizes and remains dominant over the course of lethal prostate cancer. We describe the clonal architectural heterogeneity at different stages of disease progression by sequencing serial plasma and tumor samples from 16 ERG-positive patients. By characterizing the clonality of commonly occurring deletions at 21q22, 8p21, and 10q23, we identified multiple independent clones in metastatic disease that are differentially represented in tissue and circulation. To exemplify the clinical utility of our studies, we then showed a temporal association between clinical progression and emergence of androgen receptor (AR) mutations activated by glucocorticoids in about 20% of patients progressing on abiraterone and prednisolone or dexamethasone. Resistant clones showed a complex dynamic with temporal and spatial heterogeneity, suggesting distinct mechanisms of resistance at different sites that emerged and regressed depending on treatment selection pressure. This introduces a management paradigm requiring sequential monitoring of advanced prostate cancer patients with plasma and tumor biopsies to ensure early discontinuation of agents when they become potential disease drivers.
Science Translational Medicine , résumé, 2014