Tumor clone dynamics in lethal prostate cancer
Suzanne Carreira, Alessandro Romanel, Jane Goodall, Emily Grist, Roberta Ferraldeschi, Susana Miranda, Davide Prandi, David Lorente, Jean-Sebastien Frenel, Carmel Pezaro, Aurelius Omlin, Daniel Nava Rodrigues, Penelope Flohr, Nina Tunariu, Johann S de Bono, Francesca Demichelis, Gerhardt Attard, Suzanne Carreira, Alessandro Romanel, Jane Goodall, Emily Grist, Roberta Ferraldeschi, Susana Miranda, Davide Prandi, David Lorente, Jean-Sebastien Frenel, Carmel Pezaro, Aurelius Omlin, Daniel Nava Rodrigues, Penelope Flohr, Nina Tunariu, Johann S de Bono, Francesca Demichelis, Gerhardt Attard
Abstract
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.
Conflict of interest statement
Competing interests: The ICR developed abiraterone and therefore has a commercial interest in this agent. G.A. is on the ICR list of rewards to inventors for abiraterone. J.S.d.B. has received consulting fees and travel support from Amgen, Astellas, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Dendreon, Enzon, Exelixis, Genentech, GlaxoSmithKline, Mediation, Merck, Novartis, Pfizer, Roche, Sanofi-Aventis, Supergen, and Takeda and grant support from AstraZeneca and Genentech. G.A. has received honoraria, consulting fees or travel support from Astellas, Medivation, Janssen, Millennium Pharmaceuticals, Ipsen, Takeda, and Sanofi-Aventis and grant support from Janssen, AstraZeneca, and Genentech. A.O. serves on advisory boards for Janssen, Astellas, Bayer, and AstraZeneca. F.D. is co-inventor of the patent on the detection of gene fusions in prostate cancer, filed by the University of Michigan and the Brigham and Women's Hospital. The diagnostic field of use for ETS gene fusions has been licensed to Hologic Gen-Probe.
Copyright © 2014, American Association for the Advancement of Science.
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Source: PubMed