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Sci Transl Med. 2014 Sep 17;6(254):254ra125. doi: 10.1126/scitranslmed.3009448.

Tumor clone dynamics in lethal prostate cancer.

Author information

1
The Institute of Cancer Research, London SM2 5NG, UK.
2
Centre for Integrative Biology, University of Trento, Trento 38123, Italy.
3
The Institute of Cancer Research, London SM2 5NG, UK. Royal Marsden National Health Service Foundation Trust, London SM2 5PT, UK.
4
Centre for Integrative Biology, University of Trento, Trento 38123, Italy. Institute for Computational Biomedicine, Weill Cornell Medical College, New York, NY 10021, USA. Institute for Precision Medicine, Weill Cornell Medical College, New York, NY 10021, USA. gerhardt.attard@icr.ac.uk demichelis@science.unitn.it.
5
The Institute of Cancer Research, London SM2 5NG, UK. Royal Marsden National Health Service Foundation Trust, London SM2 5PT, UK. gerhardt.attard@icr.ac.uk demichelis@science.unitn.it.

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.

PMID:
25232177
PMCID:
PMC4422178
DOI:
10.1126/scitranslmed.3009448
[Indexed for MEDLINE]
Free PMC Article

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