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Cancer Res. 2018 Aug 15;78(16):4716-4730. doi: 10.1158/0008-5472.CAN-18-0610. Epub 2018 Jun 19.

Neoadjuvant-Intensive Androgen Deprivation Therapy Selects for Prostate Tumor Foci with Diverse Subclonal Oncogenic Alterations.

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Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
Laboratory of Genitourinary Cancer Pathogenesis, National Cancer Institute, NIH, Bethesda, Maryland.
Department of Pathology, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
Genomics, Proteomics, Bioinformatics and Systems Biology Center, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
Department of Molecular Oncologic Pathology, Brigham and Women's Hospital, Boston, Massachusetts.
Department of Oncologic Pathology, Dana Farber Cancer Institute, Boston, Masschusetts.
Medical Oncology Division, University of Washington, Seattle, Washington.
Fred Hutchinson Cancer Research Center, Seattle, Washington.
Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts.


Primary prostate cancer can have extensive microheterogeneity, but its contribution to the later emergence of metastatic castration-resistant prostate cancer (mCRPC) remains unclear. In this study, we microdissected residual prostate cancer foci in radical prostatectomies from 18 men treated with neoadjuvant-intensive androgen deprivation therapy (leuprolide, abiraterone acetate, and prednisone) and analyzed them for resistance mechanisms. Transcriptome profiling showed reduced but persistent androgen receptor (AR) activity in residual tumors, with no increase in neuroendocrine differentiation. Proliferation correlated negatively with AR activity but positively with decreased RB1 expression, and whole-exome sequencing (WES) further showed enrichment for RB1 genomic loss. In 15 cases where 2 or 3 tumor foci were microdissected, WES confirmed a common clonal origin but identified multiple oncogenic alterations unique to each focus. These findings show that subclones with oncogenic alterations found in mCRPC are present in primary prostate cancer and are selected for by neoadjuvant-intense androgen deprivation therapy. In particular, this study indicates that subclonal RB1 loss may be more common than previously appreciated in intermediate- to high-risk primary prostate cancer and may be an early event, independent of neuroendocrine differentiation, in the development of mCRPC. Comprehensive molecular analyses of primary prostate cancer may detect aggressive subclones and possibly inform adjuvant strategies to prevent recurrence.Significance: Neoadjuvant androgen deprivation therapy for prostate cancer selects for tumor foci with subclonal genomic alterations, which may comprise the origin of metastatic castration-resistant prostate cancer. Cancer Res; 78(16); 4716-30. ©2018 AACR.

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