Neoadjuvant-Intensive Androgen Deprivation Therapy Selects for Prostate Tumor Foci with Diverse Subclonal Oncogenic Alterations
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- Adam G. Sowalsky
- 1Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
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- Huihui Ye
- 3Department of Pathology, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
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- Manoj Bhasin
- 4Genomics, Proteomics, Bioinformatics and Systems Biology Center, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
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- Eliezer M. Van Allen
- 5Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
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- Massimo Loda
- 6Department of Molecular Oncologic Pathology, Brigham and Women's Hospital, Boston, Massachusetts.
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- Rosina T. Lis
- 5Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
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- Laleh Montaser-Kouhsari
- 3Department of Pathology, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
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- Carla Calagua
- 1Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
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- Fen Ma
- 1Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
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- Joshua W. Russo
- 1Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
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- Rachel J. Schaefer
- 1Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
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- Olga S. Voznesensky
- 1Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
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- Zhenwei Zhang
- 5Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
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- Glenn J. Bubley
- 1Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
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- Bruce Montgomery
- 8Medical Oncology Division, University of Washington, Seattle, Washington.
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- Elahe A. Mostaghel
- 8Medical Oncology Division, University of Washington, Seattle, Washington.
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- Peter S. Nelson
- 8Medical Oncology Division, University of Washington, Seattle, Washington.
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- Mary-Ellen Taplin
- 5Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
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- Steven P. Balk
- 1Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
説明
<jats:title>Abstract</jats:title> <jats:p>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.</jats:p> <jats:p>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.</jats:p>
収録刊行物
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- Cancer Research
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Cancer Research 78 (16), 4716-4730, 2018-08-14
American Association for Cancer Research (AACR)