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Development and Validation of a Prostate Cancer Genomic Signature that Predicts Early ADT Treatment Response Following Radical Prostatectomy
Open accessPublished version of a preprint
Abstract
Purpose: Currently, no genomic signature exists to distinguish men most likely to progress on adjuvant androgen deprivation therapy (ADT) after radical prostatectomy for high-risk prostate cancer. Here we develop and validate a gene expression signature to predict response to postoperative ADT. Experimental Design: A training set consisting of 284 radical prostatectomy patients was established after 1:1 propensity score matching metastasis between adjuvant-ADT (a-ADT)-treated and no ADT–treated groups. An ADT Response Signature (ADT-RS) was identified from neuroendocrine and AR signaling–related genes. Two independent cohorts were used to form three separate data sets for validation (set I, n = 232; set II, n = 435; set III, n = 612). The primary endpoint of the analysis was postoperative metastasis. Results: Increases in ADT-RS score were associated with a reduction in risk of metastasis only in a-ADT patients. On multivariable analysis, ADT-RS by ADT treatment interaction term remained associated with metastasis in both validation sets (set I: HR = 0.18, Pinteraction = 0.009; set II: HR = 0.25, Pinteraction = 0.019). In a matched validation set III, patients with Low ADT-RS scores had similar 10-year metastasis rates in the a-ADT and no-ADT groups (30.1% vs. 31.0%, P = 0.989). Among High ADT-RS patients, 10-year metastasis rates were significantly lower for a-ADT versus no-ADT patients (9.4% vs. 29.2%, P = 0.021). The marginal ADT-RS by ADT interaction remained significant in the matched dataset (Pinteraction = 0.035). Conclusions: Patients with High ADT-RS benefited from a-ADT. In combination with prognostic risk factors, use of ADT-RS may thus allow for identification of ADT-responsive tumors that may benefit most from early androgen blockade after radical prostatectomy. We discovered a gene signature that when present in primary prostate tumors may be useful to predict patients who may respond to early ADT after surgery. Clin Cancer Res; 24(16); 3908–16. ©2018 AACR.
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Publicly available gene expression data from a matched cohort of mCRPC was downloaded from cBioportal.
“Publicly available gene expression data from a matched cohort established previously59 or mCRPC was downloaded from cBioportal (20 May 2021)94–96.”
From Genome-scale CRISPR screens identify PTGES3 as a direct modulator of androgen receptor function in advanced prostate cancer (2025) · cites this paper as [59]
The Study design section (page unavailable) describes a previously established, propensity-score-matched cohort and gene-expression profiles from men following radical prostatectomy. It does not identify that cohort as mCRPC; the profiles were retrieved from the Decipher GRID database, not cBioPortal. In the citing sentence, separate references appear to support the cBioPortal download. (LLM, conf=0.86)
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References 35 · Cited by 30
Metadata
- Authors
- Karnes, R. J., Sharma, V., Choeurng, V., Ashab, H. A.-D., Erho, N., Alshalalfa, M., Trock, B., Ross, A., Yousefi, K., Tsai, H., Zhao, S. G., Tosoian, J. J., Haddad, Z., Takhar, M., Chang, S. L., Spratt, D. E., Abdollah, F., Jenkins, R. B., Klein, E. A., Nguyen, P. L., Dicker, A. P., Den, R. B., Davicioni, E., Feng, F. Y., Lotan, T. L., & Schaeffer, E. M.
- Affiliations
- Mayo Clinic (US)
- City of Vancouver (CA)
- Johns Hopkins University (US)
- Brigham and Women's Hospital (US)
- University of Michigan (US)
- 6Department of Radiation Oncology, University of California, San Francisco, San Francisco, California.
- Henry Ford Hospital (US)
- Cleveland Clinic (US)
- Harvard University (US)
- Thomas Jefferson University (US)
- University of California, San Francisco (US)
- Northwestern University (US)
- Corresponding author
- Karnes, R. Jeffrey
- ORCID
- Karnes, R. Jeffrey
- Sharma, Vidit
- Erho, Nicholas
- Alshalalfa, Mohammed
- Trock, Bruce
- Ross, Ashley
- Tsai, Harrison
- Zhao, Shuang G.
- Tosoian, Jeffrey J.
- Haddad, Zaid
- Spratt, Daniel E.
- Abdollah, Firas
- Jenkins, Robert B.
- Klein, Eric A.
- Nguyen, Paul L.
- Dicker, Adam P.
- Den, Robert B.
- Davicioni, Elai
- Feng, Felix Y.
- Lotan, Tamara L.
- Schaeffer, Edward M.
- Venue
- Clinical Cancer Research
- Published
- 2018-08-14
- Volume
- 24
- Issue
- 16
- Pages
- 3908-3916
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- PMC
- PMC6512950
- OpenAlex
- W2804058066
- Cited by
- 30
- References
- 35
- Citations by year
- 2025: 4 · 2024: 1 · 2023: 9 · 2022: 4 · 2021: 6 · 2020: 4 · 2019: 1 · 2018: 1
- FWCI
- 2.26
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- The Medicine Forum (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Cancer Institute (U01CA196390, P50CA180995)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Prostate Cancer Treatment and Research
- Health Sciences › Medicine › Urology › Prostate Cancer Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Breast Cancer Treatment Studies
- Keywords
- prostate cancer, adjuvant androgen deprivation therapy, radical prostatectomy, gene expression signatures, metastasis risk, neuroendocrine prostate cancer, androgen receptor signaling, treatment response biomarkers, high-risk prostate cancer, propensity score matching, prognostic biomarker validation, metastasis-free survival, biochemical recurrence, prostate-specific antigen
- MeSH terms
- Aged, Androgen Antagonists, Humans, Male, Middle Aged, Neoplasm Metastasis, Neoplasm Proteins, Neoplasm Recurrence, Local, Prognosis, Prostate, Prostatectomy, Prostatic Neoplasms, Seminal Vesicles, Gene Expression Regulation, Neoplastic, Chemotherapy, Adjuvant, Prostate-Specific Antigen, Genomics, Kaplan-Meier Estimate, Transcriptome
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