Development and Validation of a Prostate Cancer Genomic Signature that Predicts Early ADT Treatment Response Following Radical Prostatectomy.

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.

• Authors: R Jeffrey Karnes, Vidit Sharma, Voleak Choeurng, Hussam Al-Deen Ashab, Nicholas Erho, Mohammed Alshalalfa, Bruce Trock, Ashley Ross, Kasra Yousefi, Harrison Tsai, Shuang G Zhao, Jeffrey J Tosoian, Zaid Haddad, Mandeep Takhar, S Laura Chang, Daniel E Spratt, Firas Abdollah, Robert B Jenkins, Eric A Klein, Paul L Nguyen, Adam P Dicker, Robert B Den, Elai Davicioni, Felix Y Feng, Tamara L Lotan, Edward M Schaeffer
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 24 Issue 16 Pg. 3908-3916 (08 15 2018) ISSN: 1557-3265 [Electronic] United States
• PMID: 29760221 (Publication Type: Journal Article)
• Copyright: ©2018 American Association for Cancer Research.

Chemical References

• Androgen Antagonists
• Neoplasm Proteins
• Prostate-Specific Antigen

Topics

• Aged
• Androgen Antagonists (administration & dosage)
• Chemotherapy, Adjuvant (methods)
• Gene Expression Regulation, Neoplastic (drug effects)
• Genomics
• Humans
• Kaplan-Meier Estimate
• Male
• Middle Aged
• Neoplasm Metastasis
• Neoplasm Proteins (genetics)
• Neoplasm Recurrence, Local (genetics, pathology)
• Prognosis
• Prostate (pathology)
• Prostate-Specific Antigen (genetics)
• Prostatectomy
• Prostatic Neoplasms (drug therapy, genetics, pathology, surgery)
• Seminal Vesicles (metabolism, pathology)
• Transcriptome