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

作者：Karnes R Jeffrey; Sharma Vidit; Choeurng Voleak; Ashab Hussam Al Deen; Erho Nicholas; Alshalalfa Mohammed; Trock Bruce; Ross Ashley; Yousefi Kasra; Tsai Harrison; Zhao Shuang G; Tosoian Jeffrey J; Haddad Zaid; Takhar Mandeep; Chang S Laura; 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

来源：Clinical Cancer Research, 2018, 24(16): 3908-3916.

DOI：10.1158/1078-0432.CCR-17-2745

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 (aADT)-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, P-interaction = 0.009; set II: HR = 0.25, P-interaction = 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 (P-interaction = 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.

• 出版日期2018-8-15