Development and validation of a prostate cancer genomic signature that predicts early ADT treatment response following radical prostatectomy

Purpose: Currently no genomic signature exists to distinguish men most likely to progress on adjuvant androgen deprivation therapy (ADT) after radical prostatectomy (RP) 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 RP 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: Hazard Ratio (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 vs no-ADT patients (9.4% vs 29.2%, p=0.021). The marginal ADT-RS by ADT interaction remained significant in the matched data set (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 RP.

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