Spratt, Daniel E.

Abstract Purpose: Current clinical parameters do not stratify indolent from aggressive prostate cancer. Aggressive prostate cancer, defined by the progression from localized disease to metastasis, is responsible for the majority of prostate cancer–associated mortality. Recent gene expression profiling has proven successful in predicting the outcome of prostate cancer patients; however, they have yet to provide targeted therapy approaches that could inhibit a patient's progression to metastatic disease. Experimental Design: We have interrogated a total of seven primary prostate cancer cohorts (n = 1,900), two metastatic castration-resistant prostate cancer datasets (n = 293), and one prospective cohort (n = 1,385) to assess the impact of TOP2A and EZH2 expression on prostate cancer cellular program and patient outcomes. We also performed IHC staining for TOP2A and EZH2 in a cohort of primary prostate cancer patients (n = 89) with known outcome. Finally, we explored the therapeutic potential of a combination therapy targeting both TOP2A and EZH2 using novel prostate cancer–derived murine cell lines. Results: We demonstrate by genome-wide analysis of independent primary and metastatic prostate cancer datasets that concurrent TOP2A and EZH2 mRNA and protein upregulation selected for a subgroup of primary and metastatic patients with more aggressive disease and notable overlap of genes involved in mitotic regulation. Importantly, TOP2A and EZH2 in prostate cancer cells act as key driving oncogenes, a fact highlighted by sensitivity to combination-targeted therapy. Conclusions: Overall, our data support further assessment of TOP2A and EZH2 as biomarkers for early identification of patients with increased metastatic potential that may benefit from adjuvant or neoadjuvant targeted therapy approaches. Clin Cancer Res; 23(22); 7072–83. ©2017 AACR.

9 Background: Early salvage radiation therapy (SRT) following radical prostatectomy (RP) has been shown to reduce biochemical recurrence and distant metastases. We aim to identify factors predictive of prostate cancer-specific mortality (PCSM) and all-cause mortality (ACM) from a consortium database from 10 academic institutions. Methods: 2,454 node-negative patients (pts) with detectable post-prostatectomy PSA ( ≥ 0.01 ng/mL) treated with SRT ± neoadjuvant/concurrent androgen deprivation therapy (N/C ADT) were included. Cumulative incidence and Kaplan-Meier methods were used to estimate rates of PCSM and ACM, respectively. Univariate and multivariable analyses (MVA) were performed by competing risks regression and Cox proportional hazards methods for PCSM and ACM. Results: Median follow-up was 5 years from SRT completion and 8 years from date of RP; 24% had pathologic Gleason score (GS) of ≤ 6, 56% GS 7, and 19% GS ≥ 8; 56% extraprostatic extension (EPE), 18% seminal vesicle invasion (SVI), 58% positive surgical margins, and 16% received N/C ADT. Median age at RP and SRT were 62 years (IQR 56-66) and 64 years (59-69), respectively. Median SRT dose was 66 Gy (IQR 65-68) and median pre-SRT PSA was 0.5 ng/mL (IQR 0.3-1.1). MVA performed from SRT completion date demonstrated higher pre-SRT PSA (HR = 2.1), higher GS (GS 7 vs. ≤ 6: HR 2.0; GS ≥ 8 vs. 6: HR 3.3) , SVI (HR 2.5), year of SRT (2000-2004, 1995-1999, 1985-1994 vs. 2005-2012; HR 2.9, HR 2.5, HR 3.6, respectively) were significantly associated with higher PCSM. These same variables were all significantly associated with higher PCSM and ACM rates calculated from both SRT completion date and date of RP. Conclusions: Initiation of early SRT at lower post-operative PSA levels following RP is associated with reduced risk of PCSM and ACM, even when calculated from RP date to account for lead time bias. Other factors significantly associated with PCSM include higher GS, SVI, and earlier year of SRT. [Table: see text]

3 Background: There is a clear need to develop a clinically relevant molecular subtyping approach for prostate cancer. We hypothesized that prostate cancer can be subtyped based on luminal versus basal lineage. Methods: We applied the PAM50 classifier, which is used clinically to identify luminal and basal cancers in breast cancer, to subtype a total of 3,782 prostate cancer samples using a high-density microarray platform run in a CLIA-certified laboratory. We examined the associations of these subtypes and clinical outcomes. Results: We demonstrate that PAM50 segregates prostate cancer into three reproducible subtypes in both retrospective cohorts and on prospective validation: luminal A (33.3%-34.3%), luminal B (28.5%-32.6%), and basal (34.1%-37.1%). Luminal B prostate cancers exhibited the worst clinical prognoses, followed by basal and luminal A subtypes (10-year biochemical recurrence-free survival: 29/39/41%; distant metastasis-free survival: 53/73/73%; prostate cancer-specific survival: 78/86/89%; overall survival: 69/80/82% respectively) on both univariable and multivariable analyses accounting for standard clinicopathologic prognostic factors. Known luminal lineage markers, such as NKX3.1 and KRT18, and the basal lineage CD49f signature, were enriched in luminal- and basal-like cancers respectively, demonstrating the connection between these subtypes and established prostate cancer biology. While both luminal-like subtypes were associated with increased AR expression and signaling, only luminal B prostate cancers were significantly associated with post-operative response to androgen deprivation therapy (ADT) in a subset analysis matching patients based on clinicopathologic variables (interaction p = 0.006, luminal B 10-year metastasis: 33% (treated) vs. 55% (untreated), non-luminal B: 37% (treated) vs. 21% (untreated)). Conclusions: These findings contribute novel insight into the biology of prostate cancer, and provide translatable clinical tools for personalizing post-operative ADT for patients with prostate cancer. Similar to breast cancer, these findings suggest that luminal/basal subtyping may be useful in treatment selection in prostate cancer.

133 Background: The genomic classifier, Decipher, has been validated to predict risk of metastasis after radical prostatectomy (RP). However, the cohort size and event rate in the previous studies did not allow for a thorough investigation into performance within individual clinicopathologic or treatment subgroups. In this study, we present the first meta-analysis of the performance of the 22-marker genomic classifier in men with prostate cancer (PCa) post-RP. Methods: MEDLINE, EMBASE, and the Decipher genomic resource information database were searched for published reports of men with PCa treated by RP between 2010 and 2016 where the benefit of the Decipher genomic classifier test was assessed. The primary end point was the ability of Decipher to independently improve prognostication of regional or distant metastasis over routine clinicopathologic factors. Meta-analysis was performed with random-effects modeling, and extent of heterogeneity between studies was determined with the I2 test. Results: Five studies (975 total patients, and 855 with individual patient genomic and clinicopathologic data) were eligible for analysis. The median follow-up was 8 years. All patients had clinical high-risk disease, yet 60.9%, 22.6%, and 16.5% of patients were classified as low, intermediate, and high-risk, respectively by Decipher and had 10-year cumulative incidence rates of metastases of 5.5%, 15.0% and 26.7% (p < 0.001), respectively. Adjusting for standard clinicopathologic variables, on multivariable analysis Decipher remained a statistically significant predictor of metastasis (hazard ratio [HR] 1.30 per 0.1 unit, 95% confidence interval [CI] 1.14-1.47, p < 0.001), and the summary HR for metastasis of Decipher across the 5 studies was 1.52 (95% CI 1.39-1.67) per 0.1 unit. Conclusions: The genomic classifier test, Decipher, has the ability to independently improve prognostication of men post-RP, as well as within nearly all clinicopathologic and treatment subgroups. Strong consideration should be given to incorporating the use of genomic testing in clinical decision making and clinical trials to better individualize treatment.

Abstract Clinical trials have established the benefit of androgen deprivation therapy (ADT) combined with radiotherapy in prostate cancer. ADT sensitizes prostate cancer to radiotherapy-induced death at least in part through inhibition of DNA repair machinery, but for unknown reasons, adjuvant ADT provides further survival benefits. Here, we show that androgen receptor (AR) expression and activity are durably upregulated following radiotherapy in multiple human prostate cancer models in vitro and in vivo. Moreover, the degree of AR upregulation correlates with survival in vitro and time to tumor progression in animal models. We also provide evidence of AR pathway upregulation, measured by a rise in serum levels of AR-regulated hK2 protein, in nearly 20% of patients after radiotherapy. Furthermore, these men were three-fold more likely to experience subsequent biochemical failure. Collectively, these data demonstrate that radiotherapy can upregulate AR signaling after therapy to an extent that negatively affects disease progression and/or survival. Cancer Res; 75(22); 4688–96. ©2015 AACR.