In prostate cancer, neuroendocrine (NE) differentiation may rarely present de novo or more frequently arises following hormonal therapy in patients with castration-resistant prostate cancer (CRPC). Its distinct phenotype is characterized by an aggressive clinical course, lack of responsiveness to hormonal therapies and poor prognosis. Importantly, a subset of CRPC patients exhibits an aggressive-variant disease with very similar clinical and molecular characteristics to small-cell prostate cancer (SCPC) even though tumors do not have NE differentiation. This aggressive-variant prostate cancer (AVPC) also shares the sensitivity of SCPC to platinum-based chemotherapy albeit with short-lived clinical benefit. As optimal treatment strategies for AVPC remain elusive, currently ongoing research efforts aim to enhance our understanding of the biology of this disease entity and improve treatment outcomes for our patients. This review is an overview of our current knowledge on prostate cancer with NE differentiation and AVPC, with a focus on their clinical characteristics and management, including available as well as experimental therapeutic strategies.

Single-cell RNA sequencing studies have suggested that total mRNA content correlates with tumor phenotypes. Technical and analytical challenges, however, have so far impeded at-scale pan-cancer examination of total mRNA content. Here we present a method to quantify tumor-specific total mRNA expression (TmS) from bulk sequencing data, taking into account tumor transcript proportion, purity and ploidy, which are estimated through transcriptomic/genomic deconvolution. We estimate and validate TmS in 6,590 patient tumors across 15 cancer types, identifying significant inter-tumor variability. Across cancers, high TmS is associated with increased risk of disease progression and death. TmS is influenced by cancer-specific patterns of gene alteration and intra-tumor genetic heterogeneity as well as by pan-cancer trends in metabolic dysregulation. Taken together, our results indicate that measuring cell-type-specific total mRNA expression in tumor cells predicts tumor phenotypes and clinical outcomes.

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Knockout of ERβ in the mouse leads to nuclear expression of epidermal growth factor receptor (EGFR) in the prostate. To examine whether ERβ plays a similar role in the human prostate, we used four cohorts of men: 1) a Swedish cohort of normal prostates and PCa (prostate cancer) of different Gleason grades; 2) men with benign prostatic hyperplasia (BPH) treated with the 5α-reductase inhibitor, finasteride, and finasteride together with the ERβ agonists, soy isoflavones; 3) men with PCa above Gleason grade 4 (GG4), treated with ADT (androgen deprivation therapy) and abiraterone (AA), the blocker of androgen synthesis for different durations; and 4) men with GG4 PCa on ADT or ADT with the AR (androgen receptor) blocker, enzalutamide, for 4 mo to 6 mo. In men with BPH, finasteride treatment induced EGFR nuclear expression, but, when finasteride was combined with isoflavones, EGFR remained on the cell membrane. In GG4 patients, blocking of AR for 4 mo to 6 mo resulted in loss of ERβ and PTEN expression and increase in patients with nuclear EGFR from 10 to 40%. In the men with GG4 PCa, blocking of adrenal synthesis of testosterone for 2 mo to 7 mo had the beneficial effect of increasing ERβ expression, but, on treatment longer than 8 mo, ERβ was lost and EGFR moved to the nucleus. Since nuclear EGFR is a predictor of poor outcome in PCa, addition of ERβ agonists together with abiraterone should be considered as a treatment that might sustain expression of ERβ and offer some benefit to patients.

5504 Background: Novel androgen signaling inhibitors (ASI) with medical castration may improve outcomes in LHRPC. We previously reported relapse free survival association with pathologic measures of tumor regression. However a wide range of persistent cancers was recorded. To build on our findings and test candidate predictors of outcome, we conducted a study examining APA effect in LHRPC. Methods: This is a phase II neoadjuvant study of 6 months APA+LHRHa +/- AA (randomized 1:1) in LHRPC (≥ cT2 + Gleason Score ≥ 8 or ≥ cT2b + Gleason ≥ 7 + PSA > 10 ng/mL) followed by radical prostatectomy (RP). We studied treatment effect by pathology measures [path. stage, tumor volume (TV), tumor cellularity % (TC), tumor epithelial volume (TEV: TC x TV)]. Tumor expression of candidate markers of outcome was assessed in the diagnostic biopsy by IHC [AR signaling (AR-N, ARC19, ARV7, PSA), PTEN, glucocorticoid receptor (GR), Ki67, p53, RB] and DNA/RNA seq. A previously identified candidate predictive molecular signature (AR-N overexpression, nARV7 absence, no GR overexpression, Ki67 ≤10%) was tested. Univariate (Fisher’s exact, Wilcoxon) and multivariate (logistic, linear models) analyses employed. Results: Sixty three -of 65 pts enrolled- had RP. PS-ECOG 0, median age 65 (43-77). Treatment was well tolerated with Grade 3 hypertension in 7 (2 APA + LHRHa). Presurgical PSA was ≤0.1 in 62/63 (98%). Organ confined disease (≤ypT2N0) found in 13/32(41%) APA+LHRHa vs. 12/31 (39%) APA+AA+LHRHa treated. 2 (3%) had pathologic complete remission (APA+AA+LHRHa), 6 (10%) minimal residual disease (5 on APA +LHRHa). Despite uniformity in PSA response, we recorded heterogeneity in measures of tumor viability: TV (0-11.5cc), TC (1-80%), TEV (0-6.1cc). ≤ypT2N0 associates with diagnostic biopsy positivity for the prespecified molecular signature (p <0.0001), PTEN expression (p: 0.004), absence of cribriform/ intraductal spread (p 0.002) but not with Gleason Score. On multivariate analysis only the prespecified biopsy signature associates with outcome (p 0.003). Findings were replicated when analyzed by TV, TC and TEV measures. Conclusions: Neoadjuvant Apalutamide plus LHRHa is tolerable and results in tumor regression in a subset of LHRPC patients. Dual ASI treatment does not further improve outcomes. Biopsy positive for a prespecified molecular signature, associated with response. Study results emphasize the need to consider biologic heterogeneity and pursue validation of predictors of response in order to improve therapeutic outcomes in LHRPC. Clinical trial information: NCT03279250 .