Integrative multi-region molecular profiling of primary prostate cancer in men with synchronous lymph node metastasis.

Localized prostate cancer is frequently composed of multiple spatially distinct tumors with significant inter- and intra-tumoral molecular heterogeneity. This genomic diversity gives rise to many competing clones that may drive the biological trajectory of the disease. Previous large-scale sequencing efforts have focused on the evolutionary process in metastatic prostate cancer, revealing a potential clonal progression to castration resistance. However, the clonal origin of synchronous lymph node (LN) metastases in primary disease is still unknown. Here, we perform multi-region, targeted next generation sequencing and construct phylogenetic trees in men with prostate cancer with synchronous LN metastasis to better define the pathologic and molecular features of primary disease most likely to spread to the LNs. Collectively, we demonstrate that a combination of histopathologic and molecular factors, including tumor grade, presence of extra-prostatic extension, cellular morphology, and oncogenic genomic alterations are associated with synchronous LN metastasis.

A mechanistic insight into the anti-metastatic role of the prostate specific antigen.

AIM: Since its discovery Prostate Specific Antigen (PSA), also referred to as kallikrein-3 (KLK3), has been used as standard circulating biomarker for prostate cancer (PCa). However, its specificity remains not adequate and its mechanism of action still elusive. Therefore, deciphering PSA role throughout PCa-pathobiology would be relevant in improving both cancer diagnosis and outcome prediction. We investigated the possible role played by PSA on/in the tumor microenvironment and over the first steps of cancer invasion. METHODS: Fresh PCa-specimens and cell lines were used for ex-vivo/in-vitro invasion assays and assessment of prostate tissue-PSA (tPSA), type 1 collagen (COL1A1) and ß1-integrin expression. Tissue Cancer Genome Atlas (TCGA) and Decipher® datasets were considered to estimate tPSA clinical relevance. RESULTS: A more precise, inverse, correspondence between tPSA and clinical/pathological parameters was found than for circulating PSA. KLK3 combined with Gleason grade and pathologic stage, better predicted cancer-related mortality. Consistently, we demonstrated that PSA inhibits prostate extracellular-matrix (ECM) invasion by PCa cells. As for the mechanism of action, we provided novel information that PSA is able to cleave COL1A1, a main component of the ECM. Finally, ß1-integrin, a crucial COL1A1 transducing-receptor involved in tumor adhesion/invasion, resulted to be downregulated in PCa specimens with higher levels of tPSA. CONCLUSIONS: By interfering with type 1 collagen and its downstream targets, PSA may hamper adhesion and path of the cancer cells through ECM and their migration ability, thus explaining the inverse correlation highlighted between prostate tPSA levels and clinically significant disease.

Depressive Symptoms and Low Sexual Desire after Radical Prostatectomy: Early and Long-Term Outcomes in a Real-Life Setting.

PURPOSE: We assessed the rate and predictors of depressive symptoms and impaired sexual desire in patients who underwent open or robot-assisted radical prostatectomy. MATERIALS AND METHODS: A total of 811 patients completed IIEF (International Index of Erectile Function) and BDI (Beck Depression Inventory) preoperatively, and 6, 12, 24 and 36 months postoperatively. Rates and predictors of depressive symptoms and impaired sexual desire were assessed with descriptive statistics and logistic regression models. RESULTS: We analyzed data on 416 patients treated with robot-assisted radical prostatectomy and 395 who underwent open radical prostatectomy. Overall the incidence of patients with postoperative BDI scores suggestive of depressive symptoms ranged between 26.3% at 6 months and 36.7% at 36 months. BDI scores were significantly higher in open than in robot-assisted radical prostatectomy cases at every analyzed postoperative time point (all p <0.01). Patients treated with robot-assisted radical prostatectomy showed higher IIEF-EF (Erectile Function) domain scores and a greater proportion of them experienced erectile function recovery at each time point compared to those treated with open radical prostatectomy (all p <0.005). Postoperatively the rate of impaired sexual desire ranged between 40.9% at 6 months and 34.1% at 24 months. IIEF-SD (Sexual Domain) scores were significantly lower in open radical prostatectomy cases at every followup (all p <0.02). Age, open radical prostatectomy and postoperative erectile dysfunction were independent predictors of BDI scores and impaired sexual desire. CONCLUSIONS: One of 3 men surgically treated for prostate cancer still report depressive symptoms months after surgery. Patients who undergo robot-assisted radical prostatectomy reported lower depressive symptoms than those treated with open radical prostatectomy. Sexual desire was highly affected after radical prostatectomy with greater impairment reported by patients who underwent open radical prostatectomy.

Testosterone Levels Correlate With Grade Group 5 Prostate Cancer: Another Step Toward Personalized Medicine.

BACKGROUND: Controversial results have shown a significant association with either low or high total testosterone (tT) levels and high risk prostate cancer (PCa). We tested the relationship between circulating tT and grade group 5 (G5) PCa at radical prostatectomy (RP) in patients with preoperative low- to intermediate-risk disease. METHODS: Serum sex hormones were assessed the day before RP in a cohort of 846 patients with low- to intermediate-risk PCa. Patients were segregated using the new 5-tiered Gleason grade groups. Restricted cubic spline functions and logistic regression analyses tested the association between sex hormones and G5 PCa. Differences in potential predictive accuracy (PA) were assessed for tT and prostate-specific antigen (PSA) levels. RESULTS: Overall, 27 men (3.2%) had G5 PCa at RP, and this group had higher PSA values than patients with G1-G4 PCa (P = 0.02). The groups did not differ in terms of preoperative mean hormonal values. Both low and high circulating tT values depicted a nonlinear U-shaped correlation with G5 PCa at RP. The lowest and highest (10th and 90th percentiles) tT values and biopsy PCa grade emerged as multivariable independent predictors of G5 PCa at RP (all P < 0.05). PA for G5 PCa did not differ between tT (area under the curve [AUC] 0.631) and PSA (AUC 0.636). CONCLUSIONS: Circulating tT was a significant predictor of G5 PCa at RP in patients with preoperative low- to intermediate-risk disease. Preoperative tT and PSA values showed similar PA for the most aggressive disease, confirming a potential role for circulating androgens in preoperative risk assessment of PCa patients. Prostate 77:234-241, 2017. © 2016 Wiley Periodicals, Inc.