Purpose: Candidates for definitive therapy for localized prostate cancer (PCa) should have life expectancy (LE) in excess of 10 years. However, LE estimation is difficult. To circumvent this problem, we developed a nomogram predicting 10-year LE for patients treated with either radical prostatectomy (RP) or external-beam radiation therapy (EBRT) and compared it with an existing tool. Patients and Methods: Between 1989 and 2000, 9,131 men were treated with either RP (n = 5,955) or EBRT (n = 3,176), without any secondary therapy and all deaths were considered unrelated to PCa. Age and Charlson comorbidity index (CCI) predicted 10-year LE in Cox regression models. We used 200 bootstrap resamples to internally validate the nomogram. Results: Median age was 66 years, median CCI was 1, median follow-up was 5.9 years and median actuarial survival was 13.8 years. Advanced age (P < .001), elevated CCI score (P < .001) and treatment type (EBRT v RP, P < .001) were independent predictors of poor 10 year LE. The nomogram predicting 10 year LE after either RP or EBRT was 84.3% accurate in split sample validation and was 2.9% (P = .007) more accurate than the existing tool. A cutoff of 70% or less was 84% accurate in identifying men who did not survive beyond 10 years. Conclusion: Our nomogram can accurately identify those individuals who do not have sufficient LE to warrant definitive PCa treatment and can help optimizing therapy decision-making.

Background: Mitochondria are suggested to be important organelles for cancer initiation and promotion. This study was designed to evaluate the prognostic value of MTC02, a marker for mitochondrial content, in prostate cancer. Methods: Immunohistochemistry of using an antibody against MTC02 was performed on a tissue microarray (TMA) containing 11,152 prostate cancer specimens. Results were compared to histological phenotype, biochemical recurrence, ERG status and other genomic deletions by using our TMA attached molecular information. Results: Tumor cells showed stronger MTC02 expression than normal prostate epithelium. MTC02 immunostaining was found in 96.5% of 8,412 analyzable prostate cancers, including 15.4% tumors with weak, 34.6% with moderate, and 46.5% with strong expression. MTC02 expression was associated with advanced pathological tumor stage, high Gleason score, nodal metastases (p < 0.0001 each), positive surgical margins (p = 0.0005), and early PSA recurrence (p < 0.0001) if all cancers were jointly analyzed. Tumors harboring ERG fusion showed higher expression levels than those without (p < 0.0001). In ERG negative prostate cancers, strong MTC02 immunostaining was linked to deletions of PTEN, 6q15, 5q21, and early biochemical recurrence (p < 0.0001 each). Moreover, multiple scenarios of multivariate analyses suggested an independent association of MTC02 with prognosis in preoperative settings. Conclusions: Our study demonstrates high-level MTC02 expression in ERG negative prostate cancers harboring deletions of PTEN, 6q15, and 5q21. Additionally, increased MTC02 expression is a strong predictor of poor clinical outcome in ERG negative cancers, highlighting a potentially important role of elevated mitochondrial content for prostate cancer cell biology.

Lysophosphatidylcholine acyltransferase 1 (LPCAT1) has been suggested to play a role in cancer. To assess its role in prostate cancer, LPCAT1 expression was analyzed on a tissue microarray containing samples from 11,152 prostate cancer patients. In benign prostate glands, LPCAT1 immunostaining was absent or weak. In prostate cancer, LPCAT1 positivity was found in 73.8% of 8786 interpretable tumors including 29.2% with strong expression. Increased LPCAT1 expression was associated with advanced tumor stage (pT3b/T4) (p < 0.0001), high Gleason score (≥4 + 4) (p < 0.0001), positive nodal involvement (p = 0.0002), positive surgical margin (p = 0.0005), and early PSA recurrence (p < 0.0001). High LPCAT1 expression was strongly linked to ERG‐fusion type prostate cancer. Strong LPCAT1 staining was detected in 45.3% of ERG positive but in only 16.7% of ERG negative tumors (p < 0.0001). Within ERG negative cancers, LPCAT1 staining was strongly increased within the subgroup of PTEN deleted cancers (p < 0.0001). Further subgroup analyses revealed that associations of high LPCAT1 expression with PSA recurrence and unfavorable tumor phenotype were largely driven by ERG negative cancers (p < 0.0001) while these effects were substantially mitigated in ERG positive cancers (p = 0.0073). The prognostic impact of LPCAT1 expression was independent of histological and clinical parameters. It is concluded, that LPCAT1 measurement, either alone or in combination, may be utilized for better clinical decision‐making. These data also highlight the potentially important role of lipid metabolism in prostate cancer biology.

Context: Robot‐assisted radical prostatectomy (RARP) has become the standard surgical procedure for localized prostate‐cancer (PCa). Nerve‐sparing surgery (NSS) during RARP has been associated with improved erectile function and continence rates after surgery. However, it remains unclear what are the most appropriate indications for NSS.Objective: The objective of this study is to systematically review the available parameters for selection of patients for NSS. The weight of different clinical variables, multiparametric magnetic‐resonance‐imaging (mpMRI) findings, and the impact of multiparametric‐nomograms in the decision‐making process on (side‐specific) NSS were assessed.Evidence acquisition: This systematic review searched relevant databases and included studies performed from January 2000 until December 2020 and recruited a total of 15 840 PCa patients. Studies were assessed that defined criteria for (side‐specific) NSS and associated them with oncological safety and/or functional outcomes. Risk of bias assessment was performed.Evidence synthesis: Nineteen articles were eligible for full‐text review. NSS is primarily recommended in men with adequate erectile function, and with low‐risk of extracapsular extension (ECE) on the side‐of NSS. Separate clinical and radiological variables have low accuracy for predicting ECE, whereas nomograms optimize the risk‐stratification and decision‐making process to perform or to refrain from NSS when oncological safety (organ‐confined disease, PSM rates) and functional outcomes (erectile function and continence rates) were assessed.Conclusions: Consensus exists that patients who are at high risk of ECE should refrain from NSS. Several multiparametric preoperative nomograms were developed to predict ECE with increased accuracy compared with single clinical, pathological, or radiological variables, but controversy exists on risk thresholds and decision rules on a conservative versus a less‐conservative surgical approach. An individual clinical judgment on the possibilities of NSS set against the risks of ECE is warranted.Patient summary: NSS is aimed at sparing the nerves responsible for erection. NSS may lead to unfavorable tumor control if the risk of capsule penetration is high. Nomograms predicting extraprostatic tumor‐growth are probably most helpful.

Microtubule-associated protein Tau (MAPT) overexpression has been linked to poor prognosis and decreased response to taxane-based therapies in several cancer types, but its relevance in prostate cancer is unknown. In this study, MAPT expression was analyzed by immunohistochemistry on a tissue microarray containing 17,747 prostate cancers. MAPT was absent in normal prostate epithelial cells but detectable in 1004 (8.2%) of 12,313 interpretable cancers. Its expression was associated with advanced tumor stage, high Gleason grade, positive lymph nodes, and early biochemical recurrence (p < 0.0001 each). For example, MAPT was found in 3.6% of 2072 Gleason ≤3 + 3 cancers but in 14.4% of 704 Gleason ≥4 + 4 cancers. High-level MAPT staining was also linked to TMPRSS2:ERG fusions (p < 0.0001). MAPT staining was seen in 15.2 and 16% of cancers with TMPRSS2:ERG fusion detected by immunohistochemistry and fluorescence in-situ hybridization, but in only 3.5 and 3.9% of cancers without ERG staining or ERG rearrangements. Moreover, an association was found between MAPT expression and PTEN deletions, with 19% MAPT positivity in 948 PTEN deleted cancers but only 7% MAPT positivity in 3895 tumors with normal PTEN copy numbers (p < 0.0001). Multivariate analysis revealed that the prognostic value of MAPT was independent from established parameters. Conventional large section analyses showed intratumoral MAPT heterogeneity in all three analyzed cancers. The results of our study identify MAPT, as a moderate prognostic marker in prostate cancer, whose clinical impact, however, may be limited due to the rarity and heterogeneity of its expression.

γ-glutamyl-hydrolase (GGH) is a ubiquitously-expressed enzyme that regulates intracellular folate metabolism for cell proliferation, DNA synthesis, and repair. Employing GGH immunohistochemistry on a tissue microarray with 12,427 prostate cancers, we found that GGH expression was negative to low in normal prostate epithelium, whereas 88.3% of our 10,562 interpretable cancers showed GGH expression. GGH staining was considered as low intensity in 49.6% and as high intensity in 38.6% of cancers. High GGH expression was linked to the TMPRSS2:ERG-fusion positive subset of cancers (p < 0.0001), advanced pathological tumor stage, and high Gleason grade (p < 0.0001 each). Further analysis revealed that these associations were merely driven by the subset of ERG-negative cancers, High GGH expression was weakly linked to early biochemical recurrence in ERG negative cancers (p < 0.0001) and independent from established histo-pathological parameters. Moreover, GGH expression was linked to features of genetic instability, including presence of recurrent deletions at 3p, 5q, 6q, and 10q (PTEN, p ≤ 0.01 each), as well as to accelerated cell proliferation as measured by Ki67 immunohistochemistry (p < 0.0001). In conclusion, the results of our study identify GGH as an ERG subtype specific molecular marker with modest prognostic relevance, which may have clinical relevance if analyzed in combination with other molecular markers.