Circulating Tumor Cells as a Predictor of Treatment Response in Clinically Localized Prostate Cancer.

PURPOSE: Using nonenrichment-based, potentially more sensitive Epic Sciences circulating tumor cell (CTC) platform, we sought to detect and characterize CTCs in untreated, high-risk localized prostate cancer and to evaluate their clinical implication. METHODS: Between 2012 and 2015, blood samples were prospectively collected from patients with National Comprehensive Cancer Network high-risk localized prostate cancer undergoing either radiotherapy (XRT) plus androgen deprivation therapy or radical prostatectomy (RP) with curative intent. Samples were analyzed with the Epic Sciences platform with 4J,6-diamidino-2-phenylindole, CD45, cytokeratin (CK), and androgen receptor (AR) N-terminal staining. CTC counts were correlated with biochemical recurrence (BCR). RESULTS: A diversity of CTC subtypes, including CK-positive, CK-negative, AR-positive, and CTC clusters, were observed in 73.3% (33 of 45) of patients with evaluable data. The median follow-up was 14.2 months (range, 0.5 to 43.7 months). BCR occurred more frequently in the RP group than XRT (15 of 26 v one of 19), with most patients in the XRT group continuing to receive androgen deprivation therapy. A higher proportion of metastatic events were observed in the RP group (five of 26 v one of 19). In the RP group, BCR and development of metastases were associated with a higher total number of CTCs, AR-positive CTCs, and CTC phenotypic heterogeneity. One patient who developed BCR and metastases quickly after RP had diverse phenotypical CTC subtypes, and single-cell genomic analyses of all detectable CTCs confirmed common prostate cancer copy number alterations and PTEN loss. CONCLUSION: CTCs can be identified in most patients with high-risk localized prostate cancer before definitive therapy using the Epic Sciences platform. If confirmed in a larger cohort with longer follow-up, phenotypic and genomic characterization of CTCs pretherapy may provide an additional means of risk stratifying patients with newly diagnosed high-risk disease and potentially help identify patients who could require multimodal therapy.

Transcriptomic heterogeneity in multifocal prostate cancer.

BACKGROUND: Commercial gene expression assays are guiding clinical decision making in patients with prostate cancer, particularly when considering active surveillance. Given heterogeneity and multifocality of primary prostate cancer, such assays should ideally be robust to the coexistence of unsampled higher grade disease elsewhere in the prostate in order to have clinical utility. Herein, we comprehensively evaluated transcriptomic profiles of primary multifocal prostate cancer to assess robustness to clinically relevant multifocality. METHODS: We designed a comprehensive, multiplexed targeted RNA-sequencing assay capable of assessing multiple transcriptional classes and deriving commercially available prognostic signatures, including the Myriad Prolaris Cell Cycle Progression score, the Oncotype DX Genomic Prostate Score, and the GenomeDX Decipher Genomic Classifier. We applied this assay to a retrospective, multi-institutional cohort of 156 prostate cancer samples. Derived commercial biomarker scores for 120 informative primary prostate cancer samples from 44 cases were determined and compared. RESULTS: Derived expression scores were positively correlated with tumor grade (rS = 0.53-0.73; all P < 0.001), both within the same case and across the entire cohort. In cases of extreme grade-discordant multifocality (co-occurrence of grade group 1 [GG1] and ≥GG4 foci], gene expression scores were significantly lower in low- (GG1) versus high-grade (≥GG4) foci (all P < 0.001). No significant differences in expression scores, however, were observed between GG1 foci from prostates with and without coexisting higher grade cancer (all P > 0.05). CONCLUSIONS: Multifocal, low-grade and high-grade prostate cancer foci exhibit distinct prognostic expression signatures. These findings demonstrate that prognostic RNA expression assays performed on low-grade prostate cancer biopsy tissue may not provide meaningful information on the presence of coexisting unsampled aggressive disease. FUNDING: Prostate Cancer Foundation, National Institutes of Health (U01 CA214170, R01 CA183857, University of Michigan Prostate Specialized Program of Research Excellence [S.P.O.R.E.] P50 CA186786-05, Weill Cornell Medicine S.P.O.R.E. P50 CA211024-01A1), Men of Michigan Prostate Cancer Research Fund, University of Michigan Comprehensive Cancer Center core grant (2-P30-CA-046592-24), A. Alfred Taubman Biomedical Research Institute, and Department of Defense.

Standardizing the definition of adverse pathology for lower risk men undergoing radical prostatectomy.

PURPOSE: Numerous definitions of adverse pathology at radical prostatectomy (RP) have been proposed and implemented for both research and clinical care, and there is tremendous variation in the specific criteria used to define adverse pathology in these settings. Given the current landscape in which magnetic resonance imaging criteria and biomarker cutoffs are validated for disparate adverse pathology definitions, we sought to identify which of these is most closely tied to biochemical recurrence (BCR) after RP. MATERIALS AND METHODS: A total of 2,837 patients who underwent RP at a single institution for localized prostate cancer (PCa) were included. We evaluated the following existing definitions of adverse pathology at RP: (1) Gleason score ≥7, (2) primary Gleason pattern ≥4, (3) Gleason score ≥7 or pathologic stage T3-4, (4) pathologic stage T3-4, (5) primary Gleason pattern ≥4 or pathologic stage T3-4. The primary outcome measure was BCR. Multiple statistical techniques were used to assess BCR prediction. RESULTS: Of the 5 definitions assessed, 1 (primary Gleason pattern ≥4 or pathologic stage T3-4, 540 patients [19% of cohort]) consistently outperformed the other definitions across all statistical measures. Additionally, a total of only 13 (6.6%) and 34 (10.3%) men with very-low-risk and low-risk cancer per National Comprehensive Cancer Network guideline, respectively, met this definition of adverse pathology at the time of RP. CONCLUSIONS: Varying definitions of adverse pathology differ in their prognostic performance. The criteria defined by either primary Gleason pattern ≥4 or pT3-4 disease appears to most accurately predict BCR in this subset of patients with lower risk PCa at the time of diagnosis. Additionally, men with very-low-risk or low-risk PCa per National Comprehensive Cancer Network guidelines are relatively unlikely to have adverse pathology at the time of surgical resection. These data may help inform the use of imaging and molecular markers as well as the intensity of surveillance in men with newly diagnosed PCa.

Metabolomic profiling reveals a role for androgen in activating amino acid metabolism and methylation in prostate cancer cells.

Prostate cancer is the second leading cause of cancer related death in American men. Development and progression of clinically localized prostate cancer is highly dependent on androgen signaling. Metastatic tumors are initially responsive to anti-androgen therapy, however become resistant to this regimen upon progression. Genomic and proteomic studies have implicated a role for androgen in regulating metabolic processes in prostate cancer. However, there have been no metabolomic profiling studies conducted thus far that have examined androgen-regulated biochemical processes in prostate cancer. Here, we have used unbiased metabolomic profiling coupled with enrichment-based bioprocess mapping to obtain insights into the biochemical alterations mediated by androgen in prostate cancer cell lines. Our findings indicate that androgen exposure results in elevation of amino acid metabolism and alteration of methylation potential in prostate cancer cells. Further, metabolic phenotyping studies confirm higher flux through pathways associated with amino acid metabolism in prostate cancer cells treated with androgen. These findings provide insight into the potential biochemical processes regulated by androgen signaling in prostate cancer. Clinically, if validated, these pathways could be exploited to develop therapeutic strategies that supplement current androgen ablative treatments while the observed androgen-regulated metabolic signatures could be employed as biomarkers that presage the development of castrate-resistant prostate cancer.

Prostate-specific antigen levels in relation to consumption of nonsteroidal anti-inflammatory drugs and acetaminophen: results from the 2001-2002 National Health and Nutrition Examination Survey.

BACKGROUND: Inflammation has been implicated in prostate carcinogenesis; therefore, the use of nonsteroidal anti-inflammatory drugs (NSAIDs) has the potential of decreasing the risk of prostate cancer. However, to the authors' knowledge the precise correlation between oral NSAID use, serum prostate-specific antigen (PSA), and prostate cancer risk is unknown. To further characterize this association, the authors evaluated serum PSA levels with regard to NSAID and acetaminophen consumption in a large cross-sectional study of men in the US. METHODS: PSA levels were determined in 1319 men aged >40 years in the 2001-2002 National Health and Nutrition Examination Survey (NHANES). Linear regressions were performed on log-transformed PSA levels, accounting for the complex survey design, to evaluate the relations between PSA and the use of NSAIDs and acetaminophen after adjusting for the effects of age, race, educational level, smoking status, body mass index, coexisting inflammatory conditions, and heart disease. RESULTS: NSAID and acetaminophen consumption displayed a negative association with PSA levels, namely, individuals who reported using NSAIDs (19.8%) or acetaminophen (1.3%) regularly had lower PSA levels than individuals who did not take these drugs, although the impact of acetaminophen was not statistically significant. PSA levels among NSAID users were 0.9 times the levels among nondrug takers (P = .038), whereas PSA levels among acetaminophen users were 0.76 times the levels in nondrug takers (P = .14). Individuals who stated they took both NSAIDs and acetaminophen (0.99%) on a regular basis had higher PSA levels (1.8 times greater), although not statistically significantly so (P = .24), than individuals who stated they did not take either of these drugs regularly. CONCLUSIONS: The findings of the current study suggest that regular NSAID consumption may reduce serum PSA levels. Whether this is indicative of a protective effect on prostate cancer risk or masks possible prostate injury resulting in reduced detection of prostate cancer is unclear. Given the widespread consumption of NSAIDs and the regular use of PSA for the assessment of prostate cancer risk, the potential implications of the current study's findings may be substantial and warrant further investigation.

Prostate-specific antigen levels in relation to cadmium exposure and zinc intake: results from the 2001-2002 National Health and Nutrition Examination Survey.

BACKGROUND: Cadmium exposure has been suggested as a risk factor for prostate cancer, and experimental literature suggests that the carcinogenic effect of cadmium is modified by the presence of zinc. We evaluated total prostate-specific antigen (PSA) levels in relation to urinary cadmium concentrations and dietary zinc intake. METHODS: PSA levels were determined in 1,320 men over the age of 40 in the 2001-2002 National Health and Nutrition Examination Survey (NHANES). Urinary cadmium concentrations were measured in about one-third of the sample population, whereas dietary zinc intake was based on participants' 24-hr recall. Information on all three variables was available for 422 men in the 2001-2002 NHANES survey. We performed linear regressions to evaluate the relationships these factors after accounting for age and other covariates. RESULTS: Little evidence for an association between cadmium and elevated PSA level was observed. However, the data provide suggestive evidence for an interaction between zinc intake and cadmium exposure (P for interaction=0.09). Among men with zinc intake less than the median level of 12.67 mg/day, an increase in 1 microg/g creatinine cadmium exposure was associated with a 35% increase in PSA level. In contrast, among men with greater than median zinc intake, little evidence for an association between cadmium and PSA was found. CONCLUSIONS: These findings suggest a protective effect of zinc intake on cadmium-induced prostatic injury, and may provide further rationale for investigating the impact of these factors individually and jointly on the etiology of prostate cancer.

Lymphovascular invasion is independently associated with overall survival, cause-specific survival, and local and distant recurrence in patients with negative lymph nodes at radical cystectomy.

PURPOSE: We hypothesized that bladder cancer patients with associated lymphovascular invasion (LVI) are at increased risk of occult metastases. METHODS: A multi-institutional group (University of Texas Southwestern [Dallas, TX], Baylor College of Medicine [Houston, TX], Johns Hopkins University [Baltimore, MD]) carried out a retrospective study of 958 patients who underwent cystectomy for bladder cancer between 1984 and 2003. Of patients with transitional-cell carcinoma (n = 776), LVI status was available for 750. LVI was defined as the presence of tumor cells within an endothelium-lined space. RESULTS: LVI was present in 36.4% (273 of 750) overall, involving 26% (151 of 581) and 72% (122 of 169) of node-negative and node-positive patients, respectively. Prevalence of LVI increased with higher pathologic stage (9.0%, 23%, 60%, and 78%, for T1, T2, T3, and T4, respectively; P < .001). Using multivariate Cox regression analyses including age, stage, grade, and number of pelvic lymph nodes removed, LVI was an independent predictor of local (HR = 2.03, P = .049), distant (HR = 2.60, P = .0011), and overall (HR = 2.02, P = .0003) recurrence in node-negative patients. LVI was an independent predictor of overall (HR = 1.84, P = .0002) and cause-specific (HR = 2.07, P = .0012) survival in node-negative patients. LVI maintained its independent predictor status in competing risks regression models (P = .013), where other-cause mortality was considered as a competing risk. LVI was not a predictor of recurrence or survival in node-positive patients. CONCLUSION: LVI is an independent predictor of recurrence and decreased cause-specific and overall survival in patients who undergo cystectomy for invasive bladder cancer and are node-negative. These patients represent a high risk group that may benefit from integrated therapy with cystectomy and perioperative systemic chemotherapy.