PSA screening, prostate biopsy, and treatment of prostate cancer in the years surrounding the USPSTF recommendation against prostate cancer screening.

BACKGROUND: The 2012 United States Preventive Services Task Force recommendation against screening for prostate cancer has impacted rates of prostate-specific antigen (PSA) screening and appears to be associated with declining prostate cancer incidence. Our objective was to characterize health care utilization that may explain these observed trends. METHODS: MarketScan claims, which capture >30 million privately insured patients in the United States, were queried for all men aged 40-64 years for the years 2008-2014. PSA testing, prostate biopsy, prostate cancer diagnosis, and definitive local treatment were determined using associated International Classification of Diseases, Ninth Revision and Current Procedural Terminology, Fourth Edition codes. RESULTS: There were approximately 6 million qualifying men with a full year of data. PSA testing, prostate biopsy, and prostate cancer detection declined significantly between 2009 and 2014, most notably after 2011. The prostate biopsy rate per 100 patients with a PSA test decreased over the study period from 1.95 (95% confidence interval [CI], 1.92-1.97) to 1.52 (95% CI, 1.50-1.54). Prostate cancer incidence per prostate biopsy increased over the study period from 0.36 (95% CI, 0.35-0.36) to 0.39 (95% CI, 0.39-0.40). Of new prostate cancer diagnoses, the proportion managed with definitive local treatment decreased from 69% (95% CI, 69%-70%) to 54% (95% CI, 53%-55%). Both PSA testing and prostate cancer incidence decreased significantly after 2011 (P < .001). CONCLUSION: In a large cohort of privately insured men, PSA testing, prostate biopsy, prostate cancer incidence, and local definitive treatment for prostate cancer decreased between 2008 and 2014, most notably after 2011. This decrease may be driven by differential referral patterns from primary care providers to urologists. Cancer 2018;124:2733-2739. © 2018 American Cancer Society.

LuCaP Prostate Cancer Patient-Derived Xenografts Reflect the Molecular Heterogeneity of Advanced Disease an--d Serve as Models for Evaluating Cancer Therapeutics.

BACKGROUND: Metastatic prostate cancer is a common and lethal disease for which there are no therapies that produce cures or long-term durable remissions. Clinically relevant preclinical models are needed to increase our understanding of biology of this malignancy and to evaluate new agents that might provide effective treatment. Our objective was to establish and characterize patient-derived xenografts (PDXs) from advanced prostate cancer (PC) for investigation of biology and evaluation of new treatment modalities. METHODS: Samples of advanced PC obtained from primary prostate cancer obtained at surgery or from metastases collected at time of death were implanted into immunocompromised mice to establish PDXs. Established PDXs were propagated in vivo. Genomic, transcriptomic, and STR profiles were generated. Responses to androgen deprivation and docetaxel in vivo were characterized. RESULTS: We established multiple PDXs (LuCaP series), which represent the major genomic and phenotypic features of the disease in humans, including amplification of androgen receptor, PTEN deletion, TP53 deletion and mutation, RB1 loss, TMPRSS2-ERG rearrangements, SPOP mutation, hypermutation due to MSH2/MSH6 genomic aberrations, and BRCA2 loss. The PDX models also exhibit variation in intra-tumoral androgen levels. Our in vivo results show heterogeneity of response to androgen deprivation and docetaxel, standard therapies for advanced PC, similar to the responses of patients to these treatments. CONCLUSIONS: The LuCaP PDX series reflects the diverse molecular composition of human castration-resistant PC and allows for hypothesis-driven cause-and-effect studies of mechanisms underlying treatment response and resistance. Prostate 77: 654-671, 2017. © 2017 The Authors. The Prostate Published by Wiley Periodicals, Inc.

Characterizing the molecular features of ERG-positive tumors in primary and castration resistant prostate cancer.

BACKGROUND: The TMPRSS2-ERG gene fusion is detected in approximately half of primary prostate cancers (PCa) yet the prognostic significance remains unclear. We hypothesized that ERG promotes the expression of common genes in primary PCa and metastatic castration-resistant PCa (CRPC), with the objective of identifying ERG-associated pathways, which may promote the transition from primary PCa to CRPC. METHODS: We constructed tissue microarrays (TMA) from 127 radical prostatectomy specimens, 20 LuCaP patient-derived xenografts (PDX), and 152 CRPC metastases obtained immediately at time of death. Nuclear ERG was assessed by immunohistochemistry (IHC). To characterize the molecular features of ERG-expressing PCa, a subset of IHC confirmed ERG+ or ERG- specimens including 11 radical prostatectomies, 20 LuCaP PDXs, and 45 CRPC metastases underwent gene expression analysis. Genes were ranked based on expression in primary PCa and CRPC. Common genes of interest were targeted for IHC analysis and expression compared with biochemical recurrence (BCR) status. RESULTS: IHC revealed that 43% of primary PCa, 35% of the LuCaP PDXs, and 18% of the CRPC metastases were ERG+ (12 of 48 patients [25%] had at least one ERG+ metastasis). Based on gene expression data and previous literature, two proteins involved in calcium signaling (NCALD, CACNA1D), a protein involved in inflammation (HLA-DMB), CD3 positive immune cells, and a novel ERG-associated protein, DCLK1 were evaluated in primary PCa and CRPC metastases. In ERG+ primary PCa, a weak association was seen with NCALD and CACNA1D protein expression. HLA-DMB association with ERG was decreased and CD3 cell number association with ERG was changed from positive to negative in CRPC metastases compared to primary PCa. DCLK1 was upregulated at the protein level in unpaired ERG+ primary PCa and CRPC metastases (P = 0.0013 and P < 0.0001, respectively). In primary PCa, ERG status or expression of targeted proteins was not associated with BCR-free survival. However, for primary PCa, ERG+DCLK1+ patients exhibited shorter time to BCR (P = 0.06) compared with ERG+DCLK1- patients. CONCLUSIONS: This study examined ERG expression in primary PCa and CRPC. We have identified altered levels of inflammatory mediators associated with ERG expression. We determined expression of DCLK1 correlates with ERG expression and may play a role in primary PCa progression to metastatic CPRC. Prostate 76:810-822, 2016. © 2016 Wiley Periodicals, Inc.

NCCN Guidelines Insights: Prostate Cancer Early Detection, Version 2.2016.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Prostate Cancer Early Detection provide recommendations for prostate cancer screening in healthy men who have elected to participate in an early detection program. The NCCN Guidelines focus on minimizing unnecessary procedures and limiting the detection of indolent disease. These NCCN Guidelines Insights summarize the NCCN Prostate Cancer Early Detection Panel's most significant discussions for the 2016 guideline update, which included issues surrounding screening in high-risk populations (ie, African Americans, BRCA1/2 mutation carriers), approaches to refine patient selection for initial and repeat biopsies, and approaches to improve biopsy specificity.

NCCN Clinical Practice Guidelines Prostate Cancer Early Detection, Version 2.2015.

Prostate cancer represents a spectrum of disease that ranges from nonaggressive, slow-growing disease that may not require treatment to aggressive, fast-growing disease that does. The NCCN Guidelines for Prostate Cancer Early Detection provide a set of sequential recommendations detailing a screening and evaluation strategy for maximizing the detection of prostate cancer that is potentially curable and that, if left undetected, represents a risk to the patient. The guidelines were developed for healthy men who have elected to participate in the early detection of prostate cancer, and they focus on minimizing unnecessary procedures and limiting the detection of indolent disease.

Dormancy in solid tumors: implications for prostate cancer.

In cancer dormancy, residual tumor cells persist in a patient with no apparent clinical symptoms, only to potentially become clinically relevant at a later date. In prostate cancer (PCa), the primary tumor is often removed and many patients experience a prolonged period (>5 years) with no evidence of disease before recurrence. These characteristics make PCa an excellent candidate for the study of tumor cell dormancy. However, the mechanisms that constitute PCa dormancy have not been clearly defined. Additionally, the definition of tumor cell dormancy varies in the literature. Therefore, we have separated tumor cell dormancy in this review into three categories: (a) micrometastatic dormancy--a group of tumor cells that cannot increase in number due to a restrictive proliferation/apoptosis equilibrium. (b) Angiogenic dormancy--a group of tumor cells that cannot expand beyond the formation of a micrometastasis due to a lack of angiogenic potential. (c) Conditional dormancy--an individual cell or a very small number of cells that cannot proliferate without the appropriate cues from the microenvironment, but do not require angiogenesis to do so. This review aims to identify currently known markers, mechanisms, and models of tumor dormancy, in particular as they relate to PCa, and highlight current opportunities for advancement in our understanding of clinical cancer dormancy.

Prostate cancer early detection, version 1.2014. Featured updates to the NCCN Guidelines.

The NCCN Guidelines for Prostate Cancer Early Detection provide recommendations for men choosing to participate in an early detection program for prostate cancer. These NCCN Guidelines Insights highlight notable recent updates. Overall, the 2014 update represents a more streamlined and concise set of recommendations. The panel stratified the age ranges at which initiating testing for prostate cancer should be considered. Indications for biopsy include both a cutpoint and the use of multiple risk variables in combination. In addition to other biomarkers of specificity, the Prostate Health Index has been included to aid biopsy decisions in certain men, given recent FDA approvals.

Exome sequencing identifies a spectrum of mutation frequencies in advanced and lethal prostate cancers.

To catalog protein-altering mutations that may drive the development of prostate cancers and their progression to metastatic disease systematically, we performed whole-exome sequencing of 23 prostate cancers derived from 16 different lethal metastatic tumors and three high-grade primary carcinomas. All tumors were propagated in mice as xenografts, designated the LuCaP series, to model phenotypic variation, such as responses to cancer-directed therapeutics. Although corresponding normal tissue was not available for most tumors, we were able to take advantage of increasingly deep catalogs of human genetic variation to remove most germline variants. On average, each tumor genome contained ~200 novel nonsynonymous variants, of which the vast majority was specific to individual carcinomas. A subset of genes was recurrently altered across tumors derived from different individuals, including TP53, DLK2, GPC6, and SDF4. Unexpectedly, three prostate cancer genomes exhibited substantially higher mutation frequencies, with 2,000-4,000 novel coding variants per exome. A comparison of castration-resistant and castration-sensitive pairs of tumor lines derived from the same prostate cancer highlights mutations in the Wnt pathway as potentially contributing to the development of castration resistance. Collectively, our results indicate that point mutations arising in coding regions of advanced prostate cancers are common but, with notable exceptions, very few genes are mutated in a substantial fraction of tumors. We also report a previously undescribed subtype of prostate cancers exhibiting "hypermutated" genomes, with potential implications for resistance to cancer therapeutics. Our results also suggest that increasingly deep catalogs of human germline variation may challenge the necessity of sequencing matched tumor-normal pairs.

Single cell transcriptomic analysis of prostate cancer cells.

BACKGROUND: The ability to interrogate circulating tumor cells (CTC) and disseminated tumor cells (DTC) is restricted by the small number detected and isolated (typically <10). To determine if a commercially available technology could provide a transcriptomic profile of a single prostate cancer (PCa) cell, we clonally selected and cultured a single passage of cell cycle synchronized C4-2B PCa cells. Ten sets of single, 5-, or 10-cells were isolated using a micromanipulator under direct visualization with an inverted microscope. Additionally, two groups of 10 individual DTC, each isolated from bone marrow of 2 patients with metastatic PCa were obtained. RNA was amplified using the WT-Ovation™ One-Direct Amplification System. The amplified material was hybridized on a 44K Whole Human Gene Expression Microarray. A high stringency threshold, a mean Alexa Fluor® 3 signal intensity above 300, was used for gene detection. Relative expression levels were validated for select genes using real-time PCR (RT-qPCR). RESULTS: Using this approach, 22,410, 20,423, and 17,009 probes were positive on the arrays from 10-cell pools, 5-cell pools, and single-cells, respectively. The sensitivity and specificity of gene detection on the single-cell analyses were 0.739 and 0.972 respectively when compared to 10-cell pools, and 0.814 and 0.979 respectively when compared to 5-cell pools, demonstrating a low false positive rate. Among 10,000 randomly selected pairs of genes, the Pearson correlation coefficient was 0.875 between the single-cell and 5-cell pools and 0.783 between the single-cell and 10-cell pools. As expected, abundant transcripts in the 5- and 10-cell samples were detected by RT-qPCR in the single-cell isolates, while lower abundance messages were not. Using the same stringency, 16,039 probes were positive on the patient single-cell arrays. Cluster analysis showed that all 10 DTC grouped together within each patient. CONCLUSIONS: A transcriptomic profile can be reliably obtained from a single cell using commercially available technology. As expected, fewer amplified genes are detected from a single-cell sample than from pooled-cell samples, however this method can be used to reliably obtain a transcriptomic profile from DTC isolated from the bone marrow of patients with PCa.

Characterization of osteoblastic and osteolytic proteins in prostate cancer bone metastases.

BACKGROUND: Approximately 90% of patients who die of Prostate Cancer (PCa) have bone metastases, which promote a spectrum of osteoblastic, osteolytic or mixed bone responses. Numerous secreted proteins have been reported to promote osteoblastic or osteolytic bone responses. We determined whether previously identified and/or novel proteins were associated with the osteoblastic or osteolytic response in clinical specimens of PCa bone metastases. METHODS: Gene expression was analyzed on 14 PCa metastases from 11 patients by microarray profiling and qRT-PCR, and protein expression was analyzed on 33 PCa metastases from 30 patients by immunohistochemistry on highly osteoblastic and highly osteolytic bone specimens. RESULTS: Transcript and protein levels of BMP-2, BMP-7, DKK-1, ET-1, and Sclerostin were not significantly different between osteoblastic and osteolytic metastases. However, levels of OPG, PGK1, and Substance P proteins were increased in osteoblastic samples. In addition, Emu1, MMP-12, and sFRP-1 were proteins identified with a novel role of being associated with either the osteoblastic or osteolytic bone response. CONCLUSIONS: This is the first detailed analysis of bone remodeling proteins in human specimens of PCa bone metastases. Three proteins not previously shown to be involved may have a role in the PCa bone response. Furthermore, our data suggests that the relative expression of numerous, rather than a single, bone remodeling proteins determine the bone response in PCa bone metastases.

Penile carcinoma: lessons learned from vulvar carcinoma.

PURPOSE: Penile carcinoma is rare in the developed world and treatment guidelines are often based on marginal clinical data. Prospective controlled studies are virtually absent and meta-analyses are rare. Vulvar carcinoma, on the other hand, has many parallels to penile carcinoma, and the level of evidence for diagnosis and treatment is more robust. Therefore, we assessed the body of literature on vulvar carcinoma to identify potential improvements in the care of patients with penile carcinoma. MATERIALS AND METHODS: A literature review was performed on vulvar carcinoma and direct comparisons were made to a similar review of the literature on penile carcinoma. RESULTS: Several aspects of vulvar carcinoma management are clearly established and deserve closer evaluation in penile carcinoma. For example, human papillomavirus is identified in a high percentage of patients with vulvar carcinoma but is understudied in penile carcinoma. Further study is of potential clinical value, especially with the development of human papillomavirus vaccines for prevention. Penile carcinoma TNM staging does not adequately stratify survival or risk of advanced disease. Staging of vulvar carcinoma is dependent on tumor size and depth of invasion measured in millimeters, as opposed to the invasion of underlying structures in penile carcinoma. Management of the inguinal nodes is more refined for vulvar carcinoma, where lymphatic mapping has been conducted and sentinel node biopsy has proven to be highly effective in multicenter trials. Finally, the efficacy of adjuvant radiation and chemotherapy has been tested in controlled trials or reported in meta-analyses for vulvar carcinoma, which are both lacking for penile carcinoma. Radiation after inguinal node dissection, for example, has been shown to enhance survival in patients with defined risk factors. Neoadjuvant chemoradiation is recommended before surgery for advanced vulvar carcinoma. CONCLUSIONS: Evidence derived from studies on vulvar carcinoma can be extrapolated to penile carcinoma to help guide clinical trials and future research directions to enhance the treatment of these patients.

A history of the Society of Urologic Oncology.

This narrative of the history of the Society of Urologic Oncology (SUO) presents the story of the founding and development of this organization and the creation and establishment of its initiatives and programs. It includes a description of how "Urologic Oncology: Seminars and Original Investigations" came to be designated as its "official journal", thus commemorating the anniversary of the Journal's twenty-five years of publication.

Positive surgical margins at radical prostatectomy predict prostate cancer specific mortality.

PURPOSE: Positive surgical margins in men undergoing radical prostatectomy for prostate cancer are associated with an increased risk of biochemical recurrence. Few data are available on the role of positive surgical margins in prostate cancer specific mortality. Using a large, population based national cancer registry we evaluated the risk of prostate cancer specific mortality associated with margin status. MATERIALS AND METHODS: The SEER cancer registry data for patients diagnosed between 1998 and 2006 were used to identify men undergoing radical prostatectomy for prostate cancer. Margin status, pathological stage, Gleason grade and postoperative radiation therapy were recorded along with demographic data. Multivariate Cox regression analysis was used to estimate the risk of prostate cancer specific mortality associated with positive surgical margins. RESULTS: A total of 65,633 patients comprised the cohort in which 291 (0.44%) prostate cancer specific deaths occurred during an average followup of 50 months. Positive surgical margins were reported in 21.2% of cases and were more common in pT3a than pT2 tumors (44% vs 18%, p <0.001) and higher grade tumors (28% vs 18%, p <0.001). The 7-year disease specific survival rates for those at highest risk for prostate cancer specific mortality (higher grade pT3a) were 97.6% for cases with negative surgical margins and 92.4% for those with positive surgical margins. Positive surgical margins were associated with a 2.6-fold increased unadjusted risk of prostate cancer specific mortality (HR 2.55, 95% CI 2.02-3.21). Positive surgical margins remained an independent predictor of prostate cancer specific mortality on multivariate analysis (HR 1.70, 95% CI 1.32-2.18). CONCLUSIONS: These data demonstrate the independent role of positive surgical margins in prostate cancer specific mortality. These findings support the importance of optimizing surgical techniques to achieve a sound oncological surgical outcome with negative surgical margins when possible.

Disseminated tumor cells in prostate cancer patients after radical prostatectomy and without evidence of disease predicts biochemical recurrence.

PURPOSE: Men with apparently localized prostate cancer often relapse years after radical prostatectomy. We sought to determine if epithelial-like cells identified from bone marrow in patients after radical prostatectomy, commonly called disseminated tumor cells (DTC), were associated with biochemical recurrence. EXPERIMENTAL DESIGN: We obtained bone marrow aspirates from 569 men prior to radical prostatectomy and from 34 healthy men with prostate-specific antigens <2.5 ng/mL to establish a comparison group. Additionally, an analytic cohort consisting of 98 patients with no evidence of disease (NED) after radical prostatectomy was established to evaluate the relationship between DTC and biochemical recurrence. Epithelial cells in the bone marrow were detected by magnetic bead enrichment with antibodies to CD45 and CD61 (negative selection) followed by antibodies to human epithelial antigen (positive selection) and confirmation with FITC-labeled anti-BerEP4 antibody. RESULTS: DTC were present in 72% (408 of 569) of patients prior to radical prostatectomy. There was no correlation with pathologic stage, Gleason grade, or preoperative prostate-specific antigens. Three of 34 controls (8.8%) had DTC present. In patients with NED after radical prostatectomy, DTC were present in 56 of 98 (57%). DTC were detected in 12 of 14 (86%) NED patients after radical prostatectomy who subsequently suffered biochemical recurrence. The presence of DTC in NED patients was an independent predictor of recurrence (hazard ratio 6.9; 95% confidence interval, 1.03-45.9). CONCLUSIONS: Approximately 70% of men undergoing radical prostatectomy had DTC detected in their bone marrow prior to surgery, suggesting that these cells escape early in the disease. Although preoperative DTC status does not correlate with pathologic risk factors, persistence of DTC after radical prostatectomy in NED patients was an independent predictor of recurrence.

Prostate cancer-associated gene expression alterations determined from needle biopsies.

PURPOSE: To accurately identify gene expression alterations that differentiate neoplastic from normal prostate epithelium using an approach that avoids contamination by unwanted cellular components and is not compromised by acute gene expression changes associated with tumor devascularization and resulting ischemia. EXPERIMENTAL DESIGN: Approximately 3,000 neoplastic and benign prostate epithelial cells were isolated using laser capture microdissection from snap-frozen prostate biopsy specimens provided by 31 patients who subsequently participated in a clinical trial of preoperative chemotherapy. cDNA synthesized from amplified total RNA was hybridized to custom-made microarrays composed of 6,200 clones derived from the Prostate Expression Database. Expression differences for selected genes were verified using quantitative reverse transcription-PCR. RESULTS: Comparative analyses identified 954 transcript alterations associated with cancer (q < 0.01%), including 149 differentially expressed genes with no known functional roles. Gene expression changes associated with ischemia and surgical removal of the prostate gland were absent. Genes up-regulated in prostate cancer were statistically enriched in categories related to cellular metabolism, energy use, signal transduction, and molecular transport. Genes down-regulated in prostate cancers were enriched in categories related to immune response, cellular responses to pathogens, and apoptosis. A heterogeneous pattern of androgen receptor expression changes was noted. In exploratory analyses, androgen receptor down-regulation was associated with a lower probability of cancer relapse after neoadjuvant chemotherapy followed by radical prostatectomy. CONCLUSIONS: Assessments of tumor phenotypes based on gene expression for treatment stratification and drug targeting of oncogenic alterations may best be ascertained using biopsy-based analyses where the effects of ischemia do not complicate interpretation.

WDR19 expression is increased in prostate cancer compared with normal cells, but low-intensity expression in cancers is associated with shorter time to biochemical failures and local recurrence.

PURPOSE: Prostate cancer is the third leading cause of cancer death in the United States, following lung and colorectal cancer. We previously identified WDR19 as a prostate-specific, androgen-regulated gene. Here, we evaluate its utility as a prostate cancer tissue marker for diagnosis and prognostic evaluation. EXPERIMENTAL DESIGN: Real-time quantitative PCR was done on a panel of prostate tissue isolated by laser capture microdissection. After generating antibodies against WDR19, tissue microarrays (TMA) were employed to compare WDR19 expression between normal, benign prostatic hyperplasia, and prostate cancer tissue. RESULTS: Using microarrays and real-time quantitative PCR, we showed that WDR19 mRNA expression was increased in cancer. We further showed that WDR19 protein is localized to cytoplasmic subcellular granules and is expressed exclusively in prostate epithelia. Large-scale immunohistochemical staining using TMAs reveals a significant percentage of increase in intensely staining tissue cores in cancer tissue when compared with normal or benign prostatic hyperplastic tissue. Based on the analysis of a separate TMA for which clinical follow-up information was available, low-intensity WDR19 staining was significantly associated with decreased time to biochemical failure (P = 0.006) and with decreased time to locoregional recurrence (P = 0.050). CONCLUSIONS: WDR19 should be added to the list of prostate cancer tissue markers. The continued expansion of a multiple-marker panel will conceivably increase the sensitivity and specificity of prostate cancer diagnosis and prognosis.

Differential expression of angiogenesis associated genes in prostate cancer bone, liver and lymph node metastases.

Our objective was to elucidate phenotypic differences between prostate cancer (PCa) liver, lymph node, and bone metastases. PCa metastases were obtained through a rapid tissue acquisition necropsy protocol. We grossly dissected metastatic foci from frozen samples and performed expression analyses using cDNA microarrays. Immunohistochemical analyses using a tissue microarray from thirty individuals with PCa metastases to lymph nodes, liver, and bone was used to confirm the gene expression changes associated with each metastatic site. Transcript alterations statistically-associated with bone metastases included increased expression of IBSP (Bone sialoprotein), F13A1 (factor XIII), and decreased expression of EFNA1 (ephrin-A1) and ANGPT2 (angiopoietin-2) when compared to liver and lymph node metastases. The metastasis-associated changes in proteins involved in coagulation and angiogenesis prompted further analysis of additional factors known to participate in the clotting cascade and blood vessel formation (angiopoitein-1, PAI-1, uPA, PAI-RBP-1 and hepsin). We also assessed tumor-associated microvessel density and distribution in liver, lymph node, and bone metastasis. Intense fibrin(ogen) and fibulin-1 staining was localized to epithelial cells at the periphery of metastatic tumors possibly to facilitate angiogenesis. The expression of hepsin, uPA, PAI-RBP1, PAI-1, and factor XIII may influence fibrinolysis and are regulated by the tumor microenvironment. The expression of angiopoietin-2 and apparent silencing of angiopoietin-1 in PCa bone, liver, and lymph node metastases may be critical for angiogenesis in this tumor type. In addition, the resulting tumor-associated microvessel density and distribution was significantly different between liver and bone metastasis possibly in response to the protein expression changes detailed above.

Tertiary Gleason pattern 5 in Gleason 7 prostate cancer predicts pathological stage and biochemical recurrence.

PURPOSE: Gleason sum 7 prostate cancers are a heterogeneous group with diverse tumor behaviors and disease outcomes. Tertiary Gleason patterns are reported with increasing frequency, particularly in prostatectomy pathology reports. We studied the pathological and biochemical outcome following radical prostatectomy in men with Gleason sum 7 and tertiary Gleason pattern 5. MATERIALS AND METHODS: We reviewed 1,110 cases of clinically localized prostate cancer treated with primary radical prostatectomy between January 1998 and August 2006 through a prospectively collected prostate cancer database. Patients who underwent neoadjuvant or adjuvant hormonal deprivation, radiation or systemic chemotherapy were excluded. RESULTS: Of the 1,110 patients 509 had Gleason sum 7 cancer. Tertiary Gleason pattern was present in 66 of 509 cases (13%) and it was absent in 443 (87%). On multivariate analysis tertiary Gleason pattern 5 was associated with higher pT stage (OR 2.55, 95% CI 1.40-4.65) and biochemical recurrence (HR 1.78, 95% CI 1.00-3.17). On subgroup analysis when patients with Gleason sum 3 + 4 + 5 and 4 + 3 + 5 were compared to their respective referent groups without the tertiary Gleason pattern, the 2 groups showed a trend toward higher pathological stage and prostate specific antigen progression. Patients with Gleason sum 3 + 4 with no tertiary pattern had higher PSA recurrence-free probability than those with Gleason sum 3 + 4 + 5 or 4 + 3 and patients with Gleason sum 4 + 3 + 5 had the lowest PSA recurrence-free probability. CONCLUSIONS: In patients with Gleason sum 7 prostate cancer tertiary Gleason grade 5 is significantly associated with higher pT stage and biochemical recurrence. Larger studies are needed to assess the predictive value of tertiary grade compared to other established parameters in predicting the long-term oncological outcome after radical prostatectomy.

Molecular alterations in prostate carcinomas that associate with in vivo exposure to chemotherapy: identification of a cytoprotective mechanism involving growth differentiation factor 15.

PURPOSE: To identify molecular alterations associating with in vivo exposure of prostate carcinoma to chemotherapy and assess functional roles modulating tumor response and resistance. EXPERIMENTAL DESIGN: Patients with high-risk localized prostate cancer (tumor-node-metastasis >or= T(2b) or prostate-specific antigen >or= 15 ng/mL or Gleason glade >or= 4+3) were enrolled into a phase II clinical trial of neoadjuvant chemotherapy with docetaxel and mitoxantrone followed by prostatectomy. Pretreatment prostate tissue was acquired by needle biopsy and posttreatment tissue was acquired by prostatectomy. Prostate epithelium was captured by microdissection, and transcript levels were quantitated by cDNA microarray hybridization. Gene expression changes associated with chemotherapy were determined by a random variance t test. Several were verified by quantitative reverse transcription PCR. In vitro analyses determining the influence of growth differentiation factor 15 (GDF15) on chemotherapy resistance were done. RESULTS: Gene expression changes after chemotherapy were measured in 31 patients who completed four cycles of neoadjuvant chemotherapy. After excluding genes shown previously to be influenced by the radical prostatectomy procedure, we identified 51 genes with significant transcript level alterations following chemotherapy. This group included several cytokines, including GDF15, chemokine (C-X-C motif) ligand 10, and interleukin receptor 1beta. Overexpression of GDF15 or exposure of prostate cancer cell lines to exogenous recombinant GDF15 conferred resistance to docetaxel and mitoxantrone. CONCLUSIONS: Consistent molecular alterations were identified in prostate cancer cells exposed to docetaxel and mitoxantrone chemotherapy. These alterations include transcripts encoding cytokines known to be regulated through the nuclear factor-kappaB pathway. Chemotherapy-induced cytokines and growth factors, such as GDF15, contribute to tumor cell therapy resistance and may serve as targets to improve responses.

Detection and characterization of circulating and disseminated prostate cancer cells.

The dissemination of prostate cancer cells to secondary sites appears to be an intermediate step in the formation of tumor metastases. However, the significance of tumor cell dissemination into the blood and bone marrow as well as the characteristics of these cells remains largely unknown. In attempts to correlate the presence of disseminated tumor cells with disease prognosis, studies have utilized a range of molecular and histologic techniques. The results of this research have been largely inconclusive in terms of clinical utility. Nevertheless, they have demonstrated that these cells are detectable and present much more often than would be expected based on the rate of prostate cancer recurrence. Further research has thus begun to focus on the isolation of individual disseminated tumor cells which can then be analyzed with techniques such as gene expression microarrays and comparative genomic hybridization in order to better characterize the cells. This review paper will examine the various methods of detecting disseminated tumor cells in patients with prostate cancer and the results of studies correlating these cells with clinical variables. Additionally, we discuss the isolation and analysis of disseminated cells and examine their potential value in helping to understand the relationship between these cells and tumor metastasis.