Advanced Prostate Cancer Cases Research Articles

Liquid Biopsy Potential Biomarkers in Prostate Cancer.

Prostate cancer (PCa) is the second most common cancer in men worldwide with an incidence of 14.8% and a mortality of 6.6%. Shortcomings in comprehensive medical check-ups in low- and middle-income countries lead to delayed detection of PCa and are causative of high numbers of advanced PCa cases at first diagnosis. The performance of available biomarkers is still insufficient and limited applicability, including logistical and financial burdens, impedes comprehensive implementation into health care systems. There is broad agreement on the need of new biomarkers to improve (i) early detection of PCa, (ii) risk stratification, (iii) prognosis, and (iv) treatment monitoring. This review focuses on liquid biopsy tests distinguishing high-grade significant (Gleason score (GS) ≥ 7) from low-grade indolent PCa. Available biomarkers still lack performance in risk stratification of biopsy naïve patients. However, biomarkers with highly negative predictive values may help to reduce unnecessary biopsies. Risk calculators using integrative scoring systems clearly improve decision-making for invasive prostate biopsy. Emerging biomarkers have the potential to substitute PSA and improve the overall performance of risk calculators. Until then, PSA should be used and may be replaced whenever enough evidence has accumulated for better performance of a new biomarker.

The association between plasma C-peptide concentration and the risk of prostate cancer: a nested case-control study within a Japanese population-based prospective study.

The association between plasma C-peptide concentration and prostate cancer is unclear. Inconsistency of results from previous studies motivates this study. Using the Japan Public Health Center-based Prospective study, 201 prostate cancer cases and 402 controls were matched by age, public health center area, residence, date and time of blood collection, and fasting duration before blood collection. Odds ratios (OR) and 95% confidence intervals (CIs) were estimated by conditional logistic regression models. Out of 201 cases, 144 were localized and 48 were advanced. The overall association between median plasma C-peptide concentration and prostate cancer was not significant (OR for the highest tertile=0.81, 95% CI: 0.43-1.56, P-trend=0.54). Although stratification of prostate cancer by stage indicated different effects of plasma C-peptide on localized and advanced cases, there was no association between plasma C-peptide concentration and advanced prostate cancer (OR=2.82, 95% CI: 0.30-26.36 for the highest category, P-trend=0.37) and localized cases (OR=0.49, 95% CI: 0.23-1.04 for the highest category, P-trend=0.06) for patients fasting at the time of blood collection. The association between plasma C-peptide concentration and prostate cancer risk differed by cancer stage. Differentiation of localized and advanced prostate cancer cases is crucial when investigating the association between plasma C-peptide concentration and the risk of prostate cancer.

The Role of Genetic Variants in the Association between Dietary Acrylamide and Advanced Prostate Cancer in the Netherlands Cohort Study on Diet and Cancer

ABSTRACTTo investigate the association between dietary acrylamide and advanced prostate cancer, we examined acrylamide-gene interactions for advanced prostate cancer risk by using data from the Netherlands Cohort Study.Participants (n = 58,279 men) completed a baseline food frequency questionnaire (FFQ), from which daily acrylamide intake was calculated. At baseline, 2,411 men were randomly selected from the full cohort for case-cohort analysis. Fifty eight selected single nucleotide polymorphisms (SNPs) and two gene deletions in genes in acrylamide metabolism, DNA repair, sex steroid systems, and oxidative stress were analyzed. After 20.3 years of follow-up, 1,608 male subcohort members and 948 advanced prostate cancer cases were available for Cox analysis.Three SNPs showed a main association with advanced prostate cancer risk after multiple testing correction: catalase (CAT) rs511895, prostaglandin-endoperoxide synthase 2 (PTGS2) rs5275, and xeroderma pigmentosum group C (XPC) rs2228001. With respect to acrylamide-gene interactions, only rs1800566 in NAD(P)H quinone dehydrogenase 1 (NQO1) and rs2301241 in thioredoxin (TXN) showed a nominally statistically significant multiplicative interaction with acrylamide intake for advanced prostate cancer risk. After multiple testing corrections, none were statistically significant.In conclusion, no clear evidence was found for interaction between acrylamide intake and selected genetic variants for advanced prostate cancer risk.

Clinical analysis of advanced prostate cancer treated by surgery in 25 patients

Objective To investigate surgical treatment for advanced prostate cancer. Methods We retrospectively reviewed 25 cases of advanced prostate cancer treated by surgery between May 2014 and February 2016. The general data of the patients were analyzed.And age, PSA before surgery, pathological stage, prostate volume, fluctuation of postoperational PSA and outcome were recorded. Results The average age of the patients was 68.1 (56~83)years old, mean PSA before surgery was 86(15.81~335)ng/mL. There was 7, 18 patients with Gleason score of 7 and ≥8 respectively. Of those patients, 8 of them were staged T3bN0, 13 of them were TxN1M0, 4 patients had putative bone metastases and were staged M1b clinically. Mean volume of the prostate was 67.2(50~145 )mL, 19 of them were treated by laproscopic radical prostatectomy, 6 patients was treated by open retropubic surgery. Extended lymphatic dissection were performed, 4~30 lymph nodes with an average of 13 were extirpated. Three patients need transfusion after surgery, 1 patient experienced delayed drainage withdraw because of lymphorrhea, no major complication was found. PSA decreased significantly after surgery, mean PSA level dropped to 1.2(0.32~4.6)ng/mL at 6 weeks after operation, and then to 0.08(0.003~0.450)ng/mL at 3 months after surgery. The patients were followed up for 5~23 months, none of them died. One patient experienced biochemical relapse, MRI showed relapse in the urethrovesical anastomosis and was treated by endoscopic resection and comfirmed to be prostate cancer relapse with the same Gleason score of 9 as the former pathological diagnosis. Conclusions Surgery is a safe modality to treat advanced prostate cancer, radical prostatectomy and extended lymph node dissection didn't necessarily mean higher risk of complication. In experienced hands, radical prostatectomy and extended lymph node dissection is a rational choice for selected patients. Key words: Prostatic Neoplasms; Prostatectomy

Abstract 4262: Inflammatory gene expression differences among prostate cancer patients exposed to the World Trade Center aftermath

Abstract Background: World Trade Center (WTC) rescue and recovery workers were exposed to a complex mixture of dust and debris after the collapse of the WTC towers. An excess incidence of prostate cancer was observed in the WTC workers and, more advanced prostate cancer cases have been associated with higher levels of WTC exposure. As inflammation is known to promote tumor development and progression and the prostate cancer etiology remains uncertain, we compared RNA expression of inflammatory markers in prostate cancer tumors from WTC patients with matched prostate cancer patients not related to WTC. Methods: RNA was prepared from formalin-fixed paraffin embedded tumors of 15 WTC prostate cancer and 14 non-WTC prostate cancers, age, race, and Gleason-score matched. Gene expression was quantified using Nanostring nCounter® PanCancer Immune Profiling Panel, which combines markers for 24 immune cell types and populations, 30 common cancer antigens and genes representing all immune response categories including key checkpoint blockade genes. Data analysis was performed using the NanoString nSolver 2.6 analysis software. Genes shown to be characteristic of innate and adaptive immune cell populations were used to derive cell-type scores indicating population abundance of each immune cell type. Comparisons of cell type scores were performed using Student’s t test. Results: WTC prostate cancers expressed high levels of genes associated with chronic inflammation: NFATC2 (Fold change=3.0, P<0.001), MRC1 (Fold change=2.0, P=0.001), CT8L (Fold change=1.5, P=0.01), CSF1 (Fold change=1.5, P=0.001), NFKB1 (Fold change=1.3, P=0.005), CXCL13 (Fold change=3.7, P=0.04), IL6 (Fold change=2.5, P=0.04) and ITCH (Fold change= 0.3, P=0.001) compared with non-WTC prostate cancers. Conversely, non-WTC prostate cancers expressed higher levels of genes associated with innate immunity: TIRAP (Fold Change=0.05, P<0.001), IRF3 (Fold change=1, P<0.001), and FADD (Fold change=0.5, P=0.005), compared with WTC prostate cancer. In cell type enrichment analysis, macrophage and CD45+ cells scored higher in non-WTC (8.83±0.75 SD and 9.09±0.78 SD) than WTC (7.81±0.73 SD and 8.53±0.53 SD) prostate cancer samples (t=3.70, P<0.001 and t=2.29, P=0.02); regulatory T cells scored higher in WTC (5.90±0.52 SD) than non-WTC (5.42±0.67 SD) prostate cancer samples (t=2.15, P=0.04). Conclusions: Compared to non-WTC prostate cancers, tumors from WTC-exposed patients show overall lower expressions of genes involved in local innate immune-system response and a higher expression of adaptive immune-system response genes. Environmental factors, such as exposure during the 9/11 aftermath, may have played a role in the development of advanced prostate cancer in these patients via high immune-tolerance. The results have implications for a role of environmental factors in prostate carcinogenesis. Citation Format: Dana Hashim, Yixuan Gong, Matthew Galsky, Charles Baker, Paolo Boffetta, Michael J. Donovan, Emanuela Taioli, William K. Oh. Inflammatory gene expression differences among prostate cancer patients exposed to the World Trade Center aftermath [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4262. doi:10.1158/1538-7445.AM2017-4262

A Tale of Two Signals: AR and WNT in Development and Tumorigenesis of Prostate and Mammary Gland

Prostate cancer (PCa) is one of the most common cancers and among the leading causes of cancer deaths for men in industrialized countries. It has long been recognized that the prostate is an androgen-dependent organ and PCa is an androgen-dependent disease. Androgen action is mediated by the androgen receptor (AR). Androgen deprivation therapy (ADT) is the standard treatment for metastatic PCa. However, almost all advanced PCa cases progress to castration-resistant prostate cancer (CRPC) after a period of ADT. A variety of mechanisms of progression from androgen-dependent PCa to CRPC under ADT have been postulated, but it remains largely unclear as to when and how castration resistance arises within prostate tumors. In addition, AR signaling may be modulated by extracellular factors among which are the cysteine-rich glycoproteins WNTs. The WNTs are capable of signaling through several pathways, the best-characterized being the canonical WNT/β-catenin/TCF-mediated canonical pathway. Recent studies from sequencing PCa genomes revealed that CRPC cells frequently harbor mutations in major components of the WNT/β-catenin pathway. Moreover, the finding of an interaction between β-catenin and AR suggests a possible mechanism of cross talk between WNT and androgen/AR signaling pathways. In this review, we discuss the current knowledge of both AR and WNT pathways in prostate development and tumorigenesis, and their interaction during development of CRPC. We also review the possible therapeutic application of drugs that target both AR and WNT/β-catenin pathways. Finally, we extend our review of AR and WNT signaling to the mammary gland system and breast cancer. We highlight that the role of AR signaling and its interaction with WNT signaling in these two hormone-related cancer types are highly context-dependent.

Soluble syndecan-1 (SDC1) serum level as an independent pre-operative predictor of cancer-specific survival in prostate cancer.

PSA-screening detects many cases of clinically non-aggressive prostate cancer (PC) leading to significant overtreatment. Therefore, pre-operatively available prognostic biomarkers are needed to help therapy decisions. Syndecan-1 (SDC1) is a promising prognostic tissue marker in several cancers including PC but serum levels of shedded SDC1-ectodomain (sSDC1) have not been assessed in PC. A total of 150 patients with PC were included in this study (n = 99 serum samples, n = 103 paraffin-embedded samples (FFPE), n = 52 overlap). SDC1 protein expression and cellular localization was evaluated by immunohistochemistry (IHC), while sSDC1 serum concentrations were measured by ELISA. Serum sSDC1 levels were compared to those of MMP7, which is known to be a protease involved in SDC1 ectodomain-shedding. Clinico-pathological and follow-up data were collected and correlated with SDC1 tissue and serum levels. Disease (PC)-specific (DSS) and overall-survival (OS) were primary endpoints. Median follow-up was 167 months in the serum- and 146 months in the FFPE-group. SDC1-reactivity was higher in non-neoplastic prostate glands compared to PC. In addition, cytoplasmatic, but not membranous SDC1 expression was enhanced in PC patients with higher Gleason-score >6 PC (P = 0.016). Soluble SDC1-levels were higher in patients with Gleason-score >6 (P = 0.043) and metastatic disease (P = 0.022) as well as in patients with progressed disease treated with palliative transurethral resection (P = 0.002). In addition, sSDC1 levels were associated with higher MMP7 serum concentration (P = 0.005). In univariable analyses, only sSDC1-levels exhibited a trend to unfavorable DSS (P = 0.077). In a multivariable pre-operative model, high pre-operative sSDC1-level (>123 ng/ml) proved to be an independent marker of adverse OS (P = 0.048) and DSS (P = 0.020). The present study does not confirm the prognostic relevance of SDC1-IHC. The significant higher sSDC1 serum levels in advanced cases of PC, suggest that SDC1 shedding might be involved in PC progression. Additionally, high sSDC1-level proved to be an independent factor of adverse OS and DSS in a multivariable pre-operative model, making evaluation of sSDC1-levels a promising tool for pre-operative risk-stratification and/or therapy monitoring. Prostate 76:977-985, 2016. © 2016 Wiley Periodicals, Inc.

Oxidative stress-related genetic variants, pro- and antioxidant intake and status, and advanced prostate cancer risk.

Increased oxidative stress has been linked to prostate cancer. We investigated oxidative stress-related genetic variants in relation to advanced prostate cancer risk and examined potential interactions with pro- and antioxidant exposures. A case-cohort analysis was conducted in the prospective Netherlands Cohort Study, which included 58,279 men ages 55 to 69 years. Cohort members completed a baseline questionnaire and provided toenail clippings, which were used to isolate DNA. Advanced prostate cancer cases were identified during 17.3 years of follow-up. The analysis included 14 genetic variants and 11 exposures. Cox regression models were used for analysis and FDR Q-values were calculated. Complete genotyping data were available for 952 cases and 1,798 subcohort members. CAT rs1001179 was associated with stage III/IV and stage IV prostate cancer risk, with HRs per minor allele of 1.16 [95% confidence intervals (CI), 1.01-1.33; P = 0.032] and 1.25 (95% CI, 1.07-1.46; P = 0.006), respectively. We tested 151 gene-environment interactions in relation to both stage III/IV and IV prostate cancer risk. Seven interactions were statistically significant after adjusting for multiple testing (FDR Q-value <0.20); for stage III/IV prostate cancer, these involved intake of β-carotene (GPX1 rs17650792, hOGG1 rs1052133) and heme iron (GPX1 rs1800668 and rs3448), and for stage IV prostate cancer, these involved intake of catechin (SOD2 rs4880) and heme iron (hOGG1 rs1052133, SOD1 rs10432782). This study of advanced prostate cancer risk showed a marginal association with a CAT polymorphism and seven novel gene-environment interactions in the oxidative stress pathway. Oxidative stress-related genes and exposures may have a joint effect on advanced prostate cancer. Cancer Epidemiol Biomarkers Prev; 24(1); 178-86. ©2014 AACR.

Abstract 1387: Convergent CREB1/FoxA1 transcriptional activity defines castration-resistant prostate cancer gene expression profile

Abstract To identify novel pathways and therapeutic targets in lethal, castration-resistant prostate cancer (CRPC), we extended our previous findings that the overexpression of several G1/S and G2/M phase cell cycle genes in CRPC vs. androgen-dependent prostate cancer (ADPC) cells relies on the cooperative activity of the transcription factors (TFs) FoxA1 and CREB1, and sought to comprehensively characterize their role in supporting CRPC growth. We have taken an integrated genomics approach to reveal the CREB1/FoxA1-coregulated gene expression profile of ADPC (LNCaP) and CRPC (LNCaP-abl) cell line models. Chromatin-immunoprecipitation combined with high-throughput sequencing (ChIP-seq) was performed using antibodies against CREB1 and FoxA1 to reveal genome-wide TF binding sites. Our results indicate that these factors adopt divergent binding patterns in each cell line and that the CREB1 and FoxA1 cistromes exhibit a higher degree of overlap in CRPC vs. ADPC. RNA-seq was also performed in each cell line following transfection with Control-, FoxA1-, or CREB1-targeting small interfering RNA (siRNA) molecules. We identified putative direct CREB1/FoxA1-coregulated genes by noting instances of TF binding near cooperatively coregulated genes (i.e. those up- or down-regulated by both CREB1 and FoxA1 knockdown). Unlike previous analyses, which found that cooperative TF activity occurs primarily in the event of TF co-occupancy of gene regulatory elements, we found that non-overlapping as well as overlapping CREB1/FoxA1 binding events were significantly enriched within cooperatively coregulated target gene loci compared to genes that were unresponsive to TF knockdown. Gene Ontology (GO) analysis of LNCaP-abl-coregulated genes found that CREB1/FoxA1 enhance the expression of critical CRPC pathways including “DNA Repair” and “Aurora Kinase,” while they repress pathways such as “Apoptosis” and, consistent with previous findings, “Androgen Receptor Signaling.” Importantly, CREB1/FoxA1-up-regulated and down-regulated pathway elements exhibit overexpression or under-expression, respectively, in LNCaP-abl vs. LNCaP as well as in public gene expression datasets of metastatic vs. primary prostate cancer. Finally, we performed several proof-of-concept analyses to demonstrate that the CREB1/FoxA1-coregulatory pathway is sensitive to compounds that target CREB1 phosphorylation, a critical event in the transactivation of CREB1 mediated in large part by the related AGC kinase family members PKA and Akt/PKB. Together these results reveal that CREB1 and FoxA1 assume overlapping roles in determining the expression of genes/networks relevant to experimental models and clinical cases of advanced prostate cancer, and though targeting transcription factors has proven challenging, this coregulatory pathway may in fact represent a therapeutic target owing to its kinase-dependent activation. Citation Format: Benjamin D. Sunkel, Dayong Wu, Xiangtao Liu, Zhenqing Ye, Victor Jin, Qianben Wang. Convergent CREB1/FoxA1 transcriptional activity defines castration-resistant prostate cancer gene expression profile. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1387. doi:10.1158/1538-7445.AM2014-1387

Eruptive nodules of the head and neck: a case report of metastatic prostate cancer

Cutaneous metastasis is an uncommon but well recognized phenomenon occurring as a result of internal malignancy. Cancers most often associated with cutaneous metastasis are melanoma and primary malignancies of the breast and head and neck. Cutaneous metastatic prostate cancer is rare, representing only 1% of cases. Herein we report a case of advanced prostate cancer with multiple cutaneous metastases and briefly review the literature highlighting the clinical and histopathological features as well as a management approach to the patient with metastatic prostate cancer involving the skin.

Advanced carcinoma of the prostate presenting as a supraclavicular mass: Case report

Advanced carcinoma of the prostate presenting initially with supraclavicular lymphadenopathy is uncommon. These are 2 cases of advanced prostate cancer that presented initially with persistent painless left supraclavicular mass. Both patients had elevated prostate specific antigen (PSA) level. This as well as histological finding of metastatic adenocarcinoma following biopsy of the neck masses necessitated referral to the urologists. Urological review revealed enlarged hard nodular prostate and transrectal prostate biopsy findings in keeping with high grade adenocarcinoma in both cases. The patients had initial clinical and biochemical response to androgen deprivation therapy with resolution of neck masses within 4-8 weeks of treatment. The authors advocate that men presenting with persistent supraclavicular masses should have a digital rectal examination (DRE) and a PSA test as part of their initial assessment.

A case of advanced prostate cancer in a patient with congenital hypogonadism associated with bilateral cryptorchidism

We report a case of advanced prostatic carcinoma in a patient with congenital hypogonadism associated with bilateral cryptorchidism. A 57-year-old man was admitted to our hospital complaining of lower abdominal pain. He had had bilateral cryptorchidism since birth and had not been treated. His serum prostate-specific antigen level was 1679 ng/ml, and a needle biopsy of the prostate revealed adenocarcinoma throughout the region. A bone scan revealed bone metastasis and retroperitoneal lymph node metastases. The patient was treated with systemic chemotherapy with docetaxel and was alive and free from disease-related symptoms nearly 1 year after the start of chemotherapy.

Abstract 3613: Toenail selenium is associated with a decreased risk of advanced prostate cancer.

Abstract Introduction: Selenium status has been associated with a reduced risk of total prostate cancer (PCa) and there is evidence that the association is more pronounced for advanced, clinically relevant PCa. This association, however, has been studied over a relatively narrow range of selenium status and data from low-selenium populations are missing. Most prior studies of selenium status and PCa have used plasma/serum selenium, which reflects recent selenium intake, and few studies have used toenail selenium, which reflects longer exposure time windows. Methods: We studied the association of toenail selenium and advanced PCa risk in the Netherlands Cohort study, which includes 58,279 men aged 55 to 69 years. The study has a case-cohort design; a random subcohort was sampled at baseline in 1986 and incident advanced (stage III/IV) PCa cases were identified during 17.3 years of follow-up. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards regression models. Results: The study population included 898 advanced PCa cases and 1,203 subcohort members. The average toenail selenium concentration among subcohort members was 0.549 μg/g (standard deviation: 0.128). Toenail selenium was associated with a reduced risk of advanced PCa and adjusted HRs for increasing quintiles of toenail selenium were 1.00 (reference), 0.69 (95% CI: 0.52, 0.90), 0.45 (95% CI: 0.34, 0.60), 0.32 (95% CI: 0.24, 0.44), and 0.24 (95% CI: 0.17, 0.33) (P for trend &amp;lt;0.01). The association was more pronounced for men diagnosed during later follow-up, and adjusted HRs (0.045 μg/g increment; size central quintile) for men diagnosed during ≤6 years, &amp;gt;6 to 12 years, and &amp;gt;12 years of follow-up were 0.91 (95% CI: 0.85, 0.98), 0.85 (95% CI: 0.75, 0.96), and 0.77 (95% CI: 0.71, 0.84), respectively. Conclusion: Toenail selenium was associated with a substantial decrease in risk of advanced PCa, particularly during later follow-up. If our results can be confirmed, a prevention trial of selenium and PCa in a low-selenium population may be justified. Selenium exerts important biological functions through its presence in selenoproteins and genetic variation in the major selenoproteins glutathione peroxidase 1 (GPX1) and selenoprotein P (SEPP1) has been associated with the risk of PCa. In a next analysis, in the same population, we will study the association of common variation in GPX1 and SEPP1 with advanced PCa risk, and we will evaluate SNP-selenium interactions. Citation Format: Milan S. Geybels, Bas A.J. Verhage, Frederik J. van Schooten, Alexandra Goldbohm, Piet A. van den Brandt. Toenail selenium is associated with a decreased risk of advanced prostate cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3613. doi:10.1158/1538-7445.AM2013-3613

Abstract 4883: Zinc and prostate cancer: a systematic review.

Abstract Background: Zinc is involved in many essential cellular functions. It has been shown that the prostate contains high concentrations of zinc, but zinc levels decrease in prostate cancer tissues. Although, experimental evidence implicates zinc in the pathogenesis of prostate cancer, epidemiological data are inconsistent. We conducted a systematic review of the literature to summarize the evidence regarding the association between zinc and prostate cancer. Methods: Relevant studies were identified by searching PubMed and the Cochrane Library databases through November 2012 and reviewing reference lists of retrieved articles. Inclusion criteria were original and peer-reviewed publications reporting the association between zinc intake or status and prostate cancer outcomes (diagnosis, progression). No reviews, editorials, or comments were included. Two investigators abstracted study information and evaluated quality independently using standardized forms. Results: Sixteen studies met inclusion criteria, including 3 cohorts, 2 nested case-control, 10 case-control, and 1 randomized clinical trial, with a total of 111,288 participants and 11,681 cases of prostate cancer. All studies measured the association between zinc levels and prostate cancer. In most studies, regardless of the study design or source of zinc, the highest dose of zinc was associated with a modest elevation of odds of prostate cancer. Four studies had decreased odds of prostate cancer for the highest dose of zinc but the confidence interval crossed one. There was evidence of a dose-response relationship and subgroup analysis revealed a protective effect of high zinc intake among advanced prostate cancer cases. Conclusions: Although the level of zinc in prostate cancer tissue is reduced, studies assessing the association of zinc intake and prostate cancer have yielded inconsistent results. We performed a systematic review to assess the role of zinc in prostate cancer. As a result of this systematic review, the evidence is still insufficient to recommend zinc supplementation for cancer patients in clinical practice. Citation Format: Abeer M. Mahmoud, Umaima Al-alem, Ebony Shah, Ken Batai, Firas Dabbous, Mohamed Ali, Rick Kittles. Zinc and prostate cancer: a systematic review. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4883. doi:10.1158/1538-7445.AM2013-4883

Association of Type 2 Diabetes Susceptibility Variants With Advanced Prostate Cancer Risk in the Breast and Prostate Cancer Cohort Consortium

Observational studies have found an inverse association between type 2 diabetes (T2D) and prostate cancer (PCa), and genome-wide association studies have found common variants near 3 loci associated with both diseases. The authors examined whether a genetic background that favors T2D is associated with risk of advanced PCa. Data from the National Cancer Institute's Breast and Prostate Cancer Cohort Consortium, a genome-wide association study of 2,782 advanced PCa cases and 4,458 controls, were used to evaluate whether individual single nucleotide polymorphisms or aggregations of these 36 T2D susceptibility loci are associated with PCa. Ten T2D markers near 9 loci (NOTCH2, ADCY5, JAZF1, CDKN2A/B, TCF7L2, KCNQ1, MTNR1B, FTO, and HNF1B) were nominally associated with PCa (P < 0.05); the association for single nucleotide polymorphism rs757210 at the HNF1B locus was significant when multiple comparisons were accounted for (adjusted P = 0.001). Genetic risk scores weighted by the T2D log odds ratio and multilocus kernel tests also indicated a significant relation between T2D variants and PCa risk. A mediation analysis of 9,065 PCa cases and 9,526 controls failed to produce evidence that diabetes mediates the association of the HNF1B locus with PCa risk. These data suggest a shared genetic component between T2D and PCa and add to the evidence for an interrelation between these diseases.

Expression of Pituitary Tumor Transforming Gene 1 is an Independent Factor of Poor Prognosis in Localized or Locally Advanced Prostate Cancer Cases Receiving Hormone Therapy

We investigated the prognostic value of pituitary tumor transforming gene 1 (PTTG1) expression according to clinicopathological features among localized or locally advanced prostate cancer cases receiving hormone therapy. A retrospective study involved 64 patients receiving combined androgen blockade treatment was performed. PTTG1 expression was determined by immunohistochemical staining using initial needle biopsy specimens for diagnosis. Associations of PTTG1 with various clinicopathological features and disease-free survival were examined via uni- and multivariate analyses. No association between PTTG1 expression and clinical T stage, Gleason score, pretreatment PSA levels, risk groups was found (p=0.682, 0.184, 0.487, 0.571, respectively). Univariate analysis revealed that increased PTTG1 expression, T3 stage and high risk group were associated with increased risk of disease progression (p=0.000, 0.042, and 0.001), and high PSA level had a tendency to predict disease progression (p=0.056). Cox hazard ratio analysis showed that PTTG1 low expression (p=0.002), PTTG1 high expression (p=0.000) and high risk group (p=0.0147) were significantly related to decreased disease-free survival. In conclusion, PTTG1 expression determined by immunohistochemical staining in needle biopsy specimens for diagnosis is a negative prognostic factor for progression in localized or locally advanced prostate cancer receiving hormone therapy.

Highlights from Recent Cancer Literature

Highlights from Recent Cancer Literature

Polymorphisms in carcinogen metabolism enzymes, fish intake, and risk of prostate cancer.

Cooking fish at high temperature can produce potent carcinogens such as heterocyclic amines and polycyclic aromatic hydrocarbons. The effects of these carcinogens may undergo modification by the enzymes responsible for their detoxification and/or activation. In this study, we investigated genetic polymorphisms in nine carcinogen metabolism enzymes and their modifying effects on the association between white or dark fish consumption and prostate cancer (PCA) risk. We genotyped 497 localized and 936 advanced PCA cases and 760 controls from the California Collaborative Case-Control Study of Prostate Cancer. Three polymorphisms, EPHX1 Tyr113His, CYP1B1 Leu432Val and GSTT1 null/present, were associated with localized PCA risk. The PTGS2 765 G/C polymorphism modified the association between white fish consumption and advanced PCA risk (interaction P 5 0.002), with high white fish consumption being positively associated with risk only among carriers of the C allele. This effect modification by PTGS2 genotype was stronger when restricted to consumption of well-done white fish (interaction P 5 0.021). These findings support the hypotheses that changes in white fish brought upon by high-temperature cooking methods, such as carcinogen accumulation and/or fatty acid composition changes, may contribute to prostate carcinogenesis. However, the gene-diet interactions should be interpreted with caution given the limited sample size. Thus, our findings require further validation with additional studies.

Candidate serum biomarkers for prostate adenocarcinoma identified by mRNA differences in prostate tissue and verified with protein measurements in tissue and blood.

Improved tests are needed for detection and management of prostate cancer. We hypothesized that differential gene expression in prostate tissue could help identify candidate blood biomarkers for prostate cancer and that blood from men with advanced prostate disease could be used to verify the biomarkers presence in circulation. We identified candidate markers using mRNA expression patterns from laser-capture microdissected prostate tissue and confirmed tissue expression using immunohistochemistry (IHC) for the subset of candidates having commercial antisera. We analyzed tissue extracts with tandem mass spectrometry (MS/MS) and measured blood concentrations using immunoassays and MS/MS of trypsin-digested, immunoextracted peptides. We selected 35 novel candidate prostate adenocarcinoma biomarkers. For all 13 markers having commercial antisera for IHC, tissue expression was confirmed; 6 showed statistical discrimination between nondiseased and malignant tissue, and only 5 were detected in tissue extracts by MS/MS. Sixteen of the 35 candidate markers were successfully assayed in blood. Four of 8 biomarkers measured by ELISA and 3 of 10 measured by targeted MS showed statistically significant increases in blood concentrations of advanced prostate cancer cases, compared with controls. Seven novel biomarkers identified by gene expression profiles in prostate tissue were shown to have statistically significant increased concentrations in blood from men with advanced prostate adenocarcinoma compared with controls: apolipoprotein C1, asporin, cartilage oligomeric matrix protein, chemokine (C-X-C motif) ligand 11 (CXCL11), CXCL9, coagulation factor V, and proprotein convertase subtilisin/kexin 6.

The Impact of Interscreening Interval and Age on Prostate Cancer Screening With Prostate-Specific Antigen

BackgroundPopulation-based screening for prostate cancer (PCa) has used serum prostate-specific antigen (PSA) since the early 1990s. However, the efficacy could be affected by screening interval, age ranges of screening, attendance, and contamination of the control group in randomised controlled trials. ObjectiveAssess the impact of the above-mentioned factors on screening efficacy. Design, setting, and participantsParameters pertaining to the natural history of PCa and sensitivity were estimated using data from the Finnish quadrennial screening program starting at 55 yr of age and terminating at 71 yr of age and comprising 80 458 men (32 000 in the screening arm and 48 458 in the control arm). We performed Markov decision analyses for different screening policies with a simulated 25-yr follow-up. InterventionPSA screening. MeasurementsThe impact of different interscreening intervals and target age ranges on advanced PCa (stage III or worse) and PCa mortality was assessed. Results and limitationsWith 65% attendance and 20% contamination, as in the Finnish trial, screening would result in an 11.1% (95% confidence interval [CI], 9.1–13.3%) reduction in advanced cancers and a 7.3% (95% CI, 5.3–9.7%) reduction in PCa death, with corresponding absolute risk difference of 2.6% (95% CI, 1.9–3.5%) and 1.8% (95% CI, 1.4–2.2%), respectively. Numbers needed to screen were 385 to prevent one case of advanced PCa and 556 to prevent one PCa death at 25 yr. Those figures remained similar from 12 yr onwards. Reduction in advanced PCa increased to 40% with annual screening and to 24% with biennial screening. When the age at screening initiation was increased by 5 yr, the benefit was reduced by 9% with annual screening and by 3% with biennial screening. ConclusionsWe predicted the impact of basic screening characteristics on the benefit of the program. The screening interval (1–4 yr) had a greater impact on mortality reduction than did the age at start of screening (55–65 yr). Clinical trial registrationInternational Standard Randomised Controlled Trial Number (ISRCTN): ISRCTN49127736.