Variation in Molecularly Defined Prostate Tumor Subtypes by Self-identified Race.

Background: Socioeconomic and health care utilization factors are major drivers of prostate cancer (PC) mortality disparities in the USA; however, tumor molecular heterogeneity may also contribute to the higher mortality among Black men. Objective: To compare differences in PC subtype frequency and genomic aggressiveness by self-identified race. Design setting and participants: Five molecular subtype classifiers were applied for 426 Black and 762 White PC patients in the Decipher Genomics Resource Information Database (GRID). Outcome measurements and statistical analysis: Differences in subtype frequency and tumor genomic risk (Decipher score >0.6) by race were evaluated using χ2 tests and multivariable-adjusted logistic regression models. Results and limitations: Subtype frequencies differed by race for four classifiers. Subtypes characterized by the presence of SPOP mutations, SPINK1 overexpression, and neuroendocrine differentiation were more common among Black men. ERG and ETS fusion-positive subtypes were more frequent among White men, with no clear differences for subtypes reflecting luminal versus basal lineage. The hypothesized low-risk Kamoun S2 subtype was associated with a lower Decipher score among White men only (p = 0.01 for heterogeneity), while the aggressive You PCS1 subtype was associated with a higher Decipher score among White men only (p = 0.001 for heterogeneity). The Tomlins ERG+ subtype was associated with a higher Decipher score relative to all other subtypes among Black men, with no association among White men (p = 0.007 for heterogeneity). Conclusions: The frequency of PC molecular subtypes differed by self-identified race. Additional studies are required to evaluate whether our observations suggest differences in the tumor genomic risk of progression by self-identified race. Patient summary: We studied five classifiers that identify subtypes of prostate tumors and found that subtypes differed in frequency between Black and White patients. Further research is warranted to evaluate how differences in tumor subtypes may contribute to disparities in prostate cancer mortality.

Comparative analysis of 1152 African-American and European-American men with prostate cancer identifies distinct genomic and immunological differences.

Racial disparities in prostate cancer have not been well characterized on a genomic level. Here we show the results of a multi-institutional retrospective analysis of 1,152 patients (596 African-American men (AAM) and 556 European-American men (EAM)) who underwent radical prostatectomy. Comparative analyses between the race groups were conducted at the clinical, genomic, pathway, molecular subtype, and prognostic levels. The EAM group had increased ERG (P < 0.001) and ETS (P = 0.02) expression, decreased SPINK1 expression (P < 0.001), and basal-like (P < 0.001) molecular subtypes. After adjusting for confounders, the AAM group was associated with higher expression of CRYBB2, GSTM3, and inflammation genes (IL33, IFNG, CCL4, CD3, ICOSLG), and lower expression of mismatch repair genes (MSH2, MSH6) (p < 0.001 for all). At the pathway level, the AAM group had higher expression of genes sets related to the immune response, apoptosis, hypoxia, and reactive oxygen species. EAM group was associated with higher levels of fatty acid metabolism, DNA repair, and WNT/beta-catenin signaling. Based on cell lines data, AAM were predicted to have higher potential response to DNA damage. In conclusion, biological characteristics of prostate tumor were substantially different in AAM when compared to EAM.

African American Specific Gene Panel Predictive of Poor Prostate Cancer Outcome.

PURPOSE: Most prostate cancer in African American men lacks the ETS (E26 transforming specific) family fusion event (ETS-). We aimed to establish clinically relevant biomarkers in African American men by studying ETS dependent gene expression patterns to identified race specific genes predictive of outcomes. MATERIALS AND METHODS: Two multicenter cohorts of a total of 1,427 men were used for the discovery and validation (635 and 792 men, respectively) of race specific predictive biomarkers. We used false discovery rate adjusted q values to identify race and ETS dependent genes which were differentially expressed in African American men who experienced biochemical recurrence within 5 years. Principal component modeling along with survival analysis was done to assess the accuracy of the gene panel in predicting recurrence. RESULTS: We identified 3,047 genes which were differentially expressed based on ETS status. Of these genes 362 were differentially expressed in a race specific manner (false discovery rate 0.025 or less). A total of 81 genes were race specific and over expressed in African American men who experienced biochemical recurrence. The final gene panel included APOD, BCL6, EMP1, MYADM, SRGN and TIMP3. These genes were associated with 5-year biochemical recurrence (HR 1.97, 95% CI 1.27-3.06, p = 0.002) and they improved the predictive accuracy of clinicopathological variables only in African American men (60-month time dependent AUC 0.72). CONCLUSIONS: In an effort to elucidate biological features associated with prostate cancer aggressiveness in African American men we identified ETS dependent biomarkers predicting early onset biochemical recurrence only in African American men. Thus, these ETS dependent biomarkers representing ideal candidates for biomarkers of aggressive disease in this patient population.

Improving risk stratification in a community-based African American population using cell cycle progression score.

BACKGROUND: Current clinical nomograms such as American Urological Association/National Comprehensive Cancer Network (AUA/NCCN) risk categories or CAPRA may not always reflect prostate cancer (PCa) risk among African American men. We evaluated the usefulness of adding a commercially available cell cycle progression (CCP) score to improve risk stratification in a community-based African American population. METHODS: Biopsy tissues from 150 African American and 60 Caucasian men were obtained from a single community urologic oncology practice in Memphis, TN. The biopsy samples were evaluated with a commercially available CCP panel (Prolaris). Clinical variables such as Gleason score, prostate-specific antigen (PSA), age, clinical stage, and extent of disease were combined to determine a single category of low-, intermediate-, or high-risk. AUA risk stratification for cancer aggressiveness was then compared between the CCP score vs. the clinical parameters to determine potential risk improvement by the CCP score. RESULTS: Based on the clinical parameters, of the 150 African American men evaluated, 20% were classified as low-risk, 40% were classified as intermediate-risk, and 40% were classified as high-risk. Of the 60 Caucasian men evaluated, 42% were low-risk, 42% were intermediate-risk, and 17% were high-risk. However, when re-evaluating the African American patients using the CCP score, 30% of the patients were determined to be more aggressive than the clinical low-risk category. Similarly, 21.67% of the patients were found to be more aggressive than the clinical intermediate-risk category, and 23.33% of the patients were more aggressive than the high-risk category. When compared to our Caucasian cohort, 12% of the low-risk patients, 8% of the intermediate-risk patients, and 10% of the high-risk patients were found to be more aggressive by the CCP score. Overall, 24% of African American men vs. 10% of Caucasian men were reclassified to a higher risk by CCP score. When we compared the mean CCP score in the African American population vs. the Caucasian population, the mean CCP score in the AUA low-risk was 3.2 vs. 2.9; 3.4 vs. 3.2 in the AUA intermediate-risk; and 3.8 vs. 3.5 in the AUA high-risk category, respectively. Despite the higher mean CCP score in the African American population, the difference between the African American men and the Caucasian men was not significant (P=0.064 for low-risk, P=0.204 for intermediate-risk, and P=0.209 for high-risk). CONCLUSIONS: Our data extends the evidence that CCP score derived from a biopsy specimen can be clinically useful. Our findings showed that the CCP score could stratify 10-year mortality risk in African American men beyond the current clinicopathologic features, which may better prepare patients for follow-up visits and discussions with their health care provider(s) and enhance their ability to select the most appropriate treatment option.

Performance of a Prostate Cancer Genomic Classifier in Predicting Metastasis in Men with Prostate-specific Antigen Persistence Postprostatectomy.

BACKGROUND: Prostate cancer patients who have a detectable prostate-specific antigen (PSA) postprostatectomy may harbor pre-existing metastatic disease. To our knowledge, none of the commercially available genomic biomarkers have been investigated in such men. OBJECTIVE: To evaluate if a 22-gene genomic classifier can independently predict development of metastasis in men with PSA persistence postoperatively. DESIGN, SETTING, AND PARTICIPANTS: A multi-institutional study of 477 men who underwent radical prostatectomy (RP) between 1990 and 2015 from three academic centers. Patients were categorized as detectable PSA (n=150) or undetectable (n=327) based on post-RP PSA nadir ≥0.1 ng/ml. OUTCOME MEASUREMENTS AND STATISITICAL ANALYSIS: Cumulative incidence curves for metastasis were constructed using Fine-Gray competing risks analysis. Penalized Cox univariable and multivariable (MVA) proportional hazards models were performed to evaluate the association of the genomic classifier with metastasis. RESULTS AND LIMITATIONS: The median follow-up for censored patients was 57 mo. The median time from RP to first postoperative PSA was 1.4 mo. Detectable PSA patients were more likely to have higher adverse pathologic features compared with undetectable PSA patients. On MVA, only genomic high-risk (hazard ratio [HR]: 5.95, 95% confidence interval [CI]: 2.02-19.41, p=0.001), detectable PSA (HR: 4.26, 95% CI: 1.16-21.8, p=0.03), and lymph node invasion (HR: 12.2, 95% CI: 2.46-70.7, p=0.003) remained prognostic factors for metastasis. Among detectable PSA patients, the 5-yr metastasis rate was 0.90% for genomic low/intermediate and 18% for genomic high risk (p<0.001). Genomic high risk remained independently prognostic on MVA (HR: 5.61, 95% CI: 1.48-22.7, p=0.01) among detectable PSA patients. C-index for Cancer of the Prostate Risk Assessment Postsurgical score, Gandaglia nomogram, and the genomic classifier plus either Cancer of the Prostate Risk Assessment Postsurgical score or Gandaglia were 0.69, 0.68, and 0.82 or 0.81, respectively. Sample size was a limitation. CONCLUSIONS: Despite patients with a detectable PSA harboring significantly higher rates of aggressive clinicopathologic features, Decipher independently predicts for metastasis. Prospective validation of these findings is warranted and will be collected as part of the ongoing randomized trial NRG GU-002. PATIENT SUMMARY: Decipher independently predicted metastasis for patients with detectable prostate-specific antigen after prostatectomy.

Characterization of germline copy number variation in high-risk African American families with prostate cancer.

BACKGROUND: Prostate cancer is a complex multi-allelic disease and the most common malignancy in men. The incidence of prostate cancer in African American men is more than twice as high as that of any other race. Despite the high prevalence of prostate cancer amongst African American men, this population has been under represented in genetic studies of prostate cancer. Although genomic copy number variations (CNVs) have been detected in prostate tumors, this is the first study describing germline CNVs in African American hereditary prostate cancer families. METHODS: Ten high-risk African American families with three or more affected individuals and with an early age of onset were recruited. From these families, 37 individuals, including 23 affected males, and 14 unaffected males, were selected for CNV analysis. Array comparative genomic hybridization was used to characterize germline CNVs unique to African American men with hereditary prostate cancer. RESULTS: Through common aberration analysis in affected family members; novel CNVs were identified at chromosomes 1p36.13 and 16q23.3. Differential analysis comparing affected and unaffected family members identified 9.4 kb duplication on chromosome 14q32.33 which segregate with prostate cancer patients in these high-risk families. CONCLUSIONS: The duplication at 14q32.33 encompasses IGHG3 gene which has been shown to have both significant gains in copy number as well as overexpression in prostate tumors in African Americans. These CNVs may represent a component of genetic predisposition which contributes to the high prevalence and mortality of prostate cancer in African American men.

Suggestive evidence of linkage identified at chromosomes 12q24 and 2p16 in African American prostate cancer families from Louisiana.

BACKGROUND: In the United States, incidence of prostate cancer in African American men is more than twice than that of any other race. Thus far, numerous disease susceptibility loci have been identified for this cancer but definite locus-specific information is not yet established due to the tremendous amount of genetic and disease heterogeneity; additionally, despite high prevalence of prostate cancer amongst African American men, this population has been under represented in genetic studies of prostate cancer. METHODS: In order to identify the susceptible locus (loci) for prostate cancer in African Americans, we have performed linkage analyses on members of 15 large high-risk families. Specifically, these families were recruited from Louisiana and represent a uniquely admixed African American population exclusive to Southern Louisiana. In addition to geographical constraints, these families were clinically homogeneous creating a well-characterized collection of large pedigrees. The families were genotyped with Illumina Infinium II SNP HumanLinkage-12 panel and extensive demographic and clinical information was documented from the hospital pathological reports and family interviews. RESULTS: We identified two novel regions, 12q24 and 2p16, with suggestive evidence of linkage under the dominant model of inheritance. CONCLUSIONS: This is the first time that chromosome 12q24 (HLOD = 2.21) and 2p16 (HLOD = 1.97) has been shown to be associated with prostate cancer in high-risk African American families. These results provide insight to prostate cancer in an exceptional, well-characterized African American population, and illustrate the significance of utilizing large unique, but homogenous pedigrees.

Racial differences in trust and regular source of patient care and the implications for prostate cancer screening use.

BACKGROUND: : Nonmedical factors may modify the biological risk of prostate cancer (PCa) and contribute to the differential use of early detection; curative care; and, ultimately, greater racial disparities in PCa mortality. In this study, the authors examined patients' usual source of care, continuity of care, and mistrust of physicians and their association with racial differences in PCa screening. METHODS: : Study nurses conducted in-home interviews of 1031 African-American men and Caucasian-American men aged > or =50 years in North Carolina and Louisiana within weeks of their PCa diagnosis. Medical records were abstracted, and the data were used to conduct bivariate and multivariate analyses. RESULTS: : Compared with African Americans, Caucasian Americans exhibited higher physician trust scores and a greater likelihood of reporting a physician office as their usual source of care, seeing the same physician at regular medical encounters, and historically using any PCa screening. Seeing the same physician for regular care was associated with greater trust and screening use. Men who reported their usual source of care as a physician office, hospital clinic, or Veterans Administration facility were more likely to report prior PCa screening than other men. In multivariate regression analysis, seeing the same provider remained associated with prior screening use, whereas both race and trust lost their association with prior screening. CONCLUSIONS: : The current results indicated that systems factors, including those that differ among different sources of care and those associated with the continuity of care, may provide tangible targets to address disparities in the use of PCa early detection, may attenuate racial differences in PCa screening use, and may contribute to reduced racial disparities in PCa mortality. Cancer 2009. Published 2009 by the American Cancer Society.

Personality predicts prostate cancer treatment decision-making difficulty and satisfaction.

OBJECTIVE: Prostate cancer (PCa) patients often must decide between several treatment modalities considered equally efficacious, but associated with different benefits and side-effects. For some, the decision-making process can be difficult, but little is known about patient characteristics and cognitive processes that might influence the difficulty of such decisions. This study investigated the roles of dispositional optimism and self-efficacy in PCa treatment decision-making difficulty and satisfaction. METHODS: One hundred and twenty-five patients with clinically localized PCa completed a mail-in paper-and-pencil survey after they had made their treatment decision, but prior to treatment. RESULTS: After adjusting for covariates, optimism and treatment decision-making self-efficacy were associated with less difficulty and greater satisfaction with the treatment decision-making process. Effects of optimism on difficulty and satisfaction were partially mediated by self-efficacy for making the treatment decision. CONCLUSIONS: Men with PCa and who are low in optimism may be at greater risk for treatment decision-making difficulty and lack of treatment decision-making satisfaction, in part, because they have lower confidence in their ability to make the decision compared with those who are more optimistic. As self-efficacy perceptions are modifiable, consideration should be given to including self-efficacy enhancing components as part of PCa treatment decision-making interventions.

How to engage the Latino or African American patient with benign prostatic hyperplasia: crossing socioeconomic and cultural barriers.

Disparities based on race and ethnicity still exist in the US healthcare system. Such disparities are reflected in the diagnosis and treatment of benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS) among African Americans and Latinos. The prevalence of risk factors for BPH and LUTS and symptom progression are higher in these populations, but treatment is less common. African American men and Latinos frequently have other serious comorbidities, such as cardiovascular disease, diabetes mellitus, and metabolic syndrome. Health plan constraints and variabilities, race/ethnicity, socioeconomic status, language, healthcare-seeking behaviors, and cultural beliefs and practices influence the treatment of BPH and LUTS, oftentimes resulting in unequal access to care or inferior quality of care. The provision of nondiscriminatory treatment poses a challenge to clinicians that can partially be addressed by improving the cultural competence of practitioners in minority communities. An awareness of the customs and healing traditions of African Americans and Latinos may also facilitate culturally appropriate care and improve outcomes, and the participation of clinicians in continuing education/professional development programs to increase knowledge about minority health issues is recommended. Conversely, improving the health literacy of African American and Latino patients with BPH and LUTS can help avoid ineffective nontraditional methods of treatment.

Managing the low-socioeconomic-status prostate cancer patient.

Management of patients with low socioeconomic status and/or low literacy who have prostate cancer presents a challenge to healthcare professionals. Improving treatment outcomes for these men requires specific educational programs to provide a better understanding of prostate cancer including careful posttreatment follow-up to ensure they have recovered well, that the cancer is not progressing and that complications are not proving troublesome. Practice nurses and health educators/navigators can play an important role in achieving these objectives. Education and knowledgeable advice can lead to earlier diagnosis of prostate cancer, improved patient participation in the treatment decision-making process and effective management of posttreatment complications.

Correlation between serum prostate-specific antigen and alpha-1-antitrypsin in men without and with prostate cancer.

Prostate specific antigen (PSA) is frequently used for prostate cancer (PCa) screening, but serum levels are also increased by prostate inflammation. Elevations in serum levels of alpha1-antitrypsin (ATT), a marker of inflammation, in cancer patients are well documented. However, an association between PSA and ATT has never been investigated. The authors, therefore, measured serum acute phase proteins (APPs) ATT, alpha1-acid glycoprotein, C-reactive protein, and alpha1-antichymotrypsin in 174 men without and 34 with newly diagnosed untreated PCa (38-80 years old). As expected, men with PCa had higher mean PSA levels than those without PCa (P < 0.00001). Men with PCa and those without PCa but with PSA >2 ng/mL (n = 68) had significantly higher ATT concentrations than those without these conditions (n = 106) (mean +/- SEM g/L): 1.94+/-0.083, 1.92+/-0.066, 1.25+/-0.043, respectively; p <0.005). Interestingly, African-American men without PCa (n=111) had higher ATT levels than Caucasian men (n=63) (1.565+/-0.045 g/l versus 1.395+/-0.056 g/l; p <0.005); and differences persisted in men with PSA >2 ng/ml (2.094+/-0.07 g/l versus 1.593 for all0.095 g/l; p<0.0002). There were no differences among groups in the levels of other APP. ATT showed the strongest correlation with PSA (r = 0.346 to 0.395; p <0.001) than any other APP (r < or =0.245). Our data suggest that men with PCa have higher ATT levels than those without PCa; and African-American men without PCa have higher ATT levels than Caucasian men. The possible implications of elevated ATT levels in African-American men on the risk of PCa are discussed.

Knowledge, attitudes and beliefs of women about the importance of prostate cancer screening.

OBJECTIVES: To understand women's knowledge, attitudes and beliefs about prostate cancer. METHODS: A survey was self-administered to 324 women age >18 years. It contained 42 questions that assessed women's knowledge about prostate cancer, possible risk factors, and opinions regarding screening and early detection. Women were grouped as married or unmarried for convenient comparisons. Chi-squared and F statistics were performed. RESULTS: Ninety-seven percent of married women reported having some influence over the healthcare decisions of their spouse. Married women's worst fear about their spouse or family member's diagnosis of prostate cancer was death. The most important benefit of prostate cancer screening was the possibility of cure, while the main hindrance was fear of the digital rectal exam. Marital status, age, educational level and income were all significantly associated with women's knowledge about prostate cancer (p<0.001). CONCLUSIONS: Women play an important role in health-related matters in the home. Educating women on prostate cancer may improve early detection efforts and reduce the devastating impact of this disease on their family.

Saposin C stimulates growth and invasion, activates p42/44 and SAPK/JNK signaling pathways of MAPK and upregulates uPA/uPAR expression in prostate cancer and stromal cells.

AIM: To determine the effect of saposin C (a known trophic domain of prosaposin) on proliferation, migration and invasion, as well as its effect on the expression of urokinase plasmonogen activator (uPA), its receptor (uPAR) and matrix metalloproteinases (MMP)-2 and -9 in normal and malignant prostate cells. In addition, we tested whether saposin C can activate p42/44 and stress-activated protein kinase/c-Jun NH2-terminal kinase (SAPK/JNK) signal transduction pathways of the mitogen-activated protein kinase (MAPK) superfamily. METHODS: We employed Western blot analysis, phospho-specific antibodies, cell proliferation assay, reverse transcriptase-polymerase chain reaction, in vitro kinase assays and migration and invasion to determine the effect of saposin C on various biological behaviors of prostate stromal and cancer cells. RESULTS: Saposin C, in a cell type-specific manner, upregulates uPA/uPAR and immediate early gene c-Jun expression, stimulates cell proliferation, migration and invasion and activates p42/44 and SAPK/JNK MAPK pathways in prostate stromal and cancer cells. Normal prostate epithelial cells were not responsive to saposin C treatment in the above studies. CONCLUSION: Saposin C functions as a multipotential modulator of diverse biological activities in prostate cancer and stromal cells. These results strongly suggest that saposin C functions as a potent growth factor for prostatic cells and may contribute to prostate carcinogenesis and/or the development of hormone-refractory prostate cancer.

TNF receptor 1 is involved in the induction of apoptosis by the cyclin dependent kinase inhibitor p27Kip1 in the prostate cancer cell line PC-3.

Loss of p27Kip1, a cyclin-dependent kinase inhibitor, is observed in aggressive prostate cancers. We demonstrated that intratumoral injections of recombinant adenovirus overexpressing p27Kip1 (Adp27) reduced the growth of prostate cancer xenografts in nude mice. Presently, we studied the mechanism(s) of cell death induced by Adp27 in prostate cancer cell line PC-3. Cells were infected with Adp27 and compared with those infected by empty virus or were non-infected. Cell cycle and typical markers of apoptosis were analyzed by flow cytometry in the presence of the following reagents: cycloheximide, pan-caspase inhibitor ZVAD-fmk, neutralizing anti-TNFR1, and anti-TNFR2. Overexpression of p27Kip1 protein and cell cycle arrest were noted within 24 h after Adp27-infection. Sub-G1 fraction, chromatin margination, and phosphatidylserine exposure were evident by the third day of treatment. Cycloheximide elevated sub-G1 fraction in Adp27-infected cells by threefold, while ZVAD-fmk reduced sub-G1 to control levels. Caspase-dependent apoptosis occurred in a third of the population, while two-thirds were ZVAD-fmk insensitive but TUNEL-positive. Flow cytometry showed increased expression of TNFR1 and TNFR2 in Adp27-infected cells. Neutralizing anti-TNFR1 decreased TUNEL-positive score, while anti-TNFR2 did not affect p27Kip1-induced apoptosis. This is the first report showing that p27Kip1 induces caspase-dependent and -independent stages of cell death that may involve TNF-signaling through TNFR1.

Increased levels of serum transferrin receptor and serum transferrin receptor/log ferritin ratios in men with prostate cancer and the implications for body-iron stores.

The serum transferrin receptor (sTfR) is a sensitive indicator of iron-deficiency erythropoiesis that is not affected by inflammation. Concentrations of this molecule are inversely correlated with body-iron stores, and increased body-iron stores are associated with an increased risk of cancer of the liver and lungs. However, an association between iron status as assessed on the basis of sTfR and prostate cancer has not been previously investigated. We measured sTfR and serum ferritin by means of an enzyme immunoassay in 27 men with newly diagnosed, untreated prostate cancer and in 72 controls. Our study population ranged in age from 38 to 78 years. The mean serum ferritin concentration in men with prostate cancer was 44.8% lower than that in men without this tumor ( P < .05). In contrast, the mean values of sTfR and sTfR/log serum ferritin were 32% and 60% higher, respectively, in men with prostate cancer than in those without this tumor ( P < .05). Differences between groups persisted after we took into account inflammation (alpha 1-acid glycoprotein > 1 g/L, C-reactive protein > 10 mg/L; P < .05). Among the entire study population and among men without inflammation, a higher percentage of subjects (29%-31%) than of controls (14%-22%) had sTfR values greater than 8 mg/L, suggestive of iron-deficiency erythropoiesis ( P < .05). The odds ratios for men with prostate cancer to have sTfR values of less than 2.9 mg/L (suggestive of increased body-iron stores) was 0, compared with 1.745 to 3.65 for the same men to have sTfR values greater than 8 mg/L. sTfR was negatively correlated with log ferritin ( r = -.422, P < .05) but did not correlate with tissue inflammation, tumor stage, or acute-phase proteins. It appears that prostate cancer is not associated with increased body-iron stores.

Serum proteomic profiling can discriminate prostate cancer from benign prostates in men with total prostate specific antigen levels between 2.5 and 15.0 ng/ml.

PURPOSE: Artificial intelligence based pattern recognition algorithms have been developed and successfully used to analyze complex serum proteomic data streams generated by surface enhanced, laser desorption ionization time-of-flight mass spectroscopy. In the current study we used a high performance, hybrid quadrupole time-of-flight mass spectrometer to generate discriminatory serum proteomic profiles to determine if this technology could be used to determine the need for prostate biopsy in men with elevated prostate specific antigen (PSA). MATERIALS AND METHODS: Serum samples were collected from 154 men with serum PSA 2.5 to 15.0 ng/ml and/or abnormal digital rectal examination prior to transrectal ultrasound guided biopsy. Serum samples were applied to WCX2 (weak cation exchange protein chip) Protein Arrays (Ciphergen Biosystems, Fremont, California) by a Biomek 2000 robotic liquid handler (Beckman-Coulter, Chaska, Minnesota) and low molecular weight (less than 20 kDa) proteomic patterns were generated with an API QSTAR Pulsar i LC/MS/MS System (Applied Biosystems, Framingham, Massachusetts). High resolution mass spectra were analyzed with a pattern recognition bioinformatics tool, that is Proteome Quest beta version 1.0 (Correlogic Systems, Inc., Bethesda, Maryland), in an attempt to identify and discover key discriminating ion signatures. Serum samples from 63 men (2 or more negative prostate biopsies in 23, 1 negative biopsy in 10 and biopsy detected prostate cancer [CaP] in 30) were used to train the diagnostic algorithm. The remaining 91 samples, including 28 of prostate cancer and 63 of 1 or more negative biopsies, were analyzed in blinded fashion. RESULTS: The most discriminatory model was found using the WCX2 chip. Testing the remaining 91 men with this model yielded 100% sensitivity and 67% specificity. In other words, if the proteomic pattern had been used to determine the need for prostate biopsy in this cohort of men with PSA between 2.5 and 15.0 ng/ml, 67% (42 of 63) with negative biopsies would have avoided unnecessary biopsy, while no cancers would have been missed. CONCLUSIONS: Our data demonstrate that high resolution mass spectroscopy can generate serum proteomic patterns that discriminate men with elevated PSA due to benign processes from men with CaP even when PSA is within the diagnostic gray zone. We are currently expanding the testing set to determine the reliability of this new technology to decrease unnecessary prostate biopsies without compromising the detection of curable CaP.