Racial differences in prostate-specific antigen levels and prostate-specific antigen densities in patients with prostate cancer

To compare serum prostate-specific antigen (PSA) levels and PSA density (PSAD) among African American (AA), white, and Hispanic men with prostate cancer (PC) seen in an urban, equal-access urology clinic. Between January 1988 and January 1993, 1,105 men were screened for PC at Cook County Hospital in Chicago, Illinois. A total of 529 men underwent transrectal ultrasound-guided prostate gland biopsies for abnormal digital rectal examination, suspect transrectal ultrasound, elevated PSA, or any combination of these abnormalities. PC was found in 246 patients (204 AAs, 22 whites, and 20 Hispanics). We analyzed the differences in PSA and PSAD among the three racial groups using univariate and multivariate analyses adjusting for race, age, clinical stage, and grade. AAs have a higher mean serum PSA levels (21.56 ng/ml) than whites (mean PSA of 10.96 ng/ml) and Hispanics (mean PSA of 8.25 ng/ml) (p = 0.04). The mean PSAD also was higher in AAs than in the other two groups (0.68 versus 0.34 for whites and 0.31 for Hispanics, p = 0.05). On a multivariate analysis, the PC stage and grade were overwhelmingly significant, whereas the race and age lost their statistical significance. AAs have higher serum PSA and PSAD than whites or Hispanics in an equal-access healthcare environment. Race is a significant factor in determining PSA and PSAD on univariate but not on multivariate analysis. Preliminary studies suggest that these differences are due to sociological, not biologic causes. These findings warrant a large, prospective study to investigate the extent and the causes of the racial differences in PSA and PSAD.     

Racial differences in prostate-specific antigen levels in patients with local-regional prostate cancer.

Prostate cancer is a significant health problem for blacks. The incidence and mortality rates are higher in blacks than in whites; blacks often present with a higher stage. Prostate-specific antigen (PSA) is a very useful serum marker in prostate cancer. We analyzed data from a cohort of 161 patients to determine whether there were any racial differences in PSA levels prior to treatment in local-regional prostate cancer. The immunoradiometric method was used to determine the PSA values. The mean PSA levels were significantly higher in blacks than in whites (P = 0.022), and the difference remained significant in multivariate analysis after adjusting for stage and grade (P = 0.020). However, when analyzed further, the difference was statistically significant in one hospital (P = 0.001) and not in another (P = 0.493). Thus, our results are not unequivocal, but our data do suggest that racial differences in PSA levels not accounted for by tumor stage or grade may exist. Assuming that the data truly reflect a racial difference, the cause(s) of this difference remains to be determined. It may exist because, within each clinical stage, blacks are presenting with a higher tumor cell burden, or it may be indicative of more aggressive biological behavior. The possibility that racial differences are due to socioeconomic factors was considered by estimating median income level from zip code of residence; although a correlation between socioeconomic status and PSA level was found, racial differences remained borderline significant (P = 0.055) after adjusting for income level (in addition to stage and grade).     

A phase I trial of a recombinant vaccinia virus expressing prostate-specific antigen in advanced prostate cancer.

A recombinant vaccinia virus encoding human prostate-specific antigen (rV-PSA) was administered as three consecutive monthly doses to 33 men with rising PSA levels after radical prostatectomy, radiation therapy, both, or metastatic disease at presentation. Dose levels were 2.65 x 10(6), 2.65 x 10(7), and 2.65 x 10(8) plaque forming units. Ten patients who received the highest dose also received 250 microg/m2 granulocyte-macrophage colony-stimulating factor (GM-CSF) as an immunostimulatory adjunct. No patient experienced any virus-related effects beyond grade I cutaneous toxicity. Pustule formation and/or erythema occurred after the first dose in all 27 men who received > or =2.65 x 10(7) plaque forming units. GM-CSF administration was associated with fevers and myalgias of grade 2 or lower in 9 of 10 patients. PSA levels in 14 of 33 men treated with rV-PSA with or without GM-CSF were stable for at least 6 months after primary immunization. Nine patients remained stable for 11-25 months; six of these remain progression free with stable PSA levels. Immunological studies demonstrated a specific T-cell response to PSA-3, a 9-mer peptide derived from PSA. rV-PSA is safe and can elicit clinical and immune responses, and certain patients remain without evidence of clinical progression for up to 21 months or longer.     

Murine six-transmembrane epithelial antigen of the prostate, prostate stem cell antigen, and prostate-specific membrane antigen: prostate-specific cell-surface antigens highly expressed in prostate cancer of transgenic adenocarcinoma mouse prostate mice

To identify genes that are differentially up-regulated in prostate cancer of transgenic adenocarcinoma mouse prostate (TRAMP) mice, we subtracted cDNA isolated from mouse kidney and spleen from cDNA isolated from TRAMP-C1 cells, a prostate tumor cell line derived from a TRAMP mouse. Using this strategy, cDNA clones that were homologous to human six-transmembrane epithelial antigen of the prostate (STEAP) and prostate stem cell antigen (PSCA) were isolated. Mouse STEAP (mSteap) is 80% homologous to human STEAP at both the nucleotide and amino acid levels and contains six potential membrane-spanning regions similar to human STEAP. Mouse PSCA (mPsca) shares 65% homology with human PSCA at the nucleotide and amino acid levels. mRNA expression of mSteap and mPsca is largely prostate-specific and highly detected in primary prostate tumors and metastases of TRAMP mice. Both mSteap and mPsca map to chromosome 5. Another known gene coding for mouse prostate-specific membrane antigen (mPsma) is also highly expressed in both primary and metastatic lesions of TRAMP mice. These results indicate that the TRAMP mouse model can be used to effectively identify genes homologous to human prostate-specific genes, thereby allowing for the investigation of their functional roles in prostate cancer. mSteap, mPsca, and mPsma constitute new tools for preventative and/or therapeutic vaccine construction and immune monitoring in the TRAMP mouse model that may provide insights into the treatment of human prostate cancer.     

A phase I trial of DNA vaccination with a plasmid expressing prostate-specific antigen in patients with hormone-refractory prostate cancer

Prostate-specific antigen (PSA) is a serine protease secreted at low levels by normal luminal epithelial cells of the prostate and in significantly higher levels by prostate cancer cells. Therefore, PSA is a potential target for various immunotherapeutical approaches against prostate cancer. DNA vaccination has been investigated as immunotherapy for infectious diseases in patients and for specific treatment of cancer in certain animal models. In animal studies, we have demonstrated that vaccination with plasmid vector pVAX/PSA results in PSA-specific cellular response and protection against tumour challenge. The purpose of the trial was to evaluate the safety, feasibility and biological efficacy of pVAX/PSA vaccine in the clinic. A phase I trial of pVAX/PSA, together with cytokine granulocyte/macrophage-colony stimulating factor (GM-CSF) (Molgramostim) and IL-2 (Aldesleukin) as vaccine adjuvants, was carried out in patients with hormone-refractory prostate cancer. To evaluate the biologically active dose, the vaccine was administered during five cycles in doses of 100, 300 and 900 microg, with three patients in each cohort. Eight patients were evaluable. A PSA-specific cellular immune response, measured by IFN-gamma production against recombinant PSA protein, and a rise in anti-PSA IgG were detected in two of three patients after vaccination in the highest dose cohort. A decrease in the slope of PSA was observed in the two patients exhibiting IFN-gamma production to PSA. No adverse effects (WHO grade >2) were observed in any dose cohort. We demonstrate that DNA vaccination with a PSA-coding plasmid vector, given with GM-CSF and IL-2 to patients with prostate cancer, is safe and in doses of 900 microg the vaccine can induce cellular and humoral immune responses against PSA protein.     

Detection of prostate-specific antigen coupled to immunoglobulin M in prostate cancer patients

Background: Several reports indicate that the main biomarkers for liver and colorectal cancer circulating in the blood stream associate with immunoglobulin M (IgM) to form stable complexes that show increased diagnostic relevance compared to circulating free biomarkers. Methods: To further investigate the association between cancer biomarkers and IgM, we assessed the presence of prostate-specific antigen (PSA) as IgM complexes in sera of patients with prostate cancer (PC) or benign prostatic hyperplasia (BPH) in comparison with PSA measurements. Results: PSA–IgM levels were significantly elevated in 40% (20/50) and 12% (6/51) of PC and BPH patients, respectively, compared to 22% (11/50) and 29% (15/51) of PSA positive patients in the same groups. Detection of cancer markedly increased from 22 to 60% by co-determination of both markers (30/50 patients). Significantly elevated levels of PSA–IgM were found in 13 out of 30 patients affected by PC with a PSA value between 4 and 10 ng/mL and only in 4 out of 34 BPH patients in the same PSA range. Conclusions: The results are the first evidence of the occurrence of PSA–IgM complexes in patients with prostate cancer. The gain achieved in cancer detection by using the combination of PSA and PSA–IgM suggests that PSA–IgM could be a complementary serological marker of prostate cancer.     

Measurements of tissue polypeptide-specific antigen and prostate-specific antigen in prostate cancer patients under intermittent androgen suppression therapy.

The present study evaluated serial serum measurements of tissue polypeptide-specific antigen (TPS) in comparison with prostate-specific antigen (PSA) for assessment of tumour progression in patients with advanced prostate cancer receiving intermittent androgen suppression therapy (IAS). Twenty-three men were recruited into an IAS trial consisting of an initial 8 months of androgen suppression, followed by cycles of treatment cessation and resumption of therapy upon increases of PSA > 20 ng ml(-1) to prolong the hormone responsiveness of the tumour cells. Periods of androgen suppression resulted in reversible reduction in serum testosterone (< 1.8 nmol I(-1)) and PSA (< 4 ng ml(-1)) and decreases in tumour volume (mean reduction for first cycle 24 +/- 10%), indicating partial growth arrest and apoptotic regression of the tumours. In contrast to PSA values, non-specifically elevated TPS values were found in 8 of 23 patients. In 15 of 23 patients, TPS fell during periods of apoptotic tumour regression and increased simultaneously with testosterone and preceded the increases in PSA by 2 months during the period of treatment cessation. Although TPS represents a highly sensitive marker of tumour proliferation in this IAS clinical model of controlled tumour regression and regrowth, its low specificity compared with PSA limits its usefulness to monitoring of prostate cancer patients with proven absence of non-specific elevations of this marker.     

Optimal prostate-specific antigen screening interval for prostate cancer

BackgroundTo identify the optimal interval for repeat prostate-specific antigen (PSA) testing to screen for prostate cancer in healthy adults.Patients and methodsA retrospective cohort study was conducted on 7332 healthy males without prostate cancer at baseline from 2005 to 2008. Participants underwent annual health checkups including PSA testing at the Center for Preventive Medicine in Japan. Participants with high PSA (≥4.0 ng/ml) underwent further examination for prostate cancer. A subgroup analysis was conducted age group (<50 years, ≥50 years).ResultsMean age was 50 years. Mean PSA at baseline was 1.2 ng/ml. In over 50-year group, for those with initial PSA of <1.0, 1.0–1.9, 2.0–2.9, and 3.0–3.9 ng/ml at baseline, the 3-year cumulative incidence of prostate cancer was 0%, 0.1%, 0.3%, and 5.7%, respectively. No prostate cancer was identified in those <50 years, regardless of PSA level.ConclusionsIf PSA screening is recommended, males >50 years with PSA of 3.0–3.9 ng/ml at baseline should undergo rescreening at 2 years. For men with PSA <3.0 ng/ml, PSA rescreening at intervals of ≥3 years is appropriate. PSA screening may not be indicated in males of <50 years of age.     

Gene silencing in androgen-responsive prostate cancer cells from the tissue-specific prostate-specific antigen promoter

The success of gene therapy using a RNA interference approach relies on small interfering RNA (siRNA) expression from a highly tissue-specific RNA polymerase II promoter rather than from ubiquitous RNA polymerase III. Accordingly, we have developed a prostate-specific vector that expresses siRNAs from the human prostate-specific antigen promoter, a RNA polymerase II promoter. Our data demonstrate androgen-dependent and tissue-specific siRNA-mediated gene silencing in the androgen-responsive prostate cancer cell line, LNCaP. The biological significance was evidenced by altered apoptotic activity through the inhibition of the apoptosis-related regulatory gene. These results demonstrate that siRNA-mediated gene silencing from a tissue-specific RNA polymerase II promoter could be a potential tool for tissue-specific gene therapy.     

Elevated levels of prostate-specific antigen (PSA) in prostate cancer cells expressing mutant p53 is associated with tumor metastasis

The underlying basis for rising levels of prostate-specific antigen (PSA) in prostate cancer is not fully understood, but attention has turned to the possibility that loss of normal p53 function might be directly involved. We have investigated the relationship between p53 function and PSA expression using in vitro and in vivo approaches. Three prostate cancer-derived p53 mutants (F134L, M237L, R273H) were introduced into LNCaP prostate cancer cells and stable transfectants established. Expression of mutant p53 was demonstrated by Western blot analysis, inactivation of wtp53 function, and a loss of p53-dependent responses to DNA damage induced by UV-irradiation and cisplatin. Levels of PSA mRNA and secreted protein were determined by RT-PCR and Western blotting, respectively. Serine protease activity was assessed using an esterase assay. In vivo effects of mutant p53 expression were examined after orthotopic implantation into prostates of nude mice. Expression of all p53 mutants was associated with elevated PSA mRNA and secreted PSA protein. In a representative line, mutant p53 was also associated with increased PSA protease-like activity compared with a control line expressing wildtype p53. Overall PSA levels, and PSA levels in serum from mice bearing tumors derived from cells expressing mutant p53, were increased compared with levels in mice bearing tumors derived from control cells. In addition, the tumors derived from cells with mutant p53 had increased vascularization and induced lymph node metastases. These data provide in vitro and in vivo support for the notion that p53 mutations directly contribute to increased levels of serum PSA, and are associated with more aggressive tumors.     

Post-therapy serum prostate-specific antigen level and survival in patients with androgen-independent prostate cancer

BACKGROUND: With an hypothesis that post-chemotherapy changes in serum prostate-specific antigen (PSA) levels might serve as a surrogate marker for assessing prostate cancer outcome (i.e., survival), we studied the relationship between pretherapy and post-therapy prognostic factors and survival in patients with androgen-independent prostate cancer. METHODS: A prognostic model for survival based on pretherapy and post-therapy parameters was developed from the clinical data on 254 patients with androgen-independent prostate cancer treated with 11 different protocol therapies at Memorial Sloan-Kettering Cancer Center. The model was validated by use of an independent dataset of 541 patients enrolled in two randomized phase III trials. RESULTS: In multivariate analysis, a post-therapy decline in PSA levels of 50% achieved in 12 weeks was a statistically significant factor associated with survival (two-sided P = .0012). A similar outcome was obtained with the use of an 8-week time frame. Elevated pretherapy level of serum lactate dehydrogenase (two-sided P = .0001), lower pretherapy level of hemoglobin (P = .0001), and younger age (two-sided P = .0430) had a statistically significant negative impact on outcome. Median survival times were 23, 17, and 9 months for low-, intermediate-, and high-risk groups of patients defined by the prognostic model, respectively. CONCLUSION: This study confirms the prognostic value of a post-therapy decline in PSA of 50% or greater from baseline in relation to survival in patients with androgen-independent prostate cancer treated with a variety of therapies. Two consecutive determinations at 4-week intervals can be used as an end point for efficacy in phase II trials of therapies in this disease.     

Detection of prostate cancer using prostate-specific antigen adjusted for the transition zone volume in patients with intermediate serum prostate-specific antigen levels

Background. The prostate-specific antigen (PSA) density of the transition zone (PSATZ) in patients with PSA values of 4.1–10 ng/ml was determined to find whether PSATZ is useful in the detection of prostate cancer. Methods. The PSA, PSA density (PSAD), and PSATZ were determined in 101 patients with intermediate levels of serum PSA. The relationship of these parameters to prostate cancer detection was examined. Results. Patients with prostate cancer had significantly higher PSAD and PSATZ values than those without prostate cancer. In patients with a PSA value of 4.1–10 ng/ml, especially in those without abnormal digital rectal examination findings, PSATZ was superior to PSA as an indicator for positive biopsy when analyzed by receiver operating characteristics curves. In those patients with a cutoff value of 0.3 ng/ml per ml of transition zone volume, PSATZ had a sensitivity of 79% and a specificity of 51%. A cutoff value of 0.3 for PSATZ provided a sensitivity of 88% and a specificity of 51% in patients without abnormal digital rectal examination findings. Conclusion. The present study demonstrated that PSATZ was superior to PSA as an indicator for positive biopsy, especially in patients with normal digital rectal examination findings. PSATZ was not superior to PSAD in the detection of prostate cancer. Received: November 17, 1999 / Accepted: April 11, 2000