Prostate cancer diagnosis in the new millennium: strengths and weaknesses of prostate‐specific antigen and the discovery and clinical evaluation of prostate cancer gene 3 (PCA3)

The decision to take a prostate biopsy is traditionally guided by a digital rectal examination and measurement of serum total prostate‐specific antigen (tPSA). However, both techniques are subject to inherent weaknesses. The prostate cancer gene 3 (PCA3), a gene‐based marker, specific for prostate cancer, supplements the predictive power of tPSA to improve diagnosis of disease. Including this new marker in the standard of care for men at risk of prostate cancer should be considered, as it presents marked potential for better decision making for a prostate biopsy and for improving overall patient care.     

Current early diagnostic biomarkers of prostate cancer

Prostate cancer （PCa） has become to have the highest incidence and the second mortality rate in western countries, affecting men＇s health to a large extent. Although prostate-specific antigen （PSA） was discovered to help diagnose the cancer in an early stage for decades, its specificity is relative low, resulting in unnecessary biopsy for healthy people and over-treatment for patients. Thus, it is imperative to identify more and more effective biomarkers for early diagnosis of PCa in order to distinguish patients from healthy populations, which helps guide an early treatment to lower disease-related mortality by noninvasive or minimal invasive approaches. This review generally describes the current early diagnostic biomarkers of PCa in addition to PSA and summarizes the advantages and disadvantages of these biomarkers.     

外周血与尿PCA3基因表达和尿PCA3评分在前列腺癌诊断中的意义

目的 探讨外周血、尿液中PCA3和PSA基因表达在前列腺癌诊断中的应用价值.方法 2009年6月至12月因前列腺疾病住院患者105例,收集前列腺按摩后的初始尿液和外周血标本,经病理证实前列腺癌37例、BPH 68例;8例泌尿系结石患者作为正常对照.应用实时定量PCR检测尿沉渣、外周血单个核细胞中PCA3、PSA mRNA表达,以β-actin为内参照. 结果 外周血PCA3的mRNA表达敏感性为48.6％,特异性为100％.尿PCA3评分经ROC曲线分析,ROC- AUC=0.908,以截断值64.6为诊断前列腺癌的临界值,前列腺癌患者中尿PCA3阳性率为81.1％,BPH患者中尿PCA3阴性率为86.8％.5例血清tPSA＜4μg/L前列腺癌患者,尿PCA3评分诊断前列腺癌4例;3例血清tPSA 4 ～ 10 μg/L前列腺癌患者,尿PCA3评分诊断前列腺癌2例;29例血清tPSA＞10.μg/L前列腺癌患者,尿PCA3评分诊断前列腺癌24例(82.8％).22例血清tPSA＜4μg/L BPH者,PCA3评分诊断阴性率为89.4％ (20/22);19例血清tPSA 4 ～ 10 μg/L BPH者中,PCA3评分诊断阴性率为84.2％ (16/19);27例血清tPSA＞ 10 μg/L BPH者中,PCA3评分诊断阴性率为81.5％ (22/27).尿PCA3评分、外周血PCA3联合检测的敏感性为86.5％,高于两者单独测定. 结论 外周血中的PCA3 mRNA表达是诊断前列腺癌的特异性指标,尿PCA3评分联合检测外周血中PCA3基因表达可以提高前列腺癌的诊断敏感性.     

The role of the prostate cancer gene 3 urine test in addition to serum prostate-specific antigen level in prostate cancer screening among breast cancer,early-onset gene mutation carriers

ObjectiveTo evaluate the additive value of the prostate cancer gene 3 (PCA3) urine test to serum prostate-specific antigen (PSA) in prostate cancer (PC) screening among breast cancer, early-onset gene (BRCA) mutation carriers. This study was performed among the Dutch participants of IMPACT, a large international study on the effectiveness of PSA screening among BRCA mutation carriers.Materials and methodsUrinary PCA3 was measured in 191 BRCA1 mutation carriers, 75 BRCA2 mutation carriers, and 308 noncarriers. The physicians and participants were blinded for the results. Serum PSA level≥3.0 ng/ml was used to indicate prostate biopsies. PCA3 was evaluated (1) as an independent indicator for prostate biopsies and (2) as an indicator for prostate biopsies among men with an elevated PSA level. PC detected up to the 2-year screening was used as gold standard as end-of-study biopsies were not performed.ResultsOverall, 23 PCs were diagnosed, 20 of which were in men who had an elevated PSA level in the initial screening round. (1) PCA3, successfully determined in 552 participants, was elevated in 188 (cutoff≥25; 34%) or 134 (cutoff≥35; 24%) participants, including 2 of the 3 PCs missed by PSA. PCA3 would have added 157 (≥25; 28%) or 109 (≥35; 20%) biopsy sessions to screening with PSA only. (2) Elevated PCA3 as a requirement for biopsies in addition to PSA would have saved 37 (cutoff≥25) or 43 (cutoff≥35) of the 68 biopsy sessions, and 7 or 11 PCs would have been missed, respectively, including multiple high-risk PCs. So far, PCA3 performed best among BRCA2 mutation carriers, but the numbers are still small. Because PCA3 was not used to indicate prostate biopsies, its true diagnostic value cannot be calculated.ConclusionsThe results do not provide evidence for PCA3 as a useful additional indicator of prostate biopsies in BRCA mutation carriers, as many participants had an elevated PCA3 in the absence of PC. This must be interpreted with caution because PCA3 was not used to indicate biopsies. Many participants diagnosed with PC had low PCA3, making it invalid as a restrictive marker for prostate biopsies in men with elevated PSA levels.     

环巴胺对人前列腺癌LNCaP细胞增殖和凋亡作用及对PCA3基因表达的影响

目的:探讨环巴胺对人前列腺癌LNCaP细胞增殖和凋亡的作用及对PCA3基因表达的影响。方法:不同浓度环巴胺(1、5、10、15μmol/L)干预LNCaP细胞,以只加入RPMI 1640培养液为空白对照组,分别在不同作用时间(24、48、72h),用MTT法检测其对细胞增殖的抑制、流式细胞术观察细胞凋亡率变化、Hoechst染色观察凋亡细胞形态变化、实时荧光定量逆转录聚合酶链反应(FQ-RT-PCR)观察对PCA3基因表达的影响。结果:5、10、15μmol/L环巴胺对LNCaP细胞增殖均有显著抑制作用,与空白对照组相比差异有显著性(P0.01),10μmol/L组于48h达到半数抑制量(IC50);10、15μmol/L组24、48、72hLNCaP细胞的凋亡率分别为37.21%、57.38%、57.98%和21.16%、71.31%、72.90%,与空白对照组相比差异均有显著性(P0.01)。随着环巴胺浓度增大和作用时间的延长,LNCaP细胞凋亡显著增加。PCA3基因的表达随着环巴胺浓度的上升呈现明显的递减趋势,较空白对照组显著降低(P0.01)。浓度为10μmol/L时,不同作用时间PCA3基因的表达均极低。结论:环巴胺浓度为10、15μmol/L作用48、72h时能够明显抑制LNCaP细胞的增殖,诱导细胞凋亡,并显著下调LNCaP细胞PCA3基因的表达。     

Correlation of serum PSA and Gleason score in Nigerian men with prostate cancer

Objective  Prostate cancer is an important cause of morbidity and mortality worldwide. While the predisposing factors are not fully understood, African descent is an important risk factor, and prostate cancer has become the number-one cancer in Nigerian men. This was a retrospective study of the correlation between serum prostate specific antigen (PSA) and Gleason grade and score in patients of Nigerian descent. Patients and Methods  The University College Hospital (UCH) Ibadan Cancer Registry was used to identify and quantify the incidence of prostate cancers occurring between 1998 and 2000. The histological slides of appropriate cases were reviewed to confirm the Gleason grade and score. The serum PSA values were retrieved from the patients' case notes and laboratory files. The data obtained were subjected to statistical analysis to look for associations and correlations. Results  The study included 67 men with prostate adenocarcinoma and PSA measurements who were diagnosed and treated at the UCH Ibadan between January 1998 and December 2000. There was a positive correlation between serum PSA and Gleason grade, as well as between serum PSA and Gleason score in our cohort of Nigerian African men with prostate cancer. PSA levels were significantly lower in patients with stage B disease than in patients with stage D disease. Conclusion  Serum PSA is significantly higher in metastatic than in localized disease. Further studies are necessary to determine biomarkers that complement serum PSA and the Gleason grading system in the prognostication of prostate cancer in African patients.     

Longitudinal PSA changes in men with and without prostate cancer: assessment of prostate cancer risk

BACKGROUND: To determine longitudinal PSA changes over a period of 10 years in patients with and without prostate cancer. METHODS: Serial PSA measurements performed over 10 years were evaluated in 353 men who eventually developed prostate cancer and in 2.462 participants of a screening program without prostatic malignancy. RESULTS: In men with cancer, mean tPSA increased from 2.28 ng/ml at 10 years before diagnosis to 6.37 ng/ml at the time of postive biopsy (PSA velocity: 0.409 ng/ml/year). PSA velocity was significantly associated with Gleason scores and pathologic stage. In the benign group (n=2.462), mean tPSA increased from 1.18 to 1.49 ng/ml over a period of 10 years (PSA velocity of 0.03 ng/ml/year). Of the subjects with tPSA levels of 2 ng/ml or less, 2 years prior to cancer diagnosis, 11.4% had tPSA values of more than 4 ng/ml at the time of biopsy. Of the 972 men with tPSA below 1 ng/ml 2 years before the most recent measurement was obtained, 966 (99.4%) had no evidence of prostate cancer 2 years later, while six were found to have malignancies (0.6%). CONCLUSIONS: Longitudinal PSA changes in men with and without prostate cancer are significantly different. Annual testing may not be required in men with baseline tPSA levels of 1 ng/ml or below, whereas in patients with levels higher than 1 ng/ml, it seems to be indicated because of the significant percentage of men presenting with tPSA levels of more than 4 ng/ml two years later.     

A comparative performance analysis of total prostate-specific antigen, percentage free prostate-specific antigen, prostate-specific antigen velocity and urinary prostate cancer gene 3 in the first, second and third repeat prostate biopsy

Study Type – Diagnostic (cohort) Level of Evidence 2b What's known on the subject? and What does the study add? Although non‐recommended PSA testing has been reported in men younger than 40 years of age, there are few recognized data on PSA in younger American men, particularly younger African‐American men, to provide age‐ and race‐specific references. Using data from an existing large study of young, male members of the US military, aged 28–36 years, the present study provides PSA reference distributions for young Caucasian‐American men (median = 0.56, 95th percentile = 1.42, range: <0.01–3.34 ng/mL) and African‐American men (median = 0.64, 95th percentile = 1.89, range: 0.12–6.45 ng/mL). Previous estimates from the literature are also summarized.

OBJECTIVE

• ? To provide race‐specific prostate‐specific antigen (PSA) reference distributions for young men less than 40 years of age who might have undergone non‐recommended PSA testing because of their family history of prostate cancer or inadvertently as part of a standard panel of tests.

MATERIALS AND METHODS

• ? We used data from a large existing study of young, male Caucasian‐ and African‐American members of the US military with stored serum in the Department of Defense serum repository.
• ? As part of this previous study, we selected a random sample of 373 Caucasian‐ and 366 African‐American men aged 28–36 years with an archived serum specimen collected for standard military purposes from 2004 to 2006.
• ? We measured serum total PSA concentration in this specimen using the Beckman Coulter Access Hybritech PSA assay.

RESULTS

• ? The PSA level ranged from <0.01 to 3.34 ng/mL among Caucasian‐American men, with a median of 0.56 ng/mL and a 95th percentile of 1.42 ng/mL.
• ? The PSA level ranged from 0.12 to 6.45 ng/mL among African‐American men, with a median of 0.64 ng/mL and 95th percentile of 1.89 ng/mL.
• ? The PSA level was significantly higher in African‐ than in Caucasian‐American men (P= 0.001).

CONCLUSION

• ? The PSA estimates, together with those summarized from the literature, provide age‐ and race‐specific PSA reference distributions for young men who might have undergone non‐recommended PSA testing.
• ? Comparisons by race could also begin to inform the timing of divergence of prostate cancer risk by race.

     

The relationship between Prostate CAncer gene 3 (PCA3) and prostate cancer significance

Study Type – Diagnostic (exploratory cohort) Level of Evidence 2b What's known on the subject? and What does the study add? Prior studies have shown that the PCA3 Score is indicative of prostate cancer significance and may aid in selecting men with clinically insignificant prostate cancer who could be candidates for active surveillance. This analysis of data from two studies enrolling 1,009 men shows that the PCA3 Score is associated with many biopsy and pathological features of the insignificant prostate cancer. The paper also provides guidance for the use of the PAC3 Assay in clinical practice.

OBJECTIVE

• ? To evaluate the relationship between Prostate CAncer gene 3 (PCA3) and prostate cancer significance.

PATIENTS AND METHODS

• ? Clinical data from two multi‐centre European open‐label, prospective studies evaluating the clinical utility of the PCA3 assay in guiding initial and repeat biopsy decisions were analysed.
• ? First‐catch urine was collected after digital rectal examination (three strokes per lobe) and the PCA3 score was determined using the PROGENSA® PCA3 assay.
• ? Transrectal ultrasound‐guided biopsy (≥8 cores) and radical prostatectomy (RP) specimens were analysed by the local pathologist. The relationship between biopsy and RP outcomes with the PCA3 score was assessed.

RESULTS

• ? Of the 1009 men enrolled, 348 (34%) had a positive biopsy. The median and mean PCA3 scores were statistically significantly lower in men with biopsy Gleason score <7 vs ≥7, with clinical stage T1c vs T2a–T2c, T3a cancers, with ≤33% vs >33% positive biopsy cores and with ‘biopsy indolent’ vs ‘biopsy significant’ prostate cancer (indolent prostate cancer defined by biopsy Epstein criteria).
• ? In all, 175 men with a positive biopsy had a RP: median and mean PCA3 scores were statistically significantly lower in men with pathological Gleason score <7 vs ≥7, and with pathological stage T2a–T2c vs T3a–T3b cancers.

CONCLUSIONS

• ? The PCA3 score may combined with traditional tools aid in identifying men with clinically insignificant prostate cancer, as shown by biopsy and RP pathological features including biopsy Epstein criteria, who could be candidates for active surveillance.
• ? Treatment selection should be based on a combination of clinical and pathological variables. If one wants to use a threshold point to guide treatment decisions in clinical practice, a PCA3 score threshold of 20 may have the highest utility for selecting men with clinically insignificant prostate cancer in whom active surveillance may be appropriate; a PCA3 score threshold of 50 may be used to identify men at high risk of harbouring significant prostate cancer who are candidates for RP.
• ? Although the association between the PCA3 score and prostate cancer aggressiveness needs further evaluation, the inclusion of the PCA3 score into patient management strategies may provide clinicians with another tool to more accurately determine the course of treatment.

     

Early detection of prostate cancer with low PSA cut-off values leads to significant stage migration in radical prostatectomy specimens

BACKGROUND: The introduction of prostate-specific antigen (PSA) contributed to a shift in tumor stage at diagnosis in patients with prostate cancer. The aim of the present study was to evaluate the effects of PSA screening with low PSA cut-off values on mean total and percent-free PSA levels in patients with prostate cancers at the time of diagnosis as well as on pathologic stage and mean Gleason scores in positive biopsies and radical prostatectomy specimens. METHODS: Data of 875 patients who were diagnosed with prostate cancers between 1996 and 2001 were analyzed. Patients were stratified into six groups according to the year of biopsy. Annual changes in total and percent-free PSA values, in Gleason scores of biopsies and radical prostatectomy specimens, and in pathologic stages of radical prostatectomy specimens were assessed. RESULTS: Mean PSA of patients diagnosed with prostate cancer decreased from 13.11 ng/ml (percent-free PSA: 11.89%) in 1996 to 7.33 ng/ml (percent-free PSA: 12.58%) in 2001 (P < 0.05). The percentage of organ-confined prostatectomy specimens increased from 64.3% in 1996 to 81.5% in 2001 (P < 0.05). However, mean Gleason scores increased from 5.23 to 6.33 over the 6 years (P < 0.05). The percentage of patients with biopsy-proven prostate cancers and PSA values below 4 ng/ml increased from 14.0% in 1996 to 39.2% in 2001. In the group with PSA values below 4 ng/ml organ-confined cancers were found in 80.0-95.2% of patients. CONCLUSIONS: PSAg screening with low cut-off levels has led to a significant reduction of mean baseline PSA levels in prostate cancer patients and to a significant increase in the percentage of organ-confined radical prostatectomy specimens, whereas mean Gleason scores have remained relatively constant.