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.

     

The value of urinary prostate cancer gene 3 (PCA3) scores in predicting pathological features at radical prostatectomy

Study Type – Diagnostic (exploratory cohort) Level of Evidence 2b What's known on the subject? and What does the study add? PCA3 scores correlate to numerous histoprognostic factors, specifically tumour volume and positive surgical margins. These results may have a clinical impact in the near future on the selection of patients eligible to undergo active surveillance and nerve‐sparing surgery.

OBJECTIVE

• ? To assess correlations between Prostate CAncer gene 3 (PCA3) levels and pathological features of radical prostatectomy (RP) specimens, which define cancer aggressiveness.

PATIENTS AND METHODS

• ? After digital rectal examination (DRE), first‐catch urine was collected from 160 patients with localized prostate cancer. The PCA3 score was calculated using the Gene Probe Progensa^? assay.
• ? PCA3 scores were then correlated to the pathological features of the RP specimens.

RESULTS

• ? PCA3 scores correlated significantly with tumour volume (r= 0.34, P < 0.01). A PCA3 score of >35 was an independent predictor in a multivariate analysis of a tumour volume >0.5 mL (odds ratio [OR] 2.7, P= 0.04).
• ? It was also an independent predictor of positive surgical margins (OR 2.4, P= 0.04). Receiver–operator characteristic curves indicated PCA3 as the most accurate predictor of positive margins (area under the curve [AUC] 0.62), in addition to a positive biopsy percentage (AUC 0.52).
• ? There was also a significant difference in the mean PCA3 score between Gleason score patient groups (6 vs ≥7) and pathological stage groups (pT0/2 vs pT3/4).

CONCLUSIONS

• ? PCA3 scores correlate to numerous histoprognostic factors, specifically tumour volume and positive surgical margins.
• ? These results may have a clinical impact in the near future on the selection of patients eligible to undergo active surveillance and nerve‐sparing surgery.

     

Gleason grading of prostate cancer in needle biopsies or radical prostatectomy specimens: contemporary approach, current clinical significance and sources of pathology discrepancies

The Gleason grading system is a powerful tool to prognosticate and aid in the treatment of men with prostate cancer. The needle biopsy Gleason score correlates with virtually all other pathological variables, including tumour volume and margin status in radical prostatectomy specimens, serum prostate-specific antigen levels and many molecular markers. The Gleason score assigned to the tumour at radical prostatectomy is the most powerful predictor of progression after radical prostatectomy. However, there are significant deficiencies in the practice of this grading system. Not only are there problems among practising pathologists but also a relative lack of interobserver reproducibility among experts.     

Differences in histopathological and biochemical outcomes in patients with low Gleason score prostate cancer

Study Type – Diagnosis (case series)
Level of Evidence 4

OBJECTIVE

To test whether the number or percentage of positive biopsy cores can be used to discriminate between patients with prostate cancer of a favourable and less favourable Gleason score (GS) ≤3 + 3, as prognostically, not all GS 3 + 3 prostate cancers are the same.

PATIENTS AND METHODS

In all, 1106 consecutive patients with a prostate‐specific antigen (PSA) level of ≤10 ng/mL and a biopsy GS of ≤3 + 3 or 3 + 4 had an open radical prostatectomy. The number of positive biopsy cores (≤2 vs ≥3) were stratified into low‐ vs high‐risk groups. Subsequently, we stratified patients according to the GS and the percentage of positive biopsy cores (<50% vs ≥50%). The pathological stage and the 5‐year biochemical recurrence (BCR)‐free survival rates were examined in univariable and multivariable models.

RESULTS

Based on the number of positive cores, the rate of extraprostatic disease was 11.7% and 23.3%, respectively, in the low‐and high‐risk GS ≤3 + 3 groups (P < 0.001). The 5‐year BCR‐free survival rates were 95.0%, 77.8%, 81.2% and 66.5% for, respectively, low‐ and high‐risk GS ≤3 + 3 and for low‐ and high‐risk GS 3 + 4 patients. Univariable and multivariable intergroup BCR rate differences were statistically significant between low‐ vs high‐risk GS 3 + 3 patients (P < 0.001), but not significant between high‐risk GS ≤3 + 3 vs low‐risk GS 3 + 4 patients (P = 0.6). Comparable results were obtained when comparisons were made according to the percentage of positive biopsy cores.

CONCLUSIONS

Our results corroborate the finding that not all patients with a biopsy GS of ≤3 + 3 prostate cancer have low‐risk disease. High‐risk GS ≤3 + 3 patients have a similar risk profile as more favourable GS 3 + 4 patients. This finding warrants consideration when deciding on treatment.     

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.     

Localized prostate cancer and robot-assisted laparoscopic radical prostatectomy: a retrospective,comparative study between pre- and post-operative Gleason scores

Introduction: To compare the pre- and post-operative Gleason scores (GS) in patients with localized prostate cancer treated with robot-assisted laparoscopic radical prostatectomy.

Materials and methods: A single center, retrospective comparison between pre- and post-operative GS. Age, prostate volume, PSA, number of biopsies, number of positive cores, biopsy GS, cTNM, final pathology GS and pTNM of 286 patients were retrieved. They were divided into risk groups.

Results: A total of 286 patients with a mean age at surgery of 64.64?±?7.81 y and mean PSA-value of 9.35?±?8.38?ng/mL. Mean prostate volume was 55.09?±?24.93?mL, mean number of biopsies was 11.90?±?4.63. Mean percentage of positive cores was 36.90?±?22.42%. A GS of <7 was seen in 23.4%, 66.8% had a GS of 7 and 9.7% of >7 in final pathology. Of the total, 38.1% were pre-operative low risk, 58.7% of them had an upgrade in GS on final pathology, 45.1% were in the intermediate risk group, 5.4% showed a downgrade, 64.3% remained stable and 30.2% had an upgrade in GS. Also, 16.8% were high risk patients of which 35.4% had a downgrade, 39.6% remained stable and 25% showed an upgrade of the GS.

Conclusions: We found a substantial underestimation of the GS in the pre-operative setting when compared to the GS in final pathology.     

Urinary nerve growth factor as an oncologic biomarker for prostate cancer aggressiveness

ObjectivesWe investigated urinary nerve growth factor (NGF) as a novel urinary biomarker for high-grade prostate cancer (PCa).Methods and materialsAfter institutional review board approval for a prospective pilot study, we enrolled men at the preoperative visit before robotic-assisted radical prostatectomy. Demographics, urinary flow parameters, and urine samples were collected. Urinary NGF and urinary creatinine were obtained in the translational science laboratory. Pathologic and postoperative demographics were collected after surgery. NGF is the primary outcome variable (dependent variable). The pathologic Gleason score (ordinal variable≤6, 7, and ≤8) served as an independent grouping variable. Multivariate analysis using a general linear model was conducted to investigate associations between independent variables and NGF (dependent variable) after adjusting for urinary concentration and volume.ResultsWe enrolled and analyzed urine samples and pathologic data from 115 subjects. Patient pathology included 24% (n = 28) Gleason score 6 or less, 68% (n = 78) Gleason score 7, and 8% (n = 9) Gleason score 8 or greater. Perineural invasion was more prevalent in higher-grade disease (P<0.001). The median NGF level was 24.1 pg/ml (range: 0.16–270.5 pg/ml) and was transformed to the log base 10 scale. Total bladder volume, urinary creatinine level, prostate-specific antigen level, and diabetes were correlated with the Log NGF. In a general linear model, adjusting for bladder volume and urinary creatinine, increasing Log₁₀ NGF was associated with higher Gleason score (Gleason category≤6, 7, and≥8; P = 0.003).ConclusionsUrinary NGF may be a biomarker for higher-grade PCa. Our pilot study suggests further investigation is warranted to determine whether urinary NGF could provide unique additional information in patients with PCa.     

Surgical margin and Gleason score as predictors of postoperative recurrence in prostate cancer with or without chromosome 8p allelic imbalance

BACKGROUND: Identification of prostate cancer patients at risk for postoperative disease recurrence is an important clinical issue. Existing pathological markers can predict disease recurrence only to a certain extent, and there is a need for more accurate predictors. METHODS: Using "counting alleles," a novel experimental method, we determined allelic status of chromosome 8p in 107 prostatectomy specimens. Statistical analyses examined the association between pathologic predictors (Gleason score, stage, surgical margin, etc.) and cancer recurrence in patients with and without 8p allelic imbalance (8p AI). RESULTS: 8p AI cancers were more likely to recur in the presence of a positive surgical margin, whereas recurrence of 8p retaining tumors was associated with the Gleason score, but not with the surgical margin. CONCLUSIONS: Our findings suggest that chromosome 8p allelic status affects the predictive value of "traditional" markers of prostate cancer recurrence. If confirmed by larger studies, these results may have important clinical implications.     

The relationship between pre-radiation therapy testosterone levels and prostate cancer aggressiveness

We investigated whether there is an association between testosterone levels and prostate cancer aggressiveness in patients treated with radiation therapy who underwent a prostatectomy or prostate radiotherapy (EBRT). A total of 380 patients who received primary or post-operative radiotherapy were identified. At the time of radiotherapy, baseline testosterone levels and body mass index (BMI) measurements were available. On multivariate analysis (MVA), higher prostate-specific antigen (PSA) levels were predictive of testosterone ≥10.4  (OR = 1.3, p = .04) and testosterone ≥12.0 nmol/L (OR = 1.3, p = .04). Patients with a Gleason score ≥8 were more likely to have testosterone <8 nmol/L than patients with a lower score (31% vs. 20%, p = .043). On univariate analysis, a Gleason score ≥8 was associated with a lower likelihood of having a normal (≥8 nmol/L) testosterone level (OR = 0.51, 95% CI: 0.3–0.9, p = .02), and on MVA adjusted for post-surgical versus primary EBRT and BMI (≥30 kg/m²), the Gleason score lost its statistical significance (p = .09). While higher PSA levels are associated with higher testosterone levels, the interaction between Gleason score and testosterone is unclear and merits further study.     

Prediction of extraprostatic extension by prostate specific antigen velocity, endorectal MRI, and biopsy Gleason score in clinically localized prostate cancer

Objectives:   To investigate the clinical value of prostate specific antigen velocity (PSAV) in predicting the extraprostatic extension of clinically localized prostate cancer.
Methods:   One hundred and three patients who underwent radical prostatectomy for clinically localized prostate cancer were included in the analysis. The correlation between preoperative parameters, including PSA-based parameters, clinical stage, and histological biopsy findings, and the pathological findings were analyzed. Logistic regression analysis was performed to identify a significant set of independent predictors for the local extent of the disease.
Results:   Sixty-four (60.2%) patients had organ confined prostate cancer and 39 (39.8%) patients had extraprostatic cancer. The biopsy Gleason score, PSA, PSA density, PSA density of the transition zone, and PSAV were significantly higher in the patients with extraprostatic cancer than in those with organ confined cancer. Multivariate logistic regression analysis indicated that the biopsy Gleason score, endorectal magnetic resonance imaging findings, and PSAV were significant predictors of extraprostatic cancer ( P  < 0.01). Probability curves for extraprostatic cancer were generated using these three preoperative parameters.
Conclusions:   The combination of PSAV, endorectal magnetic resonance imaging findings, and biopsy Gleason score can provide additional information for selecting appropriate candidates for radical prostatectomy.     

The outcome of patients with pathological Gleason score >or=8 prostate cancer after radical prostatectomy

OBJECTIVE

To analyse the outcome of patients undergoing radical prostatectomy (RP) for Gleason 8–10 clinically localized prostate cancer, and to evaluate the prognostic value of well‐known predictors of progression.

PATIENTS AND METHODS

In all, 1480 patients had RP between 1988 and 2006, of whom 180 had pathological Gleason score ≥8 and negative lymph nodes. Biochemical progression‐free survival was determined using the Kaplan‐Meier method. The effect of preoperative prostate‐specific antigen (PSA) level, pathological stage and margin status was assessed with univariate and multivariate analyses.

RESULTS

Of the 180 patients, the Gleason score in the RP specimen was 8, 9 or 10 in 70%, 27% and 3%, respectively; 24% had stage pT2 disease, 30% stage pT3a, 25% stage pT3b and 20% stage pT4a. The 5‐ and 7‐year biochemical progression‐free survival was 73 and 65% for stage pT2, 40% and 27% for stage pT3a, and 30% for stage pT3b (log rank test, P < 0.001). In the univariate model, preoperative PSA level, pathological stage and surgical margins were predictors of survival. In the multivariate analysis, preoperative PSA level and extracapsular extension predicted biochemical progression‐free survival.

CONCLUSION

Gleason 8–10 tumours have a poor prognosis. Patients with a PSA level of <10 ng/mL and stage pT2 disease have the greatest likelihood of having a longer progression‐free survival after RP.