William J. Ellis

PCA3: A Molecular Urine Assay for Predicting Prostate Biopsy Outcome

PURPOSE A urinary assay for PCA3, an mRNA that is highly over expressed in prostate cancer cells, has shown usefulness as a diagnostic test for this common malignancy. We further characterized PCA3 performance in different groups of men and determined whether the PCA3 score could synergize with other clinical information to predict biopsy outcome. MATERIALS AND METHODS Prospectively urine was collected following standardized digital rectal examination in 570 men immediately before prostate biopsy. Urinary PCA3 mRNA levels were quantified and then normalized to the amount of prostate derived RNA to generate a PCA3 score. RESULTS The percent of biopsy positive men identified increased directly with the PCA3 score. PCA3 assay performance was equivalent in the first vs previous negative biopsy groups with an area under the ROC curve of 0.70 and 0.68, respectively. Unlike serum prostate specific antigen the PCA3 score did not increase with prostate volume. PCA3 assay sensitivity and specificity were equivalent at serum prostate specific antigen less than 4, 4 to 10 and more than 10 ng/ml. A logistic regression algorithm using PCA3, serum prostate specific antigen, prostate volume and digital rectal examination result increased the AUC from 0.69 for PCA3 alone to 0.75 (p = 0.0002). CONCLUSIONS PCA3 is independent of prostate volume, serum prostate specific antigen level and the number of prior biopsies. The quantitative PCA3 score correlated with the probability of positive biopsy. Logistic regression results suggest that the PCA3 score could be incorporated into a nomogram for improved prediction of biopsy outcome. The results of this study provide further evidence that PCA3 is a useful adjunct to current methods for prostate cancer diagnosis.

Phenotypic heterogeneity of end-stage prostate carcinoma metastatic to bone ☆

To better understand the clinical and pathologic features of end-stage, androgen-independent carcinoma of the prostate (CaP), we performed rapid autopsies on 14 men who died of progressive CaP and recorded relevant clinical data. The timing of tumor progression varied widely. The median time to androgen independence was 2 years (range, 4 months to 13.6 years). The median survival after androgen independence was 1 year (range, 1 month to 3.6 years). Because osseous metastases are prevalent in progressive CaP, up to 20 bone sites were systematically sampled in each patient. Bone metastases were widespread; tumor filled the marrow in an average of 14 bone sites. Tumor histology and expression of prostate-specific antigen (PSA) and chromogranin A (CGA) were examined in all metastases and were compared with the primary tumor. Five histological patterns of metastatic tumor were observed: solid (10 patients), macroacinar (1 patient), microacinar (1 patient), clear cell (1 patient), and comedocarcinoma (1 patient). Gleason grade of the primary tumor did not predict the histological pattern of the metastases. Although >70% of tumor cells expressed PSA, the fraction of PSA-positive cells varied widely in separate metastases in some patients (standard deviation >25). Likewise, the fraction of neuroendocrine (NE) (CGA-positive) tumor cells in different metastases varied widely. For example, between 0 and 95% of tumor cells in different metastases in 1 patient had a NE phenotype. The present study highlights the heterogeneity--histologically and immunophenotypically--of metastatic CaP. Consequently, therapy directed to the phenotype of 1 metastasis may have no effect on other metastases in the same patient because of phenotypic heterogeneity.

The Inability of Prostate Specific Antigen Index to Enhance the Predictive Value of Prostate Specific Antigen in the Diagnosis of Prostatic Carcinoma

The prostate specific antigen (PSA) level has become an important but imperfect means of detecting prostatic carcinoma. PSA index (serum PSA normalized to estimated gland volume) has been suggested to improve the performance characteristics of PSA alone. In an attempt to confirm this observation, we compared serum PSA alone to the PSA index in 218 men undergoing systematic random prostatic needle biopsy. Total gland PSA index as well as nontransition zone PSA index were calculated using several constants for the estimated contribution to the serum PSA from the transition zone. The Mann-Whitney nonparametric analysis was performed to account for differences in variances within the data set. For the patient population as a whole, all methods of testing were approximately equivalent in the ability to provide a statistically significant (p < 0.01) stratification between patients with benign and malignant biopsies. In patients with a serum PSA level of 4.1 to 10.0 ng./ml. none of the tests was able to distinguish those with carcinoma from those with a benign biopsy. In men with a normal prostate on digital rectal examination serum PSA was superior to other tests in predicting biopsy results. We conclude that PSA index does not enhance the ability of serum PSA alone to predict the presence of carcinoma.

REPEAT PROSTATE NEEDLE BIOPSY: WHO NEEDS IT?

The indications for repeat prostate needle biopsy after a transrectal ultrasound guided sextant biopsy are not defined. We examined 100 sextant prostate needle biopsies without a diagnosis of malignancy, which were repeated. Carcinoma was detected in 20 repeat biopsies (20%). Stratification based on initial biopsy result revealed carcinoma in 10 of 69 cases (14.5%) without prostatic intraepithelial neoplasia or atypia, 5 of 17 (29.4%) with atypia, 5 of 5 (100%) with grade II or III prostatic intraepithelial neoplasia and 0 of 9 with grade I prostatic intraepithelial neoplasia. Examination of prostate specific antigen (PSA) levels and PSA velocity did not provide statistically significant stratification, perhaps due to the wide variance in these parameters and the small sample size. We conclude that patients with a diagnosis of glandular atypia, or grade II or III prostatic intraepithelial neoplasia on initial biopsy are at high risk for invasive carcinoma and should undergo repeat prostate needle biopsy. A rapidly increasing serum PSA level or grossly abnormal digital rectal examination may also indicate carcinoma not discovered on initial biopsy.

Improved Detection of Recurrent Bladder Cancer Using the Bard BTA stat Test

OBJECTIVES To evaluate the BTA stat Test in the detection of recurrent bladder cancer. METHODS Sensitivity and specificity were determined using frozen voided urine samples from patients with recurrent bladder cancer, volunteers, patients with nonurologic conditions, and patients with a history of bladder cancer but free of disease. Results of cytology and the original BTA Test were compared with the sensitivity of the BTA stat Test in a large subgroup of the patients with cancer. RESULTS The BTA stat Test detected 147 (67%) of 220 recurrent cancers. For those urine samples with previous cytologic and BTA Test results available, cytology had a sensitivity of 23%, the BTA Test 44%, and the BTA stat Test 58% for detection of recurrent cancer (P < 0.001, stat versus cytology). The specificity of the BTA stat Test was 72% for benign genitourinary disease and 95% in healthy volunteers. CONCLUSIONS The BTA stat Test has high sensitivity and is significantly superior to voided urine cytologic analysis in the detection of recurrent bladder cancer.

Prostate Cancer Gene 3 (PCA3): Development and Internal Validation of a Novel Biopsy Nomogram

BACKGROUND Urinary prostate cancer gene 3 (PCA3) represents a promising novel marker of prostate cancer detection. OBJECTIVE To test whether urinary PCA3 assay improves prostate cancer (PCa) risk assessment and to construct a decision-making aid in a multi-institutional cohort with pre-prostate biopsy data. DESIGN, SETTING, AND PARTICIPANTS PCA3 assay cut-off threshold analyses were followed by logistic regression models which used established predictors to assess PCa-risk at biopsy in a large multi-institutional data set of 809 men at risk of harboring PCa. MEASUREMENTS Regression coefficients were used to construct four sets of nomograms. Predictive accuracy (PA) estimates of biopsy outcome predictions were quantified using the area under the curve of the receiver operator characteristic analysis in models with and without PCA3. Bootstrap resamples were used for internal validation and to reduce overfit bias. The extent of overestimation or underestimation of the observed PCa rate at biopsy was explored graphically using nonparametric loss-calibration plots. Differences in PA were tested using the Mantel-Haenszel test. Finally, nomogram-derived probability cut-offs were tested to assess the ability to identify patients with or without PCa. RESULTS AND LIMITATIONS PCA3 was identified as a statistically independent risk factor of PCa at biopsy. Addition of a PCA3 assay improved bootstrap-corrected multivariate PA of the base model between 2% and 5%. The highest increment in PA resulted from a PCA3 assay cut-off threshold of 17, where a 5% gain in PA (from 0.68 to 0.73, p=0.04) was recorded. Nomogram probability-derived risk cut-off analyses further corroborate the superiority of the PCA3 nomogram over the base model. CONCLUSIONS PCA3 fulfills the criteria for a novel marker capable of increasing PA of multivariate biopsy models. This novel PCA3-based nomogram better identifies men at risk of harboring PCa and assists in deciding whether further evaluation is necessary.

Positive Surgical Margins at Radical Prostatectomy Predict Prostate Cancer Specific Mortality

PURPOSE Positive surgical margins in men undergoing radical prostatectomy for prostate cancer are associated with an increased risk of biochemical recurrence. Few data are available on the role of positive surgical margins in prostate cancer specific mortality. Using a large, population based national cancer registry we evaluated the risk of prostate cancer specific mortality associated with margin status. MATERIALS AND METHODS The SEER cancer registry data for patients diagnosed between 1998 and 2006 were used to identify men undergoing radical prostatectomy for prostate cancer. Margin status, pathological stage, Gleason grade and postoperative radiation therapy were recorded along with demographic data. Multivariate Cox regression analysis was used to estimate the risk of prostate cancer specific mortality associated with positive surgical margins. RESULTS A total of 65,633 patients comprised the cohort in which 291 (0.44%) prostate cancer specific deaths occurred during an average followup of 50 months. Positive surgical margins were reported in 21.2% of cases and were more common in pT3a than pT2 tumors (44% vs 18%, p <0.001) and higher grade tumors (28% vs 18%, p <0.001). The 7-year disease specific survival rates for those at highest risk for prostate cancer specific mortality (higher grade pT3a) were 97.6% for cases with negative surgical margins and 92.4% for those with positive surgical margins. Positive surgical margins were associated with a 2.6-fold increased unadjusted risk of prostate cancer specific mortality (HR 2.55, 95% CI 2.02-3.21). Positive surgical margins remained an independent predictor of prostate cancer specific mortality on multivariate analysis (HR 1.70, 95% CI 1.32-2.18). CONCLUSIONS These data demonstrate the independent role of positive surgical margins in prostate cancer specific mortality. These findings support the importance of optimizing surgical techniques to achieve a sound oncological surgical outcome with negative surgical margins when possible.

Disseminated Tumor Cells in Prostate Cancer Patients after Radical Prostatectomy and without Evidence of Disease Predicts Biochemical Recurrence

Purpose: Men with apparently localized prostate cancer often relapse years after radical prostatectomy. We sought to determine if epithelial-like cells identified from bone marrow in patients after radical prostatectomy, commonly called disseminated tumor cells (DTC), were associated with biochemical recurrence. Experimental Design: We obtained bone marrow aspirates from 569 men prior to radical prostatectomy and from 34 healthy men with prostate-specific antigens <2.5 ng/mL to establish a comparison group. Additionally, an analytic cohort consisting of 98 patients with no evidence of disease (NED) after radical prostatectomy was established to evaluate the relationship between DTC and biochemical recurrence. Epithelial cells in the bone marrow were detected by magnetic bead enrichment with antibodies to CD45 and CD61 (negative selection) followed by antibodies to human epithelial antigen (positive selection) and confirmation with FITC-labeled anti-BerEP4 antibody. Results: DTC were present in 72% (408 of 569) of patients prior to radical prostatectomy. There was no correlation with pathologic stage, Gleason grade, or preoperative prostate-specific antigens. Three of 34 controls (8.8%) had DTC present. In patients with NED after radical prostatectomy, DTC were present in 56 of 98 (57%). DTC were detected in 12 of 14 (86%) NED patients after radical prostatectomy who subsequently suffered biochemical recurrence. The presence of DTC in NED patients was an independent predictor of recurrence (hazard ratio 6.9; 95% confidence interval, 1.03-45.9). Conclusions: Approximately 70% of men undergoing radical prostatectomy had DTC detected in their bone marrow prior to surgery, suggesting that these cells escape early in the disease. Although preoperative DTC status does not correlate with pathologic risk factors, persistence of DTC after radical prostatectomy in NED patients was an independent predictor of recurrence.

Intermittent androgen suppression with leuprolide and flutamide for prostate cancer: A pilot study

OBJECTIVES To affirm the feasibility of using intermittent androgen suppression in patients with hormone-naive prostate cancer. METHODS Leuprolide and flutamide were administered for 9 to 12 months and then discontinued until prostate-specific antigen (PSA) levels reached a threshold value determined by the baseline PSA value. This constituted one cycle of treatment. Androgen suppression was then administered intermittently as described until there was evidence of androgen independence. RESULTS Twenty-two patients with PSA failure after primary therapy with surgery and/or radiation and untreated early or Stage D2 disease were treated. Twenty-one patients completed androgen suppression during cycle 1, with a median time to PSA nadir of 3.5 months (range, 2 to 12). Fifteen patients completed cycle 1 with a median time off treatment of 6 months (range, 2 to 19) or 38% (range, 17% to 64%) of a treatment cycle. Six patients continued off treatment during cycle 1 for 1+ to 31+ months. During cycle 2, 12 patients achieved a PSA nadir in a median time of 3.5 months. Two patients completed cycle 2 with a median time off treatment of 10 months (51%). Median follow-up for all patients is 26 months (range, 10 to 51). While off treatment, all patients reported a reduction of symptoms associated with androgen suppression. CONCLUSIONS Intermittent androgen suppression is a feasible alternative to continuous androgen suppression for treatment of prostate cancer, and quality of life is improved while off treatment.

RISK FACTORS FOR ACUTE URINARY RETENTION REQUIRING TEMPORARY INTERMITTENT CATHETERIZATION AFTER PROSTATE BRACHYTHERAPY: A PROSPECTIVE STUDY

PURPOSE We prospectively investigated prognostic factors for men undergoing transperineal radioactive seed implantation for prostate cancer at the University of Washington. METHODS AND MATERIALS Between February and April, 1998, 62 consecutive unselected patients were prospectively followed after brachytherapy for early-stage prostate adenocarcinoma. Pretreatment variables included age, American Urological Association (AUA) score, uroflowimetry, and prostate volume by ultrasound. Nonrandomized variables included hormonal therapy, seed type, and use of pelvic radiotherapy. Patients were contacted by phone at one week postoperatively and at one-month intervals thereafter. Follow-up continued until all patients provided the date of last catheterization. RESULTS Urinary retention rate at one week was 34% (21 of 63 patients). At one month, 29%; at three months, 18%; and at six months, 10%. Preoperative flow rate and post-void residual did not predict for retention (p =.48 and p =.58). Use of alpha blockers, hormonal therapy, type of seed (103Pd or 1251), or external beam radiotherapy had no impact on risk of retention at any followup point. Preimplant volume and AUA score predicted for retention on univariate analysis, but on multivariate analysis only postimplant volume remained significant (p =.02) for predicting retention risk and duration. CONCLUSION Patients with large prostate size (>36 g) and higher AUA score (>10) appear to be at greater risk of risk of retention as well as duration of retention as defined in our study. Further investigation will be needed to clarify the risk of urinary retention for men undergoing brachytherapy.