Higher Biochemical Recurrence Rates Research Articles

Effect of serum testosterone on treatment outcomes in patients with intermediate- to high-grade prostate cancer.

180 Background: Low serum testosterone (TS) has been suggested to be a potential marker for more aggressive prostate cancer. However, there are conflicting data regarding whether or not patients with low TS have a higher rate of biochemical recurrence following radical prostatectomy (RP). We evaluated the relationship between postoperative TS and treatment outcomes in patients with Gleason 7–10 adenocarcinoma of the prostate. Methods: Our retrospective study cohort included 462 men diagnosed with Gleason 7–10 prostate cancer who underwent RP between 1998 and 2008 at a single institution. Patients were stratified into five groups on the basis of their postoperative TS percentile within the study cohort (<10th percentile, 10–25, 25–75, 75–90, or >90th percentile). Primary endpoints for comparison were biochemical failure free survival (BFFS) and overall survival (OS). PSA >0.2 ng/dl was used to define biochemical failure. Results: In the study cohort, mean TS was 345.2 ng/dl ± 125.2 and range 107–872 ng/dl. 44 of the 462 men had TS ≤203 ng/dl. This group had a 5-year BFFS of 43% which was significantly worse than all other TS strata (p=0.0017). Range of 5-year BFFS in all other percentile groups was 61.4 – 68.6%. There was no significant difference noted between patients with TS ≥508 ng/dl (>90th percentile) and all other TS strata (p=0.694). Furthermore, no difference in OS was noted among any of the groups (p=0.842). Groups did not differ significantly with respect to age, BMI, presence of diabetes, or known cardiovascular disease. Conclusions: Patients with exceedingly low TS are at significantly increased risk for biochemical failure following RP. Further prospective study is warranted to elucidate interventions that might improve biochemical outcomes in these patients. [Table: see text]

The significance of strong histone deacetylase 1 expression in the progression of prostate cancer

Histone deacetylases (HDACs) play important roles in many types of cancer. Recently, it has been reported that HDAC1 expression in prostate cancer is significantly higher than in benign prostate cell lines and tissues. The expression of HDAC1 in association with the clinicopathological data was investigated to define its functional and pathological roles in prostate cancer. HDAC1 expression was examined immunohistochemically in 148 patients with prostate cancer. Strong expression of HDAC1 in benign prostate glands, high-grade prostatic intraepithelial neoplasia (PIN) and prostate cancer was observed in 17/148 (11%), 19/71 (27%) and 69/148 (47%) patients. Strong HDAC1 expression was correlated with high Gleason score (P = 0.025) and high pT stage (P = 0.012). Patients with strong HDAC1 expression had higher biochemical recurrence rates (P = 0.0010). Furthermore, strong HDAC1 expression had a significant impact on patient biochemical recurrence rates in multivariate analysis (P = 0.004). These results indicate that overexpression of HDAC1 contributes to progression and poor prognosis in prostate cancer. The findings may play an important role in the emergence of effective new approaches for therapy and prognostic markers of prostate cancer.

Prostate Cancer in Men 70 Years Old or Older, Indolent or Aggressive: Clinicopathological Analysis and Outcomes

Currently there is a lack of consensus on screening recommendations for prostate cancer with minimal guidance on the cessation of screening in older men. We defined the clinicopathological features and outcomes for men 70 years old or older who were diagnosed with prostate cancer. The Center for Prostate Disease Research database was queried for all men diagnosed with prostate cancer from 1989 to 2009. The patients were stratified into age quartiles and by race. Cox proportional hazard models were used to compare clinicopathological features across patient stratifications. Kaplan-Meier analysis was used to compare biochemical recurrence-free, prostate cancer specific and overall survival. Of the 12,081 men evaluated 3,650 (30.2%) were 70 years old or older. These men had a statistically significant higher clinical stage, biopsy grade and prediagnosis prostate specific antigen velocity (p < 0.0001). For those patients who underwent prostatectomy, pathological stage, grade and surgical margin status were all significantly higher in men 70 years old or older. Biochemical recurrence and secondary treatment were also more common in this age group (p < 0.0001). Multivariate analysis revealed age 70 years or older as a significant predictor of biochemical recurrence after prostatectomy (HR 1.45, p = 0.0054). Overall survival was lowest in men age 70 years or older who had surgery, but interestingly the mean time to death was comparable regardless of age. Our findings indicate that as men age, parameters consistent with more aggressive disease become more prevalent. The etiology of this trend is unknown. However, these data may have implications for current screening and treatment recommendations.

Sex hormone‐binding globulin is a significant predictor of extracapsular extension in men undergoing radical prostatectomy

Study Type--Therapy (case series) Level of Evidence 4. What's known on the subject? and What does the study add? Previous reports showed controversial evidence supporting the role of sex steroids, mainly testosterone, in the etiology and pathogenesis of prostate cancer (PCa). The bioavailability of sex steroids is significantly regulated by sex hormone-binding globulin (SHBG). In this context, SHBG levels have been shown to be significantly higher in PCa patients than in controls. Likewise, SHBG was reported to serve as an independent predictor for extra-prostatic extension of tumour [defined as cancer (≥pT3) with capsular penetration, seminal vesicle involvement, or lymph node invasion (LNI)] in patients with clinically localized PCa. The presence of non-organ-confined disease is significantly associated with higher biochemical recurrence rates. This study provides novel evidence that SHBG might serve as a significant multivariate predictor of extra capsular extension (ECE) in PCa patients submitted to radical prostatectomy, after accounting for preoperative clinically available variables such as patient's age, total PSA, clinical stage, biopsy Gleason sum, and BMI. Moreover, a clinical cut-off for circulating SHBG allows using this easily quantifiable molecule as a novel clinical parameter in PCa patients. • To examine the association between sex hormone-binding globulin (SHBG) and extracapsular extension (ECE) in men treated with retropubic radical prostatectomy (RRP). • Preoperative serum SHBG levels were measured in a cohort of 629 consecutive European Caucasian men [mean (range) age of 64 (41-78) years] who underwent RRP. • No patient received any hormonal neoadjuvant treatment. SHBG levels were measured the day before RRP (08:00-10:00 hours) in all cases at the same laboratory. • Logistic regression models tested the association between predictors [including age, prostate-specific antigen (PSA) level, clinical stage, biopsy Gleason sum, body mass index (BMI), and SHBG] and ECE. • Combined accuracy of predictors was tested in regression-based models predicting ECE at RRP. SHBG was included in the model both as a continuous and categorized variable (according to the most informative threshold level of 30 nmol/L). • In all, 92 patients (14.6%) had ECE. The mean (standard deviation; median) serum SHBG levels were significantly higher in men with ECE compared with those with no ECE at 41.1 (14.7; 37.5) vs 36.4 (16.7; 34) nmol/L (P= 0.007; 95% confidence interval -8.00, -1.29). • Univariate analyses indicated that continuously coded SHBG was significantly [odds ratio (OR) 1.01; P= 0.03] associated with ECE, with a predictive accuracy of 60.1%. • At multivariate analyses, both continuous (OR 1.01; P= 0.03) and categorical SHBG (OR 3.22; P < 0.001) were significantly associated with ECE, after accounting for age, PSA level, clinical stage, biopsy Gleason sum, and BMI. • Addition of continuously coded SHBG slightly increased the predictive accuracy of the base model based on clinically established predictors from 63.3% to 65.5% (2.0% gain; P= 0.48). • In contrast, a model based on categorized-SHBG showed bootstrap-corrected predictive accuracy of 68.4% (5.1% gain; P= 0.044). • This study shows that SHBG might serve as a significant multivariate predictor of ECE in men with prostate cancer that undergo RRP.

Phosphorylation Status of Fas-Associated Death Domain-Containing Protein Regulates Telomerase Activity and Strongly Correlates with Prostate Cancer Outcomes

Objectives: We investigated whether the phosphorylated Fas-associated death domain protein (FADD) at serine 194 regulated human telomerase reverse transcriptase (hTERT) expression, telomerase activity and cancer progression using prostate cancer cell lines and radical prostatectomy samples taken from patients receiving neoadjuvant hormonal therapy (NHT). Methods: We analyzed hTERT expression, telomerase activity and invasion capacity in prostate cancer cell lines overexpressing the wild-type or mutant form of FADD (S194D or A). FADD, phosphorylated FADD (p-FADD) and hTERT expression in viable prostate cancer cells following NHT were immunohistochemically examined using 50 prostatectomy samples. Results: Dephosphorylated FADD (S194A) overexpression enhanced hTERT expression and telomerase activity, resulting in increased cell proliferation and invasion capacity. In Kaplan-Meier survival analysis, the patients with prostate cancer expressing low levels of p-FADD and high levels of hTERT had significantly higher rates of biochemical recurrence than those with high p-FADD and low hTERT expression (p < 0.001). Conclusions: The phosphorylation status of FADD at serine 194 could strongly affect survival and invasion of prostate cancer cells via modulation of hTERT expression and telomerase activity. p-FADD and hTERT expression may have potential as new biomarkers predicting the biochemical recurrence after NHT.

Overexpression of protease‐activated receptors‐1,‐2, and‐4 (PAR‐1, ‐2, and ‐4) in prostate cancer

Although protease-activated receptors (PARs) have been described to play a role in different malignancies, their expression and biological activity in prostate cancer are mostly unknown. PAR expression in radical prostatectomy specimens was investigated by immunohistochemistry (IHC, 40 patients) and RT-PCR. Their role in LNCaP prostate cancer cell migration and Rac1/Cdc42 signaling was assessed with Boyden chamber analysis and Western blot, respectively. PAR mRNA expression was higher in cancer, and protein expression was increased in PAR-1 (45%), PAR-2 (42%), and PAR-4 (68%), compared to normal glands. Increased PAR-1 (periglandular stroma) was associated with higher rates of biochemical recurrence (median follow-up, 5 years; P = 0.006). LNCaP migration was enhanced twofold and Rac1/Cdc42 signaling was activated by stimulation of PAR-1 and PAR-2. PARs are overexpressed in prostate cancer and may serve as potential predictors of recurrence. The data suggest potential role of PARs in autocrine and paracrine mechanisms of prostate cancer.

ErbB3, Cyclin D1 and Ki67 nuclear staining predicts biochemical recurrence in prostate cancer treated by radical prostatectomy

10096 Background: The nuclear accumulation of growth factor receptor was reported to be associated to increased cell proliferation. Cyclin D1 and Ki67 are nuclear markers of cell proliferation. Deregulation of Cyclin D1 and Ki67 expression play a role in tumorigenesis and metastasis. Recently, we observed that nuclear localization of ErbB3 was associated with prostate cancer progression. The objective of this study was to determine if the association of cell proliferation markers and nuclear localization of ErbB3 could predict biochemical recurrence (BCR) in patients with prostate cancer following radical prostatectomy. Methods: Using immunohistochemistry we analyzed a tissue microarray containing 386 cores from 64 formalin-fixed paraffin embedded specimens from prostate cancer patients who had undergone radical prostatectomy. No patient had received hormone therapy prior to surgery and prior to BCR. Antibodies against Cyclin D1, ErbB3 and Ki67 proteins were used. Results: Nuclear staining was 60%, 67% and 86% for Cyclin D1, ErbB3 and Ki67 respectively. In our cohort, 29 of 64 PCa patients (45%) had a BCR after a median 3 years of follow-up. Thirty seven (37) percent of patients had positive nuclear staining for all three markers. BCR free survival probability at 3 years was not significant for each marker individually, except for ErbB3 in positive surgical margin patients. When all three markers were combined for nuclear staining Kaplan-Meier analysis BCR free was 0.4 and 0.1 for positive and negative nuclear staining respectively (p=0.0068). Univariate COX regression analysis shows a 2.98 fold (95% CI: 1.29 - 6.86, p=0.01) higher rate of BCR in patients positive for these three markers. In addition, in a multivariate model, including pre-operative PSA (p=0.19), pathologic stage (p=0.29), Gleason grade (p=0.40) and specimens that had positive nuclear staining for the 3 markers were associated with a 3.97 fold higher rate of BCR (95% CI: 1.54 - 10.25, p=0.0068). Conclusion: These results suggest that the association of cell proliferation markers and nuclear localization of ErbB3 could be useful in predicting recurrence following radical prostatectomy and guide therapeutic decisions. Large scale trials are needed to confirm these results. No significant financial relationships to disclose.