Abstract Background Decipher is a validated genomic classifier developed to determine the biological potential for metastasis after radical prostatectomy (RP). Objective To evaluate the ability of ...biopsy Decipher to predict metastasis and Prostate cancer-specific mortality (PCSM) in primarily intermediate- to high-risk patients treated with RP or radiation therapy (RT). Design, setting, and participants Two hundred and thirty-five patients treated with either RP ( n = 105) or RT ± androgen deprivation therapy ( n = 130) with available genomic expression profiles generated from diagnostic biopsy specimens from seven tertiary referral centers. The highest-grade core was sampled and Decipher was calculated based on a locked random forest model. Outcome measurements and statistical analysis Metastasis and PCSM were the primary and secondary outcomes of the study, respectively. Cox analysis and c-index were used to evaluate the performance of Decipher. Results and limitations With a median follow-up of 6 yr among censored patients, 34 patients developed metastases and 11 died of prostate cancer. On multivariable analysis, biopsy Decipher remained a significant predictor of metastasis (hazard ratio: 1.37 per 10% increase in score, 95% confidence interval CI: 1.06–1.78, p = 0.018) after adjusting for clinical variables. For predicting metastasis 5-yr post-biopsy, Cancer of the Prostate Risk Assessment score had a c-index of 0.60 (95% CI: 0.50–0.69), while Cancer of the Prostate Risk Assessment plus biopsy Decipher had a c-index of 0.71 (95% CI: 0.60–0.82). National Comprehensive Cancer Network risk group had a c-index of 0.66 (95% CI: 0.53–0.77), while National Comprehensive Cancer Network plus biopsy Decipher had a c-index of 0.74 (95% CI: 0.66–0.82). Biopsy Decipher was a significant predictor of PCSM (hazard ratio: 1.57 per 10% increase in score, 95% CI: 1.03–2.48, p = 0.037), with a 5-yr PCSM rate of 0%, 0%, and 9.4% for Decipher low, intermediate, and high, respectively. Conclusions Biopsy Decipher predicted metastasis and PCSM from diagnostic biopsy specimens of primarily intermediate- and high-risk men treated with first-line RT or RP. Patient summary Biopsy Decipher predicted metastasis and prostate cancer-specific mortality risk from diagnostic biopsy specimens.
The presence of increased B-cell tumor infiltrating lymphocytes (TILs) was seen in mouse prostate cancer (PCa) but has not been fully documented in human PCa. We, therefore, investigated the density ...of infiltrating B cells within human PCa utilizing a quantitative computational method.
Archived radical prostatectomy specimens from 53 patients with known clinical outcome and D'Amico risk category were obtained and immunohistochemically (IHC) stained for the B cell marker, CD20. Slides were reviewed by a genitourinary pathologist who manually delineated the tumoral regions of PCa. Slides were digitally scanned and a computer algorithm quantified the area of CD20 stained B-cells as a measure of B cell density within the outlined regions of prostate cancer (intra-tumoral region), versus extra-tumoral prostate tissue. Correlations were analyzed between B-cell density and demographic and clinical variables, including D'Amico risk groups and disease recurrence.
For the entire cohort, the mean intra-tumoral B cell density was higher (3.22 SE = 0.29) than in the extra-tumoral region of each prostatectomy section (2.24, SE = 0.19) (paired t test; P < 0.001). When analyzed according to D'Amico risk group, the intra-tumoral B cell infiltration in low risk (0.0377 vs. 0.0246; p = 0.151) and intermediate risk (0.0260 vs. 0.0214; p = 0.579) patient prostatectomy specimens did not show significantly more B-cells within the PCa tumor. However, patient specimens from the high-risk group (0.0301 vs. 0.0197; p < 0.001) and from those who eventually had PCa recurrence or progression (0.0343 vs. 0.0246; p = 0.019) did show significantly more intra-tumoral CD20+ B-cell staining. Extent of B-cell infiltration in the prostatectomy specimens did not correlate with any other clinical parameters.
Our study shows that higher B-cell infiltration was present within the intra-tumoral PCa regions compared to the extra-tumoral benign prostate tissue regions in prostatectomy sections. For this study we developed a new method to measure B-cells using computer-assisted digitized image analysis. Accurate, consistent quantitation of B-cells in prostatectomy specimens is essential for future clinical trials evaluating the effect of B cell ablating antibodies. The interaction of B-cells and PCa may serve as the basis for new therapeutic targets.
Purpose
Systemic inflammation, as measured by C-reactive protein, has been linked with poor prostate cancer (PC) outcomes, predominantly in white men. Whether other immune measures like white blood ...cell counts are correlated with PC progression and whether results vary by race is unknown. We examined whether complete blood count (CBC) parameters were associated with PC outcomes and whether these associations varied by race.
Methods
Analyses include 1,826 radical prostatectomy patients from six VA hospitals followed through medical record review for biochemical recurrence (BCR). Secondary outcomes included castration-resistant PC (CRPC), metastasis, all-cause mortality (ACM), and PC-specific mortality (PCSM). Cox-proportional hazards were used to assess the associations between pre-operative neutrophils, lymphocytes, platelets, neutrophil–lymphocyte ratio (NLR), and platelet-lymphocyte ratio (PLR) with each outcome. We used a Bonferroni-corrected
p
-value of 0.05/5 = 0.01 as the threshold for statistical significance.
Results
Of 1,826 men, 794 (43%) were black and 1,032 (57%) white. Neutrophil count (
p
< 0.001), NLR (
p
< 0.001), and PLR (
p
< 0.001) were significantly lower, while lymphocyte count (
p
< 0.001) was significantly higher in black versus white men. After adjusting for clinicopathological features, no CBC measures were significantly associated with BCR. There were no interactions between CBC and race in predicting BCR. Similarly, no CBC values were significantly associated with CRPC, metastases, or PCSM either among all men or when stratified by race. However, higher neutrophil count was associated with higher ACM risk in white men (
p
= 0.004).
Conclusion
Pre-operative CBC measures were not associated with PC outcomes in black or white men undergoing radical prostatectomy, except for neutrophils-positive association with risk of ACM in white men. Whether circulating immune cell markers provide insight to the pathophysiology of PC progression or adverse treatment outcomes requires further study.
Study Type – Therapy (case series) Level of Evidence 4
OBJECTIVE
To evaluate the incidence and risk factors for bladder neck contracture (BNC) in men treated with robot‐assisted laparoscopic radical ...prostatectomy (RALP) and open radical prostatectomy (ORP), as BNC is a well‐described complication of ORP and may be partially attributable to technique.
PATIENTS AND METHODS
The University of California San Francisco Urologic Oncology Database was queried for patients undergoing RALP or ORP from 2002 to 2008. Patient demographics, prostate cancer‐specific information, surgical data, and follow‐up were collected. For each surgical approach, multivariate Cox proportional hazards regression was performed to evaluate associations of demographics and clinical characteristics with BNC. Time to BNC after RP was evaluated using life table and Kaplan–Meier methods.
RESULTS
From 2002 to 2008, 988 patients underwent RP as primary treatment and had at least 12 months of follow‐up. Of these men, 695 underwent ORP and 293 underwent RALP. The mean (sd) age was 59.3 (6.80) years and 91% of men were Caucasian. D’Amico risk groups at diagnosis were low (38%), intermediate (38%), and high (24%). The BNC incidence was 2.2% (22 cases) overall, 1.4% (four) for RALP, and 2.6% (18) for ORP (P= 0.12). Patients with BNC were diagnosed a median (range) of 4.7 (1–15) months after surgery. At 18 months after surgery, the BNC‐free rate was 97% for ORP and 99% for RALP (log‐rank P= 0.13). The most common presenting complaint was slow stream, followed by urinary retention. In Cox proportional hazards regression analysis, earlier year of surgery, older age at diagnosis and higher PSA level at diagnosis were significantly associated with BNC among ORP patients. In the RALP group, none of the covariates were associated with BNC.
CONCLUSIONS
The overall incidence of BNC was low in both RALP and ORP groups. Technical factors such as enhanced magnification and a running bladder anastomosis may explain the lower BNC incidence in the RALP group.
Objective To investigate predictors of time to metastasis among men treated with androgen deprivation therapy for nonmetastatic prostate cancer who developed castration-resistant prostate cancer ...(CRPC) within the Shared Equal Access Regional Cancer Hospital cohort. Methods This is a retrospective analysis of 458 nonmetastatic CRPC men. Metastases were detected in routine bone scans or other imaging tests. Predictors of time to metastasis were analyzed using proportional hazards model with CRPC as time zero. Results A total of 256 (56%) men were diagnosed with metastatic disease over a median follow-up of 36 months. Metastasis-free survival was 79%, 65%, 52%, 47%, and 41% at 1, 2, 3, 4, and 5 years after CRPC, respectively. In multivariable analysis, Gleason score 8-10 (hazard ratio HR = 1.61; P = .026), receiving primary localized treatment (HR = 1.38; P = .028), higher prostate-specific antigen (PSA) levels at CRPC diagnosis (logPSA HR = 1.64; P < .001), and PSA doubling time ≤6 months (HR = 1.42; P = .040) were independently associated with shorter time to metastasis. Race, year of CRPC, age, and time from androgen deprivation therapy to CRPC were not associated with metastasis. Conclusion Among nonmetastatic CRPC men, nearly 60% developed metastatic disease during the first 5 years, with most of the metastasis occurring within the first 3 years. Higher Gleason score, receiving primary treatment, higher PSA, and shorter PSA doubling time were independently associated with shorter time to metastasis. Therefore, these variables can be used to stratify patients according to metastasis risk.
Objectives
To examine the association between body mass index (BMI) and aggressive biochemical recurrence (BCR) using the Shared Equal Access Regional Cancer Hospital (SEARCH) database.
Material and ...Methods
We identified 4123 men with complete data treated by radical prostatectomy between 1988 and 2015. We tested the association between BMI and BCR using Cox models, and among men with BCR, prostate‐specific antigen doubling time (PSADT) was compared across BMI categories using linear regression. Models were adjusted for age, race, prostate‐specific antigen, biopsy Gleason score, clinical stage, year and surgical centre.
Results
Overall, 922 men (22%) were of normal weight (BMI <25 kg/m2), 1863 (45%) were overweight (BMI 25–29.9 kg/m2), 968 (24%) were obese (BMI 30–34.9 kg/m2), and 370 (9%) were moderately or severely obese (BMI ≥35 kg/m2). After adjustment for multiple clinical characteristics, higher BMI was significantly associated with higher risk of BCR (P = 0.008). Among men with BCR, men in the four BMI categories had similar multivariable‐adjusted PSADT values (increasing BMI categories: 20.9 vs 21.3 vs 21.0 vs 14.9 months; P = 0.48).
Conclusion
While we confirmed that higher BMI was associated with BCR, we found no link between BMI and PSADT at the time of recurrence. Our data suggest obese men do not have more aggressive recurrences. Future studies are needed to test whether obesity predicts response to salvage therapies.
Immunotherapeutic regulation of the tumor microenvironment in prostate cancer patients is not understood. Most antibody immunotherapies have not succeeded in prostate cancer. We showed previously ...that high-risk PCa patients have a higher density of tumor infiltrating B-cells in prostatectomy specimens. In mouse models, anti-CD20 antibody ablation of B-cells delayed PCa regrowth post-treatment. We sought to determine whether neoadjuvant anti-CD20 immunotherapy with rituximab could reduce CD20+ B cell infiltration of prostate tumors in patients.
An open label, single arm clinical trial enrolled eight high-risk PCa patients to receive one cycle of neoadjuvant rituximab prior to prostatectomy. Eleven clinical specimens with similar characteristics were selected as controls. Treated and control samples were concurrently stained for CD20 and digitally scanned in a blinded fashion. A new method of digital image quantification of lymphocytes was applied to prostatectomy sections of treated and control cases. CD20 density was quantified by a deconvolution algorithm in pathologist-marked tumor and adjacent regions. Statistical significance was assessed by one sided Welch's t-test, at 0.05 level using a gatekeeper strategy. Secondary outcomes included CD3+ T-cell and PD-L1 densities.
Mean CD20 density in the tumor regions of the treated group was significantly lower than the control group (p = 0.02). Mean CD3 density in the tumors was significantly decreased in the treated group (p = 0.01). CD20, CD3 and PD-L1 staining primarily occurred in tertiary lymphoid structures (TLS). Neoadjuvant rituximab was well-tolerated and decreased B-cell and T-cell density within high-risk PCa tumors compared to controls.
This is the first study to treat patients prior to surgical prostate removal with an immunotherapy that targets B-cells. Rituximab treatment reduced tumor infiltrating B and T-cell density especially in TLSs, thus, demonstrating inter-dependence between B- and T-cells in prostate cancer and that Rituximab can modify the immune environment in prostate tumors. Future studies will determine who may benefit from using rituximab to improve their immune response against prostate cancer. Trial registration NCT01804712, March 5th, 2013 https://clinicaltrials.gov/ct2/show/NCT01804712?cond=NCT01804712&draw=2&rank=1.
The survival benefit of combined radiation therapy (RT) and androgen deprivation therapy (ADT) compared with ADT alone for clinically lymph node-positive prostate cancer remains controversial.
We ...identified patients with clinically node-positive, nonmetastatic prostate cancer diagnosed between 2000 and 2015 and treated with ADT (n = 450) or ADT-RT (n = 198) from a national Veterans Affairs database. We compared prostate cancer-specific mortality (PCSM) and all-cause mortality (ACM) between treatment groups using multivariable competing-risks regression and Cox regression, respectively. An interaction term between ADT-RT and prostate-specific antigen (PSA) level (dichotomized about the median) was included in the multivariable models.
ADT-RT was associated with improved PCSM among patients with PSA levels less than the median of 26 ng/mL (sub-distribution hazard ratio, 0.50; 95% confidence interval CI 0.28-0.88; P = .02) but not greater than the median (hazard ratio HR, 1.15; 95% CI 0.67-1.96; P = .62) (P = .038 for interaction). ADT-RT was also associated with improved ACM among patients with PSA levels less than the median (HR, 0.38; 95% CI 0.25-0.57; P < .001) but not greater than the median (HR, 0.91; 95% CI 0.60-1.38; P = .66) (P = .004 for interaction).
Definitive treatment with ADT-RT is associated with improved PCSM and ACM among patients with clinically node-positive prostate cancer and lower baseline PSA levels. Patients with clinically node-positive disease appear to be a heterogeneous cohort, with a subset who may achieve long-term survival with combined RT and ADT.
To evaluate the association between the prostate-specific antigen (PSA) nadir level and the time to nadir (TTN) with biochemical recurrence (BCR) risk after radical prostatectomy (RP) in the Shared ...Equal-Access Research Cancer Hospital (SEARCH) database.
This is a retrospective analysis of 1939 men from the SEARCH database treated with RP between 1998 and 2015 with available ultrasensitive PSA nadir within 1-6 months after RP. Uni- and multivariable analyses of PSA nadir and TTN with time from nadir to BCR were performed with Cox models (adjusted for demographics, tumor features, and preoperative PSA).
Among men with an undetectable PSA nadir, the TTN was unrelated to BCR (1.0-2.9 vs 3-6 months: hazard ratio HR 0.86, P = .46). Regardless of TTN, men with detectable nadir had an increased risk of BCR (TTN of 3-6 months: HR 1.81, P = .024; TTN of 1.0-2.99 months: HR 3.75, P <.001 vs undetectable nadir and TTN of 3-6 months). Among men with a detectable PSA at 1-3 months, 53% had a lower PSA level during follow-up 3-6 months after RP, which was undetectable in 32% and lower but still detectable in 21%.
In the post-RP setting, men with both a detectable nadir and a shorter TTN had an increased risk of BCR. Intriguingly, about half of the men with a detectable PSA in the first 3 months after RP had a lower PSA level during follow-up between 3 and 6 months after RP. If confirmed in future studies, this has important implications for patients considering adjuvant therapy based on postoperative PSA values in the first 3 months after RP.
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