Increased frequency of germline BRCA2 mutations associates with prostate cancer metastasis in a racially diverse patient population.

BACKGROUND: Germline mutations in BRCA2 have been linked to a higher risk of prostate cancer (PCa), and high frequency of BRCA1 and BRCA2 (BRCA1/2) gene alterations was recently reported in metastatic castration-resistant PCa specimens. Mutations in BRCA2 vary in racial and ethnic groups including African-American (AA) and Caucasian-American (CA) populations. METHODS: BRCA1 and BRCA2 genes were sequenced (Ion AmpliSeq targeted sequencing) in archived blood DNA specimens in 1240 PCa patients, including 30% AA patients, in three different cohorts: localized early stage (T2) PCa (N = 935); advanced PCa (50% T3-4) (N = 189); and metastatic PCa (N = 116). The sequences were analyzed for known and novel mutations in BRCA1/2. Statistical analyses were performed to determine associations of the mutations with clinico-pathological parameters. RESULTS: BRCA2 mutations with known pathogenic annotation were significantly more prevalent in men with advanced and metastatic PCa (3.1%) compared to patients with an organ-confined disease (0.7%). AA patients carried more frequently BRCA1/2 variants of unknown significance (VUS) when compared to Caucasian Americans (4.6 vs. 1.6%, respectively). Significantly, pathogenic BRCA2 mutations in men with localized early stage PCa increased the risk of distant metastasis. CONCLUSIONS: Germline variants of unknown significance in BRCA1/2 are more frequent in AA than CA PCa patients; however, the prevalence of pathogenic mutations were similar across the races. Patients carrying BRCA2 pathogenic mutations are more likely to progress to metastasis.

Elevated alkaline phosphatase velocity strongly predicts overall survival and the risk of bone metastases in castrate-resistant prostate cancer.

OBJECTIVES: In patients with a rising prostate-specific antigen (PSA) level during treatment with androgen deprivation therapy, identification of men who progress to bone metastasis and death remains problematic. Accurate risk stratification models are needed to better predict risk for bone metastasis and death among patients with castration-resistant prostate cancer (CRPC). This study evaluates whether alkaline phosphatase (AP) kinetics predicts bone metastasis and death in patients with CRPC. METHODS AND MATERIALS: A retrospective cohort study of 9,547 patients who underwent treatment for prostate cancer was conducted using the Center for Prostate Disease Research Multi-center National Database. From the entire cohort, 347 were found to have CRPC and, of those, 165 had 2 or more AP measurements during follow-up. To determine the AP velocity (APV), the slope of the linear regression line of all AP values was plotted over time. Rapid APV was defined as the uppermost quartile of APV values, which was found to be ≥6.3 IU/l/y. CRPC was defined as 2 consecutive rising PSA values after achieving a PSA nadir<4 ng/ml and documented testosterone values less than 50 ng/dl. The primary study outcomes included bone metastasis-free survival (BMFS) and overall survival (OS). RESULTS: Rapid APV and PSA doubling time (PSADT) less than 10 months were strong predictors of both BMFS and OS in a multivariable analysis. Faster PSADT was a stronger predictor for BMFS (odds ratio [OR] = 12.1, P<0.0001 vs. OR = 2.7, P = 0.011), whereas rapid APV was a stronger predictor of poorer OS (OR = 5.11, P = 0.0001 vs. OR = 3.98, P = 0.0034). In those with both a rapid APV and a faster PSADT, the odds of developing bone metastasis and death exceeded 50%. CONCLUSION: APV is an independent predictor of OS and BMFS in patients with CRPC. APV, in conjunction with PSA-based clinical parameters, may be used to better identify patients with CRPC who are at the highest risk of metastasis and death. These findings need validation in prospective studies.

Health-related quality of life for men with prostate cancer--an evaluation of outcomes 12-24 months after treatment.

OBJECTIVE: To determine the health-related quality of life (HRQoL) impact of prostate cancer interventions at 2 years post-treatment, and between the 12- and 24-month interval, to better characterize this measure. MATERIALS AND METHODS: Patients treated at the Center for Prostate Disease Research between June 2003 and February 2010 were offered enrollment into a HRQoL study that entailed a baseline evaluation before prostate biopsy and at 3, 6, 9, 12, 18, 24, and 30 months thereafter. The instruments used were the Expanded Prostate Cancer Index Composite (EPIC), EPIC Demographic, and Medical Outcomes Study Short-Form 36 (SF-36). A Student's t-test and ANOVA were used to examine the association between HRQoL scores, patient demographic, and disease features. Multivariable regression models were used to analyze change over time. Estimates of risk, corresponding confidence intervals, and P values are presented for these longitudinal findings. RESULTS: The study group was comprised of 595 patients. African Americans (AA) had slightly lower baseline raw scores in all EPIC and SF-36 HRQoL domains, but on bivariate analysis, there was no statistical difference in change of scores over time. Radical prostatectomy (RP) led to the greatest decline in urinary function. Bowel function significantly worsened with the addition of hormone therapy (HT) to external beam radiation therapy (EBRT). Sexual bother and function had a marked decline in all active treatment options. Despite these changes, there were no differences in overall satisfaction. SF-36 domains were not affected by RP, whereas EBRT and EBRT + HT had universal impact. For the 12- to 24-month interval, specifically, patients who underwent EBRT fared worse over this time period, showing continued worsening of urinary bother, hormonal function, physical role, physical component summary, and overall satisfaction. Patients who underwent RP did not show any further decline in the 12- to 24-month interval, but instead showed improvement. CONCLUSIONS: Because of the protracted nature of recovery after surgery, delayed onset of effects from radiation, potential interval decline secondary to age-related symptoms, and longevity of patients with prostate cancer, determination of long-term HRQoL outcomes is integral. Counseling with regard to these outcomes should be balanced with oncologic expectations from treatment.

Low risk prostate cancer in men ≥ 70 years old: to treat or not to treat.

OBJECTIVES: Prostate cancer (CaP) in the aging male will become an increasingly important and controversial health care issue. We evaluated the outcomes between a variety of treatments for low-risk CaP in patients 70 years of age and older. METHODS AND MATERIALS: A total of 3,650 men diagnosed with CaP between 1989 and 2009 were identified in the Center for Prostate Disease Research database to be 70 years of age or older at time of diagnosis. Of these patients, 770 men met the D'Amico criteria ([13]) for low-risk disease and were treated with radical prostatectomy, external beam radiation therapy, or watchful waiting. Cox proportional hazard models were used to compare clinicopathologic features across treatment groups. Kaplan-Meier analysis was used to compare biochemical recurrence-free, progression-free, and overall survival. RESULTS: Of the 770 patient cohort, 194 (25%) chose radical prostatectomy, 252 (33%) chose external beam radiation therapy, and 324 (42%) were initially managed by watchful waiting with 110 (34%) of this subset ultimately undergoing secondary treatment. The median follow-up was 6.4 years. There were no significant differences in distributions of race/ethnicity, number of medical comorbidities, or clinical stage across the treatment groups. Patients managed on watchful waiting without secondary treatment had the poorest overall survival on Kaplan-Meier analysis (P = 0.0001). Additionally, multivariate analysis confirmed this result for watchful waiting without secondary treatment as being a statistically significant predictor of overall mortality (HR 1.938, P = 0.0084).

The burden of prostate cancer in Asian nations.

INTRODUCTION: In this review, the International Agency for Research on Cancer's cancer epidemiology databases were used to examine prostate cancer (PCa) age-standardized incidence rates (ASIR) in selected Asian nations, including Cancer Incidence in Five Continents (CI5) and GLOBOCAN databases, in an effort to determine whether ASIRs are rising in regions of the world with historically low risk of PCa development. MATERIALS AND METHODS: Asian nations with adequate data quality were considered for this review. PCa ASIR estimates from CI5 and GLOBOCAN 2008 public use databases were examined in the four eligible countries: China, Japan, Korea and Singapore. Time trends in PCa ASIRs were examined using CI5 Volumes I-IX. RESULTS: While PCa ASIRs remain much lower in the Asian nations examined than in North America, there is a clear trend of increasing PCa ASIRs in the four countries examined. CONCLUSION: Efforts to systematically collect cancer incidence data in Asian nations must be expanded. Current CI5 data indicate a rise in PCa ASIR in several populous Asian countries. If these rates continue to rise, it is uncertain whether there will be sufficient resources in place, in terms of trained personnel and infrastructure for medical treatment and continuum of care, to handle the increase in PCa patient volume. The recommendation by some experts to initiate PSA screening in Asian nations could compound a resource shortfall. Obtaining accurate estimates of PCa incidence in these countries is critically important for preparing for a potential shift in the public health burden posed by this disease.

Clinical potential of the ERG oncoprotein in prostate cancer.

Oncogenic activation of ERG resulting from gene fusion is present in over half of all patients with prostate cancer in Western countries. Although the underlying genetic mechanisms have been extensively studied, evaluation of the ERG oncoprotein--the translational product of ERG gene fusions--has just begun. The robust correlation between ERG oncoprotein detection and gene fusion status enables rapid characterization of this protein in large patient cohorts. Recent studies have focused on characterizing the ERG oncoprotein and determining its potential role in the diagnosis and biological stratification of prostate cancer.

Racial/Ethnic patterns in prostate cancer outcomes in an active surveillance cohort.

Introduction. Concern regarding overtreatment of prostate cancer (CaP) is leading to increased attention on active surveillance (AS). This study examined CaP survivors on AS and compared secondary treatment patterns and overall survival by race/ethnicity. Methods. The study population consisted of CaP patients self-classified as black or white followed on AS in the Center for Prostate Disease Research (CPDR) multicenter national database between 1989 and 2008. Secondary treatment included radical prostatectomy (RP), external beam radiation therapy or brachytherapy (EBRT-Br), and hormone therapy (HT). Secondary treatment patterns and overall survival were compared by race/ethnicity. Results. Among 886 eligible patients, 21% were black. Despite racial differences in risk characteristics and secondary treatment patterns, overall survival was comparable across race. RP following AS was associated with the longest overall survival. Conclusion. Racial disparity in overall survival was not observed in this military health care beneficiary cohort with an equal access to health care.

Prostate cancer in men less than the age of 50: a comparison of race and outcomes.

OBJECTIVE: To compare clinicopathologic features and survival outcomes for men 50 years of age in relation to other age groups stratified by race to further define prostate cancer (CaP) in young men. Controversy exists regarding the appropriate age to undergo CaP screening, outcomes for early intervention, and whether there is unique age-associated tumor biology. We compared clinicopathologic features and survival outcomes for men <50 years of age in relation to other age groups stratified by race to further define CaP in young men. METHODS: A multi-institutional review of 12,081 records of patients diagnosed with CaP from 1989-2009 was conducted. Patients were stratified by age group, race, and decade of treatment. Demographic and clinicopathologic characteristics were compared across age groups using chi-square tests and analysis of variance. The primary study endpoints, time to biochemical recurrence and all-cause mortality, were compared across age groups using Kaplan-Meier estimation and univariable and multivariable Cox proportional hazards analysis. RESULTS: Only 4.5% of the study sample was <50 years of age. A higher percentage of African Americans diagnosed were <50 compared with Caucasians (8.3% vs 3.3%, P<.0001). Positive family history was more prevalent in the <50 cohort (36.1% vs 22.0%, P<.0001). Despite these findings, both racial subgroups for men<50 years of age demonstrated improved clinicopathologic features than other age quartiles. Furthermore, both Kaplan-Meier and Cox proportional hazard analysis demonstrated that the <50 cohort had a lower incidence of biochemical recurrence and greater overall survival. CONCLUSIONS: Race and family history appear to play a significant role in the incidence of CaP in younger men. Younger age at diagnosis is associated with more favorable outcomes and indicates that population-based screening at younger ages could potentially lead to improved survival for high-risk groups.

Prostate cancer in Asian Americans: incidence, management and outcomes in an equal access healthcare system.

UNLABELLED: Study Type--Therapy (outcomes research) Level of Evidence 2c. What's known on the subject? and What does the study add? While epidemiological studies have shown a significantly lower incidence of adenocarcinoma of the prostate in Asia than the United States, several studies have demonstrated that Asian Americans present with more advanced stages, higher tumour grades, and worse mortality-incidence ratios than Caucasian Americans. This study, conducted in an equal access military healthcare system, reveals improved pathological and survival outcomes in Asian Americans compared to other races. This may indicate that worsened outcomes previously reported among Asian Americans diagnosed with adenocarcinoma of the prostate may be related to access to care, language barriers, socioeconomic status, or cultural factors. OBJECTIVE: • To characterize the incidence, management and clinicopathological characteristics of prostate cancer (CaP) in a population of Asian Americans undergoing mandatory annual screening in an equal access healthcare system. PATIENTS AND METHODS: • Men registered into the military-based Center for Prostate Disease Research multi-institutional database from 1989-2007 with biopsy-proven CaP and categorized as Asian American, Caucasian or African American were included. • Demographic information, treatment modality, clinicopathological characteristics and outcomes were compared. RESULTS: • In total, there were 10,964 patients; 583 (5.3%) were Asian Americans. Asian Americans had lower clinical stage (P < 0.001) but worse biopsy grade (P < 0.001) than other groups. They were more likely to choose radical prostatectomy (RP) (P < 0.001) and showed a higher percentage of organ-confined disease (P < 0.001). • Asian Americans had improved biochemical recurrence free (P < 0.01) and overall survival (P < 0.001) rates compared to African Americans or Caucasians treated with RP or external radiation therapy. CONCLUSIONS: • Asian Americans with CaP treated in an equal access healthcare system have improved pathological outcomes and survival characteristics compared to other races. • Asian ethnicity's negative impact on survival noted by others appears to be the result of factors other than the tumour's intrinsic behaviour, such as language barriers, socioeconomic status and cultural norms.

Prostate cancer in men 70 years old or older, indolent or aggressive: clinicopathological analysis and outcomes.

PURPOSE: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Long-term overall survival and metastasis-free survival for men with prostate-specific antigen-recurrent prostate cancer after prostatectomy: analysis of the Center for Prostate Disease Research National Database.

OBJECTIVE: • To describe metastasis-free survival (MFS) and overall survival (OS) among men with prostate-specific antigen (PSA)-recurrent prostate cancer after radical prostatectomy who did not receive additional therapy until metastasis, using a multicentre database capturing a wide ethnic mix. PATIENTS AND METHODS: • A retrospective analysis of the Center for Prostate Disease Research National Database (comprised of five US military hospitals and one civilian centre) was performed for patients with PSA relapse (≥ 0.2 ng/mL) after radical prostatectomy who had no additional therapy until the time of radiographic metastatic disease. • We investigated factors influencing metastasis and all-cause mortality using univariate and multivariate Cox regression analysis. RESULTS: • There were a total of 346 men who underwent radical prostatectomy between May 1983 and November 2008 and fulfilled the entry criteria. All patients had information on survival and 190 men had information on metastasis. Among patients with survival data (n= 346), 10-year OS was 79% after a median follow-up of 8.6 years from biochemical recurrence. • Among men with metastasis data (n= 190), 10-year MFS was 46% after a median follow-up of 7.5 years. • In Cox regressions, four clinical factors (Gleason score, pathological stage, time to PSA relapse and PSA doubling time), as well as age, were predictive of OS and/or MFS in univariate analysis, although only PSA doubling time (≥ 9 vs 3-8.9 vs <3 months) remained independently predictive of these outcomes in multivariate analysis (P < 0.001). CONCLUSIONS: • This multicentre multi-ethnic dataset shows that OS and MFS can be extensive for men with PSA-recurrent prostate cancer, even in the absence of further therapy before metastasis. • This unique patient cohort, the second largest of its type after the Johns Hopkins cohort, confirms that PSA doubling time is the strongest determinant of OS and MFS in men with PSA-recurrent disease. • Longer follow-up and more events will be required to determine whether other variables may also contribute to these outcomes.

Fusion imaging: a novel staging modality in testis cancer.

OBJECTIVE: Computed tomography and chest radiographs provide the standard imaging for staging, treatment, and surveillance of testicular germ cell neoplasms. Positron emission tomography has recently been utilized for staging, but is somewhat limited in its ability to provide anatomic localization. Fusion imaging combines the metabolic information provided by positron emission tomography with the anatomic precision of computed tomography. To the best of our knowledge, this represents the first study of the effectiveness using fusion imaging in evaluation of patients with testis cancer. METHODS: A prospective study of 49 patients presenting to Walter Reed Army Medical Center with testicular cancer from 2003 to 2009 was performed. Fusion imaging was compared with conventional imaging, tumor markers, pathologic results, and clinical follow-up. RESULTS: There were 14 true positives, 33 true negatives, 1 false positive, and 1 false negative. Sensitivity, specificity, positive predictive value, and negative predictive value were 93.3, 97.0, 93.3, and 97.0% respectively. In 11 patient scenarios, fusion imaging differed from conventional imaging. Utility was found in superior lesion detection compared to helical computed tomography due to anatomical/functional image co-registration, detection of micrometastasis in lymph nodes (pathologic nodes < 1cm), surveillance for recurrence post-chemotherapy, differentiating fibrosis from active disease in nodes < 2.5cm, and acting as a quality assurance measure to computed tomography alone. CONCLUSIONS: In addition to demonstrating a sensitivity and specificity comparable or superior to conventional imaging, fusion imaging shows promise in providing additive data that may assist in clinical decision-making.

Assessment of circulating tumor cells (CTCs) in prostate cancer patients with low-volume tumors.

The objective of this study was to assess the incidence of circulating tumor cells (CTCs) in prostate cancer patients with low-volume tumors (less than 0.5 cc) after radical prostatectomy (RP). Blood samples were collected from 64 RP patients to assess the incidence of CTCs following RP. The specimens were processed by whole-mount section. Clinicopathological data (e.g. patient age, race, specimen weight, tumor volume, grade, stage and surgical margin status) and follow-up PSA data were compared to CTC status. Of the 64 RP patients, nine had 'low-volume prostate cancer'. Seven of these patients had detectable levels of CTCs. In two of the seven patients with detectable CTCs, PSA elevation was also observed. Isolation and detection of circulating epithelial cells is possible in low-volume prostate cancer patients. In the setting of low-volume prostate cancer, CTCs may be associated with the presence of detectable PSA levels. However, the detection of CTCs did not predict PSA failure.

Venous thromboembolism in urologic surgery: prophylaxis, diagnosis, and treatment.

Venous thromboembolism (VTE) represents one of the most common and potentially devastating complications of urologic surgery. With VTE's rapid onset of symptoms, association with a precipitous clinical course, and high mortality rate, all urologists should be well versed in appropriate prophylaxis, prompt diagnosis, and expeditious treatment. A MEDLINE(R) search was performed for articles that examined the incidence, diagnosis, and treatment of VTE in urologic surgery. Additional articles were reviewed based on cited references. There is a paucity of prospective studies on VTE in the urologic literature with most recommendations for urologic surgery patients being extrapolated from other surgical disciplines. Retrospective studies place VTE incidence rates in major urologic surgeries among the highest reported-highlighting the importance of thromboprophylaxis. Conversely, VTE was rarely reported in association with endoscopic and laparoscopic procedures making mechanical thromboprophylaxis sufficient. Recent literature reveals delayed VTE occurring after hospital discharge to be a persistent threat despite inpatient preoperative prophylaxis. Computed tomographic angiography has emerged as the test of choice for diagnosing pulmonary embolism, whereas lower extremity duplex sonography is recommended for diagnosing deep venous thrombosis. Traditional angiography is rarely used. Treatment of VTE involves therapeutic anticoagulation for various lengths of time based on presence and reversibility of patient risk factors as well as number of events. Perioperative thromboprophylaxis should be considered in all major urologic surgeries. Urologists should be familiar with incidence rates, recommended prophylaxis, appropriate diagnosis, and treatment recommendations for VTE to minimize morbidity and mortality. The limited number of prospective, randomized, controlled trials evaluating the use of thromboprophylaxis in urologic surgery demonstrates the need for further research.

Clinicopathological behavior of single focus prostate adenocarcinoma.

PURPOSE: With the increasing use of focal therapy for prostate adenocarcinoma a pathological basis for its appropriate application must be established. We determined the clinicopathological characteristics and natural history of single focus prostate cancer since this entity seems to be the ideal target for focal therapy. MATERIALS AND METHODS: We queried the Center for Prostate Disease Research database for all patients who underwent radical prostatectomy at Walter Reed Army Medical Center from 1993 through 2008. Patients with single focus prostate adenocarcinoma were compared with those who had multifocal disease. Primary outcomes were surgical margin status, pathological stage and biochemical recurrence. Secondary outcomes were Gleason score and total tumor volume. RESULTS: A total of 1,159 men were included in the study. Multifocal disease was present in 1,056 patients (99.1%) and 103 (8.9%) had single focus disease. There were statistically higher rates of positive surgical margins (41.0% vs 29.9%, p = 0.0012), Gleason score 8-10 disease (18.7% vs 10.1%, p = 0.0362) and biochemical recurrence (38.5% vs 24.2%, p = 0.0021) in the single focus and multifocal groups, respectively. The single focus group had significantly worse biochemical recurrence-free survival compared to the multifocal group (p = 0.0017). CONCLUSIONS: Single focus prostate cancer appears to have more aggressive behavior than multifocal disease. These findings support an aggressive, disciplined pretreatment evaluation to define disease site, extent and grade before focal therapy.

Advances made in the treatment of testicular cancer in the U.S. Military: 1946 to the present.

Testicular cancer is presently one of the most curable solid tumors, and thanks to diagnostic, surgical, and medical advances over the last several decades, the treatment of this tumor serves as a paradigm for multimodal treatment of solid malignancies. Due to testicular cancer's predilection for younger patients, many of the seminal improvements and discoveries were made possible as a result of initial investigatory groundwork laid by military physicians treating servicemen. This article reviews historical contributions of the United States Military Medical Departments in the arena of testicular cancer treatment in the post-World War II era.

The Center for Prostate Disease Research (CPDR): a multidisciplinary approach to translational research.

This article describes the history, structure, and contributions of the Center for Prostate Disease Research. It divides the organization into the clinical program at Walter Reed Army Medical Center, the basic science program in Rockville, MD, and the multi-center national database. The emphasis of this article is not the achievements of the individual programs but their synergy, establishing a comprehensive multidisciplinary prostate center.

The design and implementation of a multidisciplinary prostate cancer clinic.

The authors describe how a "traditional" clinical center and research organization was transformed into a multidisciplinary clinic for patients with prostate cancer. How and why the clinic was designed and implemented, as well as benefits to patients, staff, and research initiatives, are detailed.