Jennifer Cullen

A Biopsy-based 17-gene Genomic Prostate Score Predicts Recurrence After Radical Prostatectomy and Adverse Surgical Pathology in a Racially Diverse Population of Men with Clinically Low- and Intermediate-risk Prostate Cancer

BACKGROUND Biomarkers that are validated in independent cohorts are needed to improve risk assessment for prostate cancer (PCa). OBJECTIVE A racially diverse cohort of men (20% African American [AA]) was used to evaluate the association of the clinically validated 17-gene Genomic Prostate Score (GPS) with recurrence after radical prostatectomy and adverse pathology (AP) at surgery. DESIGN, SETTING, AND PARTICIPANTS Biopsies from 431 men treated for National Comprehensive Cancer Network (NCCN) very low-, low-, or intermediate-risk PCa between 1990 and 2011 at two US military medical centers were tested to validate the association between GPS and biochemical recurrence (BCR) and to confirm the association with AP. Metastatic recurrence (MR) was also evaluated. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Cox proportional hazards models were used for BCR and MR, and logistic regression was used for AP. Central pathology review was performed by one uropathologist. AP was defined as primary Gleason pattern 4 or any pattern 5 and/or pT3 disease. RESULTS AND LIMITATIONS GPS results (scale: 0-100) were obtained in 402 cases (93%); 62 men (15%) experienced BCR, 5 developed metastases, and 163 had AP. Median follow-up was 5.2 yr. GPS predicted time to BCR in univariable analysis (hazard ratio per 20 GPS units [HR/20 units]: 2.9; p<0.001) and after adjusting for NCCN risk group (HR/20 units: 2.7; p<0.001). GPS also predicted time to metastases (HR/20 units: 3.8; p=0.032), although the event rate was low (n=5). GPS was strongly associated with AP (odds ratio per 20 GPS units: 3.3; p<0.001), adjusted for NCCN risk group. In AA and Caucasian men, the median GPS was 30.3 for both, the distributions of GPS results were similar, and GPS was similarly predictive of outcome. CONCLUSIONS The association of GPS with near- and long-term clinical end points establishes the assay as a strong independent measure of PCa aggressiveness. Tumor aggressiveness, as measured by GPS, and outcomes were similar in AA and Caucasian men in this equal-access health care system. PATIENT SUMMARY Predicting outcomes in men with newly diagnosed prostate cancer is challenging. This study demonstrates that a new molecular test, the Genomic Prostate Score, which can be performed on a patients original prostate needle biopsy, can predict the aggressiveness of the cancer and help men make decisions regarding the need for immediate treatment of their cancer.

Differences in Frequency of ERG Oncoprotein Expression Between Index Tumors of Caucasian and African American Patients With Prostate Cancer

OBJECTIVE To systematically evaluate the ETS-related gene (ERG) alterations in the multifocal tumor context using whole-mount prostatectomy specimens from African and Caucasian American patients matched for age, pathologic grade and stage. Oncogenic activation of the ERG is the most common early genomic alteration in patients with prostate cancer (CaP) in Western countries. However, ERG alterations have not been systematically examined in African American patients with a known greater risk of CaP incidence and mortality. METHODS ERG oncoprotein expression was analyzed in 91 Caucasian and 91 African American patients with CaP, who were matched for age, Gleason score, and pathologic stage. A unique aspect of the present study was the evaluation of ERG in whole-mount prostatectomy sections, minimizing sampling bias and allowing the careful assessment of the ERG in the multifocal tumor context of CaP. RESULTS The frequency of ERG-positive prostate tumors was significantly greater among Caucasian Americans than among African Americans when assessed in all tumor foci (41.9% vs 23.9%, P < .0001). A markedly greater frequency of ERG oncoprotein expression was noted between the index tumors of the Caucasian Americans (63.3%) and those of the African Americans (28.6%). Also, in the African American patients, the higher grade index tumors were predominantly ERG negative. CONCLUSION ERG typing of CaP established a major difference between the index tumors of Caucasian and African American patients. ERG-negative index tumors might indicate a less favorable outcome for African American patients. The results of the present study underscore that typing of CaP for the ERG could enhance our understanding of the biologic differences between the examined ethnic groups.

Silencing of Lactotransferrin expression by methylation in prostate cancer progression.

Background: Cancer cells gain selection advantages by the coordinated silencing of protective and by the activation of cell proliferation/cell survival genes. Evaluations of epithelial cell transcriptome of benign and malignant prostate glands by laser capture microdissection (LCM) identified Lactotransferrin (LTF) as the most significantly downregulated gene in prostate cancer (CaP) cells (P

Prospective quality‐of‐life outcomes for low‐risk prostate cancer: Active surveillance versus radical prostatectomy

For patients with low‐risk prostate cancer (PCa), active surveillance (AS) may produce oncologic outcomes comparable to those achieved with radical prostatectomy (RP). Health‐related quality‐of‐life (HRQoL) outcomes are important to consider, yet few studies have examined HRQoL among patients with PCa who were managed with AS. In this study, the authors compared longitudinal HRQoL in a prospective, racially diverse, and contemporary cohort of patients who underwent RP or AS for low‐risk PCa.

Patient risk stratification using Gleason score concordance and upgrading among men with prostate biopsy Gleason score 6 or 7

PURPOSE To define the impact of discordant Gleason sum (GS) between prostate biopsy (Pbx) tissue and radical prostatectomy (RP) specimen among men initially diagnosed with Gleason 6 or 7 prostate adenocarcinoma. MATERIALS AND METHODS We evaluated patients diagnosed with GS 6 or 7 and treated primarily with RP. We defined the frequency of GS discordance between Pbx and RP pathology reports. We analyzed pretreatment parameters associated with GS discordance and compared immediate postprostatectomy outcome variables across patient groups defined by their GS and concordance. We then conducted survival analysis for biochemical recurrence across patient groups defined by their GS and concordance status. RESULTS Among patients with GS 6 on Pbx, 681/1,847 (36.86%) patients were upgraded to GS 7 or higher after RP. Surgical margin, capsular involvement, seminal vesicle, and nodal involvement status were more favorable in patients with concordant Pbx and RP specimen with GS 6 (P < 0.0001). Patients with smaller transrectal ultrasound (TRUS) prostate volume were found to have higher PSA densities and were more likely to be upgraded at RP. Multivariate survival analysis also predicted fewer biochemical recurrence events over time in men with concordant Pbx tissue and RP specimen of GS 6 vs. 6/7 or 7/7 (P = 0.0025) controlling for other relevant covariates. CONCLUSIONS GS discordance between Pbx tissue and RP specimens among prostate cancer patients initially diagnosed with either GS 6 or 7 adenocarcinoma of the prostate is substantial. This discordance has potential clinical significance in predicting oncologic outcomes.

Time to Prostate-Specific Antigen Nadir After Androgen Suppression Therapy for Postoperative or Postradiation PSA Failure and Risk of Prostate Cancer-Specific Mortality

OBJECTIVES To examine whether the time to the prostate-specific antigen (PSA) nadir was associated with prostate cancer-specific mortality (PCSM) in men with PSA failure after radical prostatectomy or radiotherapy who do not achieve an undetectable PSA level (PSA level of 0.2 ng/mL or less) after 8 months of androgen suppression therapy (AST). METHODS The cohort included 162 men with localized prostate cancer treated with AST for an increasing PSA level after radical prostatectomy or radiotherapy. Grays analysis was used to evaluate for an association between the time to PSA nadir after 8 months of AST and the time to PCSM, adjusting for established prognostic factors. The median age and follow-up after 8 months of AST was 71.2 and 1.8 years, respectively. RESULTS After adjusting for Gleason score, pre-AST PSA doubling time, PSA at AST, PSA nadir value, time to PSA failure, initial treatment, and age, the time to PSA nadir was significantly associated with PCSM (adjusted hazard ratio 2.53, 95% confidence interval 1.24 to 5.14, P = 0.01). Men with a PSA nadir greater than the median value of 0.9 ng/mL and the time to PSA nadir longer than the median of 4 months had significantly greater PCSM estimates (P <0.001) compared with men with a PSA nadir of 0.9 ng/mL or less. CONCLUSIONS The time to PSA nadir, combined with the PSA nadir level, can be used to identify men who are at high risk of PCSM after a short course of AST for entry onto clinical trials using novel systemic agents with AST.

Time to an undetectable prostate-specific antigen (PSA) after androgen suppression therapy for postoperative or postradiation PSA recurrence and prostate cancer-specific mortality

For men receiving androgen‐suppression therapy (AST) for a rising postoperative or postradiation prostate‐specific antigen (PSA) recurrence, whether the time to an undetectable (u) PSA was significantly associated with prostate cancer‐specific mortality (PCSM) was evaluated.

Prostate-specific Antigen Velocity and the Detection of Gleason Score 7 to 10 Prostate Cancer

An increasing prostate‐specific antigen (PSA) velocity is associated with a shorter survival after local therapy for prostate cancer. In this study, the authors evaluated whether PSA velocity was associated with prostate cancer detection and grade at diagnosis after adjusting for established predictors.

Patient-specific Meta-analysis of 2 Clinical Validation Studies to Predict Pathologic Outcomes in Prostate Cancer Using the 17-Gene Genomic Prostate Score

OBJECTIVE To perform patient-specific meta-analysis (MA) of two independent clinical validation studies of a 17-gene biopsy-based genomic assay as a predictor of favorable pathology at radical prostatectomy. MATERIALS AND METHODS Patient-specific MA was performed on data from 2 studies (732 patients) using the Genomic Prostate Score (GPS; scale 0-100) together with Cancer of the Prostate Risk Assessment (CAPRA) score or National Comprehensive Cancer Network (NCCN) risk group as predictors of the likelihood of favorable pathology (LFP). Risk profile curves associating GPS with LFP by CAPRA score and NCCN risk group were generated. Decision curves and receiver operating characteristic curves were calculated using patient-specific MA risk estimates. RESULTS Patient-specific MA-generated risk profiles ensure more precise estimates of LFP with narrower confidence intervals than either study alone. GPS added significant predictive value to each clinical classifier. A model utilizing GPS and CAPRA provided the most risk discrimination. In decision-curve analysis, greater net benefit was shown when combining GPS with each clinical classifier compared with the classifier alone. The area under the receiver operating characteristic curve improved from 0.68 to 0.73 by adding GPS to CAPRA, and 0.64 to 0.70 by adding GPS to NCCN risk group. The proportion of patients with LFP >80% increased from 11% using NCCN risk group alone to 23% using GPS with NCCN. Using GPS with CAPRA identified the highest proportion-31%-of patients with LFP >80%. CONCLUSION Patient-specific MA provides more precise risk estimates that reflect the complete body of evidence. GPS adds predictive value to 3 widely used clinical classifiers, and identifies a larger proportion of low-risk patients than identified by clinical risk group alone.

A prospective cohort study of treatment decision-making for prostate cancer following participation in a multidisciplinary clinic

BACKGROUND Patients diagnosed with prostate cancer (PCa) are presented with several treatment options of similar efficacy but varying side effects. Understanding how and why patients make their treatment decisions, as well as the effect of treatment choice on long-term outcomes, is critical to ensuring effective, patient-centered care. This study examined treatment decision-making in a racially diverse, equal-access, contemporary cohort of patients with PCa counseled on treatment options at a multidisciplinary clinic. METHODS A prospective cohort study was initiated at the Walter Reed National Military Medical Center (formerly Walter Reed Army Medical Center) in 2006. Newly diagnosed patients with PCa were enrolled before attending a multidisciplinary clinic. Patients completed surveys preclinic and postclinic to assess treatment preferences, reasons for treatment choice, and decisional regret. RESULTS As of January 2014, 925 patients with PCa enrolled in this study. Surgery (54%), external radiation (20%), and active surveillance (12%) were the most common primary treatments for patients with low- and intermediate-risk PCa, whereas patients with high-risk PCa chose surgery (34%) or external radiation with neoadjuvant hormones (57%). Treatment choice differed by age at diagnosis, race, comorbidity status, and calendar year in both univariable and multivariable analyses. Patients preferred to play an active role in the decision-making process and cited doctors at the clinic as the most helpful source of treatment-related information. Almost all patients reported satisfaction with their decision. CONCLUSIONS This is one of the first prospective cohort studies to examine treatment decision-making in an equal-access, multidisciplinary clinic setting. Studies of this cohort would aid in understanding and improving the PCa decision-making process.