Inger L. Rosner

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.

Update on magnetic resonance imaging, ProstaScint, and novel imaging in prostate cancer.

Purpose of review Despite marked stage migration, approximately a third of patients with clinically organ-confined prostate cancer will have extracapsular extension on pathological analysis. To improve outcomes further, alternative modalities of determining extraprostatic disease must be investigated beyond the current clinical parameters of digital rectal examination, prostate-specific antigen, and Gleason score. In addition, discerning the location of tumor in patients with biochemical recurrence directly affects treatment choice. This review highlights developments in prostate cancer imaging that may improve staging and treatment planning for prostate cancer patients. Recent findings Magnetic resonance imaging is most useful in the initial evaluation of men with prostate cancer. Its high specificity for the diagnosis of extracapsular extension is tempered by its low sensitivity. Positron emission tomography is used to assess regional and distant metastasis in many malignancies. Investigation into the most appropriate radiotracer for prostate cancer is paramount in any future applicability. The unique role of ProstaScint has been in evaluating patients with biochemical failure and in trying to discern metastasis before definitive therapy. The addition of spectroscopic imaging and nanoparticle infusion may lead to further improvements. Therefore, in differentiating local versus distant recurrence, appropriate interventions with radiotherapy or hormonal manipulation may be instituted. Summary Magnetic resonance imaging, ProstaScint, and to some extent positron emission tomography are all relevant imaging modalities for the evaluation of patients with prostate cancer. Current technological advances in each arena are improving the accuracy of diagnosis. Despite their specific limitations, use in the proper clinical setting may provide essential information to improve management decisions and disease outcomes.

Higher Expression of the Androgen-Regulated Gene PSA/HK3 mRNA in Prostate Cancer Tissues Predicts Biochemical Recurrence-Free Survival

Purpose: Alterations of the androgen receptor (AR)-mediated signaling through numerous mechanisms are increasingly recognized in prostate cancer (CaP) progression. We hypothesized that the assessment of well-defined AR transcriptional targets (e.g., PSA/HK3 mRNA) in CaP tissues will provide in vivo readout of AR dysfunctions. Moreover, quantitative expression features of PSA/HK3 mRNA in prostate tumor cells may serve as a prognostic indicator of disease progression. Experimental Design: Paired benign and malignant epithelial cells (242 specimens) were obtained from laser capture microdissection of frozen OCT-embedded tissue sections prepared from radical prostatectomy specimens of 121 patients. Quantitative expression of PSA/HK3 mRNA in the matched malignant and benign cells was analyzed by real-time reverse transcription-PCR. Results: CaP cells express significantly lower PSA/HK3 mRNA levels than matched benign cells (P = 0.0133). Moreover, low PSA/HK3 mRNA expression in malignant cells was associated with increased risk of biochemical recurrence (P = 0.0217), as well as with time to recurrence (P = 0.0371), in patients with intermediate preoperative serum prostate-specific antigen levels (2-10 ng/mL). The expression of androgen-dependent genes in clinical samples correlates with each other in patients with higher expression of PSA/HK3 mRNA but not in patients with lower expression of PSA/HK3 mRNA reflecting AR pathway dysfunction. Conclusions: Our study has unraveled a novel prognostic utility of quantitative measurements of PSA/HK3 mRNA reflecting AR transcriptional activity in CaP cells, which is independent of serum prostate-specific antigen. It also has potential in stratifying subsets of patients exhibiting progressive disease associated with dampened AR transcriptional functions who may be targeted by tailored therapeutic strategies.

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.

Anterior tumors of the prostate: clinicopathological features and outcomes.

Background:To determine whether prostate cancers detected in the anterior vs posterior zones impact clinicopathological features and patient outcomes. This information could potentially affect clinical management.Methods:A retrospective pathological review of 1528 radical prostatectomy specimens submitted between 1989 and 2011 was completed. Specimens were characterized as anterior zone vs posterior zone based on index tumor and predominant tumor volume location. The chi-square test was used to determine associations between tumor location and categorical patient features. Kaplan–Meier unadjusted analysis was used to compare biochemical recurrence-free and overall survival.Results:Tumors occurred predominantly in the anterior location in 155 (10.1%) of specimens. There was no difference between mean age, body mass index, racial distribution, family history, number of previous biopsies, clinical Gleason sum or pathological stage in the two groups. Fewer patients had clinically palpable disease in the anterior tumor group, 28.8% vs 40.7% (P=0.0150). Pretreatment PSA was lower in the anterior tumor group. Total tumor volume did differ with anterior tumors having a mean 8.3 cc vs 5.6 cc (P<0.0001) size and a higher incidence of positive margins (P=0.0008). There were no differences in biochemical recurrence-free or overall survival.Conclusions:Despite the potential for adverse pathological features in anterior-based disease, there appears to be no demographic predilection, notable delay in diagnosis or significant difference in survival outcomes.

Quantitative Expression of TMPRSS2 Transcript in Prostate Tumor Cells Reflects TMPRSS2-ERG Fusion Status

TMPRSS2–ERG fusion is the most common oncogenic rearrangement in prostate cancer (CaP). Owing to this chromosomal rearrangement one TMPRSS2 allele loses its promoter, and one of the ETS-related gene (ERG) alleles gains that promoter leading to its overexpression in these tumor cells. Some studies suggest that TMPRSS2, an androgen-regulated type II transmembrane serine protease, may have an effect on CaP progression. We hypothesized that a difference in TMPRSS2 expression may be present in vivo between CaP cells with and without TMPRSS2–ERG fusion, or a compensatory mechanism for the allelic loss of TMPRSS2 may balance that expression difference. Therefore, TMPRSS2 mRNA expression was evaluated in microdissected CaP cells with and without TMPRSS2–ERG fusion in 132 CaP patients and analyzed for its correlation with other androgen receptor (AR)-regulated genes and clinicopathological features. In vivo TMPRSS2 expression correlated with that of other AR-regulated genes, including PSA/KLK3 and PMEPA1, offering potential as AR surrogates. A significantly reduced expression of TMPRSS2 was evident in malignant cells harboring TMPRSS2–ERG fusion, but not in CaP cells without TMPRSS2–ERG fusion, further defining these two genetically distinct types of CaP.

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.

Phase II trial of docetaxel, bevacizumab, lenalidomide and prednisone in patients with metastatic castration-resistant prostate cancer.

To determine the safety and clinical efficacy of two anti‐angiogenic agents, bevacizumab and lenalidomide, with docetaxel and prednisone.

Do patients with low volume prostate cancer have prostate specific antigen recurrence following radical prostatectomy

Aims: The objective of this study was to determine the incidence of prostate specific antigen (PSA) relapse in patients with low volume prostate cancer following radical prostatectomy. Methods: Between 1993 and 2001, 50 of 717 patients had total tumour volumes of less than 0.5 cm3 following radical prostatectomy. Biochemical recurrence was defined as two consecutive values of serum PSA levels of 0.2 ng/ml or greater. Results: Median follow-up of the 50 patients was 58 months. In five of the 50 patients (10%), PSA recurrence was observed. All of these five cases had Gleason score of 3+3 (well and/or moderately differentiated), organ confined and surgical margin negative tumours. In three of the five cases, capsular incision resulted in benign glands extending into the surgical margin. Conclusions: Five of 50 cases had PSA failure. In three of the five patients, benign glands located in the margin could explain the “PSA recurrence”. However, in the other two patients, none of the pathological parameters correlated with measurable PSA levels. The explanation for their PSA failure is unclear.