Summary There is substantial heterogeneity among primary prostate cancers, evident in the spectrum of molecular abnormalities and its variable clinical course. As part of The Cancer Genome Atlas (TCGA), we present a comprehensive molecular analysis of 333 primary prostate carcinomas. Our results revealed a molecular taxonomy in which 74% of these tumors fell into one of seven subtypes defined by specific gene fusions (ERG, ETV1/4, FLI1) or mutations (SPOP, FOXA1, IDH1). Epigenetic profiles showed substantial heterogeneity, including an IDH1-mutant subset with a methylator phenotype. Androgen receptor (AR) activity varied widely and in a subtype-specific manner with SPOP and FOXA1 mutant tumors having the highest levels of AR-induced transcripts. 25% of the prostate cancers had a presumed actionable lesion in the PI3K or MAPK signaling pathways, and DNA repair genes were inactivated in 19%. Our analysis reveals molecular heterogeneity among primary prostate cancers, as well as potentially actionable molecular defects.

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BACKGROUND.Active surveillance followed by selective treatment for men who have evidence of disease progression may be an option for select patients with early‐stage prostate cancer. In this article, the authors report their experience in a contemporary cohort of men with prostate cancer who were managed with active surveillance.METHODS.All men who were managed initially with active surveillance were identified through the authors' institutional database. Selection criteria for active surveillance included: prostate‐specific antigen (PSA) <10 ng/mL, biopsy Gleason sum ≤6 with no pattern 4 or 5, cancer involvement of <33% of biopsy cores, and clinical stage T1/T2a tumor. Patients were followed with PSA measurements and digital rectal examination every 3 to 6 months and with transrectal ultrasound at 6‐ to 12‐month intervals. Beginning in 2003, patients also underwent repeat prostate biopsy at 12 to 24 months. The primary outcome measured was active treatment. Evidence of disease progression, defined as an increase in rebiopsy Gleason sum or significant PSA velocity changes (>0.75 ng/mL per year), was a secondary outcome. Chi‐square and log‐rank tests were used to compare groups. The association between clinical characteristics and receipt of active treatment was analyzed by using Cox proportional hazards regression.RESULTS.Three hundred twenty‐one men (mean age [±standard deviation]: 63.4 ± 8.5 years) selected active surveillance as their initial management. The overall median follow‐up was 3.6 years (range, 1–17 years). The initial mean PSA level was 6.5 ± 3.9 ng/mL. One hundred twenty men (37%) met at least 1 criterion for progression. Overall, 38% of men had higher grade on repeat biopsy, and 26% of men had a PSA velocity >0.75 ng/mL per year. Seventy‐eight men (24%) received secondary treatment at a median 3 years (range, 1–17 years) after diagnosis. Approximately 13% of patients with no disease progression elected to obtain treatment. PSA density at diagnosis and rise in Gleason score on repeat biopsy were associated significantly with receipt of secondary treatment. The disease‐specific survival rate was 100%.CONCLUSIONS.Selected individuals with early‐stage prostate cancer may be candidates for active surveillance. Specific criteria can be and need to be developed to select the most appropriate individuals for this form of management and to monitor disease progression. A small attrition rate can be expected because of men who are unable or unwilling to tolerate surveillance. Cancer 2008. © 2008 American Cancer Society.

Purpose We aimed to validate a previously described genetic risk score, denoted the cell-cycle progression (CCP) score, in predicting contemporary radical prostatectomy (RP) outcomes. Methods RNA was quantified from paraffin-embedded RP specimens. The CCP score was calculated as average expression of 31 CCP genes, normalized to 15 housekeeper genes. Recurrence was defined as two prostate-specific antigen levels ≥ 0.2 ng/mL or any salvage treatment. Associations between CCP score and recurrence were examined, with adjustment for clinical and pathologic variables using Cox proportional hazards regression and partial likelihood ratio tests. The CCP score was assessed for independent prognostic utility beyond a standard postoperative risk assessment (Cancer of the Prostate Risk Assessment post-Surgical [CAPRA-S] score), and a score combining CAPRA-S and CCP was validated. Results Eighty-two (19.9%) of 413 men experienced recurrence. The hazard ratio (HR) for each unit increase in CCP score (range, −1.62 to 2.16) was 2.1 (95% CI, 1.6 to 2.9); with adjustment for CAPRA-S, the HR was 1.7 (95% CI, 1.3 to 2.4). The score was able to substratify patients with low clinical risk as defined by CAPRA-S ≤ 2 (HR, 2.3; 95% CI, 1.4 to 3.7). Combining the CCP and CAPRA-S improved the concordance index for both the overall cohort and low-risk subset; the combined CAPRA-S + CCP score consistently predicted outcomes across the range of clinical risk. This combined score outperformed both individual scores on decision curve analysis. Conclusion The CCP score was validated to have significant prognostic accuracy after controlling for all available clinical and pathologic data. The score may improve accuracy of risk stratification for men with clinically localized prostate cancer, including those with low-risk disease.

Although rare, there are cases within reported series of men with GS≤6 in radical prostatectomies that have pelvic lymph node (LN) metastases. However, there are no studies as to whether pelvic LN metastases occur in tumors GS≤6 using the International Society of Urological Pathology (ISUP) updated Gleason scoring system. We performed a search of the radical prostatectomy databases at 4 large academic centers for cases of GS≤6. Only prostatectomies submitted and embedded in entirety with pelvic lymph node dissections were included. A combined total of 14,123 cases were identified out of which 22 cases had a positive LN. Histopathology review of 19 cases (3 cases unavailable for review) showed higher grade than originally reported by the pathologists in all cases. Of the 17 pre-ISUP reviewed cases, 2 were upgraded to 4+3=7 with both cribriform and poorly formed glands. One case was upgraded to 4+3=7 with tertiary pattern five displaying cribriform glands, poorly formed glands, and cords of single cells. Eleven cases were upgraded to 3+4=7 with glomeruloid structures and small to large cribriform glands (1 of these also had ductal adenocarcinoma features). Two cases had tertiary pattern 4 with small cribriform glands. One case had a prominent colloid component that would currently be graded as 4+5=9 due to large cribriform glands and solid sheets of cells within mucin. Of the two post-ISUP cases, one demonstrated tertiary pattern 4 and the other showed Gleason score 3+4=7 with irregular cribriform glands. Under-grading primarily accounts for LN positivity with GS ≤6, which has decreased significantly since the adoption of the ISUP grading system in 2005. Out of over 14,000 totally embedded RPs from multiple institutions, there was not a single case of a GS≤6 tumor with LN metastases. In contrast to prevailing assumptions, Gleason score ≤6 tumors do not appear to metastasize to lymph nodes. Rather, Gleason patterns 4 or 5, as better defined by the current ISUP updated grading system, is required for metastatic disease.

A B S T R A C T PurposeActive surveillance (AS) is an option for the initial management of early-stage prostate cancer. Current risk stratification schema identify patients with low-risk disease who are presumed to be most suitable for AS. However, some men with higher risk disease also elect AS; outcomes for such men have not been widely reported. ; log-rank P ϭ .88). Among men undergoing surgery, none were node positive and none had biochemical recurrence within 3 years. Patients and Methods ConclusionSelected men with intermediate-risk features be appropriate candidates for AS, and are not necessarily more likely to progress. AS for these men may provide an opportunity to further reduce overtreatment of disease that is unlikely to progress to advanced cancer.

Rather than being based only on clinical presentation and disease progression, decisions about treatment receipt for some men are influenced by cancer related anxiety. Men should be provided with more psychosocial support to perhaps delay treatment and the ensuing decrements in health related quality of life.

a v a i l a b l e a t w w w . s c i e n c e d i r e c t . c o m j o u r n a l h o m e p a g e : w w w . e u r o p e a n u r o l o g y . c o m Outcome measurements and statistical analysis: The Medical Outcomes Studies 36-item Short Form and the University of California, Los Angeles, Prostate Cancer Index characterized physical function, mental health, and sexual, urinary, and bowel function and bother. Repeated measures mixed-model analysis assessed change in HRQOL by treatment over time, and logistic regression was used to measure the likelihood of a clinically significant decline in HRQOL. Results and limitations: Among 3294 men, 1139 (34%) underwent nerve-sparing radical prostatectomy (NSRP), 860 (26%) underwent non-NSRP, 684 (21%) underwent brachytherapy, 386 (12%) underwent external beam radiotherapy, 161 (5%) underwent primary androgen deprivation therapy, and 64 (2%) pursued watchful waiting/active surveillance. Median follow-up was 74 mo (interquartile range: 50-102). Most treatments resulted in early declines in HRQOL, with some recovery over the next 1-2 yr and a plateau in scores thereafter. Surgery had the largest impact on sexual function and bother and on urinary function, radiation had the strongest effect on bowel function, and androgen deprivation therapy had the strongest effect on physical function. The main limitation was attrition among the cohort. Conclusions: Although most men experience initial declines in HRQOL in the first 2 yr after treatment, there is little change from 3 to 10 yr and most differences between treatments attenuated over time. Patient summary: Various treatments for prostate cancer result in a distinct constellation of adverse effects on health-related quality of life, which may have a long-term impact. These findings are helpful regarding shared decision making over choice of primary treatment. Article info