Decipher correlation patterns post prostatectomy: initial experience from 2 342 prospective patients.

BACKGROUND: Currently, there are multiple commercially available RNA-based biomarkers that are Medicare approved and suggested for use by the National Comprehensive Cancer Network guidelines. There is uncertainty as to which patients benefit from genomic testing and for whom these tests should be ordered. Here, we examined the correlation patterns of Decipher assay to understand the relationship between the Decipher and patient tumor characteristics. METHODS: De-identified Decipher test results (including Decipher risk scores and clinicopathologic data) from 2 342 consecutive radical prostatectomy (RP) patients tested between January and September 2015 were analyzed. For clinical testing, tumor specimen from the highest Gleason grade was sampled using a 1.5 mm tissue punch. Decipher scores were calculated based on a previously locked model. Correlations between Decipher score and clinicopathologic variables were computed using Spearman's rank correlation. Mixed-effect linear models were used to study the association of practice type and Decipher score. The significance level was 0.05 for all tests. RESULTS: Decipher score had a positive correlation with pathologic Gleason score (PGS; r=0.37, 95% confidence interval (CI) 0.34-0.41), pathologic T-stage (r=0.31, 95% CI 0.28-0.35), CAPRA-S (r=0.32, 95% CI 0.28-0.37) and patient age (r=0.09, 95% CI 0.05-0.13). Decipher reclassified 52%, 76% and 40% of patients in CAPRA-S low-, intermediate- and high-risk groups, respectively. We detected a 28% incidence of high-risk disease through the Decipher score in pT2 patients and 7% low risk in pT3b/pT4, PGS 8-10 patients. There was no significant difference in the Decipher score between patients from community centers and those from academic centers (P=0.82). CONCLUSIONS: Although Decipher correlated with baseline tumor characteristics for over 2 000 patients, there was significant reclassification of tumor aggressiveness as compared to clinical parameters alone. Utilization of the Decipher genomic classifier can have major implications in assessment of postoperative risk that may impact physician-patient decision making and ultimately patient management.

Efficacy of post-operative radiation in a prostatectomy cohort adjusted for clinical and genomic risk.

BACKGROUND: To date, there have been no published trials examining the impact of salvage radiation therapy (SRT) in the post-operative setting for prostate cancer (PCa). We conducted a retrospective, comparative study of post-operative radiation following radical prostatectomy (RP) for men with pT3 disease or positive margins (adverse pathological features, APF). METHODS: 422 PCa men treated at four institutions with RP and having APF were analyzed with a primary end point of metastasis. Adjuvant radiation treatment (ART, n=111), minimal residual disease (MRD) SRT (n=70) and SRT (n=83) were defined by PSA levels of <0.2, 0.2-0.49 and ⩾0.5 ng ml(-1), respectively, before radiation therapy (RT) initiation. Remaining 157 men who did not receive additional therapy before metastasis formed the no RT arm. Clinical-genomic risk was assessed by Cancer of the Prostate Risk Assessment Post-Surgical (CAPRA-S) and Decipher. Cox regression was used to evaluate the impact of treatment on outcome. RESULTS: During the study follow-up, 37 men developed metastasis with a median follow-up of 8 years. Both CAPRA-S and Decipher had independent predictive value on multivariable analysis for metastasis (P<0.05). Adjusting for clinical-genomic risk, SRT and no RT had hazard ratios of 4.31 (95% confidence interval, 1.20-15.47) and 5.42 (95% confidence interval, 1.59-18.44) for metastasis compared with ART, respectively. No significant difference was observed between MRD-SRT and ART (P=0.28). Men with low-to-intermediate CAPRA-S and low Decipher value have a low rate of metastatic events regardless of treatment selection. In contrast, men with high CAPRA-S and Decipher benefit from ART, however the cumulative incidence of metastasis remains high. CONCLUSIONS: The decision as to the timing and need for additional local therapy following RP is nuanced and requires providers and patients to balance risks of morbidity with improved oncological outcomes. Post-RP treatment can be safely avoided for men who are low risk by clinical-genomic risk, whereas those at high risk should favor enrollment in clinical trials.

Impact of NADiA ProsVue PSA slope on secondary treatment decisions after radical prostatectomy.

BACKGROUND: Selecting appropriate candidates for postprostatectomy radiotherapy is challenging, because adverse pathological features cannot accurately predict clinical recurrence. Biomarkers that identify residual disease activity may assist clinicians when counseling patients on the risks, benefits and costs of secondary treatment. NADiA ProsVue PSA slope results ≤2.0 pg ml(-1) month(-1) are predictive of a reduced risk of clinical recurrence; however, its clinical utility has not yet been studied. METHODS: We prospectively enrolled men treated by radical prostatectomy in a multicenter, institutional review board-approved clinical trial. At postsurgical follow-up, investigators (N=17) stratified men into low-, intermediate- or high-risk groups for prostate cancer recurrence based on clinicopathological findings and other factors. Investigators documented their initial treatment plan for each subject and serially collected three serum samples for ProsVue testing. After the ProsVue result was reported, investigators recorded whether or not the initial treatment plan was changed. The proportion of cases referred for secondary treatment before and after ProsVue was reported, and the significance of the difference determined. RESULTS: Complete assessments were reported for 225 men, 128 (56.9%) of whom were stratified into intermediate- and high-risk groups. Investigators reported that they would have referred 41/128 (32.0%) at-risk men for secondary treatment. However, after results were known, they referred only 15/128 (11.7%) men. The difference in proportions (-20.3%, 95% confidence interval (CI) -29.9 to -10.3%) is significant (P<0.0001). Odds of a referral was significantly reduced after results were reported (odds ratio 0.28, 95% CI 0.15-0.54, P<0.0001). CONCLUSIONS: Knowledge of a ProsVue result had significant impact on the final treatment plan. A ProsVue result ⩽2.0 pg ml(-1) month(-1) significantly reduced the proportion of men at risk of recurrence who otherwise would have been referred for secondary treatment.

Targeting cell cycle and hormone receptor pathways in cancer.

The cyclin/cyclin-dependent kinase (CDK)/retinoblastoma (RB)-axis is a critical modulator of cell cycle entry and is aberrant in many human cancers. New nodes of therapeutic intervention are needed that can delay or combat the onset of malignancies. The antitumor properties and mechanistic functions of PD-0332991 (PD; a potent and selective CDK4/6 inhibitor) were investigated using human prostate cancer (PCa) models and primary tumors. PD significantly impaired the capacity of PCa cells to proliferate by promoting a robust G1-arrest. Accordingly, key regulators of the G1-S cell cycle transition were modulated including G1 cyclins D, E and A. Subsequent investigation demonstrated the ability of PD to function in the presence of existing hormone-based regimens and to cooperate with ionizing radiation to further suppress cellular growth. Importantly, it was determined that PD is a critical mediator of PD action. The anti-proliferative impact of CDK4/6 inhibition was revealed through reduced proliferation and delayed growth using PCa cell xenografts. Finally, first-in-field effects of PD on proliferation were observed in primary human prostatectomy tumor tissue explants. This study shows that selective CDK4/6 inhibition, using PD either as a single-agent or in combination, hinders key proliferative pathways necessary for disease progression and that RB status is a critical prognostic determinant for therapeutic efficacy. Combined, these pre-clinical findings identify selective targeting of CDK4/6 as a bona fide therapeutic target in both early stage and advanced PCa and underscore the benefit of personalized medicine to enhance treatment response.

Costs of early adjuvant radiation therapy after radical prostatectomy: a decision analysis.

BACKGROUND: This analysis was carried out to evaluate the cost-effectiveness of adjuvant radiation therapy (ART) versus observation, using a decision analysis model based primarily upon the published results of the Southwest Oncology Group prospective trial (SWOG 8794). PATIENTS AND METHODS: A decision analysis model was designed to compare ART versus observation over a 10-year time horizon. Probabilities of treatment success, utilization of salvage treatments, and rates of adverse events were taken from published results of SWOG 8794. Cost inputs were based on 2010 Medicare reimbursement rates. Primary outcome measure was incremental cost per prostate-specific antigen (PSA) success (i.e. serum PSA level <0.4 ng/ml). RESULTS: ART results in a higher PSA success rate than observation with probability of 0.43 versus 0.22. The mean incremental cost per patient for ART versus observation was $6023. The mean incremental cost-effectiveness ratio was $26,983 over the 10-year period. CONCLUSIONS: ART appears cost effective compared with observation based upon this decision analysis model. Future research should consider more costly radiation therapy (RT) approaches, such as intensity-modulated RT, and should evaluate the cost-effectiveness of ART versus early salvage RT.

Laparoscopic radical prostatectomy: a review of techniques and results worldwide.

Laparoscopic radical prostatectomy (LRP) is currently performed in multiple centers world-wide, with several different surgical approaches and techniques utilized. A comprehensive review of the published literature worldwide on laparoscopic radical prostatectomy was performed to outline the evolution of this technique, and to review the published surgical, oncological and functional results. A systematic review of peer reviewed articles concerning laparoscopic radical prostatectomy was obtained using Medline query. LRP is being performed in multiple centers worldwide, using a variety of surgical approaches and technologies. Analysis of perioperative parameters, including surgical blood loss, operative time, complications and convalescence, demonstrates a low morbidity and shows a clear trend in improvement with increased experience. The functional results, as recorded by postoperative urinary and sexual functions, appear encouraging. The reported positive surgical margin rates decrease with more recent series. Oncological results and cancer control rates as measured by PSA recurrence and disease-free intervals are difficult to ascertain in the immature series published to date. LRP has witnessed tremendous popularity and widespread implementation in specialized centers worldwide. LRP represents a technically demanding laparoscopic procedure with a difficult learning curve, but can be performed systematically with standard techniques. The advantages include shorter convalescence and markedly lower operative blood loss, with quicker removal of the urinary catheter. Long-term functional and oncologic results are not yet available.

Hand-assisted laparoscopic nephroureterectomy: description of technique.

PURPOSE: Traditional treatment of transitional cell carcinoma of the upper urinary tract (UTTCC) has been nephroureterectomy by open surgical techniques, often requiring two incisions. Our experience and technique for hand-assisted laparoscopic nephroureterectomy (HALNU) is reviewed. MATERIALS AND METHODS: Thirty-two patients had HALNU performed by one of three surgeons from August 1998 to October 2000. The distal ureter and bladder cuff was resected laparoscopically and sutured closed in 15 patients and resected by combined cystoscopic and laparoscopic approach in 17 patients. RESULTS: The indication for surgery was UTTCC for 29 patients and benign conditions in 2 patients. The mean operating time (including initial cystoscopy) was 372 minutes (281-530), and the mean blood loss was 541 cc (50-3500). The mean hospital stay was 5.5 days (3-12). There were no positive surgical margins, local recurrences, trocar site seeding, or wound seeding. CONCLUSIONS: HALNU is an effective minimally invasive approach for the treatment of UTTCC.