Daniel Hettel

Intermediate-Term Outcomes for Men with Very Low/Low and Intermediate/High Risk Prostate Cancer Managed by Active Surveillance

Purpose: We compare intermediate term clinical outcomes among men with favorable risk and intermediate/high risk prostate cancer managed by active surveillance. Materials and Methods: A total of 635 men with localized prostate cancer have been on active surveillance since 2002 at a high volume academic hospital in the United States. Median followup is 50.5 months (IQR 31.1–80.3). Time to event analysis was performed for our clinical end points. Results: Of the cohort 117 men (18.4%) had intermediate/high risk disease. Overall 5 and 10‐year all cause survival was 98% and 94%, respectively. Cumulative metastasis‐free survival at 5 and 10 years was 99% and 98%, respectively. To date no cancer specific deaths had been observed. Overall freedom from intervention was 61% and 49% at 5 and 10 years, respectively. Overall cumulative freedom from failure of active surveillance, defined as metastasis or biochemical failure after local therapy with curative intent, was 97% and 91% at 5 and 10 years, respectively. Of the men 21 (9.9%) experienced biochemical failure after deferred treatment and the 5‐year progression‐free probability was 92%. Compared to men with favorable risk disease those with intermediate/high risk cancer experienced no difference in metastases, surveillance failure or curative intervention. However, patients at higher risk were at significantly increased risk for all cause mortality, likely reflecting patient selection factors. These conclusions may be limited by the small number of events and the duration of our study. Conclusions: Patients with localized prostate cancer who are on active surveillance demonstrated a low rate of active surveillance failure, prostate cancer specific mortality and metastases regardless of baseline risk.

HSD3B1 status as a biomarker of androgen deprivation resistance and implications for prostate cancer

Patients with advanced prostate cancer who receive androgen deprivation therapy (ADT) almost invariably develop castration-resistant disease. The mechanism of resistance is largely based on synthesis of intratumoral androgens from adrenal precursors, requiring enzymatic action of 3β-hydroxysteroid dehydrogenase/Δ5→4 isomerase 1 (3β-HSD1), encoded by HSD3B1. A nucleotide polymorphism (1245A>C) in HSD3B1 results in a protein variant with increased steady-state levels and subsequently increased androgen synthesis from extragonadal precursors. Multiple clinical studies have shown that patients with the variant allele have significantly worse outcomes after ADT than those without, indicating that HSD3B1 variant status is a predictive biomarker of shortened ADT response. In addition, inheritance of the HSD3B1 variant is associated with extended responses to 17α-hydroxylase/17,20-lyase (CYP17A1) inhibition with a nonsteroidal agent, adding to evidence of increased tumour dependence on extragonadal androgens in patients who inherited the HSD3B1 variant. However, steroidal drugs with a 3β-hydroxyl, Δ5-structure, such as abiraterone, are also metabolized by 3β-HSD1, and 5α-abiraterone, a downstream metabolite, has been shown to activate the androgen receptor, potentially driving cancer progression. These data indicate a potential requirement to modify the treatment framework of patients harbouring variant HSD3B1.

AR Signaling in Prostate Cancer Regulates a Feed-Forward Mechanism of Androgen Synthesis by Way of HSD3B1 Upregulation

3βHSD1 enzymatic activity is essential for synthesis of potent androgens from adrenal precursor steroids in prostate cancer. A germline variant in HSD3B1, the gene that encodes 3βHSD1, encodes for a stable enzyme, regulates adrenal androgen dependence, and is a predictive biomarker of poor clinical outcomes after gonadal testosterone deprivation therapy. However, little is known about HSD3B1 transcriptional regulation. Generally, it is thought that intratumoral androgen synthesis is upregulated after gonadal testosterone deprivation, enabling development of castration-resistant prostate cancer. Given its critical role in extragonadal androgen synthesis, we sought to directly interrogate the transcriptional regulation of HSD3B1 in multiple metastatic prostate cancer cell models. Surprisingly, we found that VCaP, CWR22Rv1, LNCaP, and LAPC4 models demonstrate induction of HSD3B1 upon androgen stimulation for approximately 72 hours, followed by attenuation around 120 hours. 3βHSD1 protein levels mirrored transcriptional changes in models harboring variant (LNCaP) and wild-type (LAPC4) HSD3B1, and in these models androgen induction of HSD3B1 is abrogated via enzalutamide treatment. Androgen treatment increased flux from [3H]-dehydroepiandrosterone to androstenedione and other downstream metabolites. HSD3B1 expression was reduced 72 hours after castration in the VCaP xenograft mouse model, suggesting androgen receptor (AR) regulation of HSD3B1 also occurs in vivo. Overall, these data suggest that HSD3B1 is unexpectedly positively regulated by androgens and ARs. These data may have implications for the development of treatment strategies tailored to HSD3B1 genotype status.

Prognostic Significance of a Negative Confirmatory Biopsy on Reclassification Among Men on Active Surveillance

OBJECTIVE To examine the association between absence of disease on confirmatory biopsy and risk of pathologic reclassification in men on active surveillance (AS). MATERIALS AND METHODS Men with grade groups 1 and 2 disease on AS between 2002 and 2015 were identified who received a confirmatory biopsy within 1 year of diagnosis and ≥3 biopsies overall. The primary outcomes were pathologic reclassification by grade (any increase in primary Gleason pattern or Gleason score) or volume (>33% of sampled cores involved or increase in the number of cores with >50% involvement). The effect of a negative confirmatory biopsy survival was evaluated using Kaplan-Meier analysis and a Cox proportional hazards modeling. RESULTS Out of 635 men, 224 met inclusion criteria (median follow-up: 55.8 months). A total of 111 men (49.6%) had a negative confirmatory biopsy. Decreased grade reclassification (69.7% vs 83.9%; P = .01) and volume reclassification (66.3% vs 87.4%; P = .004) was seen at 5 years for men with a negative confirmatory biopsy compared with those with a positive biopsy. On adjusted analysis, a negative confirmatory biopsy was associated with a decreased risk of grade reclassification (hazard ratio, 0.51; 95% confidence interval, 0.28-0.94; P = .03) and volume reclassification (hazard ratio, 0.32; 95% confidence interval, 0.17-0.61; P = .0006) at a median of 4.7 years. CONCLUSION Absence of cancer on the confirmatory biopsy is associated with a significant decrease in rate of grade and volume reclassification among men on AS. This information may be used to better counsel men on AS.

Impact of 5α-Reductase Inhibitors on Disease Reclassification among Men on Active Surveillance for Localized Prostate Cancer with Favorable Features

Purpose: We determined the effect of 5&agr;‐reductase inhibitors on disease reclassification in men with prostate cancer optimally selected for active surveillance. Materials and Methods: In this retrospective review we identified 635 patients on active surveillance between 2002 and 2015. Patients with favorable cancer features on repeat biopsy, defined as absent Gleason upgrading, were included in the cohort. Patients were stratified by those who did or did not receive finasteride or dutasteride within 1 year of diagnosis. The primary end point was grade reclassification, defined as any increase in Gleason score or predominant Gleason pattern on subsequent biopsy. This was assessed by multivariable Cox proportional hazards regression analysis. Results: At diagnosis 371 patients met study inclusion criteria, of whom 70 (19%) were started on 5&agr;‐reductase inhibitors within 12 months. Median time on active surveillance was 53 vs 35 months in men on vs not on 5&agr;‐reductase inhibitors (p <0.01). Men on 5&agr;‐reductase inhibitors received them for a median of 23 months (IQR 6–37). On actuarial analysis there was no significant difference in grade reclassification for 5&agr;‐reductase inhibitor use in patients overall or in the very low/low risk subset. The overall percent of patients who experienced grade reclassification was similar at 13% vs 14% (p = 0.75). After adjusting for baseline clinicopathological features 5&agr;‐reductase inhibitors were not significantly associated with grade reclassification (HR 0.80, 95% CI 0.31–1.80, p = 0.62). Furthermore, no difference in adverse features on radical prostatectomy specimens was observed in treated patients (p = 0.36). Conclusions: Among our cohort of men on active surveillance 5&agr;‐reductase inhibitor use was not associated with a significant difference in grade reclassification with time.

PD55-12 OLDER AGE AT DIAGNOSIS AND DISEASE VOLUME PREDICT UPGRADING ON CONFIRMATORY BIOPSY IN PROSTATE CANCER PATIENTS BEING CONSIDERED FOR ACTIVE SURVEILLANCE

RESULTS: 3669 patients underwent RP between 1/1/04 and 12/31/15. Of these, 1454, 251 and 1361 patients fulfilled criteria for very low/low, favorable intermediate, and unfavorable intermediate-risk groups, respectively. Median follow-up was 37 months. Patients in the favorable intermediate group had significantly higher rates of Gleason score upgrading (16% vs 6%; p<0.001) and non organ-confined disease (16% vs 11%; p1⁄40.035) than those in low risk group. Time to biochemical recurrence for the favorable intermediate group did not differ significantly from the low risk group (p1⁄40.057), but was significantly longer than unfavorable intermediates (p1⁄40.003) (Figure 1). CONCLUSIONS: Compared to very low/low risk prostate cancer patients, men with favorable intermediate-risk disease had significantly higher rates of more aggressive, non-organ confined disease at RP, and trended toward worse biochemical progression free survival. However, when compared to unfavorable intermediate risk patients, it appears the magnitude of these differences would not preclude AS as a reasonable option for appropriately selected patients with favorable intermediate risk prostate cancer.

Do Routine Preoperative and Intraoperative Urine Cultures Benefit Pediatric Vesicoureteral Reflux Surgery

Objective. To determine if routine preoperative and intraoperative urine cultures (UCx) are necessary in pediatric vesicoureteral (VUR) reflux surgery by identifying their association with each other, preoperative symptoms, and surgical outcomes. Materials and Methods. A retrospective review of patients undergoing ureteral reimplant(s) for primary VUR at a tertiary academic medical center between years 2000 and 2014 was done. Preoperative UCx were defined as those within 30 days before surgery. A positive culture was defined as >50,000 colony forming units of a single organism. Results. A total of 185 patients were identified and 87/185 (47.0%) met inclusion criteria. Of those, 39/87 (45%) completed a preoperative UCx. Only 3/39 (8%) preoperative cultures returned positive, and all of those patients were preoperatively symptomatic. No preoperatively asymptomatic patients had positive preoperative cultures. Intraoperative cultures were obtained in 21/87 (24.1%) patients; all were negative. No associations were found between preoperative culture results and intraoperative cultures or between culture result and postoperative complications. Conclusions. In asymptomatic patients, no associations were found between the completion of a preoperative or intraoperative UCx and surgical outcomes, suggesting that not all patients may require preoperative screening. Children presenting with symptoms of urinary tract infection (UTI) prior to ureteral reimplantation may benefit from preoperative UCx.

MP15-15 A RETROSPECTIVE REVIEW OF A LARGE ACTIVE SURVEILLANCE COHORT IN PATIENTS WITH PROSTATE CANCER AT THE CLEVELAND CLINIC

Gleason score undergrading. We compared biochemical recurrence rates (BCR) after radical prostatectomy between patients with active surveillance (AS) suitable prostate cancer versus wider defined low risk prostate cancer and the effect of Gleason score upgrading after surgery. METHODS: Two prostatectomy cohorts were combined. Lowrisk PC was defined as T1-2, Gleason 6 prostate cancer and AS-suitable prostate cancer was defined using the ‘PRIAS-criteria’ as T1-2, PSA 1⁄4<10 ng/ml, PSA density <0.2 ng/ml/ml, 1-2 positive biopsies, Gleason 3+31⁄46. Kaplan-Meier curves of patients with and without Gleason score upgrading were compared using the Log-Rank test. We hypothesized that perfect pre-operative biopsy Gleason grading would lead to 0% upgrading after surgery. RESULTS: We included 755 patients of whom 181 (24%) suitable for AS, 324 (44%) had Gleason upgrading after surgery (to 6.5 in non-AS suitable versus 6.3; p1⁄40.005), and 132 (18%) showed BCR a median of 1.0 year after prostatectomy. For the total group, the 5-year BCR rate was 27%. Regarding the entire low risk group of T1-2 Gleason 6 prostate cancer, Gleason upgrading at surgery was significantly associated with unfavorable BCR rates (Figure 1a; p<0.01). Within the selected group of more favorable risk disease suitable for AS, Gleason upgrading at surgery was not associated with BCR rates (Figure 1b; p1⁄40.936). In patients who did not have Gleason upgrading, patients who were not suitable for AS showed similar BCR rates to patients who did fulfill all AS criteria (Figure 1c; p1⁄40.155). A limitation is the retrospective design; prospective validation is needed. CONCLUSIONS: In the selected group of favorable risk patients considered suitable for AS, no unfavorable effect on BCR rates was found of Gleason undergrading. This may question the additional value of reducing biopsy undergrading with new imaging techniques. In patients not fulfilling the strict AS criteria, exclusion of Gleason upgrading resulted however in BCR rates similarly favorable to patients who were suitable for AS. This may suggest that MRI could be used to expand selection criteria for AS if Gleason upgrading could be excluded.