Chad Reichard

HSD3B1 and resistance to androgen-deprivation therapy in prostate cancer: a retrospective, multicohort study.

BACKGROUND HSD3B1 (1245A>C) has been mechanistically linked to castration-resistant prostate cancer because it encodes an altered enzyme that augments dihydrotestosterone synthesis from non-gonadal precursors. We postulated that men inheriting the HSD3B1 (1245C) allele would exhibit resistance to androgen-deprivation therapy (ADT). METHODS In this multicohort study, we determined HSD3B1 genotype retrospectively in men treated with ADT for post-prostatectomy biochemical failure and correlated genotype with long-term clinical outcomes. We used data and samples from prospectively maintained prostate cancer registries at the Cleveland Clinic (Cleveland, OH, USA; primary study cohort) and the Mayo Clinic (Rochester, MN, USA; post-prostatectomy and metastatic validation cohorts). In the post-prostatectomy cohorts, patients of any age were eligible if they underwent prostatectomy between Jan 1, 1996, and Dec 31, 2009 (at the Cleveland Clinic; primary cohort), or between Jan 1, 1987, and Dec 31, 2011 (at the Mayo Clinic; post-prostatectomy cohort) and were treated with ADT for biochemical failure or for non-metastatic clinical failure. In the metastatic validation cohort, patients of any age were eligible if they were enrolled at Mayo Clinic between Sept 1, 2009, and July 31, 2013, with metastatic castration-resistant prostate cancer. The primary endpoint was progression-free survival according to HSD3B1 genotype. We did prespecified multivariable analyses to assess the independent predictive value of HSD3B1 genotype on outcomes. FINDINGS We included and genotyped 443 patients: 118 in the primary cohort (who underwent prostatectomy), 137 in the post-prostatectomy validation cohort, and 188 in the metastatic validation cohort. In the primary study cohort, median progression-free survival diminished as a function of the number of variant alleles inherited: 6·6 years (95% CI 3·8-not reached) in men with homozygous wild-type genotype, 4·1 years (3·0-5·5) in men with heterozygous variant genotype, and 2·5 years (0·7 to not reached) in men with homozygous variant genotype (p=0·011). Relative to the homozygous wild-type genotype, inheritance of two copies of the variant allele was predictive of decreased progression-free survival (hazard ratio [HR] 2·4 [95% CI 1·1-5·3], p=0·029), as was inheritance of one copy of the variant allele (HR 1·7 [1·0-2·9], p=0·041). Findings were similar for distant metastasis-free survival and overall survival. The effect of the HSD3B1 genotype was independently confirmed in the validation cohorts. INTERPRETATION Inheritance of the HSD3B1 (1245C) allele that enhances dihydrotestosterone synthesis is associated with prostate cancer resistance to ADT. HSD3B1 could therefore potentially be a powerful genetic biomarker capable of distinguishing men who are a priori likely to fare favourably with ADT from those who harbour disease liable to behave more aggressively, and who therefore might warrant early escalated therapy. FUNDING Prostate Cancer Foundation, National Institutes of Health, US Department of Defense, Howard Hughes Medical Institute, American Cancer Society, Conquer Cancer Foundation of the American Society of Clinical Oncology, Cleveland Clinic Research Programs Committee and Department of Radiation Oncology, Gail and Joseph Gassner Development Funds.

Incidence, Risk Factors, and Complications of Postoperative Delirium in Elderly Patients Undergoing Radical Cystectomy

OBJECTIVE To identify the risk factors for, and complications associated with, the development of delirium after radical cystectomy. MATERIALS AND METHODS From July 2008 to December 2009, 59 patients, aged ≥65 years and undergoing radical cystectomy, were prospectively enrolled. The baseline cognitive status was assessed using the Mini-Mental Status Examination. Postoperative delirium was assessed using the Confusion Assessment Method. RESULTS A total of 49 patients completed the surgery and all assessments. The incidence of postoperative delirium was 29%, with duration of 1-5 days. On univariate analysis, older age and preoperative Mini-Mental Status Examination score were associated with postoperative delirium. On multivariate analysis, only age was associated with postoperative delirium (odds ratio 1.52, 95% confidence interval 1.04-2.22, P=.03). The 2 groups did not differ in pathologic stage, length of surgery, intraoperative and postoperative narcotic usage, body mass index, age-adjusted Charlson comorbidity index, activities of daily living scores, smoking history, preoperative hematocrit, estimated blood loss, urinary tract infection, interval to a regular diet, or length of hospital stay. The patients who developed postoperative delirium were more likely to undergo readmission (odds ratio 10.7, 95% confidence interval 2.2-51.8, P=.01) and reoperation (odds ratio 9.2, 95% confidence interval 1.5-55.3, P=.03) but did not differ in the 90-day and 1-year mortality rates or incidence of postoperative complications. CONCLUSION In patients aged≥65 years, a lower preoperative Mini-Mental Status Examination score and older age were significantly associated with the development of postcystectomy delirium, as measured using the Confusion Assessment Method. The patients who developed delirium were more likely to undergo readmission and reoperation. Larger studies with multiple surgeons are needed to validate these findings.

HSD3B1 and Response to a Nonsteroidal CYP17A1 Inhibitor in Castration-Resistant Prostate Cancer

Importance The HSD3B1 (1245C) germline variant encodes for a gain-of-function missense in 3&bgr;-hydroxysteroid dehydrogenase isoenzyme 1 (3&bgr;HSD1) that results in increased dihydrotestosterone synthesis from extragonadal precursors and is predictive of more rapid progression to castration-resistant prostate cancer (CRPC). Objective To determine whether the HSD3B1 (1245C) genotype is predictive of clinical response to extragonadal androgen ablation with nonsteroidal 17&agr;-hydroxylase/17,20-lyase (CYP17A1) inhibition in men with metastatic CRPC. Design, Setting, and Participants An observational study of men with metastatic CRPC treated with ketoconazole between June 1998 and December 2012 was conducted at the University of California, San Francisco. Exposures Extragonadal androgen ablation with the nonsteroidal CYP17A1 inhibitor ketoconazole among men with metastatic CRPC. Main Outcomes and Measures The primary end points of analysis were duration of ketoconazole therapy and time to disease progression stratified by HSD3B1 genotype. Disease progression was defined as either biochemical or radiographic progression, using the Prostate Cancer Working Group 3 and Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 definitions, respectively. Kaplan-Meier analysis was used to estimate time on therapy and time to disease progression. A log-rank test for trend was used to compare outcomes by HSD3B1 genotype. Results A total of 90 men (median [interquartile range] age, 61.5 [55.3-67.0] years) with metastatic CRPC were included in the analysis, with sufficient data to determine duration of ketoconazole therapy and time to disease progression in 88 and 81 patients, respectively. The median duration of therapy increased with the number of inherited HSD3B1 (1245C) variant alleles: 5.0 months (95% CI, 3.4-10.4) for 0 variant alleles; 7.5 months (95% CI, 4.9-19.2) for 1; and 12.3 months (95% CI, 1.8-not reached) for 2 (overall comparison for trend, P = .01). Median progression-free survival also increased with number of HSD3B1 (1245C) variant alleles inherited: 5.4 months (95% CI, 3.7-7.5) for 0 variant alleles; 9.7 months (95% CI, 5.6-32.9) for 1; and 15.2 months (95% CI, 7.8-not reached) for 2 (overall comparison for trend, P = .03). Conclusions and Relevance Inheritance of the HSD3B1 (1245C) variant allele, which is a predictive biomarker of resistance to castration, is also a predictive biomarker of sensitivity to extragonadal androgen ablation with a nonsteroidal CYP17A1 inhibitor. These findings signal a possible pathway of treatment stratification for patients with prostate cancer.

Applying precision medicine to the active surveillance of prostate cancer

The recent introduction of a variety of molecular tests will potentially reshape the care of patients with prostate cancer. These tests may make more accurate management decisions possible for those patients who have been “overdiagnosed” with biologically indolent disease, which represents an exceptionally small mortality risk. There is a wide range of possible applications of these tests to different clinical scenarios in patient populations managed with active surveillance. Cancer 2015;121:3435–43.

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.

Association of HSD3B1 Genotype With Response to Androgen-Deprivation Therapy for Biochemical Recurrence After Radiotherapy for Localized Prostate Cancer.

Importance The variant HSD3B1 (1245C) allele enhances dihydrotestosterone synthesis and predicts resistance to androgen-deprivation therapy (ADT) for biochemically recurrent prostate cancer after prostatectomy and for metastatic disease. Whether this is true after radiotherapy is unknown. Objective To determine whether the HSD3B1 (1245C) allele predicts worse clinical outcomes from ADT for biochemical recurrence after radiotherapy. Design, Setting, and Participants The Prostate Clinical Research Information System at Dana-Farber Cancer Institute was used to identify the study cohort, which included men treated with ADT for biochemical recurrence after primary radiotherapy between 1996 and 2013. We retrospectively determined HSD3B1 genotype. Main Outcomes and Measures Time to progression, time to metastasis, and overall survival according to genotype. Demographic and treatment characteristics were evaluated for confounders. Multivariable analyses were performed to adjust for known prognostic factors. Results A total of 218 eligible men were identified, of whom 213 (98%) were successfully genotyped. Of these, 97 of 213 (46%), 96 of 213 (45%) and 20 of 213 (9%) carried 0, 1, and 2 variant alleles. Overall variant allele frequency was 136 of 426 alleles (32%). Median patient age (interquartile range) was 69 (63-74), 72 (65-78), and 69 (65-77) years for 0, 1, and 2 variant alleles (P = .03). Demographic and treatment factors were otherwise similar. During a median follow-up of 7.9 years, median time to progression was 2.3 years (95% CI, 1.6-3.1 years) with 0 variant alleles, 2.3 years (95% CI, 1.5-3.3 years) with 1 variant allele, and 1.4 years (95% CI, 0.7-3.3 years) with 2 variant alleles (P = .68). Median time to metastasis diminished with the number of variant alleles inherited: 7.4 (95% CI, 6.7-9.7), 5.8 (95% CI, 4.9-6.5), and 4.4 (95% CI, 3.0-5.7) years, with inheritance of 0, 1, and 2 variant alleles, respectively (P = .03). Median OS was 7.7 (95% CI, 6.7-10.3), 6.9 (95% CI, 5.8-8.4), and 7.2 (95% CI, 3.8-7.9) years with inheritance of 0, 1, and 2 variant alleles, respectively (P = .31). On multivariable analysis with 0 variant alleles as the reference, the adjusted hazard ratio for metastasis was 1.19 (95% CI, 0.74-1.92) (P = .48) for 1 variant allele and 2.01 (95% CI, 1.02-3.97) (P = .045) for 2 variant alleles. Multivariable analysis did not demonstrate significant differences in TTP or OS. Conclusions and Relevance In this study, the HSD3B1 (1245C) allele was associated with more rapid development of metastases in men treated with ADT for biochemical recurrence after primary radiation therapy for prostate cancer. Notably, 105 of 213 men (49%) had received prior ADT, and 119 of 213 (56%) received an androgen receptor antagonist during salvage treatment, both of which may attenuate the effect of the variant allele.

Anterior Urethral Valve Associated With Posterior Urethral Valves: Report of 2 Cases and Review of the Literature

Anterior urethral valve (AUV) associated with posterior urethral valves (PUVs) is an extremely rare congenital urologic anomaly resulting in lower urinary tract obstruction. We present our experience with 2 children with concomitant AUV and PUV as well as a literature review. The clinical presentation of concomitant AUV and PUV is variable. Successful endoscopic management can result in improvement in renal function, reversal of obstructive changes, and improvement or resolution of voiding dysfunction.

Molecular markers in urologic oncology: prostate cancer.

Purpose of review The increased clinical availability of a wide variety of molecular tests will potentially reshape the care of both men at risk for prostate cancer and men already diagnosed. It is imperative that clinicians be familiar with indications and clinical relevance of these tests. Recent findings The continued clinical validation in new and expanded clinical cohorts and reports of clinical experience with various molecular markers is a rapidly evolving body of literature. Results of large patient series demonstrate that these markers increase the precision of available information used in clinical management decision-making and joint physician–patient discussions regarding treatment options. Summary These tests may make more accurate management decisions possible for those whom have been ‘over-diagnosed’ with biologically indolent disease which represents an exceptionally small mortality risk. They also may aid in more accurate diagnosis of significant cancer, as well as more precise application of adjuvant therapy.

A 45-year-old with neuroendocrine carcinoma of the prostate

45-year-old white man presented to his primary care provider in January 2012 with a 2-month Ahistory of increasing urinary frequency and poor stream. He denied any gross hematuria, bone pain, or significant weight loss. Digital rectal examination revealed an asymmetrically enlarged, firm, and nontender prostate; the remainder of the physical examination was unremarkable. Serum prostate-specific antigen (PSA) measured 70 ng/mL. Flomax 0.4 mg daily was started and the patient was referred for initial urologic evaluation. The patient had no significant medical history and was otherwise healthy. Surgical history was significant for an appendectomy. The patient denied any occupational exposures or family history of prostate cancer or other genitourinary malignancy. He was a nonsmoker and teatotaler. His PSA was rechecked and found to be 75 ng/mL. A 10-core transrectal ultrasound-guided prostate biopsy was performed. Pathology revealed high volume, Gleason score 7, 8, and 9 adenocarcinoma in all 10 cores with extensive perineural invasion, and seminal vesicle involvement. A computed tomography (CT) scan of the abdomen and pelvis revealed no identifiable lesions in the visceral organs, and no hydronephrosis. There was scattered retroperitoneal and bilateral pelvic adenopathy consistent with metastatic disease, with nodes ranging in size from a 1.7 1.1 cm preaortic node to a 2.3 1.3 cm right external iliac node. The prostate was heterogeneous without visible mass (Fig. 1). CT scan of the chest revealed an indeterminate 3 mm right upper lobe nodule. Bone scan was negative for scintigraphic evidence of osseous metastases. The patient was referred to a medical oncologist for therapy of clinical stage T3bN2M1a prostate cancer. Combined androgen blockade with bicalutamide and leuprolide was initiated. The patient’s PSA responded well, falling to 8.95 ng/mL and 0.42 ng/mL after 1 and 5 months of treatment, respectively.

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.