Optimizing the management of castration-resistant prostate cancer patients: A practical guide for clinicians.

BACKGROUND: Advanced prostate cancer (PC) patients, especially those with metastatic prostate cancer (mPC), often require complex management pathways. Despite the publication of clinical practice guidelines by leading urological and oncological organizations that provide a substantial and comprehensive framework, there are numerous clinical scenarios that are not always addressed, especially as new treatments become available, new imaging modalities are developed, and advances in genetic testing continue. METHODS: A 14-member expert review panel comprised of urologists and medical oncologists were chosen to provide guidance on addressing specific topics and issues regarding metastatic castration-resistant prostate cancer (mCRPC) patients. Panel members were chosen based upon their experience and expertise in the management of PC patients. Four academic members (two urologists and two medical oncologists) of the panel served as group leaders; the remaining eight panel members were from Large Urology Group Practice Association (LUGPA) practices with proven experience in leading their advanced PC clinics. The panel members were assigned to four separate working groups, each assigned a specific mCRPC topic to review and discuss with the entire panel. RESULTS: This article describes the practical recommendations of an expert panel on the management of mCRPC patients. The target reading audience for this publication is all providers (urologists, medical oncologists, radiation oncologists, or advanced practice providers) who evaluate and manage advanced PC patients, regardless of their practice setting. CONCLUSION: The panel has provided recommendations for managing mCRPC with regard to specific issues: (a) biomarker monitoring and the role of genetic and molecular testing; (b) rationale, current strategies, and optimal sequencing of the various approved therapies, including hormonal therapy, cytotoxic chemotherapy, radiopharmaceuticals and immunotherapy; (c) adverse event management and monitoring; and (d) imaging advanced PC patients. These recommendations seek to complement national guidelines, not replace them, and a discussion of where the panel agreed or disagreed with national guidelines is included.

Utility of prospective pathologic evaluation to inform clinical genetic testing for hereditary leiomyomatosis and renal cell carcinoma.

BACKGROUND: Patients with hereditary leiomyomatosis and renal cell carcinoma (HLRCC) resulting from fumarate hydratase (FH) mutations may present with skin, uterine, and renal tumors, with each having unique pathologic features. This study investigated the association between prospectively identified suspicious pathology (SP) and FH mutations when patients were referred for genetic testing. METHODS: This was an institutional review board-approved cohort study of patients receiving FH testing from 2008 to 2013. SP was defined as a report of HLRCC histologic features identified during a prospective pathologic assessment. The association between SP and FH mutations was analyzed. RESULTS: FH testing was performed in 29 patients with a median age of 37 years; 15 (52%) were female, and 18 (62%) were white. Pathologists reported SP from kidney tumors (11 of 18), leiomyomas (9 of 15: uterus [n = 8] and bladder [n = 1]), and metastatic tumors (3 of 6) in 23 of 39 associated specimens (59%) from 21 of the 29 patients (72%). Patients with SP were younger (35 vs 51 years; P = .010), and those with kidney tumors more often had stage pT3 or higher renal cell carcinoma than those without SP (100% vs 33%; P = .006). FH mutations were present in 8 patients with SP (38%) and in 1 patient without SP (13%; P = .37); 7 of these patients had kidney cancer (n for SP = 7), all with N1 disease. Analyzing SP by tissue type identified only SP from renal tumors as being significantly associated with positive testing for an FH mutation (P = .013). CONCLUSIONS: SP from kidney tumors was statistically associated with FH mutations. An expert pathologic assessment of renal tumors will facilitate the clinical identification of HLRCC cases, and this will result in genetic testing and targeted cancer screening for patients and at-risk family members. Cancer 2017;123:2452-58. © 2017 American Cancer Society.

A Contemporary Review of HPV and Penile Cancer.

Human papillomavirus (HPV) is a widespread sexually transmitted infection. In both men and women, HPV infection can result in a spectrum of genitourinary manifestations ranging from genital warts to cancer. Cervical cancer is nearly always associated with high-risk HPV infection. For men, penile cancer can develop following or independently of HPV infection. Basaloid and warty subtypes of penile squamous cell carcinoma are most frequently associated with HPV infection. Further research into the molecular alterations caused by HPV infection may provide prognostic markers and future treatment targets. Until an effective treatment for HPV infection is developed, prevention will remain the focus of disease control. For women, vaccination is increasingly utilized to prevent HPV infection and subsequent cervical cancer development. New recommendations for routine male vaccination may further reduce cancers for both men and women.

Gleason 6 Prostate Cancer: Translating Biology into Population Health.

PURPOSE: Gleason 6 (3+3) is the most commonly diagnosed prostate cancer among men with prostate specific antigen screening, the most histologically well differentiated and is associated with the most favorable prognosis. Despite its prevalence, considerable debate exists regarding the genetic features, clinical significance, natural history, metastatic potential and optimal management. MATERIALS AND METHODS: Members of the Young Urologic Oncologists in the Society of Urologic Oncology cooperated in a comprehensive search of the peer reviewed English medical literature on Gleason 6 prostate cancer, specifically focusing on the history of the Gleason scoring system, histological features, clinical characteristics, practice patterns and outcomes. RESULTS: The Gleason scoring system was devised in the early 1960s, widely adopted by 1987 and revised in 2005 with a more restrictive definition of Gleason 6 disease. There is near consensus that Gleason 6 meets pathological definitions of cancer, but controversy about whether it meets commonly accepted molecular and genetic criteria of cancer. Multiple clinical series suggest that the metastatic potential of contemporary Gleason 6 disease is negligible but not zero. Population based studies in the U.S. suggest that more than 90% of men newly diagnosed with prostate cancer undergo treatment and are exposed to the risk of morbidity for a cancer unlikely to cause symptoms or decrease life expectancy. Efforts have been proposed to minimize the number of men diagnosed with or treated for Gleason 6 prostate cancer. These include modifications to prostate specific antigen based screening strategies such as targeting high risk populations, decreasing the frequency of screening, recommending screening cessation, incorporating remaining life expectancy estimates, using shared decision making and novel biomarkers, and eliminating prostate specific antigen screening entirely. Large nonrandomized and randomized studies have shown that active surveillance is an effective management strategy for men with Gleason 6 disease. Active surveillance dramatically reduces the number of men undergoing treatment without apparent compromise of cancer related outcomes. CONCLUSIONS: The definition and clinical relevance of Gleason 6 prostate cancer have changed substantially since its introduction nearly 50 years ago. A high proportion of screen detected cancers are Gleason 6 and the metastatic potential is negligible. Dramatically reducing the diagnosis and treatment of Gleason 6 disease is likely to have a favorable impact on the net benefit of prostate cancer screening.

A multidisciplinary approach to address unmet needs in the management of patients with non-metastatic castration-resistant prostate cancer.

BACKGROUND: With the availability of second-generation androgen receptor inhibitors (SGARIs), the treatment landscape has changed dramatically for patients with nonmetastatic castration-resistant prostate cancer (nmCRPC). In clinical trials, the SGARIs (apalutamide, enzalutamide, darolutamide) increased metastasis-free survival (MFS), overall survival (OS), and patient quality of life compared to placebo. These drugs were subsequently integrated into nmCRPC clinical practice guidelines. With advances in radiographic imaging, disease assessment, and patient monitoring, nmCRPC strategies are evolving to address limitations related to tracking disease progression using prostate-specific antigen (PSA) kinetics. METHODS: A panel of 10 multidisciplinary experts in prostate cancer conducted reviews and discussions of unmet needs in the management and monitoring of patients with nmCRPC in order to develop consensus recommendations. RESULTS: Across the SGARI literature, patient MFS and OS are generally comparable for all treatments, but important distinctions exist regarding short- and long-term drug safety profiles and drug-drug interactions. With respect to disease monitoring, a substantial proportion of patients using SGARIs may experience disease progression without rising PSA levels, suggesting a need for enhanced radiographic imaging in addition to PSA monitoring. Recent data also indicate that novel prostate-specific membrane antigen positron emission tomography radiotracers provide enhanced accuracy for disease detection, as compared to conventional imaging. CONCLUSIONS: Clinical decision-making in nmCRPC has become more complex, with new opportunities to apply precision medicine to patient care. Multidisciplinary teams can ensure that patients with nmCRPC receive optimal and individualized disease management.

Phase 2 Trial of Atezolizumab in Bacillus Calmette-Guérin-unresponsive High-risk Non-muscle-invasive Bladder Cancer: SWOG S1605.

BACKGROUND: Although radical cystectomy (RC) is the standard of care for patients with bacillus Calmette-Guérin (BCG)-unresponsive high-risk non-muscle-invasive bladder cancer (NMIBC), many patients are ineligible for surgery or elect bladder preservation. OBJECTIVE: To evaluate the efficacy and safety of atezolizumab in BCG-unresponsive high-risk NMIBC. DESIGN, SETTING, AND PARTICIPANTS: This was a single-arm phase 2 trial in patients with BCG-unresponsive high-risk NMIBC who were ineligible for or declined RC. INTERVENTION: Intravenous atezolizumab every 3 wk for 1 yr. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was the pathological complete response (CR) rate for patients with carcinoma in situ (CIS) determined via mandatory biopsy at 6 mo. Event-free survival (EFS) at 18 mo for patients with non-CIS tumors and treatment-related adverse events (TRAEs) were key secondary endpoints. RESULTS AND LIMITATIONS: Of 172 patients enrolled in the trial, 166 received at least one dose of atezolizumab (safety analysis) and 129 were eligible (efficacy analysis). Of the 74 patients with CIS, 20 (27%) experienced a CR at 6 mo. The median duration of response was 17 mo, and 56% (95% confidence interval [CI] 34-77%) of the responses were durable to at least 12 mo. The 18-mo actuarial EFS rate among 55 patients with Ta/T1 disease was 49% (90% CI 38-60%). Twelve of 129 eligible patients experienced progression to muscle-invasive or metastatic disease. Grade 3-5 TRAEs occurred in 26 patients (16%), including three treatment-related deaths. The study was limited by the small sample size and a high rate of patient ineligibility. CONCLUSIONS: The efficacy of atezolizumab observed among patients with BCG-unresponsive NMIBC is similar to results from similar trials with other agents, but did not meet the prespecified efficacy threshold. Modest efficacy needs to be balanced with a significant rate of TRAEs and the risk of disease progression when considering systemic immunotherapy in early-stage bladder cancer. PATIENT SUMMARY: We tested intravenous immunotherapy (atezolizumab) in patients with high-risk non-muscle-invasive bladder cancer that recurred after BCG (bacillus Calmette-Guérin) treatment. Although we found similar outcomes to previous trials, the benefit of this therapy is modest and needs to be carefully balanced with the significant risk of side effects. This trial is registered on ClinicalTrials.gov as NCT02844816.

ABO blood group is a predictor of survival in patients undergoing surgery for renal cell carcinoma.

UNLABELLED: What's known on the subject? and What does the study add? Some evidence suggests that ABO blood type may be a risk factor for cancer incidence and prognosis. For example, a large study recently discovered an increased incidence of pancreatic cancer in patients with non-O blood type; however, it is not known whether blood group correlates with outcomes in patients with RCC. We found a significant and independent association between ABO blood group and overall survival in patients undergoing surgery for locoregional RCC. Specifically, we identified non-O blood type as a predictor of mortality. OBJECTIVE: • To determine whether ABO blood group is associated with survival after nephrectomy or partial nephrectomy for renal cell carcinoma (RCC). PATIENTS AND METHODS: • We conducted a retrospective cohort study of 900 patients who underwent surgery for locoregional RCC between 1997 and 2008 at a single institution. • Covariates included age, gender, race, American Society of Anesthesiology Physical Status, preoperative anaemia and hypoalbuminemia, tumour characteristics, lymph node status, procedure performed, transfusion status and ABO blood group. • Primary outcomes were overall (OS) and disease-specific survival (DSS). • Univariable survival analyses were performed using the Kaplan-Meier and log-rank methods. Multivariable analysis was performed using a Cox proportional hazards model. RESULTS: • The 3-year OS estimate was 75% (95%CI 70-79%) for O blood group and 68% (95% CI 63-73%) for non-O blood group (P= 0.072). The 3-year DSS was 81% (95% CI 76-85%) for O blood group and 76% (95%CI 71-80%) for non-O blood group (P= 0.053). • In the multivariable analysis for OS, non-O blood type was significantly associated with decreased OS (HR 1.68, 95%CI 1.18-2.39; P= 0.004) but not DSS (HR 1.53, 95%CI 0.97-2.41; P= 0.065). CONCLUSION: • These data suggest that ABO blood group is independently associated with OS in patients undergoing surgery for locoregional RCC. ABO blood group has not been previously recognized as a predictor of survival in RCC.

Implications of ionizing radiation in the pediatric urology patient.

PURPOSE: We reviewed the literature on the effects of ionizing radiation in pediatric patients, and discuss current recommendations and challenges facing radiologists and pediatric urologists. MATERIALS AND METHODS: We performed a MEDLINE(R) search to identify articles evaluating the risk of ionizing radiation in pediatric patients. Particular attention was focused on computerized tomography. Standard radiography, fluoroscopy and nuclear imaging were also evaluated. RESULTS: To date the literature relating radiation exposure to imaging has primarily focused on the role of the pediatrician and radiologist as decision makers. However, these imaging modalities are important to treat and monitor many conditions treated by the pediatric urologist. Conflicting reports have made clinical decision making and patient education challenging. CONCLUSIONS: A lack of consensus on the risk of radiation exposure in pediatric patients increases the need for heightened awareness by the urologist requesting radiographic evaluation. Monitoring future studies is required to better understand the impact of radiation on children and ensure prompt implementation of appropriate guidelines for patient care.

Open renal biopsy: comorbidities and complications in a contemporary series.

STUDY TYPE: Therapy (case series) Level of Evidence 4. OBJECTIVE: To report the indications and outcomes of a contemporary series of patients with contraindications to percutaneous renal biopsies (PRBs) who had an operative RB (ORB), as although ORB is a relatively infrequent procedure, it remains an important and underreported operation. PATIENTS AND METHODS: In a retrospective review of patients who had an ORB we examined comorbidities, indications, and 30-day morbidity and mortality. Preoperative comorbidities were stratified according to the Charlson comorbidity index. RESULTS: In all, 115 patients had ORB between 1991 and 2006 (mean age 48 years, range 18-83); 60% of the patients were American Society of Anesthesiologists class >or=3. The median Charlson comorbidity index score was 3, with a score of 0 in 20.9%, 1-2 in 27.8%, 3-4 in 30.4% and >or=5 in 20.9% of patients. Indications for an ORB included morbid obesity, failed PRB, coagulopathy, and solitary kidney. In all, 47.8% of patients had a serum creatinine level of <3.0 mg/dL, 34.8% of >3.0 mg/dL and 17.4% were dialysis-dependent. There were 43 complications in 36 patients. The mortality rate after surgery was 0.8%. There were eight major complications in seven patients (6.1%) including cardiac arrest, stroke, sepsis, reoperation and re-intubation. There were minor complications 34 times in 31 patients (27%), the most common being wound infection, pneumonia, intraoperative transfusion of >2 units, arrhythmia, postoperative retroperitoneal bleed, and seep vein thrombosis. CONCLUSIONS: This study shows that there are significant comorbidities in patients referred to urologists for an ORB. With a mortality rate of 0.8% and major and minor complication rates of 6.1% and 27%, respectively, the ORB, while infrequent, carries a significant risk in this population that should be included in preoperative decision making and used for patient counselling.

Locally advanced prostate cancer: the role of surgical management.

Among the heterogeneous population of patients with prostate cancer, a high-risk group with locally advanced prostate cancer (LAPC) present a diagnostic and therapeutic dilemma. Although the incidence of LAPC has decreased with screening since the introduction of prostate-specific antigen (PSA) testing, significantly many patients are still diagnosed with LAPC. These patients are by definition at higher risk of metastatic disease and worse outcomes. The role of radical prostatectomy (RP) in this population has been debated, as the combination of radiotherapy and hormonal therapy is becoming used more frequently for LAPC. Unfortunately, the clinical staging and evaluation of LAPC is a challenge that results in possibly understaging or overstaging these patients. This further complicates therapeutic decision-making, and as a result no established standard treatment has been proposed. Like other patients with prostate cancer, individualized therapeutic choices are essential and depend on a multitude of factors. Herein we examine the role of RP for managing LAPC and attempt to emphasize how the risk of distant disease and difficulty with clinical staging might favour incorporating a surgical approach as part of the therapy for patients with LAPC.

Prognostic factors in T3b renal cell carcinoma.

OBJECTIVES: We reviewed our patients with pathologic T3b renal cell carcinoma (RCC) to determine which factors influenced survival in this high risk patient group. METHODS: From April 1988 to August 2006, 722 patients underwent nephrectomy for RCC at Vanderbilt University. 128 patients (17%) had T3b disease by 2002 AJCC TNM staging criteria. 31 (24%) of these patients had known metastases at the time of nephrectomy. Patient demographics, clinical, and pathological characteristics were collected. RESULTS: There were 95 men (74%) and 33 women (26%) whose median age was 64 years (range 35-87). Median follow-up was 25.2 months (0-124). Median follow-up among those still alive at last follow up was 45.8 months (2.4-114). For overall survival (OS), disease specific survival (DSS), and recurrence free survival (RFS), non-clear cell histology, grade, presence of sarcomatoid features, LN positive disease, presence of necrosis, positive margins, and metastasis present at the time of nephrectomy were all associated with worse outcomes. Race, gender, ASA class, age, and inferior vena cava (IVC) involvement were not associated with outcome. On multivariate analysis, metastasis at the time of nephrectomy, margin involvement, and the presence of necrosis were independently associated with decreased OS and DSS. The presence of necrosis and lymph node involvement were independent predictors of worse RFS. CONCLUSIONS: Our data suggests that in patients with T3b RCC, the presence or absence of macroscopic necrosis should be included as part of the pathology report to help guide prognosis in this high risk patient group.

Effects of primary care physician density, urologist presence, and insurance status on stage of diagnosis for urologic malignancies.

OBJECTIVE: To evaluate effects of PCP density, insurance status, and urologist presence on stage of diagnosis for urologic malignancies. Cancer stage at diagnosis is an important outcome predictor. Studies have shown an inverse relationship to primary care physician (PCP) density and insurance coverage with stage of cancer diagnosis. METHODS: Data was obtained from OK2Share, an Oklahoma Central Cancer Registry, for bladder, kidney, and prostate cancer from 2000 to 2010. Physician data was obtained through the State Licensing Board. The 2010 national census was used for population data. High PCP density was defined as greater than or equal to the median value: 3.17 PCP/10,000 persons. Chi-square and multivariate logistic regressions were used to analyze effects of PCP density, insurance status, and urologist presence on advanced stage diagnosis. RESULTS: 27,086 patients were identified across 77 counties. As PCP density increased by 1 PCP/10,000 persons, the odds ratios (OR) of an advanced stage at diagnosis were 0.383, 0.468, 0.543 for bladder, kidney, and prostate cancer respectively. Compared to private insurance, being uninsured had OR of 1.61 and 2.45 respectively for kidney and prostate cancers. The OR of an advanced stage diagnosis for bladder and prostate cancer were 3.77 and 1.73, respectively, in counties with a urologist. CONCLUSIONS: Increased PCP density and insurance coverage reduced the odds of an advanced diagnosis. Implementation of policies to improve access to healthcare including through increasing PCP density and reducing the number of uninsured patients should result in diagnosis at an earlier stage, which will likely improved cancer-related outcomes.

Transition from androgenic to neurosteroidal action of 5α-androstane-3α, 17ß-diol through the type A γ-aminobutyric acid receptor in prostate cancer progression.

Androgen ablation is the standard of care prescribed to patients with advanced or metastatic prostate cancer (PCa) to slow down disease progression. Unfortunately, a majority of PCa patients under androgen ablation progress to castration-resistant prostate cancer (CRPC). Several mechanisms including alternative intra-prostatic androgen production and androgen-independent androgen receptor (AR) activation have been proposed for CRPC progression. Aldo-keto reductase family 1 member C3 (AKR1C3), a multi-functional steroid metabolizing enzyme, is specifically expressed in the cytoplasm of PCa cells; and positive immunoreactivity of the type A γ-aminobutyric acid receptor (GABAAR), an ionotropic receptor and ligand-gated ion channel, is detected on the membrane of PCa cells. We studied a total of 72 radical prostatectomy cases by immunohistochemistry, and identified that 21 cases exhibited positive immunoreactivities for both AKR1C3 and GABAAR. In the dual positive cancer cases, AKR1C3 and GABAAR subunit α1 were either expressed in the same cells or in neighboring cells. Among several possible substrates, AKR1C3 reduces 5α-dihydrotesterone (DHT) to form 5α-androstane-3α, 17ß-diol (3α-diol). 3α-diol is a neurosteroid that acts as a positive allosteric modulator of the GABAAR in the central nervous system (CNS). We examined the hypothesis that 3α-diol-regulated pathological effects in the prostate are GABAAR-dependent, but are independent of the AR. In GABAAR-positive, AR-negative human PCa PC-3 cells, 3α-diol significantly stimulated cell growth in culture and the in ovo chorioallantoic membrane (CAM) xenograft model. 3α-diol also up-regulated expression of the epidermal growth factor (EGF) family of growth factors and activation of EGF receptor (EGFR) and Src as measured by quantitative polymerase chain reaction and immunoblotting, respectively. Inclusion of GABAAR antagonists reversed 3α-diol-stimulated tumor cell growth, expression of EGF family members, and activation of EGFR and Src to the level observed in untreated cells. Results from the present study suggest that 3α-diol may act as an alternative intra-prostatic neurosteroid that activates AR-independent PCa progression. The involvement of AKR1C3-mediated steroid metabolisms in modulating GABAAR activation and promoting PCa progression requires continued studies.

Minimally Invasive Versus Open Approach for Cystectomy: Trends in the Utilization and Demographic or Clinical Predictors Using the National Cancer Database.

OBJECTIVE: To examine temporal national trends of operative approach for cystectomy and identify demographic or clinical predictive factors that influence choice of approach. METHODS: We performed a retrospective cohort study of patients who underwent cystectomy for bladder cancer between 2010 and 2013 using the National Cancer Database. Approach was stratified by open vs minimally invasive (robotic or laparoscopic). Univariate Pearson chi-square and multivariate logistic regression analysis were used to assess the relationships between demographic and hospital factors and the receipt of minimally invasive or open surgical approach. RESULTS: A total of 9439 patients met our inclusion criteria, of which 34.1% received a minimally invasive approach (MIA). Frequency of MIA increased from 26.3% in 2010 to 39.4% in 2013 (P < .0001). Univariate analysis identified statistically significant associations between year of diagnosis, sex, age, race, clinical T stage, insurance status, income, education, distance from hospital, facility type, geographic location, and facility cystectomy volume, and the choice of approach (all P < .01). On multivariate analysis, independent predictors of MIA included increasing year of diagnosis, male gender, lower clinical T stage, private insurance vs Medicaid, nonacademic vs academic program, northeastern geographic region, receipt of neoadjuvant chemotherapy, and lower cystectomy volume. CONCLUSION: Utilization of MIA for cystectomy has increased nationally over the last several years likely due to increased surgeon familiarity with robotic laparoscopic pelvic surgery. Factors associated with MIA included male sex, locally confined disease, receipt of neoadjuvant chemotherapy, lower cystectomy volume centers, and nonacademic centers.

Implementation of the AUA Castration Resistant Prostate Cancer Guidelines into Practice: Establishing a Multidisciplinary Clinic.

INTRODUCTION: AUA (American Urological Association) published guidelines on the treatment of castration resistant prostate cancer in August 2013. Urologists have remained integral members of a multifaceted team of professionals treating patients with prostate cancer. We discuss approaches to implementing a guidelines based, multidisciplinary, advanced prostate cancer treatment clinic. METHODS: A supplemented PubMed® search was performed to identify published literature evaluating the treatment of castration resistant prostate cancer. Attention was placed on studies assessing a multidisciplinary approach to treating patients with castrate resistant prostate cancer. A review of currently approved agents is provided with emphasis on administration from an integrated clinic. RESULTS: Treatment of patients with advanced prostate cancer remains a significant function of many urology clinics. Guidelines assist urologists with providing patients with the most appropriate care along with multispecialty collaboration. Several organizational approaches have been attempted, including all-in-one clinics, onsite clinics and virtual multidisciplinary clinics. Through close collaboration with medical oncologists, radiation oncologists and support staff patients with advanced prostate cancer can obtain the highest quality care. CONCLUSIONS: Urologists remain an integral member of the multidisciplinary approach to treating castrate resistant prostate cancer. AUA guidelines for castration resistant prostate cancer are a useful tool that can be incorporated into virtual multidisciplinary clinics. Through a team approach patients receive timely and appropriate care.

Outcome of genetic evaluation of patients with kidney cancer referred for suspected hereditary cancer syndromes.

OBJECTIVE: To analyze patients with kidney cancer referred for evaluation at a high-volume genetics service at a comprehensive cancer center and identify factors associated with positive tests for hereditary cancer syndromes. METHODS: A retrospective review of patients referred to the Clinical Genetics Service at Memorial Sloan-Kettering Cancer Center was performed, and patients with a personal history of kidney cancer were identified. Patient and disease characteristics were reviewed. In all, 4 variables including age at diagnosis of kidney tumor, presence of syndromic manifestations, family history of kidney cancer, and number of primary malignancies were evaluated for association with positive test results in 2 groups: patients tested for renal cell carcinoma syndromes and Lynch syndrome. Guidance for genetic testing strategy in patients with kidney cancer is provided. RESULTS: Between 1999 and 2012, 120 patients with a history of kidney cancer were evaluated by the Clinical Genetics Service. The mean age at kidney cancer diagnosis was 52 years (interquartile range: 42-63), with 57% being women. A family history of kidney cancer was reported by 39 patients (33%). Time between diagnosis of first cancer and genetic consultation was <1 year in 54%, 2 to 5 years in 23%, and>5 years in the remaining 23%. Overall, 95 patients were tested for genetic abnormalities with 27 (28%) testing positive. Testing for renal cell carcinoma (RCC)-related syndromes was performed on 43 patients, with 13 testing positive (30%). Lynch syndrome testing was positive in 9 patients (32%) after 28 were tested. In RCC-associated syndromes, young age of diagnosis was associated with positive test results. Conversely, syndromic manifestations and increasing number of primary malignancies were associated with positive Lynch testing. CONCLUSIONS: The discovery of inherited kidney cancer syndromes has provided a unique opportunity to identify patients at increased risk for cancer. Factors associated with positive genetic testing are unique to different syndromes. These data suggest that in kidney cancer patients evaluated for hereditary cancer syndromes, young age is associated with diagnosis of RCC syndromes, whereas syndromic manifestations and multiple primaries are found in Lynch syndrome. These results, along with clinical awareness, may be useful for practicing urologists to select patients with kidney cancer to refer for genetic counseling.

Clinical Evaluation of Cisplatin Sensitivity of Germline Polymorphisms in Neoadjuvant Chemotherapy for Urothelial Cancer.

BACKGROUND: Level 1 evidence has demonstrated increased overall survival with cisplatin-based neoadjuvant chemotherapy for patients with muscle-invasive urothelial cancer. Usage remains low, however, in part because neoadjuvant chemotherapy will not be effective for every patient. To identify the patients most likely to benefit, we evaluated germline pharmacogenomic markers for association with neoadjuvant chemotherapy sensitivity in 2 large cohorts of patients with urothelial cancer. PATIENTS AND METHODS: Patients receiving neoadjuvant cisplatin-based chemotherapy for muscle-invasive urothelial cancer were eligible. Nine germline single nucleotide polymorphisms (SNPs) potentially conferring platinum sensitivity were tested for an association with a complete pathologic response to neoadjuvant chemotherapy (pT0) or elimination of muscle-invasive cancer (