Tracking Cancer Evolution Reveals Constrained Routes to Metastases: TRACERx Renal.

Clear-cell renal cell carcinoma (ccRCC) exhibits a broad range of metastatic phenotypes that have not been systematically studied to date. Here, we analyzed 575 primary and 335 metastatic biopsies across 100 patients with metastatic ccRCC, including two cases sampledat post-mortem. Metastatic competence was afforded by chromosome complexity, and we identify 9p loss as a highly selected event driving metastasis and ccRCC-related mortality (p = 0.0014). Distinct patterns of metastatic dissemination were observed, including rapid progression to multiple tissue sites seeded by primary tumors of monoclonal structure. By contrast, we observed attenuated progression in cases characterized by high primary tumor heterogeneity, with metastatic competence acquired gradually and initial progression to solitary metastasis. Finally, we observed early divergence of primitive ancestral clones and protracted latency of up to two decades as a feature of pancreatic metastases.

Prospective Evaluation of Focal High Intensity Focused Ultrasound for Localized Prostate Cancer.

PURPOSE: We report short-term outcomes of focal high intensity focused ultrasound use for primary treatment of localized prostate cancer. MATERIALS AND METHODS: Single-center prospectively collected data on patients with prostate cancer who underwent primary focal high intensity focused ultrasound from January 2016 to July 2018 were included. All patients underwent a 12-core biopsy with magnetic resonance imaging-ultrasound fusion biopsy depending on the presence of targetable lesions. Any Grade Group was allowed, however only patients with localized disease were included. The primary outcome was oncologic control, defined as negative followup in-field biopsy of treated cancer. Prostate specific antigen, Sexual Health Inventory for Men, International Prostate Symptom Score and Expanded Prostate Cancer Index Composite domain scores were assessed 3-monthly till 12 months. Biopsy was performed at 6 or 12 months for high or low/intermediate risk cancer, respectively. RESULTS: Fifty-two patients with minimum followup of 12 months were included in the study. The majority of patients (67%) had cancer Grade Group 2 or greater. Fifteen patients (28.8%) underwent complete transurethral prostate resection/holmium laser enucleation of prostate procedure for debulking large prostates to avoid postoperative urinary retention. Among 30 (58%) patients who underwent followup biopsies, 25 (83%) had negative in-field biopsy results and 4 (13%) had de-novo positive out-of-field biopsy. Only 5 major complications (all grade III) in 4 patients were noted. Urinary symptoms returned to near baseline questionnaire scores within 3-6 months. Sexual function returned to baseline at 12 months. CONCLUSIONS: Focal high intensity focused ultrasound is a safe and effective treatment for patients with localized clinically significant prostate cancer with acceptable short-term oncologic and functional outcomes. The complications are minimal and patient selection is essential. Short-term oncologic outcomes are promising but longer followup is required to establish long-term oncologic outcomes.

Use and Validation of the AUA/SUO Risk Grouping for Nonmuscle Invasive Bladder Cancer in a Contemporary Cohort.

PURPOSE: We applied nonmuscle invasive bladder cancer AUA (American Urological Association)/SUO (Society of Urologic Oncology) guidelines for risk stratification and analyzed predictors of recurrence and progression. MATERIALS AND METHODS: We retrospectively reviewed the records of 398 patients with nonmuscle invasive bladder cancer treated between 2001 and 2017. Descriptive statistics were used to compare AUA/SUO risk groups. Predictors of recurrence and progression were determined by multivariable regression. Kaplan-Meier analysis was done, a Cox proportional hazards regression model was created and time dependent AUCs were calculated to determine progression-free and recurrence-free survival by risk group. RESULTS: Median followup was 37 months (95% CI 35-42). Of the patients 92% underwent bacillus Calmette-Guérin induction and 46% received at least 1 course of maintenance treatment. Of the patients 11.5% were at low, 32.5% were at intermediate and 55.8% were at high risk. In patients at low, intermediate and high risk the 5-year progression-free survival rate was 93%, 74% and 54%, and the 5-year recurrence-free survival rate was 43%, 33% and 23%, respectively. Kaplan-Meier analysis was done to stratify high grade Ta 3 cm or less tumor recurrence-free and progression-free survival in the intermediate vs the high risk group. Relative to low risk, classification as intermediate and as high risk was an independent predictor of progression (HR 9.7, 95% CI 2.23-42.0, p <0.01, and HR 36, 95% CI 8.16-159, p <0.001, respectively). Recurrence was more likely in patients at high risk than in those at low risk (HR 2.03, 95% CI 1.11-3.71, p=0.022). For recurrence and progression the 1-year AUC was 0.60 (95% CI 0.546-0.656) and 0.68 (95% CI 0.622-0.732), respectively. CONCLUSIONS: The AUA/SUO nonmuscle invasive bladder cancer risk classification system appropriately stratifies patients based on the likelihood of recurrence and progression. It should be used at diagnosis to counsel patients and guide therapy.

Health Related Quality of Life of Patients with Bladder Cancer in the RAZOR Trial: A Multi-Institutional Randomized Trial Comparing Robot versus Open Radical Cystectomy.

PURPOSE: We evaluated health related quality of life following robotic and open radical cystectomy as a treatment for bladder cancer. MATERIALS AND METHODS: Using the Randomized Open versus Robotic Cystectomy (RAZOR) trial population we assessed health related quality of life by using the Functional Assessment of Cancer Therapy (FACT)-Vanderbilt Cystectomy Index and the Short Form 8 Health Survey (SF-8) at baseline, 3 and 6 months postoperatively. The primary objective was to assess the impact of surgical approach on health related quality of life. As an exploratory analysis we assessed the impact of urinary diversion type on health related quality of life. RESULTS: Analyses were performed in subsets of the per-protocol population of 302 patients. There was no statistically significant difference between the mean scores by surgical approach at any time point for any FACT-Vanderbilt Cystectomy Index subscale or composite score (p >0.05). The emotional well-being score increased over time in both surgical arms. Patients in the open arm showed significantly better SF-8 sores in the physical and mental summary scores at 6 months compared to baseline (p <0.05). Continent diversion (versus noncontinent) was associated with worse FACT-bladder-cystectomy score at 3 (p <0.01) but not at 6 months, and the SF-8 physical component was better in continent-diversion patients at 6 months (p=0.019). CONCLUSIONS: Our data suggests lack of significant differences in the health related quality of life in robotic and open cystectomies. As robotic procedures become more widespread it is important to discuss this finding during counseling.

Predictors of Recurrence, and Progression-Free and Overall Survival following Open versus Robotic Radical Cystectomy: Analysis from the RAZOR Trial with a 3-Year Followup.

PURPOSE: The RAZOR (Randomized Open versus Robotic Cystectomy) trial revealed noninferior 2-year progression-free survival for robotic radical cystectomy. This update was performed with extended followup for 3 years to determine potential differences between the approaches. We also report 3-year overall survival and sought to identify factors predicting recurrence, and progression-free and overall survival. MATERIALS AND METHODS: We analyzed the per protocol population of 302 patients from the RAZOR study. Cumulative recurrence was estimated using nonbladder cancer death as the competing risk event and the Gray test was applied to assess significance in differences. Progression-free survival and overall survival were estimated by the Kaplan-Meier method and compared with the log rank test. Predictors of outcomes were determined by Cox proportional hazard analysis. RESULTS: Estimated progression-free survival at 36 months was 68.4% (95% CI 60.1-75.3) and 65.4% (95% CI 56.8-72.7) in the robotic and open groups, respectively (p=0.600). At 36 months overall survival was 73.9% (95% CI 65.5-80.5) and 68.5% (95% CI 59.8-75.7) in the robotic and open groups, respectively (p=0.334). There was no significant difference in the cumulative incidence rates of recurrence (p=0.802). Patient age greater than 70 years, poor performance status and major complications were significant predictors of 36-month progression-free survival. Stage and positive margins were significant predictors of recurrence, and progression-free and overall survival. Surgical approach was not a significant predictor of any outcome. CONCLUSIONS: This analysis showed no difference in recurrence, 3-year progression-free survival or 3-year overall survival for robotic vs open radical cystectomy. It provides important prospective data on the oncologic efficacy of robotic radical cystectomy and high level data for patient counseling.

Serum and urinary biomarkers for detection and active surveillance of prostate cancer.

PURPOSE OF REVIEW: To provide a comprehensive review of the available biomarkers for the detection and active surveillance of prostate cancer and simplify decision-making while choosing between them. RECENT FINDINGS: The limitations of PSA and mpMRI and the invasive nature of prostate biopsy has led to a constant search for serum and urinary biomarkers for both the detection and monitoring during active surveillance of prostate cancer. 4K, PHI and PCA3 have been validated in prospective clinical trials for initial detection of prostate cancer and recent evidence points to potential differentiation between indolent and aggressive cancer. However, the usage in monitoring tumor dynamics is debatable because of lack of conclusive evidence. The answer to the existing problems lies in high-quality studies to establish definitive evidence and also to help choose between the plethora of biomarkers available today. SUMMARY: Despite the advancements in innovation and usage of biomarkers in prostate cancer, there exists tremendous potential in improving them to fulfil the unmet need that exists today. Studies to establish conclusive evidence and integration with imaging can tremendously aid diagnosis and monitoring.

Cystic Renal Cell Carcinoma: A Report on Outcomes of Surgery and Active Surveillance in Patients Retrospectively Identified on Pretreatment Imaging.

PURPOSE: We evaluated the outcomes of surgical intervention and active surveillance in patients diagnosed with cystic renal cell carcinoma at our hypothesized radiological cutoff of greater than 50% cystic. MATERIALS AND METHODS: We identified all 430 patients with a pathologically confirmed cystic renal mass that fit our criteria from 2000 to 2015. The 292 patients with a lack of computerized tomography, tumors less than 50% cystic on imaging, multifocal tumors and prior renal cell carcinoma were excluded from study. Patients were stratified into benign or malignant subgroups, and radiological, clinicopathological and oncologic features were determined. Univariate and multivariate associations between clinicoradiological parameters in each group were analyzed. We similarly reviewed the records of a separate cohort of patients treated with active surveillance for cystic renal cell carcinoma. RESULTS: Of the 138 identified cases of cystic renal cell carcinoma 102 (73.9%) were renal cell carcinoma and 36 (26.1%) were benign masses. Of the tumors 77.5% were Fuhrman grade 1-2, 83.4% were stage pT2 or less and 65.9% showed clear cell histology. On univariate analysis male gender, a solid component and increasing Bosniak classification were significant for malignancy. In a separate cohort we identified 38 patients on active surveillance. The growth rate was 1.0 mm per year overall and 2.3 mm per year for the solid component. At a median followup of more than 4 years in all cohorts there was no evidence of recurrence or metastasis of cystic renal cell carcinoma. CONCLUSIONS: Patients with unifocal cystic renal cell carcinoma evaluated using a standardized radiological threshold of greater than 50% cystic had an excellent prognosis on active surveillance and after surgical resection.

Clinical Outcome of Patients with Fibrosis/Necrosis at Post-Chemotherapy Retroperitoneal Lymph Node Dissection for Advanced Germ Cell Tumors.

PURPOSE: Fibrosis accounts for approximately 50% of histological findings at post-chemotherapy retroperitoneal lymph node dissection, and is associated with reported relapse rates of 10% to 15%. We characterized patients with fibrosis at post-chemotherapy retroperitoneal lymph node dissection and identified predictors of adverse outcomes in this group. MATERIALS AND METHODS: We reviewed the medical records of men who underwent post-chemotherapy retroperitoneal lymph node dissection between 1989 and 2013 with histological findings of necrosis/fibrosis. With few exceptions post-chemotherapy retroperitoneal lymph node dissection after 1999 was performed with a bilateral template. Clinical, pathological and treatment related data were reported. Cox regression models were built to identify predictors of disease recurrence. RESULTS: The study cohort included 598 men with a median age of 32 years (IQR 25-38). Most cases (397 of 547, 73%) were classified as IGCCCG good risk, with no significant differences in risk classification before and after 1999 (p=0.55). Median followup was 7.3 years (IQR 3.2-12.3). The 5-year recurrence-free and overall survival rates were 94% and 96%, respectively. Overall 36 patients had disease recurrence, most of which was distant or outside the retroperitoneal lymph node dissection template. Procedures performed after 1999 and the presence of embryonal cell carcinoma on primary histology were associated with improved recurrence-free survival on multivariate analysis (p <0.01). CONCLUSIONS: Disease recurrence in patients with fibrosis at post-chemotherapy retroperitoneal lymph node dissection is an uncommon yet significant event, which is less likely to occur in patients treated after 1999 and in those with embryonal carcinoma on primary histology.

Optimum threshold of the 4Kscore for biopsy in men with negative or indeterminate multiparametric magnetic resonance imaging.

Objective: The study aims to identify the optimal 4Kscore thresholds to determine the need for a prostate biopsy when multiparametric magnetic resonance imaging (MRI) (mpMRI) is negative or indeterminate. Materials and methods: We analysed retrospective data from men in eight different institutions who underwent an mpMRI, 4Kscore and prostate biopsy for evaluation of prostate cancer. We selected men with a negative (PIRADS ≤2) or indeterminate (PIRADS 3) mpMRI. 4Kscore values were categorized into ranges of 1-7, 8-19, 20-32 and greater than 32. We evaluated the proportion of men with grade group 2 or higher (GG2+) cancer in groups defined by PIRADS and 4Kscore. We also evaluated the number of biopsies avoided and GG2+ cancer missed in each group reported depend on 4Kscore cutoff points. Results: Among 1111 men who had an mpMRI, 4Kscore and biopsy, 625 of them had PIRADS ≤3 on mpMRI: 374 negative (PIRADS ≤2) and 251 indeterminate (PIRADS 3). In men with a negative mpMRI, we found a 4Kscore cut-point of 33 resulted in an increased risk of GG2+ cancer on biopsy. In patients with an equivocal lesion on mpMRI, men with a 4Kscore cutoff ≥8 had a greater risk of GG2+ cancer on biopsy. Decision curve analysis supported the proposed cut-points in each mpMRI group. Conclusions: In men with negative and indeterminate mpMRI, we found the best 4Kscore threshold to determine the need for biopsy to be 33 and 8 respectively. Future prospective studies in independent populations are needed to confirm these findings.

Serum and urine biomarkers for detecting clinically significant prostate cancer.

Since the "prostate-specific antigen (PSA) era," we have seen an increase in unnecessary biopsies, which has ultimately lead to an overtreatment of low-risk cancers. Given the limitations of prostate-specific antigen and the invasive nature of prostate biopsy several serum and urinary biomarkers have been developed. In this paper, we provide a comprehensive review of the available biomarkers for the detection clinically significant prostate cancer namely PHI, 4Kscore, PCA3, MiPS, SelectMDx, ExosomeDX. Current literature suggests that these biomarkers can improve detection of clinically significant prostate cancer reducing overtreatment and making treatment strategies more cost-effective. Nevertheless, large prospective studies with head-to-head-comparisons of the available biomarkers are necessary to fully assess the potential of incorporating biomarkers in routine clinical practice.

Somatic mutations as preoperative predictors of metastases in patients with localized clear cell renal cell carcinoma - An exploratory analysis.

OBJECTIVE: Recurrent genomic alterations in clear cell renal cell carcinoma (ccRCC) have been associated with treatment outcomes; however, current preoperative predictive models do not include known genetic predictors. We aimed to explore the value of common somatic mutations in the preoperative prediction of metastatic disease among patients treated for localized ccRCC. MATERIALS AND METHODS: After obtaining institutional review board approval, data of 254 patients with localized ccRCC treated between 2005 and 2015 who underwent genetic sequencing was collected. The mutation status of VHL, PBRM1, SETD2, BAP1 and KDM5C were evaluated in the nephrectomy tumor specimen, which served as a proxy for biopsy mutation status. The Raj et al. preoperative nomogram was used to predict the 12-year metastatic free probability (MFP). The study outcome was MFP; the relationship between MFP and mutation status was evaluated with Cox-regression models adjusting for the preoperative nomogram variables (age, gender, incidental presentation, lymphadenopathy, necrosis, and size). RESULTS: The study cohort included 188 males (74%) and 66 females (26%) with a median age of 58 years. VHL mutations were present in 152/254 patients (60%), PBRM1 in 91/254 (36%), SETD2 in 32/254 (13%), BAP1 in 19/254 (8%), and KDM5C in 19/254 (8%). Median follow-up for survivors was 8.1 years. Estimated 12-year MFP was 70% (95% CI: 63%-75%). On univariable analysis SETD2 (HR: 3.30), BAP1 (HR: 2.44) and PBRM1 (HR: 1.78) were significantly associated with a higher risk of metastases. After adjusting for known preoperative predictors in the existing nomogram, SETD2 mutations remained associated with a higher rate of metastases after nephrectomy (HR: 2.09, 95% CI: 1.19-3.67, P = 0.011). CONCLUSION: In the current exploratory analysis, SETD2 mutations were significant predictors of MFP among patients treated for localized ccRCC. Our findings support future studies evaluating genetic alterations in preoperative renal biopsy samples as potential predictors of treatment outcome.

Voiding Cystourethrogram in Children With Unilateral Multicystic Dysplastic Kidney: Is It Still necessary?

OBJECTIVE: To evaluate the value of the voiding cystourethrogram (VCUG) in children with multicystic dysplastic kidney (MCDK) who have a normal versus abnormal contralateral kidney and bladder ultrasound (US), and assess the risk of having vesicoureteral reflux (VUR) or urinary tract infection (UTI) based on the US results. METHODS: A retrospective chart review including children with unilateral MCDK with postnatal US and VCUG available at our institution between January 2008 and September 2017 was performed. Analysis was done to find association between abnormal contralateral US and contralateral VUR and UTI. RESULTS: One hundred and fifty-six children were analyzed; 118(75.6%) patients had a normal contralateral kidney US, while 38(24.4%) had abnormal US. The rate of severe contralateral VUR (grade IV and V) was 2 (1.7%) and 5 (13.2%) in children with normal and abnormal contralateral US, respectively. The risk analysis demonstrated a significant association between severe VUR on the contralateral kidney and an abnormal contralateral US (odds ratio = 7.73; 95%CI: 1.43-41.81; P = 0.018) and no significant association with UTI (odds ratio = 1.58; 95%CI: 0.50-4.94; P = 0.435). CONCLUSION: Our data suggests, the rate of severe contralateral VUR in children with unilateral MCDK and normal contralateral kidney is low. VCUG should be considered for infants with proven MCKD and alterations on the contralateral kidney on US. Following patients with MCDK and normal contralateral kidney without the use of VCUG is a reasonable approach, unless there is development of signs and symptoms of recurrent UTI or deterioration of the renal function. We found that abnormal contralateral kidney US was associated with severe VUR.

Performance of Multiparametric MRI of the Prostate in Biopsy Naïve Men: A Meta-analysis of Prospective Studies.

OBJECTIVE: To assess the outcomes through systematic review and meta-analysis of multi-parametric magnetic resonance imaging (mpMRI) of the prostate in biopsy naïve men. METHODS: Systemic review and meta-analysis was performed to assess the performance of mpMRI on prostate cancer (PCa) detection at the time of biopsy. We used standard methods for performing a meta-analysis evaluating a diagnostic test and reported the pooled sensitivity and specificity, and the positive and negative likelihood ratios (LR) for mpMRI in the detection of any and clinically significant prostate cancer (csPCa). RESULTS: A total of 10 studies comprising 2486 patients were analyzed. Overall, if biopsies would have been performed only in men with an mpMRI suspicious for malignancy between 7.4% and 58.5% of the biopsies could have been avoided, but 2.3%-36% of any PCa and 0%-30.8% of csPCa would have been missed. The sensitivity, specificity, positive LR, and negative LR of mpMRI for any PCa detection were 0.86 (95% confidence interval [CI], 0.78-0.91), 0.67 (95% CI, 0.40-0.86), 2.6 (95% CI, 1.2-5.5), and 0.2 (95% CI, 0.12-0.32), respectively. The AUC for any PCa detection was 0.84 (95% CI, 0.75-0.90). The pooled sensitivity, specificity, positive LR, and negative LR of mpMRI for csPCa detection was 0.94 (95% CI, 0.83-0.98), 0.54 (95% CI, 0.42-0.65), 2 (95% CI, 1.5-2.7), and 0.1 (95% CI, 0.02-0.35), respectively. The AUC for csPCa detection was 0.94 (95% CI, 0.65-1). CONCLUSION: This study provides summary estimates indicating that mpMRI can accurately detect prostate cancer and help avoid unnecessary biopsies in this population.

Preoperative nomogram predicting 12-year probability of metastatic renal cancer - evaluation in a contemporary cohort.

OBJECTIVES: Preoperative models, based on patient and tumor characteristics, predict risk for adverse outcomes after nephrectomy. Changes in renal tumor characteristics over the last decades, warrant further evaluation using contemporary cohorts. We aimed to validate a previously published preoperative nomogram predicting 12-year metastasis-free probability after nephrectomy for localized renal tumors in a contemporary cohort. PATIENTS AND METHODS: After obtaining institutional review board approval, data of 1,760 patients who underwent nephrectomy for a localized renal mass between 2005 and 2011 were reviewed. Preoperative images were evaluated for the presence of tumor necrosis, lymphadenopathy, and tumor size. The study outcome was metastatic-free probability. Model discrimination was assessed with Gönen and Heller's concordance probability estimate, and calibration was evaluated. RESULTS: The cohort included 1,102 male and 658 female patients with a median age of 60 years. Most patients presented incidentally (84%). On imaging, 3% had evidence of lymphadenopathy, 55% had necrosis and median tumor diameter was 3.7 cm (interquartile range [IQR]: 2.5, 5.5). Median follow-up in non-metastatic patients was 7.7 years (IQR: 5.3, 9.7). Estimated 12-year metastatic-free probability was 88% (86%-90%). The model showed strong discrimination (concordance probability estimate [CPE]: 0.77), and fair calibration. The time-dependent receiver operating characteristic (ROC) curves showed strong discrimination at all-time points and the area under the curve (AUC) for year 12 was 0.83 (95% Confidence Interval: 0.78-0.89). CONCLUSIONS: We validated the preoperative nomogram of 12-year metastasis-free probability in a contemporary cohort despite different tumor characteristics. Future studies should evaluate the role of preoperative risk stratification in patient selection for neoadjuvant treatment.

The Association Between Small Primary Tumor Size and Prognosis in Metastatic Renal Cell Carcinoma: Insights from Two Independent Cohorts of Patients Who Underwent Cytoreductive Nephrectomy.

BACKGROUND: One of the main challenges in the management of renal cell carcinoma (RCC) is risk-stratifying patients who present with metastatic disease. Tumor size is an important predictor of survival in the localized setting; however, this feature has not been explored fully in patients presenting with M1 RCC. OBJECTIVE: To assess the impact of tumor size on survival in patients with metastatic RCC who underwent cytoreductive nephrectomy (CN). DESIGN, SETTING, AND PARTICIPANTS: We queried the Memorial Sloan Kettering (MSK) nephrectomy database for patients who presented with M1 disease and underwent CN between 1989 and 2016 (n=304). Primary tumor size was obtained from pathology reports. Data from the International Metastatic Database Consortium (IMDC) were used for validation purposes (n=778). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Overall survival (OS) estimates were computed using the Kaplan-Meier method. Cox regressions were used to test the association between tumor size and OS in univariate and multivariable analyses. Tumors ≤4cm were compared with larger masses. Secondary analyses were performed to assess the robustness of these findings. RESULTS AND LIMITATIONS: Clear cell tumors ≤4cm were significantly associated with improved OS in both the MSK (hazard ratio [HR]: 0.35, 0.17-0.72, p= 0.004) and IMDC (HR 0.54, 0.36-0.83, p= 0.004) cohorts. The association was observed even after adjusting for known prognostic factors (HR 0.40, 0.14-1.14, p= 0.09 and HR: 0.54, 0.33-0.90, p= 0.02 in the MSK and IMDC cohorts, respectively). Limitations of this study include the absence of patients who were considered poor surgical candidates as well as potential selection bias. CONCLUSIONS: The primary tumor size ≤4cm was independently associated with improved OS in patients with metastatic clear cell RCC who underwent CN. Additionally, the association between primary size and survival was found to be nonlinear. These findings suggest that there is a group of small metastatic RCCs that can convey a better overall prognosis. The potential role of primary tumor size when risk stratifying patients with M1 RCC should be explored further to determine its utility during clinical decision making. PATIENT SUMMARY: We evaluated the impact of small tumor size on prognosis in patients with metastatic kidney cancer who undergo removal of the primary tumor. Very small masses (≤4cm) were associated with better prognosis in patients with clear cell tumors.

Chromophobe Renal Cell Carcinoma: Results From a Large Single-Institution Series.

BACKGROUND: The purpose of the study was to evaluate clinical features and prognostic factors in a large single institutional cohort of chromophobe renal cell carcinoma (ChRCC) patients for identification of tumors with the highest metastatic potential. PATIENTS AND METHODS: Clinicopathological parameters of all patients with ChRCC diagnosed and surgically treated at Memorial Sloan Kettering Cancer Center between 1990 and 2016 were identified and compared with patients treated for clear-cell renal cell carcinoma (ccRCC) in the same study period using Wilcoxon test for continuous variables and Fisher exact test for categorical variables. Recurrence-free survival (RFS) and overall survival (OS) were analyzed using the Kaplan-Meier method, log rank test, and Cox proportional hazards regression. RESULTS: Four hundred ninety-six patients with ChRCC (10-year RFS, 91.7% and OS, 82.1%) and 3312 patients with ccRCC (10-year RFS, 79.4% and OS, 63.6%) were included in the analysis. Patients with ChRCC were younger (median 59 vs. 61 years; P = .0015), less frequently male (54.8% vs. 66.3%; P < .0001), showed more favorable T stages (T1-2 in 78% vs. 67%; P < .0001) and less frequent sarcomatoid differentiation (1.2 % vs. 4%; P = .0008) and showed lower rates of metastatic development compared with ccRCC patients. Larger tumor size, sarcomatoid differentiation, and higher T-stage are significantly associated with adverse RFS and OS in chromophobe tumors. CONCLUSION: ChRCC is more commonly diagnosed in female and younger patients and is associated with a more favorable clinical outcome and a lower propensity for metastatic development than ccRCC. Larger tumors and sarcomatoid differentiation of ChRCC might be considered as risk factors for metastatic development.

Characterization and Impact of TERT Promoter Region Mutations on Clinical Outcome in Renal Cell Carcinoma.

BACKGROUND: Mutations in the promoter region of the TERT gene have been detected in a variety of cancers. These mutations can potentially lead to unlimited cell divisions and result in poor clinical prognosis. OBJECTIVE: To determine the role and relevance of TERT promoter region mutations in both clear cell (ccRCC) and non-clear cell (nccRCC) renal cell carcinoma using ultra-deep and whole-genome sequencing methods on primary tumor samples. DESIGN, SETTING, AND PARTICIPANTS: DNA from 281 kidney tumors (147 ccRCC and 134 nccRCC) was sequenced between 2013 and 2015, and clinical outcomes for these patients from a single institution were retrospectively analyzed. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Differences in patient characteristics and mutational status were tested using Fisher's exact test for categorical variables and the Wilcoxon rank sum test for continuous variables. Survival times were estimated using the Kaplan-Meier method and differences were tested using the log-rank test. RESULTS AND LIMITATIONS: TERT mutations occurred in 12.2% of ccRCC and 10.4% of nccRCC cases. In >80% of the cases, mutations were located at C228T and were found to co-occur only rarely with other relevant RCC driver genes. The median follow-up among survivors overall was 2.5 yr (range 0.1-18.3). TERT promoter mutations were significantly associated with cancer-specific survival in ccRCC (hazard ratio 2.68, 95% confidence interval 1.19-6.01; p=0.013). In nccRCC, TERT mutations were significantly associated with larger tumors and metastatic development. Assessment of further relevant clinical associations was precluded in the nccRCC group by the heterogeneous and small sample size. CONCLUSIONS: Our data suggests that TERT mutational status reflects a distinct pathogenesis with an aggressive disease course in RCC. Stratifying patients with this unique tumorigenesis that leads to poor clinical outcomes could be a putative target for novel therapeutics. PATIENT SUMMARY: We show a previously unrecognized frequency of TERT promoter mutations in both clear cell and non-clear cell renal cell carcinoma. TERT promoter mutations were associated with some worse outcomes in patients with clear cell renal cell carcinoma.

Characterizing recurrent and lethal small renal masses in clear cell renal cell carcinoma using recurrent somatic mutations.

INTRODUCTION: Small renal masses (SRMs) with evidence of clear cell renal cell carcinoma (ccRCC) are understudied. Current algorithms for the management of SRMs include surgical resection, ablation, and active surveillance. We sought to identify genomic biomarkers that could potentially refine the management of ccRCC in SRMs, especially in patients being evaluated for active surveillance. METHODS: We identified patients who had SRMs (4cm or less) at time of surgery, had sequencing performed on their primary tumor and had a diagnosis of ccRCC. Patients were selected from 3 publicly available cohorts, The Cancer Genome Atlas (n = 110), University of Tokyo (n = 37), The International Cancer Genome Consortium (n = 31), and from our own institutional prospective database (n = 25). Among this cohort we analyzed mutations present in at least 5% of tumors, assessing for the enrichment of mutations and progression-free survival using the composite endpoint of recurrence or death of disease. Analysis was adjusted for multiple testing. A Cox regression model was used to assess clinical variables with significant mutations. RESULTS: In total, 203 patients were available for analysis. Median follow-up was 43.1 months among survivors. Mutations in VHL, PBRM1, SETD2, BAP1, KDM5C, and MTOR were present in more than 5% of tumors. Twenty-three patients (11.3%) had recurrence or died of their disease. Mutations in KDM5C were associated with inferior survival from either recurrence or death from disease, adjusted P 0.033. CONCLUSIONS: We identified mutations in SRMs in ccRCC that are associated with recurrence and lethality. The strongest association was seen in those with KDM5C mutations. Use of these genomic biomarkers may improve stratification of patients with SRMs and for those who may be appropriate for active surveillance. Prospective evaluation of these markers is needed.