Objective

To utilize a population-based approach to address the role of adjuvant TT in the management of RCC.

Methods

Patients with RCC (2006-2013) in the SEER database were stratified by metastatic disease at the time of diagnosis (cM0/cM1). cM0 patients following surgical excision were stratified into low and high-risk (ASSURE and S-TRAC criteria). Multivariable analyses performed to identify predictors of TT receipt; Fine and Gray competing risks analyses used to identify predictors of cancer-specific mortality (CSM). Subset analyses included patients with clear cell histology and high-risk cM0. Survival analyses were used to evaluate overall survival (OS) and cancer-specific survival (CSS) for all cohorts, stratified on TT receipt.

Results

79,926 patients included (71,682 cM0, 8,244 cM1); median follow-up for the entire cohort was 40.1 months. Of 31,453 patients with histologic grade data, 18,328 and 13,125 were low- and high-risk cM0, respectively. TT utilization in cM1 patients peaked at 50.6% and was associated with reduced CSM (HR 0.73, p<0.01). In contrast, TT utilization (presumed salvage therapy) never exceeded 2.2% in the entire cM0 cohort and 3.5% in the high-risk cM0 cohort. On competing risks analysis, TT receipt was associated with increased CSM in all cohorts.

Conclusion

When compared to the cM1 patients, TT receipt in cM0 patients does not provide any cancer-specific survival benefit, even in the small percentage of patients that eventually progress to metastatic disease. Competing risks mortality further limit any potential benefit in this population. Based on current evidence, adjuvant TT cannot be recommended for RCC patients.

Objectives

To evaluate the utilization and outcomes of perioperative chemotherapy in non-metastatic UTUC patients over the past decade using a large national database.

Methods

All patients aged 18 and older diagnosed with non-metastatic UTUC between 2004 and 2013 were identified within the Surveillance, Epidemiology and End Results (SEER) database. Relevant clinical data was collected and predictors of cancer specific mortality (CSM) and other cause mortality (OCM) were analyzed.

Results

The total cohort included 8,762 patients. Of these, 1,402 (16%) patients received chemotherapy, including only 35% of high-risk patients (>pT2 or N1). Treated patients had higher CSM (21.3% vs. 13.1%, p<0.001). Predictors of chemotherapy utilization included residence in Midwest states, tumor located in the ureter, higher stage and grade. Predictors of CSM included older age, residence in southern states, receipt of chemotherapy (HR = 1.151, 95% CI: 1.003-1.32, p=0.044), higher stage and grade. OCM was predicted by male gender, older age, ureteral tumor, and higher stage. A subset analysis of patients younger than 65 showed similar predictors, while an analysis of high risk patients demonstrated that chemotherapy receipt did not predict CSM or OCM.

Conclusions

In this large contemporary non-metastatic UTUC cohort, chemotherapy utilization was found to be quite infrequent, but increasing steadily. Perioperative chemotherapy had no effect on CSM in high-risk patients, while correlated to higher CSM in the younger patients.

Background

We examine the practical application of multiparametric MRI (mpMRI) prostate biopsy data using established pre-RP nomograms and its potential implications on RP intraoperative decision-making. We hypothesize that current nomograms are suboptimal in predicting outcomes with mpMRI targeted biopsy (TBx) data.

Materials and methods

Patients who underwent mpMRI-based TBx prior to RP were assessed using the MSKCC and Briganti nomograms with the following iterations: (1) Targeted (T) (targeted only), (2) Targeted and Systematic (TS) and (3) Targeted Augmented (TA) (targeted core data; assumed negative systematic cores for 12 total cores). Nomogram outcomes, lymph node involvement (LNI), extracapsular extension (ECE), organ-confined disease (OCD), seminal vesicle invasion (SVI), were compared across iterations. Clinically significant impact on management was defined as a change in LNI risk above or below 2% (Δ2) or 5% (Δ5).

Results

A total of 217 men met inclusion criteria. Overall, the TA iteration had more conservative nomogram outcomes than the T. Moreover, TA better predicted RP pathology for all four outcomes when compared with the T. In the entire cohort, Δ2 and Δ5 were 16.6-25.8% and 20.3-39.2%, respectively. In the subset of 190 patients with targeted and systematic cores, TA was a better approximation of TS outcomes than T in 71% (MSKCC) and 82% (Briganti) of patients.

Conclusion

In established pre-RP nomograms, mpMRI-based TBx often yield variable and discordant results when compared with systematic biopsies. Future nomograms must better incorporate mpMRI TBx core data. In the interim, augmenting TBx data may serve to bridge the gap.

Introduction

Shared decision-making is widely recommended when men are considering prostate cancer screening with prostate-specific antigen (PSA). The role of patients' trust in cancer information from their physician in such decisions is unknown.

Methods

We identified male respondents ≥18 years of age from the Health Information National Trends Survey, a population-based survey of people living in the U.S. (2011-014). We assessed the association between degree of trust in cancer information from respondent's physician with patient-reported receipt of PSA-screening and patient-reported discussion of PSA screening with their physician.

Results

Among 5069 eligible respondents, 3606 (71.1%) men reported trusting cancer information from their physician "a lot," 1186 (23.4%) "somewhat," 219 (4.3%) "a little," and 58 (1.1%) "not at all." A total of 2655 (52.4%) men reported receiving PSA screening. The degree of trust an individual had in his physician for cancer information was strongly associated with his likelihood of having received PSA screening (p_trend<0.0001) (54.9% "a lot" vs. 27.6% "not at all"). These findings persisted after multivariable regression. Similarly, men who had high levels of trust in their physician were more likely to have discussed PSA screening with a strong trend across strata (p_trend<0.0001).

Conclusions

The level of trust an individual has in cancer information from his physician is strongly associated with his likelihood of discussing and undergoing PSA screening. As rationale, implementation of PSA screening requires shared decision-making, and the level of trust an individual has in his physician has important implications for dissemination of PSA screening guidelines.

Introduction

Active surveillance (AS) is standard of care in low-risk prostate cancer (PCa). This study describes a novel total cancer location (TCLo) density metric and aims to determine its performance in predicting clinical progression (CP) and grade progression (GP).

Methods

This was a retrospective study of patients on AS after confirmatory biopsy (CBx). We excluded patients with Gleason ≥7 at CBx and <2 years followup. TCLo was the number of locations with positive cores at diagnosis (DBx) and CBx. TCLo density was TCLo/prostate volume (PV). CP was progression to any active treatment while GP occurred if Gleason ≥7 was identified on repeat biopsy or surgical pathology. Independent predictors of time to CP or GP were estimated with Cox regression. Kaplan-Meier analysis compared progression-free survival (PFS) curves between TCLo density groups. Test characteristics of TCLo density were explored with receiver operating characteristic (ROC) curves.

Results

We included 181 patients who had CBx from 2012-2015 and met inclusion criteria. The mean age of patients was 62.58 years (standard deviation [SD] 7.13) and median followup was 60.9 months (interquartile range [IQR] 23.4). A high TCLo density score (>0.05) was independently associated with time to CP (hazard ratio [HR] 4.70; 95% confidence interval [CI] 2.62-8.42; p<0.001) and GP (HR 3.85; 95% CI 1.91-7.73; p<0.001). ROC curves showed TCLo density has greater area under the curve than number of positive cores at CBx in predicting progression.

Conclusions

TCLo density is able to stratify patients on AS for risk of CP and GP. With further validation, it could be added to the decision-making algorithm in AS for low-risk localized PCa.

Background

The development of noninvasive tests for the early detection of aggressive prostate tumors is a major unmet clinical need. miRNAs are promising noninvasive biomarkers: they play essential roles in tumorigenesis, are stable under diverse analytical conditions, and can be detected in body fluids.

Methods

We measured the longitudinal stability of 673 miRNAs by collecting serial urine samples from 10 patients with localized prostate cancer. We then measured temporally stable miRNAs in an independent training cohort (n = 99) and created a biomarker predictive of Gleason grade using machine-learning techniques. Finally, we validated this biomarker in an independent validation cohort (n = 40).

Results

We found that each individual has a specific urine miRNA fingerprint. These fingerprints are temporally stable and associated with specific biological functions. We identified seven miRNAs that were stable over time within individual patients and integrated them with machine-learning techniques to create a novel biomarker for prostate cancer that overcomes interindividual variability. Our urine biomarker robustly identified high-risk patients and achieved similar accuracy as tissue-based prognostic markers (area under the receiver operating characteristic = 0.72, 95% confidence interval = 0.69 to 0.76 in the training cohort, and area under the receiver operating characteristic curve = 0.74, 95% confidence interval = 0.55 to 0.92 in the validation cohort).

Conclusions

These data highlight the importance of quantifying intra- and intertumoral heterogeneity in biomarker development. This noninvasive biomarker may usefully supplement invasive or expensive radiologic- and tissue-based assays.

INTRODUCTION:Urinary biomarkers are being developed to detect bladder cancer recurrence/progression in patients with non-muscle-invasive bladder cancer (NMIBC). We conducted a questionnaire-based study to determine what diagnostic accuracy and cost would such test(s) need for both patients and urologic oncologists to comfortably forgo surveillance cystoscopy in favour of these tests. METHODS:Surveys were administered to NMIBC patients at followup cystoscopy visit and to physician members of the Society of Urologic Oncology. Participants were questioned about acceptable false-negative (FN) rates and costs for such alternatives, in addition to demographics that could influence chosen error rates and costs. RESULTS:A total of 137 patient and 51 urologic oncologist responses were obtained. Seventy-seven percent of patients were not comfortable with urinary biomarker(s) alternatives to repeat cystoscopy, with a further 14% willing to accept such alternatives only if the FN rate were 0.5% or lower. Seventy-five percent of urologic oncologists were comfortable with an alternative urinary biomarker test(s), with 37% and 33% willing to accept FN rates of 5% and 1%, respectively. Forty-seven percent of patients were not willing to pay out-of-pocket for such tests, while 61% of urologic oncologists felt that a price range of $100-500 would be reasonable. CONCLUSIONS:This is the first survey evaluating patient and urologic oncologist perspectives on acceptable error rates and costs for urinary biomarker alternatives to surveillance cystoscopy for patients with NMIBC. Despite potential responder bias, this study suggests that urinary biomarker(s) will require sensitivity equivalent to that of cystoscopy in order to completely replace it in surveillance of patients with NMIBC.

Men diagnosed with low-risk prostate cancer (PC) are increasingly electing active surveillance (AS) as their initial management strategy. While this may reduce the side effects of treatment for prostate cancer, many men on AS eventually convert to active treatment. PC is one of the most heritable cancers, and genetic factors that predispose to aggressive tumors may help distinguish men who are more likely to discontinue AS. To investigate this, we undertook a multi-institutional genome-wide association study (GWAS) of 5,222 PC patients and 1,139 other patients from replication cohorts, all of whom initially elected AS and were followed over time for the potential outcome of conversion from AS to active treatment. In the GWAS we detected 18 variants associated with conversion, 15 of which were not previously associated with PC risk. With a transcriptome-wide association study (TWAS), we found two genes associated with conversion (MAST3, p = 6.9×10^-7 and GAB2, p = 2.0×10^-6). Moreover, increasing values of a previously validated 269-variant genetic risk score (GRS) for PC was positively associated with conversion (e.g., comparing the highest to the two middle deciles gave a hazard ratio [HR] = 1.13; 95% Confidence Interval [CI]= 0.94-1.36); whereas, decreasing values of a 36-variant GRS for prostate-specific antigen (PSA) levels were positively associated with conversion (e.g., comparing the lowest to the two middle deciles gave a HR = 1.25; 95% CI, 1.04-1.50). These results suggest that germline genetics may help inform and individualize the decision of AS-or the intensity of monitoring on AS-versus treatment for the initial management of patients with low-risk PC.

Genome-wide association studies (GWAS) and fine-mapping efforts to date have identified more than 100 prostate cancer (PrCa)-susceptibility loci. We meta-analyzed genotype data from a custom high-density array of 46,939 PrCa cases and 27,910 controls of European ancestry with previously genotyped data of 32,255 PrCa cases and 33,202 controls of European ancestry. Our analysis identified 62 novel loci associated (P < 5.0 × 10^-8) with PrCa and one locus significantly associated with early-onset PrCa (≤55 years). Our findings include missense variants rs1800057 (odds ratio (OR) = 1.16; P = 8.2 × 10^-9; G>C, p.Pro1054Arg) in ATM and rs2066827 (OR = 1.06; P = 2.3 × 10^-9; T>G, p.Val109Gly) in CDKN1B. The combination of all loci captured 28.4% of the PrCa familial relative risk, and a polygenic risk score conferred an elevated PrCa risk for men in the ninetieth to ninety-ninth percentiles (relative risk = 2.69; 95% confidence interval (CI): 2.55-2.82) and first percentile (relative risk = 5.71; 95% CI: 5.04-6.48) risk stratum compared with the population average. These findings improve risk prediction, enhance fine-mapping, and provide insight into the underlying biology of PrCa¹.

Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling.