Mayo Adhesive Probability Score Does Not Have Prognostic Ability in Locally Advanced Renal Cell Carcinoma

Nephrectomy remains standard treatment for renal cell carcinoma (RCC). The Mayo Adhesive Probability (MAP) score is predictive of adherent perinephric fat and associated surgical complexity, and is determined by assessing perinephric fat and stranding. MAP has additionally predicted progression-free survival (PFS), though primarily reported in stage T1-T2 RCC. Here, we examine MAP’s ability to predict overall survival (OS) and PFS in T3-T4 RCC. From our prospectively maintained RCC database, patients that underwent radical nephrectomy (2009-2016) with available abdominal imaging (<90 days preop) and T3/T4 RCC underwent MAP scoring. Survival analyses were conducted with MAP scores as individual (0-5) and dichotomized (0-3 vs 4-5) using Kaplan-Meier method. Multivariable Cox proportional hazard regression models for PFS and OS were built with backward elimination. 141 patients were included. 134 (95%) and 7 (5%) had pT3 and pT4 disease, respectively. 46.1% of patients had an inferior vena cava thrombus. Mean MAP score was 3.22±1.52, with 75 (53%) patients having a score between 0-3 and 66 (47%) having a score of 4-5. Both male gender (p=0.006) and clear cell histology (p=0.012) were associated with increased MAP scores. On Kaplan-Meier and multivariable analysis, no significant associations were identified between MAP and PFS (HR=1.01, 95% CI 0.85-1.20, p=0.93) or OS (HR=1.01, 95% CI 0.84-1.21, p=0.917). In this cohort of patients with locally advanced RCC, high MAP scores were not predictive of worse PFS or OS

Elevated preoperative neutrophil-to-lymphocyte ratio may be associated with decreased overall survival in patients with metastatic clear cell renal cell carcinoma undergoing cytoreductive nephrectomy

Objective: Inflammatory serum markers have proven to be a powerful predictive tool of patient prognosis in cancer treatment for a wide variety of solid organ malignancies, predominantly in the context of localized disease. In this study we evaluated the preoperative neutrophil-to-lymphocyte ratio (NLR) as a predictive tool in patients with metastatic clear cell renal cell carcinoma (RCC). Methods: Sixty-four patients with metastatic clear cell RCC undergoing nephrectomy were selected. Only patients with preoperative NLR were included for survival analysis. Patients were categorized into high and low NLR score determined by plotting the NLR ROC curve. Multivariable analysis was performed. Results: Median age was 60.8 years (38.2–81.2). Median follow-up time was 8.1 months (0.1–106.3). Fuhrman grade distribution was: 2 (3.1%) grade 1, 6 (9.4%) grade 2, 24 (37.5%) grade 3 and 32 (50.0%) grade 4. Median NLR score was 3.5 (1.4–31.0). NLR ≥ 4 was associated with decreased overall survival compared to NLR < 4 (p = 0.017). Multivariable survival analysis showed NLR ≥ 4 as an independent predictor of survival (Hazard ratio (HR) 2.41, 95%CI 1.05–5.50, p = 0.03). Conclusion: Elevated preoperative NLR is associated with poor prognosis in patients with metastatic kidney cancer. Preoperative NLR is a useful tool, which can predict prognosis, stratify patients for postoperative surveillance, and help guide decisions for therapy

Major histocompatibility complex I upregulation in clear cell renal cell carcinoma is associated with increased survival

Objective: To examine the prognostic value of tumor major histocompatibility complex I (MHCI) expression on survival and recurrence in patients with clear cell renal cell carcinoma (RCC). Methods: Fifty-three patients that underwent nephrectomy at our institution for clear cell RCC (T1–T3) with ≥4 years of follow-up were queried from our nephrectomy database. Immunohistochemical staining for MHCI was performed on tumor specimens and MHCI expression was quantified with an automated image analysis technique. Patients were divided into high and low MHCI expression groups in order to study the relationship between MHCI expression and prognosis using the Kaplan–Meier method and log-rank test. Results: Overall survival and recurrence free survival were increased in the high MHCI expression group compared to the low MHCI expression group (log-rank, p = 0.036 and p = 0.028, respectively). Patients alive at the end of the study had higher MHCI expression (mean positivity score 0.82) than those that died of disease (mean positivity score 0.76, t test, p = 0.030). Patients that did not develop recurrence during the study period had higher MHCI expression (mean positivity score 0.83) than those that did develop recurrence (mean positivity score 0.78), but this difference was not significant (t test, p = 0.079). Conclusion: Our data demonstrate that high MHCI expression confers improved overall and recurrence free survival in patients with clear cell RCC and could serve as an important prognostic tool in identifying high-risk patients. Keywords: Renal cell carcinoma, Prognosis, MHCI, Biomarke

Association Between Combined TMPRSS2:ERG and PCA3 RNA Urinary Testing and Detection of Aggressive Prostate Cancer.

Importance Potential survival benefits from treating aggressive (Gleason score, ≥7) early-stage prostate cancer are undermined by harms from unnecessary prostate biopsy and overdiagnosis of indolent disease. Objective To evaluate the a priori primary hypothesis that combined measurement of PCA3 and TMPRSS2:ERG (T2:ERG) RNA in the urine after digital rectal examination would improve specificity over measurement of prostate-specific antigen alone for detecting cancer with Gleason score of 7 or higher. As a secondary objective, to evaluate the potential effect of such urine RNA testing on health care costs. Design, Setting, and Participants Prospective, multicenter diagnostic evaluation and validation in academic and community-based ambulatory urology clinics. Participants were a referred sample of men presenting for first-time prostate biopsy without preexisting prostate cancer: 516 eligible participants from among 748 prospective cohort participants in the developmental cohort and 561 eligible participants from 928 in the validation cohort. Interventions/Exposures Urinary PCA3 and T2:ERG RNA measurement before prostate biopsy. Main Outcomes and Measures Presence of prostate cancer having Gleason score of 7 or higher on prostate biopsy. Pathology testing was blinded to urine assay results. In the developmental cohort, a multiplex decision algorithm was constructed using urine RNA assays to optimize specificity while maintaining 95% sensitivity for predicting aggressive prostate cancer at initial biopsy. Findings were validated in a separate multicenter cohort via prespecified analysis, blinded per prospective-specimen-collection, retrospective-blinded-evaluation (PRoBE) criteria. Cost effects of the urinary testing strategy were evaluated by modeling observed biopsy results and previously reported treatment outcomes. Results Among the 516 men in the developmental cohort (mean age, 62 years; range, 33-85 years) combining testing of urinary T2:ERG and PCA3 at thresholds that preserved 95% sensitivity for detecting aggressive prostate cancer improved specificity from 18% to 39%. Among the 561 men in the validation cohort (mean age, 62 years; range, 27-86 years), analysis confirmed improvement in specificity (from 17% to 33%; lower bound of 1-sided 95% CI, 0.73%; prespecified 1-sided P = .04), while high sensitivity (93%) was preserved for aggressive prostate cancer detection. Forty-two percent of unnecessary prostate biopsies would have been averted by using the urine assay results to select men for biopsy. Cost analysis suggested that this urinary testing algorithm to restrict prostate biopsy has greater potential cost-benefit in younger men. Conclusions and Relevance Combined urinary testing for T2:ERG and PCA3 can avert unnecessary biopsy while retaining robust sensitivity for detecting aggressive prostate cancer with consequent potential health care cost savings

Genetic factors associated with prostate cancer conversion from active surveillance to treatment

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 PC, 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

The Movember Foundation's GAP3 cohort

Objectives: The Movember Foundation launched the Global Action Plan Prostate Cancer Active Surveillance (GAP3) initiative to create a global consensus on the selection and monitoring of men with low-risk prostate cancer (PCa) on active surveillance (AS). The aim of this study is to present data on inclusion and follow-up for AS in this unique global AS database. Patients and Methods: Between 2014 and 2016, the database was created by combining patient data from 25 established AS cohorts worldwide (USA, Canada, Australasia, UK and Europe). Data on a total of 15 101 patients were included. Descriptive statistics were used to report patients' clinical and demographic characteristics at the time of PCa diagnosis, clinical follow-up, discontinuation of AS and subsequent treatment. Cumulative incidence curves were used to report discontinuation rates over time. Results: At diagnosis, the median (interquartile range [IQR]) patient age was 65 (60–70) years and the median prostate-specific antigen level was 5.4 (4.0–7.3) ng/mL. Most patients had clinical stage T1 disease (71.8%), a biopsy Gleason score of 6 (88.8%) and one tumour-positive biopsy core (60.3%). Patients on AS had a median follow-up time of 2.2 (1.0–5.0) years. After 5, 10 and 15 years of follow-up, respectively, 58%, 39% and 23% of patients were still on AS. The current version of GAP3 has limited data on magnetic resonance imaging (MRI), quality of life and genomic testing. Conclusions: GAP3 is the largest worldwide collaboration integrating patient data from men with PCa on AS. The results will allow individual patients and clinicians to have greater confidence in the personalized decision to either delay or proceed with active treatment. Longer follow-up and the evaluation of MRI, new genomic markers and patient-related outcomes will result in even more valuable data and eventually in better patient outcomes

Reasons for Discontinuing Active Surveillance: Assessment of 21 Centres in 12 Countries in the Movember GAP3 Consortium

BackgroundCareful assessment of the reasons for discontinuation of active surveillance (AS) is required for men with prostate cancer (PCa).ObjectiveUsing Movember's Global Action Plan Prostate Cancer Active Surveillance initiative (GAP3) database, we report on reasons for AS discontinuation.Design, setting, and participantsWe compared data from 10296 men on AS from 21 centres across 12 countries.Outcome measurements and statistical analysisCumulative incidence methods were used to estimate the cumulative incidence rates of AS discontinuation.Results and limitationsDuring 5-yr follow-up, 27.5% (95% confidence interval [CI]: 26.4-28.6%) men showed signs of disease progression, 12.8% (95% CI: 12.0-13.6%) converted to active treatment without evidence of progression, 1.7% (95% CI: 1.5-2.0%) continued to watchful waiting, and 1.7% (95% CI: 1.4-2.1%) died from other causes. Of the 7049 men who remained on AS, 2339 had follow-up for &gt;5yr, 4561 had follow-up for &lt;5yr, and 149 were lost to follow-up. Cumulative incidence of progression was 27.5% (95% CI: 26.4-28.6%) at 5yr and 38.2% (95% CI: 36.7-39.9%) at 10yr. A limitation is that not all centres were included due to limited information on the reason for discontinuation and limited follow-up.ConclusionsOur descriptive analyses of current AS practices worldwide showed that 43.6% of men drop out of AS during 5-yr follow-up, mainly due to signs of disease progression. Improvements in selection tools for AS are thus needed to correctly allocate men with PCa to AS, which will also reduce discontinuation due to conversion to active treatment without evidence of disease progression.Patient summaryOur assessment of a worldwide database of men with prostate cancer (PCa) on active surveillance (AS) shows that 43.6% drop out of AS within 5yr, mainly due to signs of disease progression. Better tools are needed to select and monitor men with PCa as part of AS