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Abstract Renal cell carcinomas (RCC) with overlapping histomorphologic features poses diagnostic challenges. This is exemplified in RCCs with eosinophilic cytoplasm that include eosinophilic solid and cystic RCC (ESC RCC), RCCs in germline aberrations of tuberous sclerosis complex (TSC) genes mutated (TSC RCC) individuals, and other RCC subtypes. We used next-generation sequencing (NGS) technology to molecularly profile seven ESC RCC tumors. Mutational and copy number analysis of NGS data revealed mutually exclusively somatic bi-allelic loss of TSC1 or TSC2 genes—both negative regulators of the mammalian target of rapamycin (mTOR) pathway in 85% (6/7) of evaluated cases. Thus, lack of germline TSC aberration in matched non-neoplastic renal parenchyma distinguishes ESC RCC from TSC RCC. Immunohistochemistry data shows mTOR pathway activation in all tumors, thus supporting a pathognomonic role for TSC aberrations in ESC RCC. Our study clarifies the molecular identity of ESC RCC, provides basis for the revision of current RCC classification, and may guide future therapeutic strategies. Patient summary Molecular characterization of eosinophilic solid and cystic renal cell carcinomas (ESC RCC) revealed recurrent and mutually exclusive somatic homozygous loss of tuberous sclerosis complex family genes. This observation provides greater insight into the unique biology of this novel type of tumor and potentially expands the therapeutic options for ESC RCC patients. Take Home Message Next generation sequencing characterization of eosinophilic solid and cystic renal cell carcinoma revealed mutually exclusive, somatic, bi-allelic loss of either TSC1 or TSC2 , a pattern distinct from the morphologically similar tuberous sclerosis complex renal cell carcinoma, in which the Knudson's two-hit in tumor suppressor genes always includes a germline component. [ABSTRACT FROM AUTHOR]

Background There is a critical need for improved prognostic discrimination in patients with renal cell carcinoma (RCC) given the increasing awareness that some patients may be managed with active surveillance, while others with higher-risk disease might benefit from adjuvant therapy following surgery. Objective To determine whether a multigene proliferation signature predicts long-term oncologic outcomes in surgically resected RCC. Design, setting, and participants The cell cycle proliferation (CCP) score was determined after radical nephrectomy for localized clear cell, papillary, or chromophobe RCC in 565 patients. Outcome measurements and statistical analysis The primary end point was disease-specific mortality (DSM), and disease recurrence was a secondary end point. Association with outcomes was evaluated by Cox proportional hazards survival analysis. The CCP score was compared with the Karakiewicz nomogram, and a composite (R-CCP) score was developed. Results and limitations A total of 68 patients (12%) recurred and 32 (6%) died of disease within 5 yr of nephrectomy. The CCP score was an independent predictor of recurrence (hazard ratio [HR] 1.50, 95% confidence interval [CI] 1.07–2.09) and DSM (HR 2.49, 95% CI 1.53–4.04) after adjusting for clinical variables using the baseline nomogram. The composite R-CCP score gave a Harrell's concordance index of 0.87 and stratified patients into low- ( n = 338) and high-risk ( n = 202) categories with 99% and 84% cancer-specific survival probabilities, respectively ( p < 0.001). Conclusions The CCP score is a significant, independent predictor of long-term oncologic outcomes in patients who have undergone nephrectomy for RCC. Combining the molecular classifier with baseline clinical variables allows for accurate, patient-specific risk assessment for use in guiding clinical management. Patient summary In this study, we sought to understand how well gene expression information from individual kidney tumors can predict cancer recurrence and death following surgical removal. We found that the combination of the gene expression test and clinical characteristics provides an accurate prognostic assessment to help inform clinical decisions. [ABSTRACT FROM AUTHOR]

The long noncoding RNA SChLAP1 is overexpressed in a subset of prostate cancers (PCa), and high SChLAP1 expression by in situ hybridization (ISH) independently predicts biochemical recurrence after radical prostatectomy. Importantly, although biochemical recurrence is a significant clinical outcome, it is not a validated surrogate for PCa-related mortality. Thus, we evaluated the association between SChLAP1 expression and development of lethal PCa in a large cohort of American men with PCa and long-term follow-up. SChLAP1 ISH was performed on tissue microarrays containing representative formalin-fixed, paraffin-embedded PCa tissue from all patients and scored using a semiquantitative method (ISH score range 0–400). Hazard ratios (HRs) for the association between SChLAP1 expression and time to development of lethal PCa were estimated using multivariable Cox regression analysis. Of the 937 patients evaluated, 89 (9.5%) had high SChLAP1 expression (ISH score ≥100), which in patients treated with radical prostatectomy was strongly associated with development of lethal PCa independent of age, Gleason score, pathologic stage, and PTEN status (HR 2.2, 95% confidence interval 1.1–4.1). These results suggest that SChLAP1 may be a useful tissue-based biomarker for identifying PCa patients at higher risk of lethal progression. Patient summary We examined expression of the RNA molecule SChLAP1 in a large group of prostate cancer patients with long-term follow-up and found that patients with high SChLAP1 expression had a significantly higher chance of developing lethal disease. [ABSTRACT FROM AUTHOR]

Genomic biomarkers have the potential to better predict the outcome and select the most appropriate treatment for patients with kidney cancer; however, further research is needed before any of the biomarkers currently developed are adopted into clinical practice. Dramatic gains in our understanding of the molecular biology of clear cell renal cell carcinoma (ccRCC) have created a foundation for clinical translation to improve patient care. To review and contextualize clinically impactful data surrounding genomic biomarkers in ccRCC. A systematic literature search was conducted focusing on genomic-based biomarkers with an emphasis on studies assessing clinical outcomes. The advancement of tumor sequencing techniques has led to a rapid increase in the knowledge of the molecular underpinnings of ccRCC and with that the discovery of multiple candidate genomic biomarkers. These include somatic gene mutations such as VHL , PBRM1, SETD2, and BAP1 ; copy number variations; transcriptomic multigene signatures; and specific immune cell populations. Many of these biomarkers have been assessed for their association with survival and a smaller number as potential predictors of a response to systemic therapy. In this scoping review, we discuss many of these biomarkers in detail. Further studies are needed to continue to refine and validate these molecular tools for risk stratification, with the ultimate goal of improving clinical decision-making and patient outcomes. While no tissue or blood-based biomarkers for ccRCC have been incorporated into routine clinical practice to date, the field continues to expand rapidly. There remains a critical need to develop and validate these tools in order to improve the care for patients with kidney cancer. Genomic biomarkers have the potential to better predict outcome and select the most appropriate treatment for patients with kidney cancer; however, further research is needed before any of these currently developed biomarkers are adopted into clinical practice. [ABSTRACT FROM AUTHOR]

Molecular biomarkers aim to address the established limitations of clinicopathologic factors to accurately risk stratify patients with prostate cancer (PCa). Questions remain as to whether sufficient evidence supports adoption of these biomarkers for clinical use. To perform a systematic review of the available evidence supporting the clinical utility of the Decipher genomic classifier (GC). The review was performed as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines by searching PubMed and conference abstracts from January 2010 to June 2020. Evidence was then graded using the criteria of Simon et al (Simon RM, Paik S, Hayes DF. Use of archived specimens in evaluation of prognostic and predictive biomarkers. J Natl Cancer Inst 2009;101:1446–52) and American Urology Association (AUA) criteria. In total, 42 studies and 30 407 patients were included. GC performance data were available for localized, postprostatectomy, nonmetastatic castration-resistant, and metastatic hormone-sensitive PCa as part of retrospective studies (n = 12 141), prospective registries (n = 17 053), and prospective and post hoc randomized trial analyses (n = 1213). In 32 studies (n = 12 600), the GC was independently prognostic for all study endpoints (adverse pathology, biochemical failure, metastasis, and cancer-specific and overall survival) on multivariable analysis and improved the discrimination over standard of care in 24 studies (n = 8543). GC use changed the management in active surveillance (number needed to test [NNT] = 9) and postprostatectomy (NNT = 1.5–4) settings in five studies (n = 4331). Evidence strength was levels 1 and 2 by the Simon criteria for all disease states other than high-risk PCa, and grades A and B by AUA criteria depending on disease state. Consistent data are now present from diverse levels of evidence, which when viewed together, have demonstrated clinical utility of the GC in PCa. The utility of the GC is strongest for intermediate-risk PCa and postprostatectomy decision-making. In this paper, we review the evidence of the Decipher genomic classification tool for men with prostate cancer. We found consistent evidence that the test helps identify which cancers are more or less aggressive, which in turn aids in personalized treatment decision-making. The Decipher genomic classifier is a risk-stratification tool for men with prostate cancer that, when combined with standard clinicopathologic factors, demonstrates superior performance to clinicopathologic factors alone. This has been shown to change management in prospective trials and identify patients less likely to benefit from treatment intensification. [ABSTRACT FROM AUTHOR]

Active surveillance (AS) is an accepted management strategy for some patients with renal cell carcinoma, but limited tools are available to identify optimal AS candidates. While renal mass biopsy provides diagnostic information, risk stratification based on biopsy is limited. In a retrospective, multi-institutional cohort that underwent renal mass biopsy followed by surgery, we assessed the ability of the cell cycle proliferation (CCP) score from clinical biopsy specimens to predict adverse surgical pathology (ie, grade 3–4, pT stage ≥3, metastasis at surgery, or papillary type II). Of 202 patients, 98 (49%) had adverse surgical pathology. When added to a baseline model including age, sex, race, lesion size, biopsy grade, and histology, CCP score was significantly associated with adverse pathology when modeled as a binary (odds ratio [OR]: 2.44 for CCP score >0, p = 0.02) and a continuous (OR: 1.72 per one unit increase, p = 0.04) variable. Discriminative performance measured by the area under the curve (AUC) improved from 0.73 in the baseline model to 0.75 and 0.76 in models including the CCP score. In the subgroup of patients with nephrectomy CCP score available (n = 67), the biopsy-based model outperformed the nephrectomy-based model (AUC 0.78 vs 0.75). These data support prospective assessment of biopsy CCP score to confirm clinical validity and assess potential utility in AS-eligible patients. In patients with localized renal cell carcinoma who underwent renal mass biopsy followed by surgery, the cell cycle proliferation score from clinical biopsy specimens could predict adverse surgical pathology. In patients with localized renal cell carcinoma who underwent tumor biopsy followed by partial or radical nephrectomy, the cell cycle proliferation score derived from biopsy tissue provided independent prognostic information regarding the risk of adverse surgical pathology. [ABSTRACT FROM AUTHOR]

Renal cell carcinomas (RCCs) are a heterogeneous group of neoplasms. Recent sequencing studies revealed various molecular features associated with histologic RCC subtypes, including chromophobe renal cell carcinoma (ChRCC). To characterize the gene expression and biomarker signatures associated with ChRCC. We performed integrative analysis on RNA sequencing data available from 1049 RCC specimens from The Cancer Genome Atlas and in-house studies. Our workflow identified genes relatively enriched in ChRCC, including Forkhead box I1 (FOXI1), Rh family C glycoprotein (RHCG), and LINC01187. We assessed the expression pattern of FOXI1 and RHCG protein by immunohistochemistry (IHC) and LINC01187 mRNA by RNA in situ hybridization (RNA-ISH) in whole tissue sections representing a cohort of 197 RCC cases, including both primary and metastatic tumors. The FOXI1 and RHCG IHC staining, as well as the LINC01187 RNA-ISH staining, was evaluated in each case for intensity, pattern, and localization of expression. All primary and metastatic classic ChRCCs demonstrated homogeneous positive labeling for FOXI1, RHCG proteins, and LINC01187 transcript. Unclassified RCC with oncocytic features, oncocytoma, and hybrid oncocytic tumor, as well as all but two cases of eosinophilic ChRCC also stained positive. Importantly, metastatic and primary RCC of all other subtypes did not demonstrate any unequivocal staining for FOXI1, RHCG, or LINC01187. In normal kidney, FOXI1, RHCG, and LINC01187 were detected in the distal nephron segment, specifically in intercalated cells. Two cases of eosinophilic ChRCC with focal expression of FOXI1 and LINC01187 , and Golgi-like RHCG staining were found to contain MTOR gene mutations upon DNA sequencing. We demonstrate a pipeline for the identification and validation of RCC subtype–specific biomarkers that can aid in the confirmation of cell of origin and may facilitate accurate classification and diagnosis of renal tumors. FOXI1 , RHCG , and LINC01187 are lineage-specific signature genes for chromophobe renal cell carcinoma. We performed integrative RNA sequencing analysis from >1000 renal cell carcinoma (RCC) specimens, identified genes enriched in chromophobe RCC, experimentally validated the expression pattern of the top three genes (FOXI1 , RHCG , and LINC01187), and revealed that the cell of origin of chromophobe RCC is intercalated cells. [ABSTRACT FROM AUTHOR]

Abstract Background Integrated molecular profiling has identified intrinsic expression-based bladder cancer molecular subtypes. Despite frequent histological diversity, robustness of subtypes in paired conventional (urothelial) and squamous components of the same bladder tumor has not been reported. Objective To assess the impact of histological heterogeneity on expression-based bladder cancer subtypes. Design, setting, and participants We performed clinically applicable, targeted DNA and/or RNA sequencing (multiplexed DNA and RNA sequencing [mxDNAseq and mxRNAseq, respectively]) on 112 formalin-fixed paraffin-embedded (FFPE) bladder cancer samples, including 12 cases with paired urothelial/squamous components and 21 bladder cancer cell lines. Outcome measurements and statistical analysis Unsupervised hierarchical and consensus clustering of target gene expression enabled derivation of basal/luminal molecular subtyping. Results and limitation Across 21 bladder cancer cell lines, our custom mxRNAseq panel was highly concordant with whole transcriptome sequencing, and assessed targets robustly determined expression-based basal/luminal subtypes from The Cancer Genome Atlas data (in silico) and internally sequenced FFPE tissues. Frequent deleterious TP53 (56%) and activating hotspot PIK3CA (30%) somatic mutations were seen across 69 high-quality tissue samples. Potentially targetable focal ERBB2 (6%) or EGFR (6%) amplifications were also identified, and a novel subgene copy-number detection approach is described. Combined DNA/RNA analysis showed that focally amplified samples exhibit outlier EGFR and ERBB2 expression distinct from subtype-intrinsic profiles. Critically, paired urothelial and squamous components showed divergent basal/luminal status in three of 12 cases (25%), despite identical putatively clonal prioritized somatic genomic alterations. Limitations include lack of profiled paired normal tissues for formal somatic alteration determination, and the need for formal analytical and clinical validation. Conclusions Our results support the feasibility of clinically relevant integrative bladder cancer profiling and challenge the intrinsic nature of expression subtypes in histologically diverse bladder cancers. Patient summary A targeted RNA sequencing assay is capable of assessing gene expression-based subtypes in individual components of clinical bladder cancer tissue specimens. Different histological components of the same tumor may yield divergent expression profiles, suggesting that expression-based subtypes should be interpreted with caution in heterogeneous cancers. Take Home Message Different histological components of heterogeneous bladder cancer tumors may exhibit divergent expression profiles, complicating interpretation of expression-based molecular subtypes assessed in bulk tumor specimens. This presents important considerations for potential precision medicine applications of current molecular subtypes, warranting further study. [ABSTRACT FROM AUTHOR]

Abstract Background Intermediate clinical endpoints (ICEs) prognostic for overall survival (OS) are needed for men receiving postprostatectomy radiation therapy (PORT) to improve clinical trial design. Objective To identify a potential ICE for men receiving PORT. Design, setting, and participants We performed an institutional review board–approved multi-institutional retrospective study of 566 men consecutively treated with PORT at tertiary care centers from 1986 to 2013. The median follow-up was 8.2 yr. Outcome measurements and statistical analysis Biochemical failure (BF), distant metastases (DM), and castrate-resistant prostate cancer (CRPC) were evaluated for correlation with OS and assessed as time-dependent variables in a multivariable Cox proportional hazards model and in landmark analyses at 1, 3, 5, and 7 yr after PORT. Cross-validated concordance (c) indices were used to assess model discrimination. Results and limitations OS at 1, 3, 5, and 7 yr after PORT was 98%, 95%, 90%, and 82%, respectively. In a time-varying model controlling for clinical and pathologic variables, BF (hazard ratio [HR] 2.32, 95% confidence interval [CI] 1.45–3.71; p < 0.001), DM (HR 6.52, 95% CI 4.20–10.1; p < 0.001), and CRPC (HR 2.47, 95% CI 1.56–3.92; p < 0.001) were associated with OS. In landmark analyses, 5-yr DM had the highest c index when adjusting for baseline covariates (0.78), with 5-yr DM also providing the greatest increase in discriminatory power over a model only including baseline covariates. These findings require validation in prospective randomized data. Conclusions While limited by the retrospective nature of the data, 5-yr DM is associated with lower OS following PORT, outperforming the prognostic capability of BF and CRPC at 1, 3, 5, or 7 yr after treatment. Confirmation of this ICE as a surrogate for OS is needed from randomized trial data so that it can be incorporated into future clinical trial design. Patient summary We assessed potential intermediate clinical endpoints prognostic for overall survival in a cohort of men receiving radiotherapy after prostatectomy. We identified the development of metastatic disease within 5 yr after treatment as the strongest predictor of overall survival. Take Home Message We assessed potential intermediate clinical endpoints prognostic for overall survival in a cohort of men receiving radiotherapy after prostatectomy. We identified the development of metastatic disease within 5 yr after treatment as the strongest predictor of overall survival. [ABSTRACT FROM AUTHOR]

Background Prostate cancer patients who have a detectable prostate-specific antigen (PSA) postprostatectomy may harbor pre-existing metastatic disease. To our knowledge, none of the commercially available genomic biomarkers have been investigated in such men. Objective To evaluate if a 22-gene genomic classifier can independently predict development of metastasis in men with PSA persistence postoperatively. Design, setting, and participants A multi-institutional study of 477 men who underwent radical prostatectomy (RP) between 1990 and 2015 from three academic centers. Patients were categorized as detectable PSA ( n = 150) or undetectable ( n = 327) based on post-RP PSA nadir ≥0.1 ng/ml. Outcome measurements and statisitical analysis Cumulative incidence curves for metastasis were constructed using Fine-Gray competing risks analysis. Penalized Cox univariable and multivariable (MVA) proportional hazards models were performed to evaluate the association of the genomic classifier with metastasis. Results and limitations The median follow-up for censored patients was 57 mo. The median time from RP to first postoperative PSA was 1.4 mo. Detectable PSA patients were more likely to have higher adverse pathologic features compared with undetectable PSA patients. On MVA, only genomic high-risk (hazard ratio [HR]: 5.95, 95% confidence interval [CI]: 2.02–19.41, p = 0.001), detectable PSA (HR: 4.26, 95% CI: 1.16–21.8, p = 0.03), and lymph node invasion (HR: 12.2, 95% CI: 2.46–70.7, p = 0.003) remained prognostic factors for metastasis. Among detectable PSA patients, the 5-yr metastasis rate was 0.90% for genomic low/intermediate and 18% for genomic high risk ( p < 0.001). Genomic high risk remained independently prognostic on MVA (HR: 5.61, 95% CI: 1.48–22.7, p = 0.01) among detectable PSA patients. C-index for Cancer of the Prostate Risk Assessment Postsurgical score, Gandaglia nomogram, and the genomic classifier plus either Cancer of the Prostate Risk Assessment Postsurgical score or Gandaglia were 0.69, 0.68, and 0.82 or 0.81, respectively. Sample size was a limitation. Conclusions Despite patients with a detectable PSA harboring significantly higher rates of aggressive clinicopathologic features, Decipher independently predicts for metastasis. Prospective validation of these findings is warranted and will be collected as part of the ongoing randomized trial NRG GU-002. Patient summary Decipher independently predicted metastasis for patients with detectable prostate-specific antigen after prostatectomy. [ABSTRACT FROM AUTHOR]