The effect of a fermented soy beverage among patients with localized prostate cancer prior to radical prostatectomy.

BACKGROUND: Fermented soy products have shown to possess inhibitory effects on prostate cancer (PCa). We evaluated the effect of a fermented soy beverage (Q-Can®), containing medium-chain triglycerides, ketones and soy isoflavones, among men with localized PCa prior to radical prostatectomy. METHODS: We conducted a placebo-controlled, double-blind randomized trial of Q-Can®. Stratified randomization (Cancer of the Prostate Risk Assessment (CAPRA) score at diagnosis) was used to assign patients to receive Q-Can® or placebo for 2-5 weeks before RP. Primary endpoint was change in serum PSA from baseline to end-of-study. We assessed changes in other clinical and pathologic endpoints. The primary ITT analysis compared PSA at end-of-study between randomization arms using repeated measures linear mixed model incorporating baseline CAPRA risk strata. RESULTS: We randomized 19 patients, 16 were eligible for analysis of the primary outcome. Mean age at enrollment was 61, 9(56.2%) were classified as low and intermediate risk, and 7(43.8%) high CAPRA risk. Among patients who received Q-Can®, mean PSA at baseline and end-of-study was 8.98(standard deviation, SD 4.07) and 8.02ng/mL(SD 3.99) compared with 8.66(SD 2.71) to 9.53ng/mL(SD 3.03), respectively, (Difference baseline - end-of-study, p = 0.36). There were no significant differences in Gleason score, clinical stage, surgical margin status, or CAPRA score between treatment arms (p > 0.05), and no significant differences between treatment arms in end-of-study or change in lipids, testosterone and FACT-P scores (p > 0.05). CONCLUSIONS: Short exposure to Q-Can® among patients with localized PCa was not associated with changes in PSA levels, PCa characteristics including grade and stage or serum testosterone. Due to early termination from inability to recruit, study power, was not achieved.

Utilization of A Third-Party Partnership in Tele-genetic Risk Assessment Program in Genitourinary Oncology.

OBJECTIVE: To meet the increasing demands of genetic risk assessment for genitourinary cancers due to expanded clinical guidelines, we established an academic/industry partnership to create a streamlined workflow to overcome the barriers to access to care. MATERIALS AND METHODS: Genome Medical offers multilingual genetic counseling. A pilot program evaluated patients at risk for hereditary genitourinary syndromes. Between 1/1/20 and 07/01/22, all patients in need of germline testing were offered hybrid in-clinic telehealth pre-test counseling and when indicated, genetic testing. Post-test counseling was offered based on results and encouraged if positive. Testing results, patient satisfaction, and costs were evaluated. RESULTS: A total of 146 of 182 (80.0%) patients agreed to participate, with 130 (89.0%) completing pre-test counseling. Median age was 65 (range 22-95), with 91% being male and approximately 60% having prostate cancer. The median time from referral to pre-test counseling was 11 days (IQR 7-20). After assessment, testing was recommended for 127 (97.7%) of which 123 (96.8%) completed testing. The median time from testing to result release was 15 days (IQR 10 - 20.8). Forty (32.5%) had post-test counseling. Reimbursement by private insurers increased annually from $17.2 to $52.4. Patient satisfaction was high with a mean Genetic Counselor Satisfaction Scale of 27.9 out of 30. CONCLUSIONS: Our program provided high patient satisfaction, rapid access to genetic counseling, prompt genetic testing, timely release of results, and was cost-effective compared to traditional models. This approach is scalable across community and academic settings and across cancer types.

Adjuvant Everolimus in Patients with Completely Resected, Very High-risk Renal Cell Carcinoma of Clear Cell Histology: Results from the Phase 3 Placebo-controlled SWOG S0931 (EVEREST) Trial.

BACKGROUND AND OBJECTIVE: EVEREST is a phase 3 trial in patients with renal cell cancer (RCC) at intermediate-high or very high risk of recurrence after nephrectomy who were randomized to receive adjuvant everolimus or placebo. Longer recurrence-free survival (RFS) was observed with everolimus (hazard ratio [HR] 0.85, 95% confidence interval [CI] 0.72-1.00; p = 0.051), but the nominal significance level (p = 0.044) was not reached. To contextualize these results with positive phase 3 trials of adjuvant sunitinib and pembrolizumab, we conducted a secondary analysis in a similar population of EVEREST patients with very high-risk disease and clear cell histology. METHODS: Postnephrectomy patients with any clear cell component and very high-risk disease, defined as pT3a (grade 3-4), pT3b-c (any grade), T4 (any grade), or node-positive status (N+), were identified. A Cox regression model stratified by performance status was used to compare RFS and overall survival (OS) between the treatment arms. KEY FINDINGS AND LIMITATIONS: Of 1499 patients, 717 had clear cell histology and very high-risk disease; 699 met the eligibility criteria, of whom 348 were randomized to everolimus arm, and 351 to the placebo arm. Patient characteristics were similar between the arms. Only 163/348 (47%) patients in the everolimus arm completed all treatment as planned, versus 225/351 (64%) in the placebo arm. Adjuvant everolimus resulted in a statistically significant improvement in RFS (HR 0.80; 95%CI 0.65-0.99, p = 0.041). Evidence of a survival benefit was not seen (HR 0.85; 95%CI 0.64-1.14, p = 0.3) CONCLUSIONS AND CLINICAL IMPLICATIONS: In patients with clear cell RCC at very high-risk for recurrence, adjuvant everolimus resulted in significantly improved RFS compared to placebo but resulted in a high discontinuation rate due to adverse events. Although the treatment HR for OS was consistent with RFS findings, it did not reach statistical significance. With a focus on risk stratification tools and/or biomarkers to minimize toxicity risk in those not likely to benefit, this information can help inform the design of future adjuvant trials in high-risk RCC PATIENT SUMMARY: We assessed treatment with everolimus in comparison to placebo after complete surgical removal of clear-cell kidney cancer at very high risk of recurrence. We found that survival outcomes were better for patients treated with everolimus, although these patients had a higher rate of side effects.

Sarcomatoid and Rhabdoid Renal Cell Carcinoma: Clinical, Pathologic, and Molecular Genetic Features.

Renal cell carcinoma (RCC) with sarcomatoid and rhabdoid morphologies has an aggressive biological behavior and a typically poor prognosis. The current 2022 WHO classification of renal tumors does not include them as distinct histologic entities but rather as transformational changes that may arise in a background of various distinct histologic types of RCC. The sarcomatoid component shows malignant spindle cells that may grow as intersecting fascicles, which is reminiscent of pleomorphic undifferentiated sarcoma. The rhabdoid cells are epithelioid cells with eccentrically located vesicular nuclei with prominent nucleoli and large intracytoplasmic eosinophilic inclusions. Studies have shown that RCCs with sarcomatoid and rhabdoid differentiation have distinctive molecular features. Sarcomatoid RCC harbors shared genomic alterations in carcinomatous and rhabdoid components, but also enrichment of specific genomic alterations in the sarcomatoid element, suggesting molecular pathways for development of sarcomatoid growth from a common clonal ancestor. Rhabdoid differentiation also arises through clonal evolution although less is known of specific genomic alterations in rhabdoid cells. Historically, treatment has lacked efficacy, although recently immunotherapy with PD-1/PD-L1/CTLA-4 inhibitors has produced significant clinical responses. Reporting of sarcomatoid and rhabdoid features in renal cell carcinoma is required by the College of American Pathologists and the International Collaboration on Cancer Reporting. This manuscript reviews the clinical, pathologic, and molecular features of sarcomatoid RCC and rhabdoid RCC with emphasis on the morphologic features of these tumors, significance of diagnostic recognition, the molecular mechanisms of tumorigenesis and differentiation along sarcomatoid and rhabdoid lines, and advances in treatment, particularly immunotherapy.

Multi-ancestry genome-wide association study of kidney cancer identifies 63 susceptibility regions.

Here, in a multi-ancestry genome-wide association study meta-analysis of kidney cancer (29,020 cases and 835,670 controls), we identified 63 susceptibility regions (50 novel) containing 108 independent risk loci. In analyses stratified by subtype, 52 regions (78 loci) were associated with clear cell renal cell carcinoma (RCC) and 6 regions (7 loci) with papillary RCC. Notably, we report a variant common in African ancestry individuals ( rs7629500 ) in the 3' untranslated region of VHL, nearly tripling clear cell RCC risk (odds ratio 2.72, 95% confidence interval 2.23-3.30). In cis-expression quantitative trait locus analyses, 48 variants from 34 regions point toward 83 candidate genes. Enrichment of hypoxia-inducible factor-binding sites underscores the importance of hypoxia-related mechanisms in kidney cancer. Our results advance understanding of the genetic architecture of kidney cancer, provide clues for functional investigation and enable generation of a validated polygenic risk score with an estimated area under the curve of 0.65 (0.74 including risk factors) among European ancestry individuals.

NCCN Guidelines® Insights: Kidney Cancer, Version 2.2024.

The NCCN Guidelines for Kidney Cancer provide multidisciplinary recommendations for diagnostic workup, staging, and treatment of patients with renal cell carcinoma (RCC). These NCCN Guidelines Insights focus on the systemic therapy options for patients with advanced RCC and summarize the new clinical data evaluated by the NCCN panel for the recommended therapies in Version 2.2024 of the NCCN Guidelines for Kidney Cancer.

Gain of Chromosome 5q Predicts a Favorable Prognosis in Localized Renal Cell Carcinoma.

Approximately 65% of renal cell carcinomas (RCC) are diagnosed at a localized stage. We investigated the chromosome 5q gain impact on disease-free survival (DFS) in RCC patients. Overall, 676 patients with stages 1-2 RCC and having cytogenetic analysis were included. Gain of 5q was observed in 108 patients, more frequently in clear cell (ccRCC) than non-clear cell tumors. Gain of 5q is likely an independent prognostic factor since the concerned patients had a decreased recurrence risk in stages 1-2 RCC, confirmed in multivariable analysis. Detecting 5q gain could enhance recurrence risk assessment, allowing tailored post-surgery surveillance, and reducing unnecessary treatments.

CD70 is Consistently Expressed in Primary and Metastatic Clear Cell Renal Cell Carcinoma.

BACKGROUND: CD70 is commonly overexpressed in renal cell carcinoma and is minimally expressed in normal human tissue, making it a potential therapeutic target for patients with advanced renal cell carcinoma. The expression frequency of CD70 in metastatic renal cell carcinoma is not well established. MATERIALS AND METHODS: We assessed CD70 immunohistochemistry in 391 primary renal tumors and 72 metastatic renal cell carcinomas on a tissue microarray including 26 sets of paired primary and metastatic tumors. RESULTS: CD70 was frequently overexpressed in clear cell carcinoma, with a significantly lower expression rate in papillary renal cell carcinoma (P < .0001). No expression of CD70 was detected in other types of renal tumors and normal renal parenchyma. In clear cell renal cell carcinoma, CD70 expression was significantly correlated with hypoxia pathway proteins, corroborating with a recent study suggesting that CD70 is a downstream target gene of hypoxia-inducible factor. While higher expression levels were observed in males and non-Caucasians, CD70 expression was not associated with tumor grade, sarcomatoid differentiation, stage, or cancer-specific survival. Further, analysis of 26 paired primary and metastatic tumors from same individuals revealed a concordance rate of 85%. CONCLUSION: Our findings validated CD70 as a promising therapeutic target for patients with metastatic clear cell renal cell carcinoma. The utility of primary tumor tissue as surrogate samples for metastatic clear cell carcinoma awaits future CD70-targeted clinical trials.

Social determinants as predictors of resection and long-term mortality in Black patients with non-small cell lung cancer.

BACKGROUND: Minorities diminished returns theory posits that socioeconomic attainment conveys fewer health benefits for Black than White individuals. The current study evaluates the effects of social constructs on resection rates and survival for non-small cell lung cancer (NSCLC). METHODS: Patients with potentially resectable NSCLC stage IA to IIIA were identified using the 2004 to 2017 National Cancer Database. Patients were stratified into quartiles based on population-level education and income. Logistic regression was used to predict risk-adjusted resection rates. Mortality was assessed with Cox proportional hazard modeling. RESULTS: Of the 416,025 patients identified, 213,643 (51.4%) underwent resection. Among White patients, the lowest income (adjusted odds ratio 0.76, 95% confidence interval 0.74-0.78, P < .01) and education quartiles (adjusted odds ratio 0.82, 95% confidence interval 0.79-0.84, P < .01) were associated with decreased odds of resection. The lowest education quartile among Black patients was not associated with lower resection rates. The lowest income quartile (adjusted odds ratio 0.67, 95% CI 0.61-0.74, P < .01) was associated with reduced resection. White patients in the lowest education and income quartiles experienced increased hazard of 5-year mortality (adjusted hazard ratio 1.13, 95% CI 1.11-1.15, P < .01 and adjusted hazard ratio 1.08, 95% CI 1.06-1.11, P < .01 respectively). In Black patients, there were no significant differences in 5-year survival between Black patients in the highest education and income quartiles and those in the lowest quartiles. CONCLUSION: Among Black patients with NSCLC, educational attainment is not associated with increased resection rates. In addition, higher education and income were not associated with improved 5-year survival. The diminished gains experienced by Black patients, compared to Whites patients, illustrate the presence of pervasive race-specific mechanisms in observed inequalities in cancer outcomes.

Persistent racial disparities in refusal of resection in non-small cell lung cancer patients at high-volume and Black-serving institutions.

BACKGROUND: Surgical resection is the standard of care for early-stage non-small cell lung cancer. Black patients have higher surgical refusal rates than White patients. We evaluated factors associated with the refusal of resection and subsequent non-small cell lung cancer outcomes. METHODS: We identified patients with non-small cell lung cancer stages IA to IIIA eligible for surgical resection (lobectomy or pneumonectomy) listed between 2004 and 2017 in the National Cancer Database. We stratified hospitals by the proportion of Black patients served and lung cancer resection volume. We used multivariable regression models to identify factors associated with refusal of resection and assessed 5-year mortality using Kaplan-Meier analysis and Cox proportional hazard modeling. RESULTS: Of 221,396 patients identified, 7,753 (3.5%) refused surgery. Black race was associated with increased refusal (adjusted odds ratio 2.06, 95% confidence interval 1.90-2.22). Compared to White race, Black race was associated with increased refusal across the highest (adjusted odds ratio 2.29, 95% confidence interval 1.94-2.54), intermediate (adjusted odds ratio 2.05, 95% confidence interval 1.78-2.37), and lowest (adjusted odds ratio 1.77, 95% confidence interval 1.58-1.99) volume tertiles. Similarly, Black race was associated with increased refusal across the highest (adjusted odds ratio 1.97, 95% confidence interval 1.78-2.17), intermediate (adjusted odds ratio 2.08, 95% confidence interval 1.80-2.40), and lowest (adjusted odds ratio 1.53, 95% confidence interval 1.13-2.06) Black-serving tertiles. However, surgical resection yielded similar 5-year survival for Black and White patients. CONCLUSION: Racial disparities in non-small cell lung cancer surgery refusal persist regardless of hospital volume or proportion of Black patients served. These findings suggest that a better understanding of patient and patient-provider level interventions could facilitate a better understanding of treatment decision-making.

Summary of Research: Adjuvant Nivolumab Plus Ipilimumab Versus Placebo for Localized Renal Cell Carcinoma After Nephrectomy (CheckMate 914): A Double-Blind, Randomized, Phase 3 Trial.

This is a summary of a research article reporting Part A of the CheckMate 914 study (NCT03138512; EudraCT 2016-004502-34). Following surgery to remove renal cell carcinoma (RCC), people with a high risk of the cancer returning received nivolumab plus ipilimumab (adjuvant therapy) or placebo to see if this risk was reduced. The results of this study showed that the risk of RCC returning or death was not changed with adjuvant nivolumab plus ipilimumab treatment compared with placebo. In addition, people treated with nivolumab plus ipilimumab had more side effects compared with people treated with placebo (89% versus 57%).

Adjuvant everolimus after surgery for renal cell carcinoma (EVEREST): a double-blind, placebo-controlled, randomised, phase 3 trial.

BACKGROUND: Patients undergoing resection of renal cell carcinoma are at risk of disease relapse. We evaluated the effectiveness of the mammalian target of rapamycin inhibitor everolimus administered after surgery. METHODS: In this randomised, double-blind, phase 3 trial, we enrolled adults with histologically confirmed renal cell carcinoma who had undergone a full surgical resection and were at intermediate-high or very high risk of recurrence at 398 academic and community institution centres in the USA. After nephrectomy, patients were randomly assigned (1:1) via a central web-based application using a dynamic balancing algorithm to receive 10 mg oral everolimus daily or placebo for 54 weeks. The primary endpoint was recurrence-free survival. Efficacy analyses included all eligible, randomly assigned patients; safety analysis included all patients who received treatment. This trial is registered with ClinicalTrials.gov, NCT01120249 and is closed to new participants. FINDINGS: Between April 1, 2011, and Sept 15, 2016, a total of 1545 patients were randomly assigned to receive everolimus (n=775) or placebo (n=770), of whom 755 assigned to everolimus and 744 assigned to placebo were eligible for inclusion in the efficacy analysis. With a median follow-up of 76 months (IQR 61-92), recurrence-free survival was longer with everolimus than with placebo (5-year recurrence-free survival 67% [95% CI 63-70] vs 63% [60-67]; stratified log-rank p=0·050; stratified hazard ratio [HR] 0·85, 95% CI 0·72-1·00; p=0·051) but did not meet the prespecified p value for statistical significance of 0·044. Recurrence-free survival was longer with everolimus than with placebo in the very-high-risk group (HR 0·79, 95% CI 0·65-0·97; p=0·022) but not in the intermediate-high-risk group (0·99, 0·73-1·35; p=0·96). Grade 3 or higher adverse events occurred in 343 (46%) of 740 patients who received everolimus and 79 (11%) of 723 who received placebo. INTERPRETATION: Postoperative everolimus did not improve recurrence-free survival compared with placebo among patients with renal cell carcinoma at high risk of recurrence after nephrectomy. These results do not support the adjuvant use of everolimus for renal cell carcinoma after surgery. FUNDING: US National Institutes of Health, National Cancer Institute, National Clinical Trials Network, Novartis Pharmaceuticals Corporation, and The Hope Foundation.

Disparate Utilization of Breast Conservation Therapy in the Surgical Management of Early-Stage Breast Cancer.

BACKGROUND: Despite evidence suggesting oncologic equipoise of breast conservation therapy (BCT) for early-stage (stages I and II) breast cancer, mastectomy is still widely utilized. PATIENTS AND METHODS: The 2004-2015 National Cancer Database was used to tabulate all adult women receiving mastectomy or BCT for early-stage breast cancer. Multivariable regression was used to evaluate factors associated with utilization of BCT, relative to mastectomy. RESULTS: Of 1,079,057 women meeting study criteria, 57.4% underwent BCT. BCT patients were older and more commonly White, compared to mastectomy. They were more commonly privately insured, in the highest income quartile, and treated at metropolitan, nonacademic institutions. After adjustment, increasing age (AOR 1.01/year), Black race (AOR 1.21, Ref: White), and care at a community hospital (AOR 1.08, Ref: Academic; all P< .05) were associated with increased odds of undergoing BCT. Conversely, Asian or Pacific Islander (AAPI) race (AOR 0.74), Medicare (AOR 0.89) or Medicaid (AOR 0.95) coverage, and being in the lowest (AOR 0.95) and second lowest (AOR 0.98, all P< .05) income quartiles were associated with reduced odds of undergoing BCT. Finally, increasing tumor size (AOR 0.97, P< .05) was associated with decreased adjusted odds of undergoing BCT. CONCLUSION: Our results suggest persistent socioeconomic and racial disparities in BCT utilization for early-stage breast cancer. Directed strategies should be implemented in order to reduce treatment inequality in this patient population.

FH Variant Pathogenicity Promotes Purine Salvage Pathway Dependence in Kidney Cancer.

Fumarate accumulation due to loss of fumarate hydratase (FH) drives cellular transformation. Germline FH alterations lead to hereditary leiomyomatosis and renal cell cancer (HLRCC) where patients are predisposed to an aggressive form of kidney cancer. There is an unmet need to classify FH variants by cancer-associated risk. We quantified catalytic efficiencies of 74 variants of uncertain significance. Over half were enzymatically inactive, which is strong evidence of pathogenicity. We next generated a panel of HLRCC cell lines expressing FH variants with a range of catalytic activities, then correlated fumarate levels with metabolic features. We found that fumarate accumulation blocks de novo purine biosynthesis, rendering FH-deficient cells reliant on purine salvage for proliferation. Genetic or pharmacologic inhibition of the purine salvage pathway reduced HLRCC tumor growth in vivo. These findings suggest the pathogenicity of patient-associated FH variants and reveal purine salvage as a targetable vulnerability in FH-deficient tumors. SIGNIFICANCE: This study functionally characterizes patient-associated FH variants with unknown significance for pathogenicity. This study also reveals nucleotide salvage pathways as a targetable feature of FH-deficient cancers, which are shown to be sensitive to the purine salvage pathway inhibitor 6-mercaptopurine. This presents a new rapidly translatable treatment strategy for FH-deficient cancers. This article is featured in Selected Articles from This Issue, p. 1949.

Contemporary care patterns in the management of small renal masses.

OBJECTIVES: Incidental small renal masses (SRMs) now account for the majority of new diagnoses of renal cancers. Although there are established management guidelines, referral and management patterns can vary. We aimed to explore identification, practice patterns, and management of identified SRMs in an integrated health system. STUDY DESIGN: Retrospective analysis. METHODS: We identified patients with a newly diagnosed SRM measuring 3 cm or less from January 1, 2013, to December 31, 2017, at Kaiser Permanente Southern California. These patients were flagged at the time of radiographic identification to ensure adequate notification of findings. Diagnostic modality, referral, and treatment patterns were analyzed. RESULTS: Of 519 patients with SRMs, 65% were found on abdominal CT and 22% on renal/abdominal ultrasounds. Within 6 months, 70% of patients consulted with a urologist. Initial management patterns were as follows: active surveillance (60%), partial/radical nephrectomy (18%), and ablation (4%). Among 312 patients on surveillance, 14% eventually received treatment. The majority of patients (69.4%) did not receive guideline-recommended chest imaging for initial staging. Urologist visit within 6 months of SRM diagnosis was associated with increased adherence to staging (P = .003) and subsequent surveillance imaging (P < .001). CONCLUSIONS: In this contemporary analysis of an integrated health system's experience, referral to a urologist was associated with guideline-concordant staging and surveillance imaging. Frequent utilization of active surveillance with a low rate of progression to active treatment was noted in both groups. These findings shed light on care patterns upstream of urologic evaluation and support the need for clinical pathways to be implemented at the time of radiologic diagnosis.

Comparative analyses define differences between BHD-associated renal tumour and sporadic chromophobe renal cell carcinoma.

BACKGROUND: Birt-Hogg-Dubé (BHD) syndrome, caused by germline alteration of folliculin (FLCN) gene, develops hybrid oncocytic/chromophobe tumour (HOCT) and chromophobe renal cell carcinoma (ChRCC), whereas sporadic ChRCC does not harbor FLCN alteration. To date, molecular characteristics of these similar histological types of tumours have been incompletely elucidated. METHODS: To elucidate renal tumourigenesis of BHD-associated renal tumours and sporadic renal tumours, we conducted whole genome sequencing (WGS) and RNA-sequencing (RNA-seq) of sixteen BHD-associated renal tumours from nine unrelated BHD patients, twenty-one sporadic ChRCCs and seven sporadic oncocytomas. We then compared somatic mutation profiles with FLCN variants and RNA expression profiles between BHD-associated renal tumours and sporadic renal tumours. FINDINGS: RNA-seq analysis revealed that BHD-associated renal tumours and sporadic renal tumours have totally different expression profiles. Sporadic ChRCCs were clustered into two distinct clusters characterized by L1CAM and FOXI1 expressions, molecular markers for renal tubule subclasses. Increased mitochondrial DNA (mtDNA) copy number with fewer variants was observed in BHD-associated renal tumours compared to sporadic ChRCCs. Cell-of-origin analysis using WGS data demonstrated that BHD-associated renal tumours and sporadic ChRCCs may arise from different cells of origin and second hit FLCN alterations may occur in early third decade of life in BHD patients. INTERPRETATION: These data further our understanding of renal tumourigenesis of these two different types of renal tumours with similar histology. FUNDING: This study was supported by JSPS KAKENHI Grants, RIKEN internal grant, and the Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute (NCI), Center for Cancer Research.

Current Landscape of Genomic Biomarkers in Clear Cell Renal Cell Carcinoma.

CONTEXT: 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. OBJECTIVE: To review and contextualize clinically impactful data surrounding genomic biomarkers in ccRCC. EVIDENCE ACQUISITION: A systematic literature search was conducted focusing on genomic-based biomarkers with an emphasis on studies assessing clinical outcomes. EVIDENCE SYNTHESIS: 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. CONCLUSIONS: 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. PATIENT SUMMARY: 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.

Fumarate Hydratase Variants and Their Association With Paraganglioma/Pheochromocytoma.

OBJECTIVE: To clarify the link between germline variants in fumarate hydratase (FH), hereditary leiomyomatosis and renal cell cancer (HLRCC), and paraganglioma (PGL) and pheochromocytoma (PCC) we utilize a well-annotated hereditary cancer testing database. METHODS: Records of 120,061 patients receiving germline testing were obtained. FH variants were classified into 4 categories: autosomal dominant (AD) HLRCC variants, autosomal recessive (AR) fumarase deficiency (FMRD), variants, previously reported as PGL/PCC FH variants, and variants of unknown significance (VUS) not previously associated with PGL/PCC (NPP-VUS). Rates of PGL/PCC were compared with those with negative genetic testing. RESULTS: About 1.3% of individuals carried FH variants which were more common among individuals with PGL/PCC compared to those without (3.1% vs 1.3%, P < .0001). PGL/PCC rates were higher among individuals with PGL/PCC FH variants compared to those with negative genetic testing (22.2% vs 0.9%, P < .0001). Neither AD HLRCC variants (0.3% vs 0.9%, P = .35) nor AR FMRD variants (1.4% vs 0.9%, P = .19) carried an increased prevalence of PGL/PCC. An increased prevalence of PGL/PCC was detected in those with NPP-VUS (2.0% vs 0.9%, P = .0023). CONCLUSIONS: Certain FH variants confer an increased risk of PGL/PCC, but not necessarily HLRCC. While universal screening for PGL/PCC among all individuals with FH variants does not appear warranted, it should be considered in select high-risk PGL/PCC FH variants.