ABSTRACT
Deregulation of metabolism and disruption of genome integrity are hallmarks of cancer1. Increased levels of the metabolites 2-hydroxyglutarate, succinate and fumarate occur in human malignancies owing to somatic mutations in the isocitrate dehydrogenase-1 or -2 (IDH1 or IDH2) genes, or germline mutations in the fumarate hydratase (FH) and succinate dehydrogenase genes (SDHA, SDHB, SDHC and SDHD), respectively2-4. Recent work has made an unexpected connection between these metabolites and DNA repair by showing that they suppress the pathway of homology-dependent repair (HDR)5,6 and confer an exquisite sensitivity to inhibitors of poly (ADP-ribose) polymerase (PARP) that are being tested in clinical trials. However, the mechanism by which these oncometabolites inhibit HDR remains poorly understood. Here we determine the pathway by which these metabolites disrupt DNA repair. We show that oncometabolite-induced inhibition of the lysine demethylase KDM4B results in aberrant hypermethylation of histone 3 lysine 9 (H3K9) at loci surrounding DNA breaks, masking a local H3K9 trimethylation signal that is essential for the proper execution of HDR. Consequently, recruitment of TIP60 and ATM, two key proximal HDR factors, is substantially impaired at DNA breaks, with reduced end resection and diminished recruitment of downstream repair factors. These findings provide a mechanistic basis for oncometabolite-induced HDR suppression and may guide effective strategies to exploit these defects for therapeutic gain.
Subject(s)
Chromatin/metabolism , DNA Repair , Homologous Recombination , Neoplasms/metabolism , Signal Transduction , Ataxia Telangiectasia Mutated Proteins/metabolism , Cell Line, Tumor , Chromatin/drug effects , DNA Breaks/drug effects , DNA Repair/drug effects , Homologous Recombination/drug effects , Humans , Jumonji Domain-Containing Histone Demethylases/antagonists & inhibitors , Lysine Acetyltransferase 5/metabolism , Methylation/drug effects , Neoplasms/drug therapy , Neoplasms/genetics , Neoplasms/pathology , Poly(ADP-ribose) Polymerase Inhibitors/pharmacology , Signal Transduction/drug effectsABSTRACT
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.
Subject(s)
Carcinoma, Renal Cell , Kidney Neoplasms , United States , Adult , Humans , Everolimus/therapeutic use , Carcinoma, Renal Cell/drug therapy , Carcinoma, Renal Cell/surgery , Neoplasm Recurrence, Local/drug therapy , Sirolimus/therapeutic use , Adjuvants, Immunologic/therapeutic use , Kidney Neoplasms/drug therapy , Kidney Neoplasms/surgeryABSTRACT
OBJECTIVE: To evaluate the clinical significance of subtyping (type 1 vs 2) of papillary renal cell carcinoma (PRCC) in patients treated with targeted therapy, as well as the concordance, sensitivity and positive predictive value (PPV) of local review pathology review. METHODS: Patients with advanced refractory PRCC were randomised to receive sunitinib or cabozantinib, crizotinib or savolitinib, stratified by PRCC subtype (type 1, type 2, or not otherwise specified [NOS]/mixed) by local review. Central review was retrospectively conducted by three expert genitourinary pathologists who independently reviewed cases. The sensitivity and PPV of local review were estimated and outcomes [objective response rate (ORR), progression-free survival (PFS)] were summarised for treatment groups stratified by subtypes by central review. RESULTS: Amongst the 147 patients reviewed, the prevalence of individual subtypes varied by local or central review (type 1: 17.7% vs 29.3%; type 2: 53.1% vs 45.6%; NOS/mixed: 29.3% vs 25.2%), respectively. Individual cases were frequently reclassified and local pathology review demonstrated low sensitivity (type 1: 48%, 95% confidence interval [CI] 33, 65; type 2: 67%, 95% CI 55, 78; NOS/mixed: 43%, 95% CI 27, 61). The PPVs of local review were 80%, 57.7% and 37% for type 1, 2 and NOS/mixed, respectively. Compared to sunitinib, cabozantinib demonstrated improved PFS for both type 1 and type 2 PRCC subgroups (7.4 vs 9.0 and 2.9 vs 5.6 months, respectfully) as well as higher ORR. CONCLUSIONS: The PRCC subtype assignment did not identify a subset of patients with greater clinical benefit from cabozantinib, with significant discordance between local and central review. Our findings confirm the limited clinical value of pathological subtyping of metastatic PRCC, in line with the recent World Health Organisation 2022 guidelines. PATIENT SUMMARY: In this study, categorising papillary renal cell carcinoma into type 1 or 2 subtypes showed limited concordance between central and local pathological review and did not enrich for patients more likely to benefit from cabozantinib in the S1500 PAPMET trial.
ABSTRACT
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.
Subject(s)
Prostatectomy , Prostatic Neoplasms , Humans , Male , Prostatic Neoplasms/surgery , Prostatic Neoplasms/pathology , Prostatectomy/methods , Middle Aged , Double-Blind Method , Aged , Prostate-Specific Antigen/blood , Soy Foods , Fermentation , Beverages , Isoflavones/therapeutic use , Isoflavones/administration & dosage , Glycine max , Preoperative Care/methodsABSTRACT
BACKGROUND: There is growing evidence that partial nephrectomy (PN) and percutaneous cryoablation (PCA) yield comparable outcomes for patients with cT1a renal cell carcinoma (RCC), although the cost-effectiveness of both treatments still needs to be assessed. PURPOSE: To perform a cost-effectiveness analysis of PN and PCA for patients with cT1a RCC. MATERIALS AND METHODS: A decision analysis was created over a 5-year span from a healthcare payer's perspective computing expected costs and outcomes of PN and PCA in terms of quality-adjusted life-years (QALYs) and incremental cost-effectiveness (ICER). After each treatment, the following states were modelled using data from the recent literature: procedural complications, no evidence of disease (NED), local recurrence, metastases, and death from RCC- or non-RCC-related causes. Probabilistic and deterministic sensitivity analyses were performed. RESULTS: PCA and PN yielded health benefits of 3.68 QALY and 3.67 QALY. Overall expected costs were $20,491 and $26,478 for PCA and PN. On probabilistic sensitivity analysis, PCA was more cost-effective than PN in 84.78% of Monte Carlo simulations. PCA was more cost-effective until its complication risk was at least 38% higher than PN. PCA was more cost-effective than PN when (i) PCAs annual local recurrence risk was < 3.5% higher than that of PN in absolute values; (ii) PCAs annual metastatic risk was < 1.0% higher than that of PN; or (iii) PCAs annual cancer-specific mortality risk < 0.65% higher than that of PN. PCA remained cost-effective until its procedural cost is above $13,875. CONCLUSION: PCA appears to be more cost-effective than PN for the treatment of cT1a RCC, although the currently available evidence is of limited quality. PCA may be the better treatment strategy in the majority of scenarios varying procedural complications, recurrence, metastatic risk, and RCC-mortality in clinically plausible ranges. KEY POINTS: ⢠For patients with cT1a RCCs, PCA yields a comparable health benefit at lower costs compared to PN, making PCA the dominant and therefore more cost-effective treatment strategy over PN. ⢠PCA was more cost-effective than PN when (i) PCAs annual local recurrence risk was < 3.5% higher than PN in absolute values; (ii) PCAs annual metastatic risk was < 1.0% higher than PN; or (iii) PCAs annual cancer-specific mortality risk < 0.65% higher than PN. ⢠PCA is more cost-effective than PN for the treatment of cT1a RCC, and it remained so in the majority of scenarios varying procedural complications, recurrence, metastatic risk, and RCC mortality.
Subject(s)
Carcinoma, Renal Cell , Cryosurgery , Kidney Neoplasms , Humans , Carcinoma, Renal Cell/surgery , Carcinoma, Renal Cell/secondary , Kidney Neoplasms/surgery , Kidney Neoplasms/pathology , Cost-Benefit Analysis , Cryosurgery/adverse effects , Nephrectomy , Treatment OutcomeABSTRACT
With the expansion in cross-sectional imaging over the past few decades, there has been an increase in the number of incidentally detected renal masses and an increase in the incidence of renal cell carcinomas (RCCs). The complete characterization of an indeterminate renal mass on CT or MR images is challenging, and the authors provide a critical review of the best imaging methods and essential, important, and optional reporting elements used to describe the indeterminate renal mass. While surgical staging remains the standard of care for RCC, the role of renal mass CT or MRI in staging RCC is reviewed, specifically with reference to areas that may be overlooked at imaging such as detection of invasion through the renal capsule or perirenal (Gerota) fascia. Treatment options for localized RCC are expanding, and a multidisciplinary group of experts presents an overview of the role of advanced medical imaging in surgery, percutaneous ablation, transarterial embolization, active surveillance, and stereotactic body radiation therapy. Finally, the arsenal of treatments for advanced renal cancer continues to grow to improve response to therapy while limiting treatment side effects. Imaging findings are important in deciding the best treatment options and to monitor response to therapy. However, evaluating response has increased in complexity. The unique imaging findings associated with antiangiogenic targeted therapy and immunotherapy are discussed. An invited commentary by Remer is available online. Online supplemental material is available for this article. ©RSNA, 2021.
Subject(s)
Carcinoma, Renal Cell , Embolization, Therapeutic , Kidney Neoplasms , Carcinoma, Renal Cell/diagnostic imaging , Carcinoma, Renal Cell/therapy , Humans , Kidney , Kidney Neoplasms/diagnostic imaging , Kidney Neoplasms/therapy , Magnetic Resonance ImagingABSTRACT
PURPOSE: Everolimus decreases tumor volume of renal angiomyolipomas in patients with tuberous sclerosis. No prospective data are available regarding the effect of everolimus on the growth kinetics in patients with sporadic angiomyolipomas. We sought to determine the safety and efficacy of everolimus in the volumetric reduction of sporadic angiomyolipomas. MATERIALS AND METHODS: This multi-institutional, prospective, phase II trial, enrolled patients with 3 cm or larger sporadic angiomyolipomas who were candidates for surgical resection or percutaneous angioembolization. Patients received 10 mg everolimus daily for 4 planned 28-day cycles. Response was defined as a 25% or greater volumetric reduction of patient angiomyolipoma. Baseline, 4, 6 and 12-month volumetric analyses were performed using magnetic resonance imaging. Everolimus was discontinued in those with less than 25% volumetric reduction after 4 cycles. Those with 25% or greater volumetric reduction received 2 additional cycles. The primary outcomes were the efficacy of everolimus in the volumetric reduction of angiomyolipomas by 25% or more, and the safety and tolerability of everolimus. RESULTS: Overall 20 patients were enrolled at 5 centers. Of these patients 11 (55%) completed 4 cycles and 7 (35%) completed 6 cycles. Efficacy was demonstrated, with 10 of 18 (55.6%) patients exhibiting a 25% or greater reduction in tumor volume at 4 months (median 58.5%) and 10 of 14 (71.4%) patients exhibiting a 25% or greater reduction in tumor volume at 6 months (median 58.2%). Four (20%) patients were withdrawn due to protocol defined toxicities and 8 (40%) self-withdrew from the study due to side effects. CONCLUSIONS: Everolimus was effective in causing volumetric reduction of angiomyolipomas by 25% or greater in most patients but was associated with a high rate of treatment discontinuation.
Subject(s)
Angiomyolipoma/drug therapy , Antineoplastic Agents/therapeutic use , Everolimus/therapeutic use , Kidney Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Angiomyolipoma/etiology , Angiomyolipoma/pathology , Female , Humans , Kidney Neoplasms/etiology , Kidney Neoplasms/pathology , Magnetic Resonance Imaging , Male , Middle Aged , Prospective Studies , Tuberous Sclerosis/complicationsABSTRACT
INTRODUCTION: Renal mass biopsy (RMB) may not be indicated when the results are unlikely to impact management, such as in young and/or healthy patients and in elderly and/or frail patients. We analyzed the utility of RMB in three patient cohorts stratified by age-adjusted Charlson comorbidity index score (ACCI). MATERIALS AND METHODS: We identified patients with cT1a renal tumors in the National Cancer Database from 2004-2014. We combined age and Charlson-Deyo scores to identify young and/or healthy patients ('healthy-ACCI'), elderly and/or frail patients ('frail-ACCI'), and a reference cohort. We performed multivariable logistic regression to identify predictors of RMB and treatment. We evaluated the impact of RMB on management by analyzing the proportion of high-grade disease on final pathology as a surrogate for risk stratification. RESULTS: We identified 36,720 healthy-ACCI, 2,516 frail-ACCI, and 18,989 reference-ACCI patients. Healthy-ACCI patients were less likely to undergo RMB (7.5% versus 10.8%; p < 0.001) while frail-ACCI patients underwent RMB at similar rates (11.8% versus 10.8%; p = 0.14) compared with reference-ACCI patients. On multivariable logistic regression, in both healthy-ACCI and frail-ACCI patients, RMB was associated with decreased odds of surgical treatment, and increased odds of ablation and surveillance (all p < 0.01). In the frail-ACCI patients, higher grade disease at surgery was identified in the RMB cohort (32.9% versus 23.5%, p = 0.05). CONCLUSIONS: RMB is performed less frequently in healthy-ACCI patients compared with the reference cohort. RMB is associated with decreased odds of surgical treatment and increased odds of surveillance and ablation in all cohorts. In frail-ACCI patients who underwent surgery, RMB may provide additional risk stratification as these patients had lower rates of low-grade disease.
Subject(s)
Kidney Neoplasms/pathology , Kidney Neoplasms/therapy , Kidney/pathology , Age Factors , Aged , Biopsy/standards , Cohort Studies , Female , Humans , Male , Middle Aged , Practice Guidelines as Topic , Retrospective StudiesABSTRACT
To date, studies on papillary renal-cell carcinoma (pRCC) have largely focused on coding alterations in traditional drivers, particularly the tyrosine-kinase, Met. However, for a significant fraction of tumors, researchers have been unable to determine a clear molecular etiology. To address this, we perform the first whole-genome analysis of pRCC. Elaborating on previous results on MET, we find a germline SNP (rs11762213) in this gene predicting prognosis. Surprisingly, we detect no enrichment for small structural variants disrupting MET. Next, we scrutinize noncoding mutations, discovering potentially impactful ones associated with MET. Many of these are in an intron connected to a known, oncogenic alternative-splicing event; moreover, we find methylation dysregulation nearby, leading to a cryptic promoter activation. We also notice an elevation of mutations in the long noncoding RNA NEAT1, and these mutations are associated with increased expression and unfavorable outcome. Finally, to address the origin of pRCC heterogeneity, we carry out whole-genome analyses of mutational processes. First, we investigate genome-wide mutational patterns, finding they are governed mostly by methylation-associated C-to-T transitions. We also observe significantly more mutations in open chromatin and early-replicating regions in tumors with chromatin-modifier alterations. Finally, we reconstruct cancer-evolutionary trees, which have markedly different topologies and suggested evolutionary trajectories for the different subtypes of pRCC.
Subject(s)
Carcinoma, Renal Cell/genetics , Kidney Neoplasms/genetics , Proto-Oncogene Proteins c-met/genetics , RNA, Long Noncoding/genetics , Carcinoma, Renal Cell/pathology , Chromatin/genetics , DNA Methylation/genetics , Female , Gene Expression Regulation, Neoplastic , Genome, Human , Humans , Introns/genetics , Kidney Neoplasms/pathology , Male , Middle Aged , Mutation , Polymorphism, Single NucleotideABSTRACT
Molecular chaperone heat shock protein 90 (HSP90) is involved in oncogenic signaling pathways including epithelial-mesenchymal transition (EMT), a key process in tumor initiation, progression, metastasis, and chemoresistance. The molecular mechanisms underlying the involvement of HSP90 in EMT are still under investigation. In this study, we identified a previously unrecognized role of HSP90 in cooperating with signal transducer and activator of transcription 3 (STAT3) to regulate TWIST1 transcription in cancer cells. The HSP90 inhibitor 17-N-allylamino-17-demethoxygeldanamycin suppressed TWIST1 mRNA expression and promoter activity in epithelial ovarian cancer, renal clear cell cancer, and nasopharyngeal cancer cell lines. The interactions between HSP90 and transcription factors were visualized in cancer cell lines and tumor tissues using proximity ligation assays. Our findings reveal that HSP90 promotes the binding of STAT3 to the TWIST1 promoter, leading to the transcription of TWIST1. The inhibition of HSP90 downregulates STAT3 activity and TWIST1 transcription, thereby suppressing EMT and potentially inhibiting tumor progression, metastasis, and chemoresistance in different types of cancers. SIGNIFICANCE STATEMENT: Our study provides new evidence that HSP90 promotes EMT through enhancing TWIST1 transcription, which can be suppressed by HSP90 inhibitors. The HSP90 inhibitor inhibits EMT, thus potentially slowing down tumor growth, invasion, dissemination, metastasis, and drug resistance. These findings will hopefully pave the way for new therapeutic opportunities to target EMT and metastasis using HSP90 inhibitors.
Subject(s)
Benzoquinones/pharmacology , Kidney Neoplasms/genetics , Lactams, Macrocyclic/pharmacology , Nasopharyngeal Neoplasms/genetics , Nuclear Proteins/genetics , Ovarian Neoplasms/genetics , STAT3 Transcription Factor/metabolism , Twist-Related Protein 1/genetics , Cell Line, Tumor , Drug Resistance, Neoplasm/drug effects , Epithelial-Mesenchymal Transition/drug effects , Female , Gene Expression Regulation, Neoplastic/drug effects , HSP90 Heat-Shock Proteins/antagonists & inhibitors , HSP90 Heat-Shock Proteins/metabolism , Humans , Kidney Neoplasms/drug therapy , Kidney Neoplasms/metabolism , Nasopharyngeal Neoplasms/drug therapy , Nasopharyngeal Neoplasms/metabolism , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/metabolism , Phosphorylation/drug effects , Promoter Regions, Genetic/drug effects , Tissue Array Analysis , Transcription, Genetic/drug effectsABSTRACT
PURPOSE OF REVIEW: To describe current paradigms for genetic testing, screening, and treatment of patients with inherited kidney cancer syndromes. RECENT FINDINGS: We describe various new aspects of hereditary kidney cancer. Recent data now support that hereditary kidney cancer may account for 5-8% of kidney cancers diagnosed. Methods of testing have evolved including the introduction of multigene next-generation sequencing panels. We continue to learn more about the natural history and management of classic hereditary cancer syndromes. New emerging conditions with lower kidney cancer penetrance have been recognized adding the growing list of syndromes associated with kidney cancer development. The surgical management strategies of enucleation remain however systemic therapy options are being explored both for localized and advanced settings. SUMMARY: Genetic predisposition to kidney cancer is likely more common than once thought. Knowledge of clinical manifestation and genetic testing strategies are needed to properly identify and treat patient and their families.
Subject(s)
Carcinoma, Renal Cell/genetics , Genetic Predisposition to Disease/genetics , Kidney Neoplasms/genetics , Neoplastic Syndromes, Hereditary/genetics , Carcinoma, Renal Cell/diagnosis , Carcinoma, Renal Cell/therapy , Genetic Testing , High-Throughput Nucleotide Sequencing , Humans , Kidney Neoplasms/diagnosis , Kidney Neoplasms/therapy , Mass Screening , Neoplastic Syndromes, Hereditary/diagnosis , Neoplastic Syndromes, Hereditary/therapyABSTRACT
Patients with high-risk renal cell carcinoma (RCC) experience high rates of recurrence despite definitive surgical resection. Recent trials of adjuvant tyrosine kinase inhibitor therapy have provided conflicting efficacy results at the cost of significant adverse events. PD-1 blockade via monoclonal antibodies has emerged as an effective disease-modifying treatment for metastatic RCC. There is emerging data across other solid tumors of the potential efficacy of neoadjuvant PD-1 blockade, and preclinical evidence supporting a neoadjuvant over adjuvant approach. PROSPER RCC is a Phase III, randomized trial evaluating whether perioperative nivolumab increases recurrence-free survival in patients with high-risk RCC undergoing nephrectomy. The neoadjuvant component, intended to prime the immune system for enhanced efficacy, distinguishes PROSPER from other purely adjuvant studies and permits highly clinically relevant translational studies.
Subject(s)
Carcinoma, Renal Cell/therapy , Clinical Protocols , Kidney Neoplasms/therapy , Perioperative Care , Antineoplastic Agents, Immunological/administration & dosage , Antineoplastic Agents, Immunological/adverse effects , Antineoplastic Agents, Immunological/therapeutic use , Biomarkers, Tumor , Carcinoma, Renal Cell/etiology , Carcinoma, Renal Cell/pathology , Combined Modality Therapy/methods , Combined Modality Therapy/trends , Disease Susceptibility , Humans , Kidney Neoplasms/etiology , Kidney Neoplasms/pathology , Molecular Targeted Therapy , Neoadjuvant Therapy , Neoplasm Staging , Nephrectomy , Perioperative Care/methods , Perioperative Care/trends , Treatment OutcomeABSTRACT
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.
Subject(s)
Black or African American , Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Carcinoma, Non-Small-Cell Lung/mortality , Carcinoma, Non-Small-Cell Lung/surgery , Lung Neoplasms/mortality , Lung Neoplasms/surgery , Social Determinants of Health , White PeopleABSTRACT
Importance: Clinical trial data on adjuvant therapy in patients with non-clear cell renal cell carcinoma (RCC) are scant. Objective: To evaluate the effect of adjuvant everolimus after nephrectomy on recurrence-free survival (RFS) and overall survival (OS) in patients with localized papillary and chromophobe RCC. Design, Setting, and Participants: This prespecified subgroup analysis of a phase 3 randomized clinical trial, EVEREST, included patients enrolled between April 1, 2011, and September 15, 2016. Eligible patients had fully resected RCC at intermediate-high risk (pT1 grade 3-4, N0 to pT3a grade 1-2, N0) or very-high risk (pT3a grade 3-4 to pT4 any grade or N+) for recurrence who had received radical or partial nephrectomy. Final analyses was completed in March 2022. Intervention: The intervention group received 54 weeks of everolimus (10 mg orally daily); the control group received a matching placebo. Main Outcomes and Measures: The main outcomes were RFS, OS, and rates of adverse events. For testing the hazard ratio (HR) for treatment effect, a Cox regression model was used for both OS and RFS. Results: Of 1545 adult patients with treatment-naive, nonmetastatic, fully resected RCC in EVEREST, 109 had papillary RCC (median [range] age, 60 [19-81] years; 82 [75%] male; 50 patients [46%] with very high-risk disease) and 99 had chromophobe RCC (median [range] age 51 [18-71] years; 53 [54%] male; 34 patients [34%] with very high-risk disease). Among 57 patients with papillary RCC in the intervention group, 26 (46%) completed 54 weeks of treatment, and among 53 patients with chromophobe RCC in the intervention group, 26 (49%) completed 54 weeks of treatment. With a median (IQR) follow-up of 76 (61-96) months, adjuvant everolimus did not improve RFS compared with placebo in either papillary RCC (5-year RFS: 62% vs 70%; HR, 1.19; 95% CI, 0.61-2.33; P = .61) or chromophobe RCC (5-year RFS: 79% vs 77%; HR, 0.89; 95% CI, 0.37-2.13; P = .79). In the combined non-clear RCC cohort, grade 3 or higher adverse events occurred in 48% of patients who received everolimus and 9% of patients who received placebo. Conclusions and Relevance: In this clinical trial assessing the use of adjuvant everolimus, postoperative everolimus did not show evidence of improved RFS among patients with papillary or chromophobe RCC, and results from the study do not support adjuvant everolimus for this cohort. However, since the lower bounds of the 95% CIs were 0.61 and 0.89, respectively, potential treatment benefit in these subgroups cannot be ruled out. Trial Registration: ClinicalTrials.gov Identifier: NCT01120249.
Subject(s)
Carcinoma, Renal Cell , Everolimus , Kidney Neoplasms , Humans , Everolimus/therapeutic use , Male , Carcinoma, Renal Cell/drug therapy , Carcinoma, Renal Cell/surgery , Female , Middle Aged , Kidney Neoplasms/drug therapy , Kidney Neoplasms/surgery , Aged , Chemotherapy, Adjuvant/methods , Antineoplastic Agents/therapeutic use , Nephrectomy/methods , AdultABSTRACT
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.
ABSTRACT
PURPOSE: In the United States, renal cell carcinoma (RCC) incidence is higher among blacks than among whites. Risk of RCC is elevated among end-stage renal disease patients, although no studies have looked at differences by race in the relationship between chronic renal failure and RCC. METHODS: We investigated RCC risk in relation to chronic renal failure in a population-based case-control study of blacks and whites in Chicago and Detroit. Data, including information on kidney disease, were collected from interviews with 1,217 RCC cases (361 blacks, 856 whites) and 1,235 controls (523 blacks, 712 whites). Odds ratios (OR) and 95 % confidence intervals (CI) were estimated using unconditional logistic regression. RESULTS: Risk of RCC was increased in relation to chronic renal failure (OR 4.7, 95 % CI 2.2-10.1) and dialysis (OR 18.0, 95 % CI 3.6-91). The association remained after defining exposure as those who had chronic renal failure ≥10 years prior to RCC diagnosis. Chronic renal failure was more strongly associated with RCC among blacks than among whites (OR 8.7, 95 % CI 3.3-22.9 and 2.0, 0.7-5.6, respectively; p (interaction) = 0.03) and among those without a history of diabetes relative to diabetic subjects (OR 8.3, 95 % CI 3.1-22.7 and 1.9, 0.6-5.9, respectively; p (interaction) = 0.03). CONCLUSIONS: These results suggest that chronic renal failure is a strong risk factor for RCC, particularly among black and non-diabetic subjects. Our findings of differences in risk estimates by race, to our knowledge the first such report, require replication.
Subject(s)
Carcinoma, Renal Cell/ethnology , Carcinoma, Renal Cell/epidemiology , Kidney Failure, Chronic/ethnology , Kidney Failure, Chronic/epidemiology , Kidney Neoplasms/ethnology , Kidney Neoplasms/epidemiology , Adult , Aged , Black People/statistics & numerical data , Carcinoma, Renal Cell/complications , Case-Control Studies , Chicago/epidemiology , Female , Humans , Illinois/epidemiology , Kidney Failure, Chronic/etiology , Kidney Neoplasms/complications , Male , Michigan/epidemiology , Middle Aged , United States/epidemiology , White People/statistics & numerical data , Young AdultABSTRACT
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.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Healthcare Disparities , Lung Neoplasms , Treatment Refusal , Humans , Carcinoma, Non-Small-Cell Lung/surgery , Lung Neoplasms/surgery , Racial Groups , Black or African American , White , Hospitals, High-VolumeABSTRACT
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.