Non-clear Cell Carcinoma Research Articles

Identification of biomarkers of chromophobe renal cell carcinoma by weighted gene co-expression network analysis

BackgroundChromophobe renal cell carcinoma (ChRCC) is the second common subtype of non-clear cell renal cell carcinoma (nccRCC), which accounting for 4–5% of renal cell carcinoma (RCC). However, there is no effective bio-marker to predict clinical outcomes of this malignant disease. Bioinformatic methods may provide a feasible potential to solve this problem.MethodsIn this study, differentially expressed genes (DEGs) of ChRCC samples on The Cancer Genome Atlas database were filtered out to construct co-expression modules by weighted gene co-expression network analysis and the key module were identified by calculating module-trait correlations. Functional analysis was performed on the key module and candidate hub genes were screened out by co-expression and MCODE analysis. Afterwards, real hub genes were filter out in an independent dataset GSE15641 and validated by survival analysis.ResultsOverall 2215 DEGs were screened out to construct eight co-expression modules. Brown module was identified as the key module for the highest correlations with pathologic stage, neoplasm status and survival status. 29 candidate hub genes were identified. GO and KEGG analysis demonstrated most candidate genes were enriched in mitotic cell cycle. Three real hub genes (SKA1, ERCC6L, GTSE-1) were selected out after mapping candidate genes to GSE15641 and two of them (SKA1, ERCC6L) were significantly related to overall survivals of ChRCC patients.ConclusionsIn summary, our findings identified molecular markers correlated with progression and prognosis of ChRCC, which might provide new implications for improving risk evaluation, therapeutic intervention, and prognosis prediction in ChRCC patients.

Non-Clear Cell Renal Cell Carcinomas: From Shadow to Light.

Non-clear cell renal cell carcinomas (RCCs) account for up to 25% of kidney cancers and encompass distinct diseases with distinct pathologic features, different molecular alterations, and various patterns of response to systemic therapies. Recent advances in molecular biology and large collaborative efforts helped to better define the oncogenic mechanisms at play in papillary, chromophobe, collecting duct, medullary, translocation, and sarcomatoid RCCs. Papillary RCCs are divided into several subsets of tumors characterized by distinct gene expression profiles, chromatin remodeling genes, cell cycle changes, and alterations of the MET pathway. Chromophobe RCC genomic analysis revealed mostly metabolic pathway alterations with mitochondrial dysfunctions. Translocation RCCs are characterized by MITF fusions and wide genomic reprogramming. Collecting duct carcinomas are distinct entities from upper tract urothelial carcinomas associated with high T-cell infiltration and metabolic alterations. Medullary RCCs present alterations of the INI1 gene and rhabdoid features at pathologic analysis. Finally, sarcomatoid RCCs represent sarcomatoid differentiation for any subsets of RCCs with specific alterations associated with mesenchymal dedifferentiation. From the standpoint of systemic therapy, more than a decade of using VEGF and mTOR inhibitors showed that they generally had limited efficacy in non-clear cell RCCs compared with clear cell RCCs. MET inhibitors are actively being developed for papillary RCC with a specific focus on MET-driven tumors. Other strategies under investigation include CDK4/6 inhibitors in tumors with cell cycle alterations and EZH2 inhibitors in RCCs with INI1 loss. The emergence of immune checkpoint inhibitors and combination strategies enlarges the spectrum of investigational treatments. Better understanding of driver and passenger alterations and better patient stratification along with dedicated clinical networks will be key to improving the management of these rare tumors.

Cabozantinib for the treatment of patients with metastatic non-clear cell renal cell carcinoma: A retrospective analysis

BackgroundCabozantinib prolongs overall survival (OS) and progression-free survival (PFS) in patients with metastatic clear cell renal cell carcinoma (RCC) that progressed on first-line vascular endothelial growth factor receptor–tyrosine kinase inhibitor (VEGFR-TKI). The role of cabozantinib has not been established in non-clear cell renal cell carcinoma (nccRCC). MethodsThis is a retrospective study of 30 patients with nccRCC who received cabozantinib from January 2013 to January 2017. Information collected included baseline characteristics, toxicity, dose reductions, PFS and OS. A fellowship trained abdominal radiologist, blinded to patient history and clinical data, assessed radiographic response using RECIST, v1.1. ResultsWith a median follow-up of 20.6 months (95% confidence interval [CI]: 11.4–28.8), median PFS was 8.6 months (95% CI: 6.1–14.7), and median OS was 25.4 months (95% CI: 15.5–35.4). Of the 28 patients with measurable disease, 4 had partial responses (2 papillary, 1 chromophobe and 1 unclassified RCC), 18 had stable disease (64.2%) and 6 had progressive disease (21.4%), resulting in a 14.3% objective response rate and a 78.6% disease control rate. Two patients with papillary RCC who had experienced disease progression on savolitinib achieved durable partial response and stable disease, respectively, following treatment with cabozantinib. Of the 21 patients who started cabozantinib at 60 mg/d, 12 (57.1%) required dose reduction due to toxicity. ConclusionIn this retrospective study, cabozantinib produced a clinically meaningful benefit in patients with metastatic nccRCC, the majority of whom had disease progression on prior VEGFR-TKIs. Prospective trials of cabozantinib in nccRCC are warranted.

Tumor growth velocity: A modified tumor growth rate defining tumor progression during sorafenib treatment in patients with metastatic renal cell carcinoma.

To investigate the role of tumor growth velocity in defining tumor progression in metastatic renal cell carcinoma patients treated with the vascular endothelial growth factor tyrosine kinase inhibitor, sorafenib. A modified calculation for tumor growth velocity was introduced to evaluate the tumor growth velocity, before and after sorafenib withdrawal. Known prognostic factors together with tumor growth velocity before drug withdrawal and tumor growth velocity after drug withdrawal were compared using a χ2 -test from a contingency table, and partial likelihood test from a Cox regression model for overall survival. A total of 114 patients who reached progressive disease and withdrew from sorafenib were enrolled after a median follow-up period of 107.8months. Tumor growth velocity before drug withdrawal was 7.347±4.040, and tumor growth velocity after drug withdrawal was 11.647±5.937 (P<0.001). Higher tumor growth velocity before drug withdrawal was correlated with a higher risk Memorial Sloan Kettering Cancer Center score (P=0.022), Karnofsky Performance Status<80 (P=0.028), non-clear cell carcinoma (P=0.037), higher tumor nucleus grade (P<0.001) and best treatment response (P<0.001). Patients with tumor growth velocity before drug withdrawal>5.0 had shorter overall survival (P<0.001). On multivariate analysis, factors associated with overall survival were high/intermediate Memorial Sloan Kettering Cancer Center risk score (hazard ratio 2.119, P=0.006), non-clear histological subtype (hazard ratio 1.900, P=0.031), tumor growth velocity before drug withdrawal≥5.0 (hazard ratio 2.758, P<0.001) and progressive disease as best response (hazard ratio 2.069, P=0.001). Significantly faster tumor growth can be observed if sorafenib is discontinued in the case of disease progression. Thus, we suggest not to withdraw targeted agents until tumor growth velocity is>5.0.

Should CARMENA Really Change our Attitude Towards Cytoreductive Nephrectomy in Metastatic Renal Cell Carcinoma? A Systematic Review and Meta-Analysis Evaluating Cytoreductive Nephrectomy in the Era of Targeted Therapy.

Cytoreductive nephrectomy in metastatic renal cell carcinoma (mRCC) patients has been common clinical practice due to evidence that resection of the primary tumor results in a survival benefit regardless of systemic treatment. Recently, the first large phase III randomized, non-inferiority prospective clinical trial evaluating this surgical approach demonstrated that systemic treatment alone was not inferior to primary surgery plus systemic treatment. Our aim was to evaluate if cytoreductive nephrectomy results in a survival benefit over systemic treatment alone in patients with mRCC and in specific subgroups, including patients with brain metastases, poor performance status, poor prognosis according to IMDC or MSKCC criteria, and clear cell and non-clear cell histologies. We identified 16 published studies providing complete data for the comparison between cytoreductive nephrectomy + systemic treatment versus systemic treatment alone, and selected 9 for subgroup analysis. The inverse variance technique was applied for the meta-analysis of hazard ratios (HR), and, due to the intrinsic heterogeneity of the data, we adopted a random effects model. Risk of bias among the studies was estimated by the Newcastle-Ottawa Scale (NOS). Our analysis suggested a survival benefit for patients receiving cytoreductive nephrectomy (pooled HR of 0.48, 95% confidence interval of 0.42-0.56) in the overall population. Survival advantages were also observed in patients with clear cell and non-clear renal cell carcinoma, while no benefit was evident in patients with brain metastasis, poor performance status, and poor risk. Cytoreductive nephrectomy seems to result in a survival benefit in both clear cell and non-clear cell histology, while no survival advantage was found in patients with specific clinical features. Despite a high level of heterogeneity, our results highlight the importance of a good selection of patients to whom a primary surgical approach could be proposed.

Implications of Programmed Death Ligand-1 Positivity in Non-Clear Cell Renal Cell Carcinoma

The purpose of this study was to assess the prognostic value of programmed death ligand-1 (PD-L1) positivity in a non-clear cell renal cell carcinoma (non-ccRCC) cohort. PD-L1 expression was evaluated by immunohistochemistry (IHC) using formalin-fixed paraffin-embedded (FFPE) specimens from 45 non-ccRCC patients with available tissue. PD-L1 positivity was defined as ≥1% of staining. Histopathological characteristics and oncological outcomes were correlated to PD-L1 expression. Cancer-specific survival (CSS) and recurrence-free survival (RFS) stratified by PD-L1 status were estimated using the Kaplan–Meier method. Median age was 58 years and median follow-up was 40 months. Non-ccRCC subtypes included sarcomatoid (n = 9), rhabdoid (n = 6), medullary (n = 2), Xp11.2 translocation (n = 2), collecting duct (n = 1), papillary type I (n = 11), and papillary type II (n = 14). PD-L1 positivity was noted in nine (20%) patients. PD-L1 positivity was significantly associated with higher Fuhrman nuclear grade (P = 0.048) and perineural invasion (P = 0.043). Five-year CSS was 73.2 and 83% for PD-L1 positive and negative tumors, respectively (P = 0.47). Five-year RFS was 55.6 and 61.5% for PD-L1 positive and negative tumors, respectively (P = 0.58). PD-L1 was expressed in a fifth of non-ccRCC cases and was associated with adverse histopathologic features. Expression of biomarkers such PD-L1 may help better risk-stratify non-ccRCC patients to guide treatment decisions and follow-up strategies.

Comparison of three risk stratification models for non-clear cell renal cell carcinoma patients treated with temsirolimus as first-line therapy

Background/AimsFor metastatic renal cell carcinoma (RCC), various prognostic scoring systems have been developed. However, owing to the low prevalence of nonclear cell RCC, the three most commonly used tools were mainly developed based on patients with clear cell histology. Accordingly, this study applied three prognostic models to Korean non-clear cell RCC patients treated with first-line temsirolimus.MethodsThis study analyzed data for 74 patients with non-clear cell RCC who were treated with temsirolimus as the first-line therapy at eight medical centers between 2011 and 2016. The receiver-operating characteristic (ROC) curves for the different prognostic models were analyzed.ResultsTwenty-seven (36.5%), 24 (32.4%), and 44 patients (59.5%) were assigned to the poor prognosis groups of the Memorial Sloan-Kettering Cancer Center (MSKCC), International Metastatic RCC Database Consortium (IMDC), and Advanced Renal Cell Carcinoma (ARCC) risk stratification models, respectively. All three prognostic models reliably discriminated the risk groups to predict progression-free survival and overall survival (p < 0.001). The area under the ROC curve (AUC) for progression and survival was highest for the ARCC model (0.777; 0.734), followed by the IMDC (0.756; 0.724) and the MSKCC (0.742; 0.712) models. Furthermore, the sensitivity and specificity for predicting progression were highest with the ARCC model (sensitivity 63.6%, specificity 85.7%), followed by the MSKCC (sensitivity 58.2%, specificity 86.5%) and the IMDC models (sensitivity 56.4%, specificity 85.7%).ConclusionsAll three prognostic models accurately predicted the survival of the non-clear cell RCC patients treated with temsirolimus as the first-line therapy. Furthermore, the ARCC risk model performed better than the other risk models in predicting survival.

Treatment outcomes of metastatic nonclear cell renal cell carcinoma: A single institution retrospective analysis.

Introduction:Nonclear cell (NCC) metastatic renal cell carcinoma (mRCC) is a biologically heterogeneous entity. We report the outcomes of NCC mRCC treated with first-line vascular endothelial growth factor (VEGF) inhibitors or mammalian target of rapamycin (mTOR) inhibitors at our institute. This is first such report from India.Methods:This is a retrospective analysis of the 40 consecutive patients of NCC mRCC treated between January 2013 and June 2015 in routine clinical practice at our institute. The primary endpoint analyzed was overall survival (OS) with respect to the type of first-line treatment and tumor histology.Results:The most common histological subtype was papillary in 25 patients (62.5%) followed by sarcomatoid in six (15%), chromophobe in 5 (12.5%), translocation-associated in one patient, and other nonspecified in three patients. First-line treatment was sorafenib in 14 (35%), sunitinib in 9 (22.5%), pazopanib in 8 (20%), everolimus in seven (17.5%), and best-supportive care (BSC) in two (5%) patients. Partial response, stable disease, and progression was observed in six (15%), 13 (32.5%), and nine (22.5%) cases, respectively, as the best response to first-line treatment. The median OS was 11.7 months and median event-free survival was 6.1 months in the whole cohort. The median OS in months for different first-line treatments were as follows: sorafenib (16.2), sunitinib (11.7), pazopanib (not reached, mean-23.9 ± 6.0), everolimus (4.1) and BSC (0.6) and for different histological subtypes were as follows: papillary (9.8), chromophobe (not reached, mean-30.3 ± 8.4), sarcomatoid (4.1), and others (7.9).Conclusions:Chromophobe histology has a better outcome compared to other histological subtypes, and anti-VEGF tyrosine kinase inhibitors are preferable first-line agents compared to mTOR inhibitors.

Patterns of Relapse and Implications for Post-Nephrectomy Surveillance for Patients with High-Risk Non-Clear Cell Renal Cell Carcinoma: Subgroup Analysis of the Phase 3 ECOG-ACRIN E2805 Trial

PurposeThe natural history of non-clear cell renal cell carcinomas (non-ccRCC) following surgery with curative intent remains poorly defined, with post-operative surveillance informed by guidelines largely intended for clear cell RCC (ccRCC). We evaluated the patterns of relapse and potential implications for post-nephrectomy surveillance for patients with non-ccRCC enrolled in the largest randomized trial of adjuvant anti-angiogenic therapy for high-risk RCC (E2805). Materials and MethodsThis was a retrospective analysis of patients with completely resected non-ccRCC. Participants received up to 54 weeks of post-operative therapy with sunitinib, sorafenib, or placebo, as well as surveillance imaging at standardized intervals for 10 years. For recurrence rates (RR) by site, the cumulative incidence was estimated accounting for competing risks. The adequacy of strict adherence to post-nephrectomy surveillance guidelines was evaluated. Results403 non-ccRCC patients were enrolled, and 36% of non-ccRCC tumors recurred over a median follow-up period of 6.2 years. Five-year RRs were comparable between non-ccRCC and ccRCC (N = 1541) patients (34.6% vs 39.5%) [95% CIs (29.8 – 39.4) and (36.9 – 42.1), respectively]. However, non-ccRCC patients were significantly more likely to develop abdominal sites of relapse (5-year RR 26.4% vs 18.2%, p = 0.0008), and were significantly less likely to relapse in the chest (5-year RR 13.7% vs 20.9%, p = 0.0005). Current surveillance guidelines would potentially capture approximately 90% of relapses at any site. ConclusionsNon-ccRCC may exhibit a distinct pattern of relapse when compared to ccRCC. Our findings emphasize the importance of cross-sectional, long-term imaging for patients with high-risk resected non-ccRCC.

Abstract 5354: Novel genomic alterations in renal medullary carcinoma tumors

Abstract Introduction: Renal medullary carcinoma (RMC) is an rare but aggressive non-clear cell carcinoma that occurs predominantly in young African American (AA) men who carry the sickle cell trait. Our knowledge of the molecular basis for the initiation and progression of this cancer remains inadequate to establish standard of care treatments. As a result, even with surgery and chemotherapy, outcomes have remained dismal, with a median overall survival of approximately 13 months. Most patients with RMC exhibit deletion of the SMARCB1 gene, which encodes for a subunit of the SWI/SNF chromatin remodeling complex. Subtypes of RMC without SMARCB1 loss but harbor a rare gene fusion between Vinculin and Anaplastic Lymphoma Kinase have also been reported. We hypothesize that whole exome sequencing (WES) of RMC tumors will identify novel genomic alterations responsible for RMC tumor initiation and progression, which may provide actionable targets for treatment. Methods: Formalin fixed paraffin embedded (FFPE) RMC tumor and adjacent tissue specimens of 21 African American patients were obtained from the Joint Pathology Center. DNA were isolated from tumor and normal tissues with the Qiagen FFPE All Prep kit and measured by using the Qubit fluorometer. Integrity of the DNA samples were evaluated by using the Advanced Analytics Fragment Analyzer. WES DNA libraries were prepared from DNA samples that passed quality control using the Illumina TruSeq WES kit. Paired end sequencing (2x75) was performed on the Illumina HiSeq3000 platform. RMC tissues sections were analyzed for the expression of SMARCB1, VHL, HIF2A, AURKA, and EZH2 proteins by immunohistochemistry (IHC). Results: Somatic copy number alterations were estimated from the WES of seven RMC cases. These include recurrent large scale DNA alterations involving chromosome 7 and 8 amplification and chromosome 15 deletion. Focal DNA copy number alterations were also identified in the cohort, including deletion of SMARCB1. Analysis of somatic sequence mutations detected a canonical hotspot mutation (R132C) in IDH1 and recurrent non-silent mutations on RBM47 and NF2. Evaluation by IHC showed the loss of SMARCB1 expression in all cases assayed. Upregulation of EZH2 and AURKA, which are negatively regulated by SMARCB1, were detected in 3 of 21 and 11 of 21 cases, respectively. Focal HIF2A staining was detected in 7 of 21 tumor cases. Conclusions: The recurrent somatic sequence mutations, gene amplifications and deletions identified in this study reveal potential novel oncogenic drivers of RMC. Further validation of these genomic alterations may offer additional insight into the initiation and progression of RMC and provide actionable targets for establishing standard of care treatments. Source of Funding: The work is supported a grant award (HU0001-14-2-0041) to ST from the Collaborative Health Initiative Research Program (CHIRP), a precision medicine-based collaborative effort between the NIH and the DOD. Citation Format: Jesse Fox, Denise Young, Yingjie Song, Heng Cheng Hu, Anthony Soltis, Matthew D. Wilkerson, Clifton L. Dalgard, Inger L. Rosner, Isabell A. Sesterhenn, Shiv Srivastava, Shyh-Han Tan. Novel genomic alterations in renal medullary carcinoma tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5354.

Cabozantinib (Cabo) in advanced non-clear cell renal cell carcinoma (nccRCC): A retrospective multicenter analysis.

4579Background: Cabo shows robust clinical activity in advanced clear cell RCC. nccRCC, a heterogeneous mix of diseases, have been underrepresented in clinical trials and effective systemic therapy...

Nivolumab (nivo) for patients (pts) with metastatic non-clear cell renal cell carcinoma (nccRCC): A single-institution experience.

4585Background: Nivo is approved for refractory metastatic renal cell carcinoma (RCC). However, the clinical activity of nivo in nccRCC is unknown as these patients were excluded from the trial pop...

Patterns of relapse and implications for post-nephrectomy surveillance for patients with high-risk non-clear cell renal cell carcinoma: Subgroup analysis of the phase 3 ECOG-ACRIN E2805 trial.

4564Background: Non-clear cell renal cell carcinomas (non-ccRCC) comprise a diverse subgroup, with biology and clinical behavior that is distinct from clear cell RCC (ccRCC). However, the natural h...

PT011 - A systematic review and meta-analysis comparing the effectiveness and adverse effects of different systemic treatments for non-clear cell renal cell carcinoma

PT011 - A systematic review and meta-analysis comparing the effectiveness and adverse effects of different systemic treatments for non-clear cell renal cell carcinoma

Clinical activity of nivolumab in patients with non-clear cell renal cell carcinoma

BackgroundNivolumab is approved for patients with metastatic renal cell carcinoma (mRCC) refractory to prior antiangiogenic therapy. The clinical activity of nivolumab in patients with non-clear cell RCC subtypes remains unknown as these patients were excluded from the original nivolumab trials.MethodsPatients from 6 centers in the United States who received at least one dose of nivolumab for non-clear cell mRCC between 12/2015 and 06/2017 were identified. A retrospective analysis including patient characteristics, objective response rate according to RECIST v1.1 and treatment-related adverse events (TRAEs) was undertaken.ResultsForty-one patients were identified. Median age was 58 years (33–82), 71% were male, and majority had ECOG PS 0 (40%) or 1 (47%). Histology included 16 papillary, 14 unclassified, 5 chromophobe, 4 collecting duct, 1 Xp11 translocation and 1 MTSCC (mucinous tubular and spindle cell carcinoma). Among 35 patients who were evaluable for best response, 7 (20%) had PR and 10 (29%) had SD. Responses were observed in unclassified, papillary and collecting duct subtypes. In the entire cohort, median follow-up was 8.5 months and median treatment duration was 3.0 months. Median PFS was 3.5 months and median OS was not reached. Among responders, median time to best response was 5.1 months, and median duration of response was not reached as only 2 out of 7 responders had disease progression during follow-up. TRAEs of any grade were noted in 37% and most commonly included fatigue (12%), fever (10%) and rash (10%). Nivolumab treatments were postponed in 34% and discontinued in 15% of patients due to intolerance. No treatment-related deaths were observed.ConclusionsNivolumab monotherapy demonstrated objective responses and was well tolerated in a heterogeneous population of patients with non-clear cell mRCC. In the absence of other data in this treatment setting, this study lends support to the use of nivolumab for patients with metastatic non-clear cell renal cell carcinoma.

Expression and Distribution of Galectin-3 in Chromophobe and Papillary Carcinomas.

Probably due to their low occurrence, chromophobe and papillary renal cell carcinomas are less well characterized and, currently, there are no reliable prognostic markers for this group of patients. Moreover, the optimal therapy for patients with non-clear renal cell carcinoma (RCC) is unknown yet. Although elevated levels of Galectin-3 (Gal-3) were associated with poor prognosis in conventional RCC, the impact of this protein on carcinogenesis of chromophobe and papillary entities has not been previously described. Gal-3 expression was investigated in 34 consecutive cases of RCCs, including 19 papillary carcinomas and 15 chromophobe carcinomas. Immunohistochemical analysis of Gal-3 in tumor cells showed 3 patterns of expression: membranous, cytoplasmic and nuclear staining. Most tumors included in our study showed a cytoplasmic expression and it was almost equally distributed between the histologic subtypes. However, only nuclear staining of Gal-3 was associated with both Fuhrman grade and tumor stage (p=0.016 and p=0.032, respectively) in chromophobe subtype. Our results indicate that the nuclear expression of Gal-3 has an essential role in the development of chromophobe carcinoma. The association with advanced tumor stage and nuclear grade suggests that this protein is an indicator of aggressiveness in the chromophobe subtype, thus targeting anti-nuclear transport may prove an effective therapy for this particular group of patients.

Programmed Death Ligand 1 in Non-Clear Cell Renal Cell Carcinoma and Correlation with Tumor Microenvironment and Prognostic Factors

Programmed Death Ligand 1 in Non-Clear Cell Renal Cell Carcinoma and Correlation with Tumor Microenvironment and Prognostic Factors

Survival after Cytoreductive Nephrectomy in Metastatic Non-clear Cell Renal Cell Carcinoma Patients: A Population-based Study

BackgroundThe benefit of cytoreductive nephrectomy (CNT) for cancer-specific mortality (CSM)-free survival is unclear in contemporary metastatic non-clear cell renal cell carcinoma (non-ccmRCC) patients. ObjectiveTo assess the role of CNT in non-ccmRCC patients. Design, setting, and participantsWithin Surveillance, Epidemiology, and End Results registry (2001–2014), we identified patients with non-ccmRCC. InterventionCNT versus no CNT in non-ccmRCC patients. Outcome measurements and statistical analysisMultivariable logistic regression, cumulative incidence, competing-risks regression models, incremental survival benefit (ISB), conditional survival, and landmark analyses were performed. Sensitivity analyses focused on histological subtypes and most contemporary patients (2010–2014). Results and limitationsOf 851 patients with non-ccmRCC, 67.6% underwent CNT. In multivariable logistic regression, year of diagnosis in contemporary (p<0.001) and intermediate (p=0.008) tertiles, as well as age ≥75 yr (p<0.001) yielded lower CNT rates. Cumulative incidence showed 2-yr CSM of 52.6% versus 77.7%, respectively, after CNT versus no CNT. CSM after CNT versus no CNT was invariably lower in all histologic subtypes and in contemporary patients. Multivariable competing-risks regression models predicting CSM favored CNT (hazard ratio [HR]: 0.38, confidence interval: 0.30–0.47, p<0.001) in all patients and in all subgroups defined by histologic subtypes (HR: 0.14–0.43, all p≤0.02), as well as in contemporary patients (HR: 0.32, p<0.001). The ISB analyses yielded statistically significant and clinically meaningful CSM-free survival benefit of +3 mo after CNT versus no CNT in individuals with observed CSM-free survival ≤24 mo. The 2-yr CSM-free survival increased from baseline of 46.1% versus 19.4% (Δ=26.7%, p<0.001) to 70.3% versus 54.4% (Δ=15.9%, p=0.005) after CNT versus no CNT, in patients that survived 12 mo, respectively. Landmark analyses rejected bias favoring CNT. Data were retrospective. ConclusionsCSM is lower after CNT for non-ccmRCC in all histologic subtypes and in contemporary patients except for unproven ISB in collecting duct patients. This observation should encourage greater CNT consideration in non-ccmRCC. Patient summaryCytoreductive nephrectomy appears to improve survival in metastatic non-clear cell renal cell carcinoma, but it is used infrequently.

Non-Clear Cell Renal Cell Carcinoma: Current Management and Best Practice.

The treatment of metastatic renal cell carcinoma (mRCC) has evolved markedly over the past several decades; first with the introduction of targeted therapies and more recently with data supporting checkpoint inhibition. However, the vast majority of studies to date have explored the benefit of agents specifically in the context of clear cell disease. For the estimated 15–20% of patients with non-clear cell histology, there is little consensus around best practice. Herein, we discuss emerging datasets providing biologic characterization of non-clear cell RCC and identify trials that exploit this biology.

Addressing the best treatment for non-clear cell renal cell carcinoma (nccRCC): a meta-analysis of randomized clinical trials comparing VEGFR-TKis versus mTORi targeted therapies

Addressing the best treatment for non-clear cell renal cell carcinoma (nccRCC): a meta-analysis of randomized clinical trials comparing VEGFR-TKis versus mTORi targeted therapies