Non-clear Renal Cell Carcinoma Research Articles

Intraoperative tumor capsule injury in patients with renal cell carcinoma receiving partial nephrectomy.

We investigated the impact of intraoperative tumor capsule injury (TCI) during robot-assisted partial nephrectomy (RAPN) or laparoscopic partial nephrectomy (LPN) on oncological outcomes, as well as underlying factors of intraoperative TCI for improving surgical outcomes. A total of 253 patients who underwent RAPN or LPN between 2010 and 2022 were retrospectively analyzed and were divided into two groups: non-TCI and TCI groups. The background was compared between two groups. We investigated the surgical records or video to evaluate TCI and seek the possible causes for TCI. Multivariate logistic regression analysis was performed to identify prognostic factors for cancer recurrence. Of the 253 patients, 227 have renal cell carcinoma (RCC), with 29 patients having TCI. The TCI group had larger tumors, a lower rate of trifecta achievement, higher bleeding, higher T stage, and a lower rate of clear cell RCC (ccRCC) histological types as compared to non-TCI group. Disease recurrence rate was 13.8% with TCI and 1.0% with non-TCI (odds ratio 15.7; 95% confidence interval, 2.73-90.1; p = 0.003). Univariate and multivariate analyses confirmed TCI as an independent prognostic factor for disease-free survival. Compared with ccRCC, non-clear cell RCC (non-ccRCC) was found to have a higher probability of TCI and a significantly thinner capsule thickness on pathological evaluation. TCI had a negative impact on oncological outcomes. Surgeons should consider thickness of tumor capsules, especially in cases with non-ccRCC, to minimize the risk of TCI during partial nephrectomy.

Immune-Based and Novel Therapies in Variant Histology Renal Cell Carcinomas.

Renal cell carcinoma (RCC) is a heterogeneous disease that represents the most common type of kidney cancer. The classification of RCC is primarily based on distinct morphological and molecular characteristics, with two broad categories: clear cell RCC (ccRCC) and non-clear cell RCC (nccRCC). Clear cell RCC is the predominant subtype, representing about 70-80% of all RCC cases, while non-clear cell subtypes collectively make up the remaining 20-30%. Non-clear cell RCC encompasses many histopathological variants, each with unique biological and clinical characteristics. Additionally, any RCC subtype can undergo sarcomatoid dedifferentiation, which is associated with poor prognosis and rapid disease progression. Recent advances in molecular profiling have also led to the identification of molecularly defined variants, further highlighting the complexity of this disease. While immunotherapy has shown efficacy in some RCC variants and subpopulations, significant gaps remain in the treatment of rare subtypes. This review explores the outcomes of immunotherapy across RCC subtypes, including rare variants, and highlights opportunities for improving care through novel therapies, biomarker-driven approaches, and inclusive clinical trial designs.

Post-marketing surveillance data for avelumab + axitinib treatment in patients with advanced renal cell carcinoma in Japan: Subgroup analyses by pathological classification.

Clinical trials have demonstrated the efficacy and safety of avelumab + axitinib in patients with advanced clear cell renal cell carcinoma (ccRCC). However, information is limited regarding the activity of avelumab + axitinib in patients with non-clear cell RCC (nccRCC). In Japan, post-marketing surveillance (PMS) of patients with RCC receiving avelumab + axitinib treatment in general clinical practice was undertaken. We report ad hoc analyses of PMS data according to RCC pathological classification. Of 328 patients with RCC who received ≥1 dose of avelumab and were enrolled between December 2019 and May 2021, 271 (82.6%) had ccRCC, 22 (6.7%) had nccRCC, and 35 (10.7%) had missing or unknown RCC pathology. Among patients with nccRCC, pathological subtypes were papillary in 12 (3.7%), translocation in 3 (0.9%), acquired cystic disease associated in 3 (0.9%), chromophobe in 2 (0.6%), mucinous tubular and spindle cell in 1 (0.3%), and Bellini duct in 1 (0.3%). Among patients with ccRCC or nccRCC, any-grade adverse drug reactions of safety specifications occurred in 140 (51.7%) and 15 (68.2%), and of grade ≥3 in 48 (17.7%) and 6 (27.3%), respectively. The objective response rate in patients with ccRCC or nccRCC was 36.9% and 22.7%, respectively; in patients with papillary tumors, it was 33.3%. Median overall survival was not reached in patients with ccRCC or nccRCC, and 12-month overall survival rates were 86.8% and 76.7%, respectively. Overall, subgroup analyses of PMS data suggest that avelumab + axitinib improved clinical outcomes in nccRCC in addition to ccRCC.

Can quantitative perfusion CT-based biomarkers predict renal cell carcinoma subtypes?

To assess diagnostic accuracy of perfusion CT (pCT) based biomarkers in differentiating clear-cell renal cell carcinoma (ccRCC) from non-ccRCC. This retrospective study comprised 95 patients with RCCs (70 ccRCCs and 25 non-ccRCCs) who had perfusion CT (pCT) before surgery between January 2017 and December 2022. Two readers independently recorded PCT parameters [blood flow (BF), blood volume (BV), mean transit time (MTT), and time to peak (TTP)] by drawing a circular ROI on the tumor. The open-source program "Labelme" was used to create a polygonal bounding box to outline tumor borders. The intraclass correlation coefficient (ICC) was used to determine interreader agreement. The pCT model was evaluated using multivariable logistic regression analysis with the STATA 18 program to determine the importance of each of these characteristics in predicting the type of tumor. Clear cell RCC had significantly greater MIP and lower TTP values than non-clear cell RCC (p < 0.05). RCCs showed considerably higher TTP, MTT, and lower MIP values than the normal renal cortex (p < 0.05). At a threshold of 129 HU, MIP had an AUC of 0.78, sensitivity and specificity of 80% and 70%, respectively, according to ROC analysis. pCT has a high diagnostic accuracy in distinguishing between ccRCC and non-ccRCC tumors; Clinical relevance: A non-invasive, accurate, reliable, and reproducible imaging biomarker for RCC subtype prediction is possible on pCT, which may be significant for evaluating the response to antiangiogenic therapy.

Non-clear cell renal cell carcinoma narrative review: where we are in 2024.

Advances in non-clear cell renal cell carcinoma (RCC) have lagged behind clear cell RCC due to the heterogeneity and relative rarity of the disease. However, more advanced molecular and genetic testing has allowed us to gain a more detailed and nuanced appreciation of these malignancies. This has laid the foundation for the identification of the distinct mutational and molecular patterns such as succinate dehydrogenase (SDH)-deficient RCC, fumarate hydratase (FH)-deficient RCC, and translocation RCC, so that clinicians can create a more personalized approach to their clinical management. Particularly for the rare non-papillary RCC variant histologies, clinical trial representation is lacking. In the discussed studies, no histology enrolled more than 29 patients of any particular RCC aside from Papillary. As such, evidence-based management decisions can be challenging to make for this patient population. We have collected the most up-to-date available evidence to describe the pathophysiology, molecular, and pathologic characteristics of the more commonly seen non-clear cell RCC variants, including papillary, chromophobe, translocation, FH-deficient, as well as a group of "unclassified" RCCs. Additionally, we provide an overview of the available evidence from recent clinical trials for non-clear cell RCC and current treatment paradigms. The diagnostic approach for renal malignancies is rapidly changing, favoring a more molecular and genetically based approach. These techniques will allow for a more detailed understanding of the clinical behavior of these cancers. Most data for non-clear cell RCC are from single-arm phase 2 clinical trials. The clinical response to vascular endothelial growth factor (VEGF)-tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) varies greatly by histology. Molecularly targeted therapy as monotherapy or when combined with immunotherapy have efficacy in non-clear cell RCC, though there are differences in treatment response by histology.

Systemic therapy for non-clear cell renal cell carcinomas: A systematic review.

Renal cell carcinoma (RCC) is the most common kidney cancer, with clear cell RCC being the predominant subtype. However, non-clear cell RCC constitutes a significant proportion of cases, presenting distinct challenges in treatment due to its varied histological subtypes. Despite recent advancements, the optimal therapeutic approach for non-clear cell RCC remains uncertain due to limited high-quality evidence. This systematic review aims to evaluate the efficacy of systemic therapies in nccRCC subgroups. A comprehensive literature search identified studies from 2010 to 2024, using PubMed and Clinicaltrials.gov databases focusing on clinical trials and treatment outcomes. Results highlight the evolving therapeutic landscape, with targeted agents and immunotherapy demonstrating promising anti-tumor effects. Notably, tyrosine kinase inhibitors (TKIs) such as sunitinib and mTOR inhibitors like temsirolimus have shown efficacy across different subtypes. Combination therapies, including immunotherapy-based regimens, have also shown favorable outcomes. immune checkpoint inhibitors such as nivolumab and pembrolizumab demonstrated encouraging antitumor activity. Furthermore, specific targeting of signaling pathways, such as the c-MET pathway, has demonstrated efficacy in certain PapillaryRCC. While combination therapies, including immunotherapies, have shown positive outcomes, immune checkpoint inhibitors like nivolumab and pembrolizumab have demonstrated encouraging antitumor activity. Additionally, targeting the c-MET pathway has proven effective in certain papillary RCC. Further research is warranted to establish optimal treatment strategies and improve outcomes for patients with non-clear cell RCC. Systemic therapy for non-clear cell RCC is complex and evolving. Further research is needed to delineate optimal treatment strategies for different histological subtypes and improve patient outcomes.

Comparison of the efficacy of sunitinib and pazopanib in patients with advanced non-clear renal cell carcinoma

Non-clear cell renal cell carcinoma (non-ccRCC) is a highly heterogeneous disease group, accounting for approximately 25% of all RCC cases. Due to its rarity and especially heterogeneity, phase III trial data is limited and treatment options generally follow those of clear cell RCC. In the literature, there exists a number of studies with sunitinib, cabozantinib, and everolimus, but data on the efficacy of pazopanib are limited. Our aim in this study was to compare the efficacy of pazopanib and sunitinib, in a multicenter retrospective cohort of non-ccRCC patients. Our study included patients diagnosed with non-ccRCC who received pazopanib or sunitinib treatment as first-line therapy from 22 tertiary hospitals. We compared the progression-free survival (PFS), overall survival (OS), and response rates of pazopanib and sunitinib treatments. Additionally, we investigated prognostic factors in non-ccRCC. PFS and response rates of sunitinib and pazopanib were found to be similar, while a numerical difference was observed in OS. Being 65 years and older, being in the intermediate or poor risk group according to the International Metastatic Renal Cell Carcinoma Database Consortium, having liver metastases, presence of a sarcomatoid component, and having de novo metastatic disease were found to be significantly associated with shorter PFS. Pazopanib treatment appears to have similar efficacy in the treatment of non-ccRCC compared to sunitinib. Though randomized controlled trials are lacking and will probably be never be available, we suggest that pazopanib could be a preferred agent like sunitinib and cabozantinib.

Adjuvant Everolimus in Non–Clear Cell Renal Cell Carcinoma

Clinical trial data on adjuvant therapy in patients with non-clear cell renal cell carcinoma (RCC) are scant. 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. 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. The intervention group received 54 weeks of everolimus (10 mg orally daily); the control group received a matching placebo. 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. 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. 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. ClinicalTrials.gov Identifier: NCT01120249.

Germline Susceptibility to Renal Cell Carcinoma and Implications for Genetic Screening.

Genetic susceptibility to nonsyndromic renal cell carcinoma (RCC) remains poorly understood, especially for different histological subtypes, as does variations in genetic predisposition in different populations. The objectives of this study were to identify risk genes for RCC in the Canadian population, investigate their clinical significance, and evaluate variations in germline pathogenic variants (PVs) among patients with RCC across the globe. We conducted targeted sequencing of 19 RCC-related and 27 cancer predisposition genes for 960 patients with RCC from Canada and identified genes enriched in rare germline PVs in RCC compared with cancer-free controls. We combined our results with those reported for patients from Japan, the United Kingdom, and the United States to investigate PV variations in different populations. Furthermore, we evaluated the performance of referral criteria for genetic screening for including patients with rare PVs. We identified 39 germline PVs in 56 patients (5.8%) from the Canadian cohort. Compared with cancer-free controls, PVs in CHEK2 (odds ratio [OR], 4.8 [95% CI, 2.7 to 7.9], P = 3.94 × 10-5) and ATM (OR, 4.5 [95% CI, 2.0 to 8.7], P = .016) were significantly enriched in patients with clear cell, whereas PVs in FH (OR, 215.1 [95% CI, 64.4 to 597.8], P = 6.14 × 10-9) were enriched in patients with non-clear cell RCCs. PVs in BRCA1, BRCA2, and ATM were associated with metastasis (P = .003). Comparative analyses showed an enrichment of TP53 PVs in patients from Japan, of CHEK2 and ATM in patients from Canada, the United States and the United Kingdom, and of FH and BAP1 in the United States. CHEK2, ATM, and FH are risk genes for RCC in the Canadian population, whereas PVs in BRCA1/2 and ATM are associated with risk of metastasis. Globally, clinical guidelines for genetic screening in RCC fail to include more than 70% of patients with rare germline PVs.

Identification of novel biomarkers to distinguish clear cell and non-clear cell renal cell carcinoma using bioinformatics and machine learning.

Renal cell carcinoma (RCC), accounting for 90% of all kidney cancer, is categorized into clear cell RCC (ccRCC) and non-clear cell RCC (non-ccRCC) for treatment based on the current NCCN Guidelines. Thus, the classification will be associated with therapeutic implications. This study aims to identify novel biomarkers to differentiate ccRCC from non-ccRCC using bioinformatics and machine learning. The gene expression profiles of ccRCC and non-ccRCC subtypes (including papillary RCC (pRCC) and chromophobe RCC (chRCC)), were obtained from TCGA. Differential expression genes (DEGs) were identified, and specific DEGs for ccRCC and non-ccRCC were explored using a Venn diagram. Gene Ontology and pathway enrichment analysis were performed using DAVID. The top ten expressed genes in ccRCC were then selected for machine learning analysis. Feature selection was operated to identify a minimum highly effective gene set for constructing a predictive model. The expression of best-performing gene set was validated on tissue samples from RCC patients using immunohistochemistry techniques. Subsequently, machine learning models for diagnosing RCC were developed using H-scores. There were 910, 415, and 835 genes significantly specific for DEGs in ccRCC, pRCC, and chRCC, respectively. Specific DEGs in ccRCC enriched in PD-1 signaling, immune system, and cytokine signaling in the immune system, whereas TCA cycle and respiratory, signaling by insulin receptor, and metabolism were enriched in chRCC. Feature selection based on Decision Tree Classifier revealed that the model with two genes, including NDUFA4L2 and DAT, had an accuracy of 98.89%. Supervised classification models based on H-score of NDUFA4L2, and DAT revealed that Decision Tree models showed the best performance with 82% accuracy and 0.9 AUC. NDUFA4L2 expression was associated with lymphovascular invasion, pathologic stage and pT stage in ccRCC. Using integrated bioinformatics and machine learning analysis, NDUFA4L2 and DAT were identified as novel biomarkers to differential diagnosis ccRCC from non-ccRCC.

Genomic alterations and clinical outcomes in patients with non-clear cell RCC: Indiana University experience.

Genomic alterations and clinical outcomes in patients with non-clear cell RCC: Indiana University experience.

Clear cell and non-clear cell renal cell carcinoma in young adults: clinicopathological features, survival outcomes and prognostic factors.

Renal cell carcinoma (RCC) is infrequent among young adults. Few studies reported the outcome of RCC in young adults by pathological subtypes. The purpose of this study was to explore the clinicopathological features, survival outcomes and prognostic factors of young adult patients with clear cell (CCRCC) and non-clear cell renal cell carcinoma (NCCRCC). This study included young adult patients aged 18-40years who were diagnosed as renal cell carcinoma (RCC) between 2012 and 2022 at Peking University Third Hospital. All patients underwent either partial nephrectomy or radical nephrectomy, and some received adjuvant therapy. A comparative analysis was performed to investigate the differences in clinicopathological characteristics between the cohort of CCRCC and NCCRCC. Kaplan-Meier survival analysis was utilized to plot survival curves for young adults with RCC. The univariate and multifactorial prognostic analyses were conducted using the log-rank test and COX proportional hazards model. A total of 300 RCC patients aged 18-40years were performed, of which 201 were diagnosed with CCRCC (67%) and 99 were diagnosed with NCCRCC(33%). The NCCRCC included 29 cases (9.7%) of chromophobe RCC, 28 cases (9.3%) of MiT family translocation RCC, 22 cases (7.3%) of papillary RCC, 11 cases (3.7%) of low malignant potential multifocal cystic RCC, and 6 cases of unclassified RCC (2.0%), 2 cases of mucinous tubule and spindle cell carcinoma (0.7%), and 1 case of FH-deficient RCC (0.3%).The mean age was 33.4±6.1years old. The overall and progression free 5-year survival rate was 99.1 and 95.3%, respectively. The NCCRCC cohort demonstrated a statistically significant decrease in progression-free survival (PFS) rate when compared to the CCRCC cohort (p<0.001). There was no statistically significant difference observed in overall survival (OS) (p=0.069). Pathological stage was a significant independent predictor for OS (p=0.045). Pathological stage and nuclear grade were both independent predictors for PFS (p=0.020; p=0.005). The clinical and pathological features of young adults diagnosed with CCRCC exhibit notable distinctions from those of NCCRCC patients. The survival outcome was significantly influenced by the pathological stage, while both the nuclear grade and pathological stage had a significant impact on tumor progression. This study offered significant contributions to the understanding of the clinicopathological characteristics and prognostic determinants of renal cell carcinoma (RCC) in young adults.

Characterization of FOLH1 Expression in Renal Cell Carcinoma.

Given the emergence of PSMA-targeted diagnostic agents and therapeutics, we sought to investigate patterns of FOLH1 expression in RCC and their impacts on RCC outcomes. We conducted a pooled multi-institutional analysis of patients with RCC having undergone DNA and RNA next-generation sequencing. FOLH1-high/low expression was defined as the ≥75th/<25th percentile of RNA transcripts per million (TPM). Angiogenic, T-effector, and myeloid expression signatures were calculated using previously defined gene sets. Kaplan-Meier estimates were calculated from the time of tissue collection or therapy start. We included 1,724 patients in the analysis. FOLH1 expression was significantly higher in clear cell (71%) compared to non-clear cell RCC tumors (19.0 versus 3.3 TPM, p < 0.001) and varied by specimen site (45% primary kidney/55% metastasis, 13.6 versus 9.9 TPM, p < 0.001). FOLH1 expression was correlated with angiogenic gene expression (Spearman = 0.76, p < 0.001) and endothelial cell abundance (Spearman = 0.76, p < 0.001). While OS was similar in patients with FOLH1-high versus -low ccRCC, patients with FOLH1-high clear cell tumors experienced a longer time on cabozantinib treatment (9.7 versus 4.6 months, respectively, HR 0.57, 95% CI 0.35-0.93, p < 0.05). We observed differential patterns of FOLH1 expression based on histology and tumor site in RCC. FOLH1 was correlated with angiogenic gene expression, increased OS, and a longer duration of cabozantinib treatment.

Increased level of serum leucine-rich-alpha-2-glycoprotein 1 in patients with clear cell renal cell carcinoma

BackgroundCurrently, no useful serum markers exist for clear cell renal cell carcinoma (ccRCC), making early detection challenging as diagnosis relies solely on imaging tests. Radiation exposure is also a concern due to multiple required CT examinations during treatment. Renal cell carcinoma (RCC) histological types include ccRCC and non-clear cell RCC (non-ccRCC); however, treatment response to medications varies which necessitates accurate differentiation between the two. Therefore, we aimed to identify a novel serum marker of RCC. Increased LRG1 expression in the serum has been demonstrated in multiple cancer types. However, the expression of LRG1 expression in the serum and cancer tissues of patients with RCC has not been reported. Since ccRCC is a hypervascular tumor and LRG1 is capable of accelerating angiogenesis, we hypothesized that the LRG1 levels may be related to ccRCC. Therefore, we examined LRG1 expression in sera from patients with RCC.MethodsUsing an enzyme-linked immunosorbent assay, serum levels of leucine-rich-alpha-2-glycoprotein 1 (LRG1) were measured in 64 patients with ccRCC and 22 patients non-ccRCC who underwent radical or partial nephrectomy, as well as in 63 patients without cancer.ResultsMedian values of serum LRG1 and their inter-quartile ranges were 63.2 (42.8–94.2) µg/mL in ccRCC, 23.4 (17.7–29.6) µg/mL in non-ccRCC, and 36.0 (23.7–56.7) µg/mL in patients without cancer, respectively (ccRCC vs. non-ccRCC or patients without cancer: P < 0.001). C-reactive protein (CRP) levels (P = 0.002), anemia (P = 0.037), hypercalcemia (P = 0.023), and grade (P = 0.031) were independent predictors of serum LRG1 levels in ccRCC. To assess diagnostic performance, the area under the receiver operating characteristic curve of serum LRG1 was utilized to differentiate ccRCC from non-cancer and non-ccRCC, with values of 0.73 (95% CI, 0.64–0.82) and 0.91 (95% CI, 0.82–0.96), respectively.ConclusionsLRG1 served as a serum marker associated with inflammation, indicated by CRP, anemia, hypercalcemia, and malignant potential in ccRCC. Clinically, serum LRG1 levels may assist in differentiating ccRCC from non-ccRCC with excellent diagnostic accuracy.

Papillary Renal Cell Carcinoma: Outcomes for Patients Receiving First-line Immune-based Combinations or Tyrosine Kinase Inhibitors from the ARON-1 Study

Background and objectivePapillary renal cell carcinoma (pRCC) is the most frequent histological subtype of non-clear cell RCC (nccRCC). Owing to the heterogeneity of nccRCC, patients are often excluded from large phase 3 trials focused on clear cell RCC, so treatment options for nccRCC remain limited. Our aim was to investigate the efficacy of first-line treatment with tyrosine kinase inhibitors (TKIs) or immuno-oncology (IO)-based combinations in patients with pRCC. MethodsWe performed a multicenter retrospective analysis of real-world data collected for patients with advanced pRCC treated in 40 centers in 12 countries as part of the ARON-1 project (NCT05287464). The primary endpoints were overall survival (OS), progression-free survival (PFS), the overall response rate (ORR), and time to second progression (PFS2). OS, PFS, and PFS2 were estimated using the Kaplan-Meier method and results were compared between the treatment groups using a log-rank test. Univariate and multivariable analyses were carried out using Cox proportional-hazard models. Key findings and limitationsWe included 200 patients with metastatic pRCC, of whom 73 were treated with IO-based combinations and 127 with TKIs. Median OS was 22.5 mo in the TKI group 28.8 mo in the IO group (p = 0.081). Median PFS was 6.4 mo in the TKI group and 17.4 mo in the IO group (p < 0.001). The ORR was higher in the IO group than in the TKI group (41% vs 27%; p = 0.037). Conclusions and clinical implicationsOur results show that IO-based combinations have superior efficacy outcomes to TKIs for first-line treatment of metastatic pRCC. Patient summaryThe ARON-1 project collects clinical data for patients with kidney cancer treated in multiple centers worldwide to assess outcomes in the real-world setting. We analyzed data for patients with metastatic kidney cancer of a specific subtype to evaluate the efficacy of different first-line treatments. Patients treated with immune-based combinations had better outcomes than patients treated with tyrosine kinase inhibitors.

Cancer-specific mortality in non-metastatic T1a renal cell carcinoma treated with radiotherapy versus partial nephrectomy.

Radiotherapy (RT) represents a treatment option for small renal masses with proven feasibility and tolerability. However, it has never been directly compared to partial nephrectomy (PN) with cancer-specific mortality (CSM) as an endpoint. Within the Surveillance, Epidemiology, and End Results database (2004-2020), we identified T1aN0M0 renal cell carcinoma (RCC) patients treated with RT or PN. We relied on 1:1 propensity score matching (PSM) for age, tumor size and histology. Subsequently, cumulative incidence plots and multivariable competing risks regression (CRR) models were fitted. The same methodology was then re-applied to a subset of patients with tumor size 21-40mm. Of 40,355 patients with T1aN0M0 RCC, 40,262 underwent PN (99.8%) vs 93 underwent RT (0.2%). RT patients were older (median age 72 vs 60years, p < 0.001) and harbored larger tumor size (median size 28 vs 25mm, p < 0.001) and a higher proportion of non-clear cell RCC (49% vs 22%, p < 0.001). After 1:1 PSM (92 RT versus 92 PN patients), cumulative incidence plots' derived CSM was 21.3 vs 4%, respectively. In multivariable CRR models, RT independently predicted higher CSM (hazard ratio (HR) 4.3, p < 0.001). In the subgroup with tumor size 21-40mm, after 1:1 PSM (72 RT versus 72 PN patients), cumulative incidence plots derived CSM was 21.3% vs 4%, respectively. In multivariable CRR models, RT also independently predicted higher CSM (HR 4.7, p = 0.001). In T1aN0M0 RCC patients, relative to PN, RT is associated with significantly higher absolute and relative CSM, even in patients with tumor size 21-40mm.

Abstract 1846: Integrative histopathologic, proteomic, phosphoproteomic, genomic, and transcriptomic characterization of renal cell carcinoma

Abstract Although histologically defined subtypes exist, renal cell carcinoma (RCC) is a heterogenous disease, resulting in various treatment outcomes and prognosis. Here, we conduct comprehensive profiling of RCC with histopathologic, proteomic, phosphoproteomic, genomic, and transcriptomic analyses on tumor and paired adjacent normal tissues from 113 patients. RCC tumors are distinctly separated from corresponding normal tissues through multi-omics clustering, a distinction further supported by pathway analysis. In addition, various hallmarks of cancer were differentially observed at the individual patient level, highlighting the intertumoral heterogeneity of RCC. Proteomic subtyping classifies RCC tumors into four subtypes (C1-4) with distinct phosphoproteomic, genomic, and transcriptomic characteristics with prognostic and predictive implications. Among these subtypes, C1-3 were almost composed of clear cell RCC (ccRCC; 96.8%), whereas C4 was composed of non-clear cell RCC (nccRCC) or other types of cancer (100.0%). Among each subtype, C1 (N=37) exhibits the strongest adaptive immune response and angiogenesis with favorable prognosis after surgical resection. C2 (N=39) was characterized with enrichment in DNA repair pathways and alteration in VHL (100.0%) along with BAP1 (24.0%) genes. C3 (N=19) was associated with enrichment in inflammatory response with dismal prognosis and therapeutic resistance to tyrosine kinase inhibitors targeting vascular endothelial growth factor receptors. C4 (N=18) was exclusively enriched with nccRCC with active mitochondrial and oxidation phosphorylation. Transglutaminase 2 (TGM2), a crosslinking enzyme, is identified as a potential marker with therapeutic implication for ccRCC. Collectively, this study reports a large-scale multi-omics-based approach of RCC, providing insights into biologic underpinning and evidence for rational treatment selection as well as linking the multi-omics-derived phenotypes to clinical outcomes of ccRCC. Citation Format: Woo Sun Kwon, Chang Gon Kim, Harim Koo, Woo Kyun Bae, Eu Chang Hwang, Won Sik Ham, Nam Hoon Cho, Jason K. Sa, Jong Bae Park, Sun Young Rha. Integrative histopathologic, proteomic, phosphoproteomic, genomic, and transcriptomic characterization of renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1846.

Metastasis suppressor kisspeptin (KISS1) in serum of patients with renal cell carcinoma

Background. The most important problems in improvement of treatment outcomes in patients with renal cell carcinoma (RCC) are search and validation of molecular markers for its early diagnosis and prognosis. Genes suppressing distant metastasizing but not affecting the primary tumor are called metastasis suppressors. Study of these genes and their products not only improves understanding of the mechanisms of tumor progression, but has practical value for diagnosis, prognosis, and establishment of new molecular targets for antitumor therapy. One of such genes is KISS1 with its product kisspeptin (KISS1) protein.Aim: comparative evaluation of KISS1 concentration in blood serum of practically healthy persons and patients with renal cancer; analysis of correlations between the marker’s level and clinical and morphological characteristics of the disease.Materials and methods. 140 patients with RCC (88 men, 52 women) aged between 29 and 82 years were included in the study. Among them, clear cell RCC was diagnosed in 84 patients, papillary in 38, chromophobe in 18. The control group was comprised of 40 healthy persons of matched age and sex. Pre-treatment KISS1 concentration in blood serum was measured using a direct enzyme immunoassay kit (Kisspeptin 1 – KISS1, Cloud-Clone Corp., USA).Results. Median serum KISS1 concentration in the control group was 51.7 pg/mL which was significantly lower than in the total RCC patient group – 243.6 pg/mL (p &lt;0.0001). ROC analysis of diagnostic value of serum KISS1 level was performed both for the total RCC group and for each of its three histological types. In the total group the sensitivity of the test was 75 %, specificity – 80 % (AUC 0.877; 95 % confidence interval (CI) 0.827–0.927; optimal cut-off level 130.8 pg/mL; р &lt;0.0001). For clear cell RCC, both sensitivity and specificity were 85 % (AUC 0.941; 95 % CI 0.902– 0.979; cut-off 141.8 pg/mL; p &lt;0.0001). In non-clear cell RCC types, sensitivity of this marker was only 58 % while the specificity remained 80 % (for papillary RCC AUC 0.787; 95 % CI 0.684–0.889; cut-off level 135.5 pg/mL; p &lt;0.0001, and for chromophobe RCC AUC 0.774; 95 % CI 0.617–0.929; cut-off level 132.1 pg/mL; p &lt;0.001). KISS1 level increased with disease progression: it is significantly higher at more advanced stages above stage I, and in patients with distant metastases compared to those without metastases. Higher serum KISS1 level is also observed in patients with poorly differentiated high-grade (per Furhman) clear cell RCC and papillary RCC (G3–G4) than in those with well differentiated low-grade (G1–G2) tumors.Conclusion. KISS1 level is significantly increased in patients with RCC compared to healthy controls and is a stagedependent marker of this disease. It has relatively high diagnostic sensitivity and specificity (both 85 %) for the most frequent histological type of RCC – clear cell RCC. Thus, clinical significance of kisspeptin in RCC requires further investigation.

Prognostic significance of pT3a staging subclassifications in renal cell carcinoma: Not all pT3a are equal

ObjectiveTo examine the prognostic significance of perinephric fat, renal sinus fat, and renal vein invasion in patients with pT3a renal cell carcinoma (RCC) by histologic type. MethodsA population-based retrospective cohort study of patients with pT3aN0M0 RCC was performed using Surveillance, Epidemiology, and End Results (SEER) data for the years 2010 through 2019. Cox proportional hazards models were used to examine the relationship between pT3a subclassification groups and cancer-specific survival (CSS) by histological subtype (clear cell, papillary, chromophobe, and other). ResultsThe cohort consisted of 10,170 patients with pT3a RCC, including 8,446 (83.0%) with clear cell RCC and 1,724 (17.0%) with nonclear cell RCC (nccRCC). Median follow up was 36 months. Differences in CSS by pT3a subclassification groups were observed in all histological subtypes but were most pronounced in nccRCC, specifically papillary RCC. Compared to perinephric fat (PF) invasion only, renal vein (RV) invasion (HR = 4.9, 95%CI: 2.5–9.3, P < 0.01), renal sinus fat invasion (HR = 3.0, 95%CI: 1.4–6.2), RV and PF invasion (HR = 7.5, 95%CI: 3.5–16.0), and combination of all three characteristics (HR = 4.4, 95%CI: 1.2–15.5) were associated with worse CSS in patients with papillary RCC. ConclusionWe examined the prognostic role of pT3a staging subclassifications in RCC by histologic subtype and observed survival differences, particularly in papillary RCC. Our findings highlight the need to refine pT3a staging criteria to help guide individualized, multimodal treatment strategies for locally advanced RCC.

The incidence, pathogenesis, and management of non-clear cell renal cell carcinoma.

Renal cell carcinoma (RCC) is the most common type of kidney cancer and is divided into two distinct subtypes, clear cell renal cell carcinoma (ccRCC) and non-clear cell renal cell carcinoma (nccRCC). Although many treatments exist for RCC, these are largely based on clinical trials performed in ccRCC and there are limited studies on the management of nccRCC. Non-clear cell RCC consists of multiple histological subtypes: papillary, chromophobe, translocation, medullary, collecting duct, unclassified, and other rare histologies. Due to variations in pathogenesis and therapeutic response, therapy should be tailored to specific variant histologies. For patients with localized nccRCC, surgical resection remains the gold standard. In the metastatic setting, the standard of care has yet to be clearly defined, and most guidelines recommend clinical trial participation. General therapeutic options include immunotherapy, either as monotherapy or in combination, targeted therapies such as vascular endothelial growth factor tyrosine kinase inhibitors and MET inhibitors, and chemotherapy in certain subtypes. Here we present a review of the incidence and pathogenesis of the various subtypes, as well as available clinical data to support therapeutic recommendations for these subtypes. We also highlight currently available clinical trials in nccRCC and future directions in investigating novel treatment modalities tailored to patients with variant histology.