This review focuses on contemporary research into potential prognostic and therapeutic biomarkers for advanced renal cell carcinoma (RCC) published over the past 18 months. Beyond serum lab values, there is no consensus on the use of specific biomarkers for this purpose. Potential biomarkers being investigated consist of genetic, protein, immunologic, and radiologic candidates.

New insights in genomic biomarkers include a better understanding of VHL mutational heterogeneity, tumor mutational burden, and the importance of genes like PBRM1 and SETD2 . Protein biomarkers such as C-reactive protein (CRP) and PDZK1 have demonstrated utility in predicting disease progression, therapeutic response, and survival, while immunologic biomarkers like PSMD2, cytokines, and Tregs continue to shed light on the tumor microenvironment and immune evasion. Emerging imaging biomarkers, from CAIX-targeted radiotracers to PSMA-based PET-CT, offer noninvasive diagnostic and prognostic tools that may revolutionize RCC management.

There are several promising biomarkers currently under investigation for use in advanced RCC.

Immuno-oncology (IO) is one of the fastest growing therapeutic areas within oncology. IO agents work indirectly via the host's adaptive and innate immune system to recognize and eradicate tumor cells. Despite checkpoint inhibitors being only introduced to the market since 2011, they have become the second most approved product category. Current Food and Drug Administration (FDA)-approved classes of IO agents include: immune checkpoint inhibitors (ICIs), chimeric antigen receptor T-cell therapy (CAR-T), bi-specific T-cell engager (BiTE) antibody therapy, T-cell receptor (TCR) engineered T cell therapy, tumor-infiltrating lymphocyte (TIL) therapy, cytokine therapy, cancer vaccine therapy, and oncolytic virus therapy. Cancer immunotherapy has made progress in multiple cancer types including melanoma, non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), and urothelial carcinoma; however, several cancers remain refractory to immunotherapy. Future directions of IO include exploration in the neoadjuvant/perioperative setting, combination strategies, and optimizing patient selection through improved biomarkers.

Ubiquitin-specific protease 35 (USP35) has gained attention as a regulator in cancer progression. However, its specific role in kidney clear cell carcinoma (KIRC) remains unclear.

USP35 expression in KIRC tumor and normal tissues was evaluated using TCGA data. Correlations between USP35 expression, clinical parameters, and survival outcomes were examined. Functional enrichment analyses were performed to explore the pathways associated with USP35 expression. Immune-related analyses were conducted to assess the effect of USP35 on immune cell recruitment and neoantigen presentation. Drug sensitivity analyses were used to identify potential therapeutic agents targeting USP35.

USP35 was significantly overexpressed in KIRC tumor tissues compared to normal tissues, and its high expression correlated with advanced disease stages and poor survival outcomes. Gene set enrichment analysis revealed that high USP35 expression was associated with oncogenic pathways, including glycerophospholipid and linoleic acid metabolism, while low expression linked to nitrogen and purine metabolism. USP35 also modulated immune responses, affecting immune cell recruitment and neoantigen presentation, suggesting a role in immune evasion. Drug sensitivity analysis showed that high USP35 expression correlated with increased sensitivity to paclitaxel, bosutinib, and lapatinib. In vitro knockdown of USP35 significantly reduced KIRC cell proliferation, migration, and epithelial-mesenchymal transition (EMT), further supporting its role in tumor progression.

USP35 is overexpressed in KIRC and associated with poor prognosis, likely promoting tumor progression through oncogenic pathways and immune modulation. Its correlation with drug sensitivity positions USP35 as a potential therapeutic target, warranting further investigation into its mechanistic functions and therapeutic applications.

The numbers of tumor-infiltrating immune cells (TIICs) expressing programmed death (PD)-1 or PD-ligand 1 (PD-L1) reportedly predict prognosis and resistance to targeted drugs in clear cell renal cell carcinoma (ccRCC). The impact of local tumor microenvironment based on immunosuppressive TIICs on recurrence and prognosis has not been fully investigated in localized ccRCC.

A total of 105 patients with pT1b ccRCC were included. Immunostaining for PD-1 and PD-L1 were performed. PD-1-positive TIICs and PD-L1-positive TIICs were counted in the tumor periphery (TP) and the tumor nest (TN).

Patients with elevated PD-1-positive TIIC scores and those with elevated PD-L1-positive TIIC scores had significantly lower recurrence-free survival (RFS) rates than their counterparts (3-year RFS rates; patients with high vs. low PD-1-positive TIIC score of TN = 73.9% vs. 95.0%, those with high vs. low PD-1-positive TIIC score of TP = 73.8% vs. 93.8%, those with high vs. low PD-L1-positive TIIC score of TN = 70.9% vs. 93.0%, and those with high vs. low PD-L1-positive TIIC score of TP = 80.3% vs. 92.6%). Univariate analysis showed that high PD-1-positive scores, high PD-L1-positive scores, high PD-L1-positive tumor cell score, high-grade tumor, tumor necrosis, and lymphovascular invasion were significantly associated with RFS. Multivariate analysis revealed that tumor necrosis [hazard ratio (HR) = 2.841, P = .0269] and PD-1-positive TIIC score of TN (HR = 6.135, P = .0023) were independent risk factors for RFS. Risk stratification using the two factors efficiently predicts recurrence (3-year RFS rates: 96.4% with 0 factor, 83.8% with 1 factor, and 61.4% with 2 factors).

PD-1-positive TIIC score of TN and tumor necrosis may efficiently predict recurrence in pT1b ccRCC.

Avelumab + axitinib was approved for the treatment of advanced renal cell carcinoma (aRCC) in Japan in December 2019. We report long-term real-world subgroup analyses with first-line avelumab + axitinib in patients with aRCC by International Metastatic RCC Database Consortium (IMDC) risk classification from the J-DART2 study in Japan.

J-DART2 was a multicenter, noninterventional, retrospective study examining characteristics, treatment patterns, and outcomes in patients with aRCC who started first-line avelumab + axitinib in Japan between December 2019 and October 2022.

Data from 150 patients across 19 sites were analyzed. IMDC risk was favorable in 39 patients (26.0%), intermediate (1 risk factor) in 46 (30.7%), intermediate (2 risk factors) in 36 (24.0%), and poor in 29 (19.3%). Baseline characteristics were generally consistent across IMDC risk subgroups. In subgroups with favorable, intermediate (1 risk factor), intermediate (2 risk factors), and poor risk, median progression-free survival was 31.0, 15.3, 16.4, and 8.1 months; median overall survival (OS) was not reached, but 24-month OS rates were 95.2%, 91.3%, 85.3%, and 57.6%, respectively. Objective response rates were 54.5%, 56.8%, 47.1%, and 54.2%, respectively. High-dose corticosteroid treatment for immune-related adverse events was administered in 5.1%, 8.7%, 8.3%, and 6.9% of patients, respectively.

Subgroup analyses from J-DART2 confirm the long-term real-world effectiveness of first-line avelumab + axitinib across IMDC risk groups in patients with aRCC in Japan. Our findings were consistent with previous analyses by IMDC risk and support the favorable benefit-risk profile of avelumab + axitinib in clinical practice in Japan.

Although there are multiple treatment options, oncologists lack appropriate biomarkers for determining the efficacy and toxicity of immunotherapy. In this study, we aimed to use a combination of the clinical parameters of IMDC risk groups at the time of diagnosis to predict the effectiveness of immunotherapy.

This multicenter cross-sectional study retrospectively analyzed non-small cell lung cancer (NSCLC) patients receiving nivolumab for the prognostic effects of clinical factors, including the IMDC score.

Two hundred and five patients were enrolled in this study. There was no favorable group because the TTI was less than 1 year in the entire study group in the IMDC. The IMDC score and IMDC groups showed significant differences in PFS (p < 0.001; p < 0.001, respectively). Intermediate and poor-risk groups had PFS of 8 and 3 months PFS, respectively. The IMDC group showed a significant effect on OS (p = 0.002). The intermediate- and poor-risk groups had 12- and 4-month OS, respectively. The TTI risk factor excluded patient numbers in the favorable, intermediate, and poor risk groups were 47, 129, and 29, respectively, in the revised IMDC group (rIMDC). The prognostic effect of the rIMDC score and groups remained significant (p < 0.001 and p < 0.001, respectively). The classical IMDC had a significant effect on PFS in the multivariate analysis (p = 0.016). Also, rIMDC score in multivariate analysis resulted with significant effect on OS (p = 0.035).

To date, this is the first study to prove that the IMDC may be a valuable option for predicting both prognosis and treatment efficacy in NSCLC patients receiving especially second or further lines nivolumab treatment.

Despite numerous meta-analyses comparing the efficacy and safety of immunotherapy-based combination therapies, the optimal therapeutic combinations remain unclear. This study aims to evaluate the optimal application of all immunotherapy-based combination therapy for advanced/metastatic renal cell carcinoma, focusing on efficacy and safety.

We systemically searched the Web of Science, Cochrane Library, and PubMed for studies regarding the first-line immunotherapy-based combination therapy in patients with advanced or metastatic renal cell carcinoma until April 15, 2024. We used network meta-analysis using a random effect model to facilitate direct and indirect treatment comparisons across outcomes.

Seven clinical studies, including 5542 patients with metastatic renal cell carcinoma, were included in the network meta-analysis analysis. Regarding progression-free survival and overall survival, combined Toripalimab + Axitinib significantly outperformed other immunotherapy-based combination therapies. This regimen significantly improved progression-free survival in the intermediate/poor risk group when stratified by prognosis prediction risks compared to sunitinib alone. For the objective response rate, Avelumab + Axitinib was the most preferred strategy in the favorable-risk group, while Nivolumab + Cabozantinib was favored in the intermediate/poor-risk group compared to other immunotherapy-based combinations. The combinations of Nivolumab + Ipilimumab and Atezolizumab + Bevacizumab had favorable safety profiles.

Immunotherapy-based combination therapies significantly improved progression-free survival, overall survival and objective response rate in patients with metastatic renal cell carcinoma compared to sunitinib monotherapy. However, careful monitoring and personalized treatment strategies are required to balance efficacy and safety in patients with underlying conditions. Future research should focus on optimizing treatment protocols and elucidating the mechanisms of adverse events.

In the phase III JAVELIN Renal 101 trial (NCT02684006), first-line treatment with avelumab + axitinib resulted in significantly longer progression-free survival (PFS) and a higher objective response rate (ORR) versus sunitinib in patients with advanced renal cell carcinoma (aRCC). We report the final analysis, including the primary analysis of overall survival (OS).

Patients with untreated aRCC (any prognostic risk score) were enrolled. The primary endpoints were OS and PFS in the programmed death-ligand 1-positive (PD-L1+) population. ORR, duration of response, safety, and patient-reported outcomes (PROs) were also assessed.

The minimum follow-up was 68 months in all patients. The median OS with avelumab + axitinib versus sunitinib, respectively, was 43.2 months [95% confidence interval (CI) 36.5-51.7 months] versus 36.2 months (95% CI 29.8-44.2 months) in the PD-L1+ population [hazard ratio (HR) 0.86 (95% CI 0.701-1.057); P = 0.0755] and 44.8 months (95% CI 39.7-51.1 months) versus 38.9 months (95% CI 31.4-45.2 months) in the overall population [HR 0.88 (95% CI 0.749-1.039); P = 0.0669]. Investigator-assessed PFS remained prolonged with avelumab + axitinib versus sunitinib [5-year event-free rate in the overall population, 12.0% (95% CI 8.9% to 15.6%) versus 4.4% (95% CI 2.5% to 7.3%)]. ORR in the overall population was 59.7% (95% CI 55.0% to 64.3%) with avelumab + axitinib versus 32.0% (95% CI 27.7% to 36.5%) with sunitinib; duration of response was ≥5 years in 16.4% (95% CI 12.0% to 21.4%) versus 9.2% (95% CI 4.6% to 15.7%), respectively. Rates of grade ≥3 treatment-related adverse events were 66.8% versus 61.5%, respectively. PROs were similar between arms.

JAVELIN Renal 101 provides the longest follow-up to date for immune checkpoint inhibitor + tyrosine kinase inhibitor combination treatment from a phase III trial in aRCC. OS analyses favored avelumab + axitinib versus sunitinib but did not reach statistical significance; subsequent treatment may have impacted results. Avelumab + axitinib provided long-term efficacy benefits versus sunitinib, including prolonged PFS, a nearly doubled ORR, and more durable responses, with a manageable long-term safety profile.

The intricacies of tumour microenvironment, particularly the extracellular matrix (ECM), underscore its pivotal function in modulating tumour progression and drug resistance. Among the key regulators of ECM remodelling and homeostasis, the lysyl oxidases (LOXs) emerge as promising therapeutic targets of tumour treatment. Despite their significance, a holistic evaluation of the LOX family's genomics and clinical implications across diverse cancer types remains elusive. Herein, this study aimed to investigate the correlation between LOX family expression and patient outcomes, drug responsiveness and tumour microenvironment (TME) characteristics in a cohort of 33 tumours based on The Cancer Genome Atlas (TCGA) database. Notably, patients exhibiting elevated LOX family expression suffer from worse prognosis and resistance to a spectrum of antitumor therapies, encompassing chemotherapy, endocrine therapy, targeted therapy and immunotherapy, in contrast to counterparts with subdued LOX family expression levels. Furthermore, enrichment analysis indicated that the LOX family fosters tumour progression and drug resistance. These findings were further validated by multiplex immunofluorescence staining in breast, gastric and rectal cancer, as well as breast cancer organoids. Altogether, this study unravels the intricate association between the LOX family and tumour progression, alongside multidrug resistance. We have gained further insights into the roles of LOX family genes in various tumour types, offering a novel avenue for future research into the relationship between LOX family genes and tumorigenesis.

The fragility index (FI) has been applied as a supplement to the noncomprehensive P-values to assess the robustness of randomized controlled trials (RCTs). The objective of this study is to evaluate the statistical robustness of RCTs of advanced/metastatic renal cell cancer (a/mRCC) using the FI.

RCTs related to a/mRCC published in the 4 highest-impact general medical journals and the 25 highest-impact urological journals between January 1, 2000, and December 31, 2023, were identified from PubMed database. The FI was calculated by using Fisher's exact test. Spearman's correlation analysis was conducted to assess potential correlates regarding FI.

16 eligible RCTs were screened with a median total sample size of 654.5 (IQR, 461-847) and a median patients lost to follow-up of 14 (IQR, 3-23). The median FI was 12.5 (IQR, 8.5-27), suggesting that a switch in outcomes in only 13 patients would have reversed the significance of the trials. The number of patients lost to follow-up exceeded or equaled to the FI in 7 (44%) RCTs. P-values were negatively associated with the FI, while the number of patients lost to follow-up and patients enrolled were not statistically significant.

Not all RCTs associated with a/mRCC are as statistically robust as previously considered and should therefore be construed carefully. We suggest that additional reporting of FI in urological RCTs as a supplement to the P-value to assist readers in concluding reliably by considering the fragility of the outcomes.

Systemic therapy for advanced renal cell carcinoma (aRCC) has become increasingly diverse. In the 1st-line setting, various combination therapies are available, with little comparative data on the efficacy of the therapies. The aim of this study was to compare the current 1st-line combination therapies under real-life conditions and to investigate risk factors in the patient population.

Patients with aRCC who started 1st-line IO/IO or IO/TKI combination  therapy between 03/2019 and 10/2023 were included. The primary endpoints were progression-free survival (PFS) and overall survival (OS). Secondary endpoints were time on treatment (ToT), duration of response (DoR), subsequent therapies, the evaluation of risk factors and their influence on PFS and OS. Survival data were analysed using Kaplan-Meier estimates with log-rank tests, risk factors for PFS and OS using Cox regression analysis.

A total of 59 patients, mainly men (79.7%) with a median age of 64.8 years were included. The median follow-up was 21 months. The comparison of IO/IO vs. IO/TKI demonstrated a median PFS of 6 (2.08-9.92) vs. 14 (9.06-18.94) months (47 events; HR IO/TKI vs. IO/IO: 0.53 (0.29-0.99); p = 0.039) and a median OS of 20 (15.07-24.94) vs. 33 (21.68-44.32) months (32 deaths; HR IO/TKI vs. IO/IO: 0.74 (0.36-1.51); p = 0.403). Off all risk factors analysed only synchronous metastases proved to be of independent predictive value for PFS (HR 2.38; 95% CI 1.11-5.11; p = 0.026) and OS (HR 3.47; 95% CI 1.15-10.44; p = 0.027).

An IO/TKI therapy showed a significantly improved PFS in the real-world setting compared to an IO/IO combination. In terms of OS, the improved treatment response of the IO/TKI group did not prevail.

Dramatic advances in biological discoveries, since the 1990s, have continued to reshape the treatment paradigm of metastatic renal cell carcinoma (RCC). Von Hippel Lindau (VHL) gene alterations are associated with pro-angiogenic activity and are central to the pathogenesis of clear cell RCC (ccRCC), the most predominant histologic subtype of RCC. Antiangiogenic strategies revolving around this VHL/HIF/VEGF axis have been shown to improve survival in metastatic ccRCC. The discovery of immune checkpoints and agents that target their inhibition introduced a new treatment paradigm for patients with RCC. While initially approved as monotherapy, studies investigating immune checkpoint inhibitor combinations have led to their approval as the new standard of care, providing durable responses and unprecedented improvements in clinical outcome. Despite these advances, the projected 14 390 deaths in 2024 from RCC underscore the need to continue efforts in expanding and optimizing treatment options for patients with metastatic RCC. This article reviews key findings that have transformed the way we understand and treat metastatic RCC, in addition to highlighting novel treatment strategies that are currently under development.

The treatment landscape of metastatic clear cell renal cell carcinoma (ccRCC) has rapidly evolved with the approval of multiple immune checkpoint inhibitor (ICI)-based combinations. However, clinical data on changes in treatment patterns and attrition before and after ICI-based combinations approval are lacking.

To assess treatment patterns and attrition rates in patients with metastatic ccRCC before and after the approval of ICI-based combinations.

This cohort study used patient-level data from a nationwide deidentified electronic health record-derived database, originating from around 280 cancer clinics in the US. Patients diagnosed with metastatic ccRCC who received first-line therapy between January 1, 2011, and January 20, 2023, were included. Those treated for 2 or more malignant neoplasms or enrolled in clinical trials were excluded.

Line of therapy initiation before and after April 16, 2018.

Treatments received in each line of therapy and attrition rate were summarized using frequencies and percentages.

Of 12 707 patients with metastatic ccRCC within the database, 8534 were eligible and included (median [IQR] age, 66 [59-74] years; 6032 male [70.7%]; 629 Black [8.1%], 697 Hispanic [9.0%], 5493 White [71.0%]). Before April 16, 2018, the most common first-line therapy was tyrosine kinase inhibitor (TKI) monotherapy (3595 of 4561 patients [78.8%]). Following the approval of ICI-based combinations in 2018, most patients (2392 of 3973 patients [60.2%]) received ICI-based combinations as first-line therapy for metastatic ccRCC. TKI monotherapy remained the most common second- and third-line therapy in patients treated before and after April 16, 2018. Before 2018, 2639 patients (57.9%) and 1458 patients (31.9%) received second-line and third-line therapies, respectively, compared with 1494 (37.6%) and 562 (14.1%) after 2018.

In this cohort study of 8534 patients with metastatic ccRCC, although ICI-based combinations are the preferred first-line therapy due to their proven superiority over TKI monotherapy, many patients were not receiving them; high attrition rates were observed in subsequent lines. These findings highlight the need to optimize treatment selection by implementing current guidelines in clinical practice.

Translating findings on the genomic landscape of metastatic clear-cell renal cell carcinoma (mccRCC) into clinical practice remains challenging. A better understanding of the molecular features of mccRCC could identify a prognostic and/or predictive role for ccRCC genomic alterations.

In this real-world observational study based on the nationwide (US-based) de-identified Flatiron Health-Foundation Medicine, Inc. clinico-genomic database (FH-FMI-CGDB), we investigate the frequency and co-occurrence of genomic alterations in mccRCC patients and assess their prognostic role. Patients (n = 858) were adults diagnosed with mccRCC, with FH electronic health records between 2011 and 2022.

The top 10 mutated genes were VHL (73.9%), PBRM1 (42.4%), SETD2 (25.3%), CDKN2A (20.0%), BAP1 (16.4%), CDKN2B (16.0%), KDM5C (14.5%), TP53 (12.9%), PTEN (11.7%), and TERT (9.2%). Eight genes showed prognostic value: CDKN2A, CDKN2B, TP53, PTEN, NF2, PIK3CA, and MTAP were linked to worse prognosis, whereas PBRM1 was associated with better overall survival (OS). Two of the three identified gene clusters had prognostic value: cluster 1 (VHL, SETD2, PBRM1, KDM5C, NFE2L2) correlated with better OS [adjusted hazard ratio (aHR) 0.63, P < 0.001], whereas cluster 3 (CDKN2A, CDKN2B, BAP1, NF2, MTAP) correlated with shorter OS (aHR 1.36, P = 0.023).

We identified eight genes and two gene clusters with prognostic significance for mccRCC. Future research will explore the predictive value of gene clusters in various treatments.

Cell plasticity emerges as a novel cancer hallmark and is pivotal in driving tumor heterogeneity and adaptive resistance to different therapies. Cancer stem-like cells (CSCs) are considered the root of cancer. While first defined as tumor-initiating cells with the potential to develop a heterogeneous tumor, CSCs further demonstrate their roles in cancer metastasis and adaptive therapeutic resistance. Generally, CSCs come from the malignant transformation of somatic stem cells or the de-differentiation of other cancer cells. The resultant cells gain more plasticity and are ready to differentiate into different cell states, enabling them to adapt to therapies and metastatic ecosystems. Therefore, CSCs are likely the nature of tumor cells that gain cell plasticity. However, the phenotypic plasticity of CSCs has never been systematically discussed. Here, we review the distinct intrinsic signaling pathways and unique microenvironmental niches that endow CSC plasticity in solid tumors to adapt to stressful conditions, as well as emerging opportunities for CSC-targeted therapy.

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.

Combination systemic therapies (CSTs) of immuno-oncologic (IO) and VEGF-inhibiting agents (VEGFi) have become the standard of care for management of metastatic clear cell renal cell carcinoma (m-ccRCC). However, treatment outcomes vary between patients, with no established biomarkers to determine optimal CST regimens (IO/IO or IO/VEGFi). Prostate Specific Membrane Antigen (PSMA), encoded by the FOLH1 gene, is a marker of tumor neovasculature in ccRCC, the downstream target of VEGFi. We evaluated the relation between FOLH1 expression and angiogenesis, as well as clinical outcomes, in 5 m-ccRCC ST trials.

using Spearman's rank correlation (SPRC) test, we assessed the correlation between FOLH1 expression and gene expression signature (GES) scores corresponding to angiogenic and immunologic features of the tumor microenvironment (TME) of m-ccRCC in our trial cohorts. Using Cox proportional hazard regression (Cox-PHR), we assessed the association between FOLH1 expression level, summarized by within-study quantiles (qFOLH1), and progression-free and overall survival (PFS, OS).

Increased FOLH1 expression was significantly associated with higher TME angiogenesis GES scores (SPRC +0.5, P < 0.001), but did not consistently correlate with immune feature GES scores. Meta-analysis of PFS in the sunitinib TKI arm of trial cohorts showed an overall positive association with qFOLH1 (HR = 0.89; 95% CI = 0.85-0.94, P < 0.0001). qFOLH1 was not significantly associated with OS in the sunitinib arms of the two trials with OS data (COMPARZ, HR 0.87, 95% CI 0.71-1.07, P = 0.17; and Checkmate-214, HR 0.89, 95% CI 0.67-1.17, P = 0.70).

PSMA-encoding FOLH1 gene expression correlates with neoangiogenesis and predicts PFS in m-ccRCC patients treated with sunitinib TKI, suggesting that PSMA PET could be explored as a noninvasive biomarker for guiding CST choice (IO/IO or IO/VEGFi) as well as prediction of treatment response to VEGFi in m-ccRCC patients.

Surgery for inferior vena cava tumor thrombus (IVC-TT) in patients with renal cell carcinoma (RCC) is highly invasive and is associated with perioperative mortality. This study aimed to assess the efficacy of presurgical systemic therapy (PT) on perioperative outcomes in RCC patients with IVC-TT.

A total of 68 patients with right-sided RCC and level ≥ II IVC-TT were included in this study. The tumor response to PT was investigated, and we compared surgical outcomes and perioperative complications between patients with PT (n = 23) and those who underwent immediate surgical resection (non-PT, n = 45).

In the PT group, while 15 patients were treated with tyrosine kinase inhibitors (TKIs) alone, a combination of immune-oncology (IO) therapy and TKIs (IO + TKI) was used in 8 patients. Eleven of 23 (47.8%) patients in the PT group showed a reduction in the level of TT. PT significantly reduced the operation time, intraoperative blood loss, the need for extracorporeal circulation, the incidence of grade ≥ III perioperative complications, and the duration of hospitalization after surgery.

Our findings suggest that PT may be effective in reducing surgical invasiveness in RCC patients with IVC-TT. Further prospective studies are needed to identify the optimal drug regimen for PT and to clarify its survival benefits.

A better understanding of the molecular alterations that underlie urologic malignancies and advances in targeted therapies has impacted classification, prognostication, and treatment. In bladder tumors, these advances include the development of antibody-drug conjugates targeting nectin-4 and Trop-2, as well as human epidermal growth factor receptor 2 and immunotherapy. In prostate cancer, assessment of the percentage of Gleason pattern 4, presence of cribriform glands, and molecular alterations, including PTEN and mismatch repair protein loss, have become standard for clinical care. In renal malignancies, alterations in TSC1/2, mammalian target of rapamycin, anaplastic lymphoma kinase, and other genes impact classification and therapeutic decisions.

Personalized cancer vaccines (PCVs) can generate circulating immune responses against predicted neoantigens1-6. However, whether such responses can target cancer driver mutations, lead to immune recognition of a patient's tumour and result in clinical activity are largely unknown. These questions are of particular interest for patients who have tumours with a low mutational burden. Here we conducted a phase I trial (ClinicalTrials.gov identifier NCT02950766) to test a neoantigen-targeting PCV in patients with high-risk, fully resected clear cell renal cell carcinoma (RCC; stage III or IV) with or without ipilimumab administered adjacent to the vaccine. At a median follow-up of 40.2 months after surgery, none of the 9 participants enrolled in the study had a recurrence of RCC. No dose-limiting toxicities were observed. All patients generated T cell immune responses against the PCV antigens, including to RCC driver mutations in VHL, PBRM1, BAP1, KDM5C and PIK3CA. Following vaccination, there was a durable expansion of peripheral T cell clones. Moreover, T cell reactivity against autologous tumours was detected in seven out of nine patients. Our results demonstrate that neoantigen-targeting PCVs in high-risk RCC are highly immunogenic, capable of targeting key driver mutations and can induce antitumour immunity. These observations, in conjunction with the absence of recurrence in all nine vaccinated patients, highlights the promise of PCVs as effective adjuvant therapy in RCC.

Combination therapy comprising immune checkpoint inhibitors and molecular targeted therapies can be effective for metastatic non-clear cell renal cell carcinoma. We describe a patient with metastatic papillary renal cell carcinoma that was completely pathologically resectable after combination treatment comprising lenvatinib and pembrolizumab and robot-assisted radical nephrectomy.

A 35-year-old man was referred to our department for examination of a renal tumor that was diagnosed as left renal cell carcinoma with lymph node metastasis (cT3aN1M0). Because metastasis affected the renal artery, combination therapy comprising lenvatinib and pembrolizumab was initiated. After 6 months of treatment, the patient underwent robot-assisted radical nephrectomy. The pathological results indicated papillary renal cell carcinoma with no viable cells in the lymph nodes.

Combination therapy comprising lenvatinib and pembrolizumab for unresectable papillary renal cell carcinoma may effectively allow radical resection and deferred cytoreductive nephrectomy.

Immune checkpoint plus tyrosine kinase inhibition (IO + TKI) has emerged as the first-line therapy in metastatic renal cell carcinoma (RCC), but no biomarker can predict its efficacy. Thymidine kinase 1 (TK1) is closely associated with immune evasion in tumors.

Metastatic RCC patients treated by IO + TKI were enrolled from two cohorts (ZS-MRCC, n = 45; Javelin-101, n = 726). High-risk localized RCC were also enrolled (ZS-HRRCC, n = 40). TK1 was assessed by RNA-sequencing in all cohorts, and the immune contexture was assessed by flow cytometry and immunohistochemistry.

Higher TK1 expression was found in patients resistant to IO + TKI therapy (p = 0.025). High-TK1 group showed poor progression-free survival (PFS) in both the ZS-MRCC cohort (P = 0.008) and the Javelin-101 cohort (P = 0.036). By multivariate Cox regression, high-TK1 was determined as an independent factor for poor PFS (hazard ratio (HR) = 3.855, P = 0.002). High-TK1 expression was associated with decreased granzyme B+ CD8+ T cells (ρ=-0.22, P = 0.18), increased PD1+ CD4+ T cells (ρ = 0.33, P = 0.04), increased PDL1+ macrophages (ρ = 0.45, P < 0.001), and increased regulatory T cells (ρ = 0.35, P = 0.03). A novel random forest (RF) risk score was built by machine learning based on TK1 and immunologic parameters. Combined IO + TKI therapy surpassed sunitinib monotherapy in the low RF risk score group (HR = 0.158, P < 0.001), but was inferior to sunitinib in the high RF risk score group (HR, 2.195, P < 0.001).

High-TK1 expression could be a potential indicator for therapeutic resistance, poor PFS and immune evasion in metastatic RCC under IO + TKI therapy. The novel RF risk score may help stratify patients for IO + TKI therapy.

Effectiveness and safety of second-line tyrosine kinase inhibitors (TKIs) in patients with metastatic renal cell carcinoma (mRCC) for whom first-line immuno-oncology (I-O) combination therapy was discontinued because of adverse events (AEs) remain to be determined.

Clinicopathological data were retrospectively collected from 34 institutions between August 2018 and January 2022 for 243 patients with mRCC who received second-line TKIs after first-line I-O combination therapy. Two patients who requested discontinuation of first-line I-O combination therapy were excluded. Oncological outcomes and safety were compared between patients who discontinued first-line I-O combination therapy because of progressive disease (Group PD) and AEs (Group AE). First- and second-line overall survival (OS) were defined as the time from the start of first- and second-line therapy to death, respectively. Propensity score matching was applied to adjust prognostic factors between the 2 groups.

There were 179 patients in Group PD and 62 patients in Group AE. Objective response rate and disease control rate were similar between the 2 groups. Progression-free survival (PFS), second-line OS, and first-line OS were significantly longer in Group AE than in Group PD (median 13.6 months vs. 8.5 months, P = 0.005; median not reached [NR] vs. 19.5 months, P = .005; median NR vs. 30.8 months, P = .012, respectively). After propensity score matching, PFS and second-line OS were still significantly longer and first-line OS tended to be longer in Group AE than in Group PD. There were no significant differences in the occurrence of AEs of any grade, including severe grades of 3 or greater, between the 2 groups.

Second-line TKIs are safe and at least as effective in patients with mRCC who discontinued first-line I-O combination therapy because of AEs as they are in patients who discontinued because of PD.

Surgical removal of primary tumors reverses tumor-mediated immune suppression in pre-clinical models with metastatic disease. However, how cytoreductive surgery in the metastatic setting modulates the immune responses in patients, especially in the context of immune checkpoint therapy (ICT), is not understood. We report the first prospective, pilot, non-comparative clinical trial (NCT02210117) to evaluate the feasibility, clinical benefits, and immunologic changes of combining three different ICT-containing strategies with cytoreductive surgery or biopsy for patients with metastatic clear cell renal cell carcinoma. Primary safety endpoint of this trial has been met, with 43 patients completing cytoreductive surgery, 36 patients undergoing post-ICT biopsy, and 25 patients without either procedure due to progressive disease or toxicities or withdrawal of consent (total N = 104). Patients receiving ICT with cytoreductive surgery or biopsy, did not experience additional ICT- or procedure-related toxicities. The median overall survival was 54.7 months for patients who received ICT plus cytoreductive surgery. Immune-monitoring studies demonstrated that cytoreductive surgery increased antigen-presenting dendritic cell population and decreased KDM6B-expressing immune-suppressive myeloid cells in the peripheral blood. This study highlighted the feasibility of combining ICT with cytoreductive surgery in a metastatic setting and demonstrated the potential enhancement of immune responses following ICT plus cytoreductive surgery.

Prostate, bladder and kidney neoplasms are among the most prevalent genitourinary (GU) cancers worldwide. Significant therapeutic advancements in recent years have substantially improved patient outcomes. In response to this rapid progress, the Santiago de Compostela Health Research Institute (IDIS) has organized the annual 'Cambados Consensus Forum on Genitourinary Tumors' (Pontevedra, Spain) since 2018. This 2-day multidisciplinary meeting gathers Spanish medical oncologists, radiation oncologists, urologists, and hospital pharmacists to present and discuss the latest evidence in the field, merging from international congresses or journal publications. This review provides an overview of the most recent evidence regarding therapeutic advances in prostate cancer, renal cell carcinoma, and bladder cancer presented at the 2024 meeting (October), with a special focus on practice-changing innovations.

DPH2, also known as DPH2L2, is one of two human genes similar to yeast dph2. One DPH2 variant has been linked to diphthamide syndrome, a disorder affecting ribosome function. While studies on DPH2 in a single cancer type have been documented, no comprehensive investigations of DPH2 across pan-cancer have been reported, its role in tumor pathogenesis and development remains unclear.

The predictive significance and immune and biological roles of DPH2 in 33 different cancer types were investigated. We conducted a comprehensive analysis of DPH2 in pan-cancer using various bioinformatics tools, including expression, prognosis, its association with immune infiltration, cell death, methylation, and many other aspects. In addition, qRT-PCR and immunohistochemistry experiments confirmed DPH2 expression in prostate adenocarcinoma (PRAD) tissues, DPH2 biological function in PRAD was assessed using in vitro experiments, and used immunofluorescence to validate the proteins associated with DPH2.

The DPH2 expression was high in most tumors and showed significant correlations with OS and PFI. Our experimental findings confirmed that DPH2 is highly expressed in PRAD, while DPH2 knockdown inhibited prostate cancer cell proliferation, invasion, and migration. Furthermore, our data suggest that DPH2 may significantly influence immune cell infiltration. DPH2 was significantly correlated with cell death-related genes. DPH2 can influence cancer progression through changes in DNA methylation levels, or N6-methyladenosine site modification. GSEA and GSVA revealed that DPH2 levels were significantly associated with enrichment for oncogenic and immune-related pathways. Drug sensitivity analysis revealed that the elevated DPH2 expression is linked to development of resistance against numerous anticancer medications.

DPH2 has potential as a novel prognostic biomarker that may significantly impact tumor onset and progression. Consequently, DPH2 could serve as a target for new cancer treatments.

BACKGROUND Globally, esophageal cancer ranks as the sixth leading cause of cancer-related mortality. This retrospective study from a single center in Turkey aimed to evaluate hematological inflammatory biomarkers in complete blood count (CBC) data and outcomes in 113 patients with advanced esophageal carcinomas. MATERIAL AND METHODS We conducted a retrospective analysis of 113 patients with metastatic esophageal cancer composed of squamous (92), adenocarcinoma (18), and small cell (3) histology. We investigated neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), platelet-to-lymphocyte ratio (PLR), neutrophil-to-platelet lymphocyte ratio (NLPR), neutrophile-to-monocyte ratio (NMR), systemic inflammation index (SII), systemic inflammatory response index (SIRI), and aggregate index of systemic inflammation (AISI) in terms of prognosis. RESULTS The initial treatment for 25.7% of patients consisted of a carboplatin-paclitaxel combination. In response to the initial round of chemotherapy, 52.2% of patients showed improvement (15% complete, 37.2% partial), while 18.6% experienced disease progression. Neutropenia was observed as the most prevalent severe (grades 3-4) adverse reaction, affecting 19.8% of patients. Higher NLR, PLR, SII, NLPR, SIRI, and AISI values were associated with worse survival (P=0.016, P=0.008, P=0.011, P=0.028, P=0.014, P=0.001, respectively), whereas higher LMR was correlated with better survival (P=0.001). The NMR analysis showed no significant association (P=0.46). Multivariate analysis identified independent prognostic factors except histology, PLR, and NLPR. CONCLUSIONS Research indicates that inflammatory indicators obtained from complete blood count analyses possess prognostic significance for individuals with metastatic esophageal cancer. These biomarkers demonstrate diverse capacities in forecasting the course of the disease. These simple and inexpensive markers need further confirmation to guide individualized treatment planning.

Background: Clear cell renal cell carcinoma (ccRCC) incidence and death have considerably changed in recent years. Our study aimed to investigate the incidence, survival, and tumor characteristics of ccRCC in the year of diagnosis. Methods: Our study participants were selected from the SEER database (2000-2017). Age-standardized incidence rates were calculated to compare incidence rates across time. In addition, we used Kaplan-Meier curves to calculate overall survival (OS) and Cox proportional hazards models to explore risk factors associated with mortality outcomes in patients with ccRCC. Results: In the SEER analysis from 2000 to 2017, the increasing trend in age-adjusted incidence of ccRCC has remained relatively stable over the years, increasing from 2.63 per 100,000 in 2000 to 8.79 per 100,000 in 2017. The increase in the incidence of patients at a localized stage plays a decisive role in the overall increase in the incidence of ccRCC. Conclusions: In the general population, patients diagnosed between 2009-2017 had a higher survival rate than those diagnosed between 2000-2008, which is consistent with all stages of the tumor. The incidence of ccRCC increases steadily with the year of diagnosis, while overall survival has significantly improved.

This multicenter, randomized phase III trial evaluated the efficacy and safety of perioperative camrelizumab (an anti-PD-1 antibody) plus low-dose rivoceranib (a VEGFR-2 inhibitor) and S-1 and oxaliplatin (SOX) (SOXRC), high-dose rivoceranib plus SOX (SOXR), and SOX alone (SOX) for locally advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma.

Patients with T3-4aN + M0 G/GEJ adenocarcinoma were randomly assigned (1:1:1) to receive perioperative treatment with SOXRC, SOXR, or SOX. The primary end points were pathologic complete response (pCR) and event-free survival. The Independent Data Monitoring Committee recommended stopping enrollment in the SOXR group on the basis of the safety data of the first 103 randomly assigned patients in the three groups. The patients were then randomly assigned 1:1 to the SOXRC or SOX groups. This report presents the pCR results obtained per protocol for the first 360 randomly assigned patients who had the opportunity for surgery in the SOXRC and SOX groups.

In the SOXRC and SOX groups, of the 180 patients in each group, 99% and 98% of patients received neoadjuvant therapy, 91% and 94% completed planned neoadjuvant therapy, and 86% and 87% underwent surgery, respectively. The pCR was significantly higher in the SOXRC group at 18.3% (95% CI, 13.0 to 24.8) compared with 5.0% (95% CI, 2.3 to 9.3) in the SOX group (difference of 13.7%; 95% CI, 7.2 to 20.1; odds ratio of 4.5 [95% CI, 2.1 to 9.9]). The one-sided P value was <.0001, crossing the prespecified statistical significance threshold of P = .005. Surgical complications and grade ≥3 neoadjuvant treatment-related adverse events were 27% versus 33% and 34% versus 17% for SOXRC and SOX, respectively.

The SOXRC regimen significantly improved pCR compared with SOX alone in patients with G/GEJ adenocarcinoma with a tolerable safety profile.