ARG2 and NOS2 as predictive biomarkers in renal cell carcinoma

Advanced imaging techniques for diagnosis have increased awareness on the benefits of brain screening, facilitated effective control of extracranial disease, and prolonged life expectancy of metastatic renal cell carcinoma (mRCC) patients. Brain metastasis (BM) in patients with mRCC (RCC-BM) is associated with grave prognoses, a high degree of morbidity, dedicated assessment, and unresponsiveness to conventional systemic therapeutics. The therapeutic landscape of RCC-BM is rapidly changing; however, survival outcomes remain poor despite standard surgery and radiation, highlighting the unmet medical needs and the requisite for advancement in systemic therapies. Immune checkpoint inhibitors (ICIs) are one of the most promising strategies to treat RCC-BM. Understanding the role of brain-specific tumor immune microenvironment (TIME) is important for developing rationale-driven ICI-based combination strategies that circumvent tumor intrinsic and extrinsic factors and complex positive feedback loops associated with resistance to ICIs in RCC-BM via combination with ICIs involving other immunological pathways, anti-antiangiogenic multiple tyrosine kinase inhibitors, and radiotherapy; therefore, novel combination approaches are being developed for synergistic potential against RCC-BM; however, further prospective investigations with longer follow-up periods are required to improve the efficacy and safety of combination treatments and to elucidate dynamic predictive biomarkers depending on the interactions in the brain TIME.

Download Full-text

Efficacy and Safety of Nivolumab and Ipilimumab for Advanced or Metastatic Renal Cell Carcinoma: A Multicenter Retrospective Cohort Study

Current Oncology ◽

10.3390/curroncol28020133 ◽

2021 ◽

Vol 28 (2) ◽

pp. 1402-1411

Author(s):

Koji Iinuma ◽

Koji Kameyama ◽

Kei Kawada ◽

Shota Fujimoto ◽

Kimiaki Takagi ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Metastatic Renal Cell Carcinoma ◽

Renal Cell ◽

Objective Response ◽

Predictive Biomarkers ◽

Progression Free Survival ◽

Predictive Marker ◽

Efficacy And Safety ◽

Lymphocyte Ratio

We conducted a multicenter, retrospective study to evaluate the efficacy and safety of combination nivolumab plus ipilimumab (NIVO+IPI) in 35 patients with advanced or metastatic renal cell carcinoma (mRCC). In this study, we focused on patients who received NIVO+IPI and were stratified into intermediate- or poor-risk disease according to the International Metastatic Renal Cell Carcinoma Database Consortium model at five institutions in Japan. The primary endpoint was overall survival (OS). Secondary endpoints were disease control rate (DCR), best overall response (BOR), objective response rate (ORR), and progression-free survival (PFS). In addition, we evaluated the role of inflammatory cell ratios, namely neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR), as predictive biomarkers in patients with mRCC. The median follow-up period was 1 year, and the 1-year OS rate was 95.8%. The ORR and DCR were 34.3% and 80.0%, respectively. According to BOR, four patients (11.4%) achieved complete response. According to NLR stratification, the 1-year PFS rates were 82.6% and 23.7% when the NLR was ≤4.6 and >4.6, respectively (p = 0.04). Based on PLR stratification, the 1-year PFS rates were 81.7% and 34.3% when the PLR was ≤188.1 and >188.1, respectively (p = 0.033). Although 71.4% of the patients experienced treatment-related adverse events (TRAEs) with NIVO+IPI, only four patients discontinued NIVO+IPI due to grade 3/4 TRAEs. Patients treated with NIVO+IPI as a first-line therapy for advanced or mRCC achieved relatively better oncological outcomes. Therefore, NIVO+IPI may have potential advantages and may lead to a treatment effect compared to those receiving targeted therapies. In addition, PLR >188.1 may be a useful predictive marker for mRCC patients who received NIVO+IPI.

Download Full-text

MET Expression in Primary and Metastatic Clear Cell Renal Cell Carcinoma: Implications of Correlative Biomarker Assessment to MET Pathway Inhibitors

BioMed Research International ◽

10.1155/2015/192406 ◽

2015 ◽

Vol 2015 ◽

pp. 1-7 ◽

Cited By ~ 2

Author(s):

Brian Shuch ◽

Ryan Falbo ◽

Fabio Parisi ◽

Adebowale Adeniran ◽

Yuval Kluger ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Clear Cell ◽

Predictive Biomarkers ◽

Cell Renal Cell Carcinoma ◽

Primary Tumors ◽

Distant Tissue ◽

Significant Expression ◽

Metastatic Sites

Aims. Inhibitors of the MET pathway hold promise in the treatment for metastatic kidney cancer. Assessment of predictive biomarkers may be necessary for appropriate patient selection. Understanding MET expression in metastases and the correlation to the primary site is important, as distant tissue is not always available.Methods and Results. MET immunofluorescence was performed using automated quantitative analysis and a tissue microarray containing matched nephrectomy and distant metastatic sites from 34 patients with clear cell renal cell carcinoma. Correlations between MET expressions in matched primary and metastatic sites and the extent of heterogeneity were calculated. The mean expression of MET was not significantly different between primary tumors when compared to metastases (P=0.1). MET expression weakly correlated between primary and matched metastatic sites (R=0.5) and a number of cases exhibited very high levels of discordance between these tumors. Heterogeneity within nephrectomy specimens compared to the paired metastatic tissues was not significantly different (P=0.39).Conclusions. We found that MET expression is not significantly different in primary tumors than metastatic sites and only weakly correlates between matched sites. Moderate concordance of MET expression and significant expression heterogeneity may be a barrier to the development of predictive biomarkers using MET targeting agents.

Download Full-text

Personalized Management of Advanced Kidney Cancer

American Society of Clinical Oncology Educational Book ◽

10.1200/edbk_201215 ◽

2018 ◽

pp. 330-341 ◽

Cited By ~ 5

Author(s):

Jeffrey Graham ◽

Daniel Y. C. Heng ◽

James Brugarolas ◽

Ulka Vaishampayan

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Kidney Cancer ◽

Metastatic Renal Cell Carcinoma ◽

Renal Cell ◽

Predictive Biomarkers ◽

Treatment Selection ◽

Great Success ◽

Personalized Care ◽

Oncogenic Pathways

The treatment of renal cell carcinoma represents one of the great success stories in translational cancer research, with the development of novel therapies targeting key oncogenic pathways. These include drugs that target the VEGF and mTOR pathways, as well as novel immuno-oncology agents. Despite the therapeutic advancements, there is a paucity of well-validated prognostic and predictive biomarkers in advanced kidney cancer. With a number of highly effective therapies available across multiple lines, it will become increasingly important to develop a more tailored approach to treatment selection. Prognostic clinical models, such the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model, are routinely used for prognostication in clinical practice. The IMDC model has demonstrated a predictive capability in the context of these treatments including immune checkpoint inhibition. A number of promising molecular markers and gene expression signatures are being explored as prognostic and predictive biomarkers, but none are ready to be widely used for treatment selection. In this review, we will explore the current landscape of personalized care in metastatic renal cell carcinoma. This will include a focus on both prognostic and predictive factors as well as clinical applications of biology in kidney cancer.

Download Full-text

A phase I study of BMS-936558 plus sunitinib or pazopanib in patients with metastatic renal cell carcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.tps2614 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. TPS2614-TPS2614

Author(s):

Hans J. Hammers ◽

Brian I. Rini ◽

Gary R. Hudes ◽

Marc S. Ernstoff ◽

Christian K. Kollmannsberger ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Phase I ◽

Cell Carcinoma ◽

Disease Progression ◽

Metastatic Renal Cell Carcinoma ◽

Dose Escalation ◽

Renal Cell ◽

Phase I Study ◽

Predictive Biomarkers ◽

Treatment Naïve

TPS2614 Background: Standard treatments for metastatic renal cell carcinoma (mRCC) block the vascular endothelial growth factor pathway (eg, sunitinib, pazopanib) or mammalian target of rapamycin pathway (e.g., temsirolimus, everolimus). However, most patients (pts) develop resistance and complete responses are rare. Upregulation of programmed death-1 (PD-1) in tumor infiltrating lymphoctyes, and its ligand PD-L1 in tumors, is associated with more aggressive disease and poor prognosis. Blocking the PD-1/PD-L1 interaction is a novel immunotherapeutic approach for mRCC. In preliminary results of a phase I trial, the anti-PD-1 monoclonal antibody BMS-936558 had antitumor activity in pts with advanced tumors, including objective responses (ORs) in 6 of 18 pts with mRCC. Here we describe a phase I study planned to evaluate the safety, tolerability, and maximum tolerated dose (MTD) of BMS-936558, when combined with sunitinib or pazopanib in pts with mRCC. Methods: This open-label study will have two parallel treatment arms (BMS-936558 plus sunitinib and BMS-936558 plus pazopanib) conducted in two parts (dose escalation and dose expansion). Pts must have received ≥1 prior systemic therapy to be eligible for dose escalation. Only treatment-naïve pts will be eligible for dose expansion. Up to 36 pts (18 per arm) will be treated in the dose-escalation phase. After determining the MTD of BMS-936558, treatment-naïve pts will be enrolled to expansion cohorts allowing 24 pts to be treated at the MTD of each arm. Each treatment cycle will be 6 weeks, with BMS-936558 dosed on Days 1 and 22 and sunitinib or pazopanib given according to product label. Adverse events will be graded according to NCI CTCAE v4.0. Disease will be assessed every 6 weeks for the first four assessments and then every 12 weeks until disease progression. Pts will be treated until unacceptable toxicity, disease progression, or withdrawal of consent. The safety profile in pts treated at the MTD will be used to determine the recommended phase II study dose of BMS-936558 in each combination arm. Secondary objectives will include OR rate and duration of response based on RECIST 1.1. Exploratory analyses will investigate predictive biomarkers of BMS-936558.

Download Full-text

Cytogenetic changes in renal cell carcinoma: Basis for sensitivity and resistance to everolimus.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.5_suppl.403 ◽

2012 ◽

Vol 30 (5_suppl) ◽

pp. 403-403

Author(s):

Imogen Rose Caldwell ◽

Paul Oei ◽

Daniel Ng ◽

Peter C.C. Fong ◽

Reuben James Broom

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

In Situ Hybridisation ◽

Predictive Biomarkers ◽

Mtor Inhibitors ◽

Fluorescence In Situ Hybridisation ◽

Translational Study ◽

Cytogenetic Changes ◽

Tissue Specimens

403 Background: The mTOR inhibitors have improved outcomes for pts with metastatic renal cell carcinoma (mRCC) but the duration of benefit is variable. Currently there are no predictive biomarkers for pre-selecting pts who are likely to respond to these agents. We undertook an exploratory translational study evaluating cytogenetic changes in the context of response to everolimus therapy. Methods: 10 pts with mRCC treated with everolimus therapy were enrolled. Pre-treatment paraffin-embedded tissue specimens were analysed for cytogenetic changes using fluorescence in situ hybridisation (FISH) and clinical data including PFS (RECIST 1.1) were obtained. The gene probes chosen for this analysis were; VHL, FHIT, FGFR1/3, PDGFb, PDGFRb, EGFR, MYC and IGH@. Results: Results are displayed in the table below. The median PFS was 8.25mo (months). Eight pts were treated 1st-line (on clinical trial), one 2nd-line and one 3rd-line. The longest responder (PFS 25.5mo, 3rd-line) had a normal VHL status but loss of FHIT. Two pts with the longest PFS and one with a PFS of 5.5mo had gain of both PDGFb and PDGFRb. Gain of FGFR1 and FGFR3 was seen in two and three pts respectively. Two specimens were unsuitable for full analysis. Conclusions: Loss of FHIT but a normal VHL status was seen in one pt with mRCC who had an enduring response to everolimus. Concomitant gain of PDGFband PDGFRb was observed in three pts with a good response. FGFR1/3 may be of relevance in the setting of alternative targeted therapies. Further research evaluating the utility of these potential biomarkers is required. [Table: see text]

Download Full-text

Identification and validation of predictive biomarkers (BM) for everolimus (EVE) in metastatic renal cell carcinoma: Analysis of 442 patients on RECORD-3.

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.15_suppl.4531 ◽

2014 ◽

Vol 32 (15_suppl) ◽

pp. 4531-4531

Author(s):

Martin Henner Voss ◽

David Chen ◽

Mahtab Marker ◽

Mark Hamilton ◽

Creton Kalfoglou ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Metastatic Renal Cell Carcinoma ◽

Renal Cell ◽

Predictive Biomarkers

Download Full-text

Multiplatform molecular analysis of biomarkers in renal cell carcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2015.33.7_suppl.501 ◽

2015 ◽

Vol 33 (7_suppl) ◽

pp. 501-501 ◽

Cited By ~ 1

Author(s):

Thai Huu Ho ◽

Sherri Z. Millis ◽

Nancy Doll ◽

Zoran Gatalica ◽

Sandeep K. Reddy ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Targeted Therapy ◽

Cell Carcinoma ◽

Renal Cell ◽

Collecting Duct ◽

Predictive Biomarkers ◽

Molecular Profiling ◽

Aberrant Expression ◽

Duct Carcinoma ◽

The Impact

501 Background: Predictive biomarkers of response to targeted therapy are lacking in renal cell carcinoma (RCC). We evaluated a cohort of RCC patients referred for molecular profiling to identify potentially actionable recurrent molecular aberrations. Methods: 166 consecutive renal cases referred to Caris Life Sciences over 2 yrs were evaluated with central pathology review. Cases were subtyped into clear cell (ccRCC), n=100, papillary (PRCC), n=20, sarcomatoid, n=10, translocation, n=6, medullary, n=4 or unclassified, n=26. 63% of cases were metastatic. Testing included a combination of sequencing (Sanger or next generation sequencing [NGS]), protein expression (immunohistochemistry [IHC]), and/or gene amplification (CISH or FISH). Results: ccRCC had a 52% loss of PTEN, while PRCC had a 21% loss (p value=0.02). 100% of ccRCC with sarcomatoid features (4) showed aberrant expression of PD-L1 and were infiltrated with PD-1+ tumor infiltrating lymphocytes; 100% of 10 non-ccRCC sarcomatoids also had aberrant expression of PD-L1. Loss of PBRM1 expression was observed in 60% of ccRCC. Loss of histone 3 lysine 36 trimethylation (H3K36me3), which is associated with SETD2 mutations, was observed in 30% of ccRCC. TOP2A was overexpressed in ccRCC at 30% and in non-ccRCC at 50%. 100% of ccRCC and PRCC overexpressed EGFR; a single unclassified renal cell carcinoma did not overexpress EGFR. 50% of cases had cMET overexpression, amplification, or mutation. HER2 was not amplified or overexpressed in any RCC; a single rare HER2 mutation (R816H) was found in a collecting duct carcinoma. VHL mutations were identified in 50% of ccRCC tumors. We observed lower rates of TP53 (14%), ATM (6%), and PIK3CA(4% ccRCC, 7% PRCC) mutations compared to other cancers. Conclusions: Multiplatform molecular profiling of renal cell carcinoma identifies potential predictive biomarkers in ccRCC. The documented activity of everolimus in ccRCC (RECORD-1 trial) may be attributable to PIK3CA pathway alterations. RCC with sarcomatoid features may respond to PD1/PD-L1 targeted immunotherapies. The impact of molecular profiling in ccRCC to predict responses to currently available targeted therapy has important implications for trial design and patient selection.

Download Full-text

Prognostic and predictive biomarkers for clear cell renal cell carcinoma utilizing next generation sequencing.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e16070 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e16070-e16070

Author(s):

Jamal Zekri ◽

Abdelrazak Meliti ◽

Mohammed Abhas Baghdadi ◽

Turki Sobahy ◽

Saba Imtiaz

Keyword(s):

Renal Cell Carcinoma ◽

Next Generation Sequencing ◽

Cell Carcinoma ◽

Renal Cell ◽

Clear Cell ◽

Predictive Biomarkers ◽

High Potential ◽

Next Generation ◽

Cell Renal Cell Carcinoma ◽

Generation Sequencing

e16070 Background: The management of the clear cell renal cell carcinoma (cc-RCC) has evolved over the past decade. Clinical patients’ and tumor characteristics have a limited role in predicting the outcome of these patients. The search for reliable prognostic and predictive biomarkers should be pursued in particular during the current era of next generation sequencing (NGS) technology. Methods: Formalin-Fixed Paraffin-Embedded (FFPE) tissue specimens of cc-RCC were sequenced using NGS and a customized gene panel testing for 72 tumor-related genes. High potential variants were defined by mutation effect (stop-loss, stop-gain, frame-shift substitutions or non-synonymous SNV) and class (pathogenic or likely pathogenic). Cases with identical variants were identified. Results: In total, all 47 cases had 69,052 variants, of which 20,453 were classified as high potential variants. Identical alterations in 15 genes were present in all samples. These genes are: MUC3A, MUC12, MUC7, SRRT, MUC2, MUC5AC, MUC5B, MUC22, MUC6, CR1, MUC4, MUC16, MUC19, MUC17 and MERTK. The numbers of identical and non-identical variants in these 15 genes were counted for each sample. Median number of variants was 377 and was selected as a cut off to define cases with high ( > 377) and low (≤377) variants number (HVN and LVN respectively). For the whole cohort, HVN was associated with shorter overall survival compared to LVN (Median 50 months vs. not reached; Log Rank P = 0.041). In the 11 patients who received anti-angiogenic tyrosine kinase inhibitors (TKIs), HVN was associated with a trend of shorter progression free survival (Median 5 vs. 10 months; Log Rank P = not significant). Conclusions: Alterations in SRRT, CR1, MERTK and MUCIN family genes are very common in RCC. HVN ( > 377) is associated with worse prognosis and may predict decreased benefit from anti-angiogenic TKIs.

Download Full-text

Resistance to Pembrolizumab and Axitinib in Renal Cell Carcinoma: Clinical and Genomic Evaluation

Journal of Kidney Cancer and VHL ◽

10.15586/jkcvhl.2020.135 ◽

2020 ◽

Vol 7 (1) ◽

pp. 7-11

Author(s):

Panagiotis J. Vlachostergios

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Predictive Biomarkers ◽

Angiogenesis Inhibitors ◽

Cell Renal Cell Carcinoma ◽

Angiogenic Therapy ◽

Combined Use ◽

Selection Of Patients ◽

Selection Of

Clear cell renal cell carcinoma (ccRCC) represents the most common subtype of renal cell carcinoma (RCC). In spite of recent advances in the treatment armamentarium and outcomes with the combined use of immune checkpoint and angiogenesis inhibitors, prediction of responses and selection of patients remain a challenge. This is a case of ccRCC with recurrence to the liver 1 year following right radical nephrectomy, who rapidly progressed on frontline therapy with axitinib/pembrolizumab. The clinical course and targeted tumor sequencing findings are discussed. In addition to established clinical prognostication in RCC, several surrogate markers of efficacy or/and resistance have been proposed for immu-notherapy or/and anti-angiogenic therapy. Since the majority of patients will still progress after these combinations, it is becoming increasingly important to develop robust predictive biomarkers to guide patient selection and sequencing of targeted therapies.

Download Full-text