Biomarkers Towards New Era of Therapeutics for Metastatic Renal Cell Carcinoma
Abstract
With the improved knowledge of molecular oncology and the introduction of targeted therapies as well as immunotherapies, there has been significant progress in the treatment of patients with metastatic renal cell carcinoma (mRCC). At present, treatment decisions are still made mainly based on clinical factors because no validated prognostic and predictive biomarkers for mRCC exist. Currently, inflammatory markers, genetic markers, and immune checkpoint molecules are candidate biomarkers for more personalized treatment of mRCC. RCC has been considered to be an inflammatory tumor and its underlying inflammatory mechanism would play some roles in forming resistance to systemic therapy. The von Hippel-Lindau (VHL) gene is inactivated by either mutation or methylation in over 80% of clear cell RCC (ccRCC). Thus, most, if not all, ccRCC may have deregulation of the VHL pathway. For some reason, VHL status is difficult to use as a prognostic marker. Polybromo 1 (PBRM1) is the second most frequently mutated gene in ccRCC and loss of function mutations in the PBRM1 gene have been shown to be associated with improved survival in patients with mRCC treated with systemic therapies. The expression of programmed death ligand 1 (PD-L1) on tumor cells in RCC seems to be associated with a higher tumor stage, a worse response to tyrosine kinase inhibitor (TKI) therapy, and a worse prognosis. Future challenges are required to develop and validate predictive biomarkers in order to establish a more personalized treatment for mRCC.
Evolving Frontline Treatment Landscape for Advanced or Metastatic Renal Cell Carcinoma
Abstract
The treatment landscape of metastatic renal cell carcinoma (mRCC) is evolving very rapidly. Until recently, targeted monotherapy with vascular endothelial growth factor (VEGF)-tyrosine kinase inhibitors (TKIs) such as sunitinib, pazopanib and cabozantinib were considered the predominant frontline treatment options. In 2018, combination immune checkpoint inhibitor (ICI) therapy with ipilimumab and nivolumab was approved by the United States’ Food and Drug Administration (FDA) for intermediate- and poor-risk patients. Subsequently, the FDA approved combination regimens consisting of a VEGF-TKI with an immune checkpoint inhibitor for all risk categories: pembrolizumab-axitinib and avelumb-axitinib. In the context of these new developments and several ongoing trials in treatment naïve clear-cell mRCC, there remains a dilemma among treating physicians about the choice of the most appropriate therapy as well as how to sequence these agents. In this review, we aim to highlight the available data on immunotherapy-based combinations and to provide a contemporary perspective on the optimal approach to patients with mRCC.
First-Line Immune Checkpoint Inhibitor-Based Therapy for Metastatic Renal Cell Carcinoma: A Systematic Review
Abstract
Background:
Immune checkpoint inhibitors (CPIs) have come to the forefront as a major component of the management of metastatic renal cell carcinoma ( mRCC). Over a short period of time, several studies have shown benefit in using these agents in the first-line setting.
Objective:
In this systematic review, the available evidence regarding the use of CPI-based regimens in previously untreated mRCC was reviewed.
Methods:
A systematic search for phase II and III studies was conducted of the PubMed and Embase databases as per the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. The search retrieved abstracts to February 1, 2020. Data was compiled and summarized in narrative and tabular formats.
Results:
Fifty-five abstracts from 11 clinical trials were included, including four phase III clinical trials and seven phase II trials. The most recent phase III data demonstrates overall survival (OS) benefit for ipilimumab plus nivolumab (for intermediate and poor risk patients) and pembrolizumab plus axitinib combination regimens over sunitinib. Two other regimens (avelumab plus axitinib and atezolizumab plus bevacizumab) have shown benefits in progression free survival, but not in OS to date. Toxicity data shows varying patterns of adverse events between the four treatments. Phase II data indicate CPI has activity as a single agent, and in patients with non-clear cell subtypes of RCC.
Conclusions:
CPI-based regimens improve outcomes in virtually all subgroups of mRCC patients when used as front-line therapy. This is certain to change the landscape of mRCC treatment.
Skeletal-Related Events in Patients with Metastatic Renal Cell Carcinoma: A Systematic Review
Abstract
About one-third of advanced renal cell carcinoma (RCC) patients have bone metastases, which subsequently leads to the development of skeletal-related events (SREs), broadly defined to include surgery and radiation to bone, bone pain, pathological fracture, spinal cord compression, or hypercalcemia. The cumulative impact of SREs in RCC has not been well studied. SREs increase morbidity and mortality of RCC patients, although many interventions do significantly reduce their rates of development and improve prognosis. We performed a systematic review from the existing literature in PubMed from January 2002 through September 2019 and summarized the body of evidence regarding the development, prevention, prognosis and treatment of SREs in advanced RCC patients.
Examining the Association of Academic Rank and Productivity with Metrics of Twitter Utilization Amongst Kidney Cancer Specialists
Abstract
BACKGROUND:
Twitter has emerged as an important platform for conversation surrounding cancer-related topics. As use has proliferated, a better classification of physicians engaging in cancer discussions on Twitter is warranted.
OBJECTIVES:
To better characterize the medical specialists involved in disseminating kidney cancer information on social media through academic and Twitter metrics.
METHODS:
Clinical practitioners with an expertise in kidney cancer were identified. Demographics, metrics of academic rank and productivity, and Twitter usage data were collected. Correlations were calculated for the generation of a model predictive of the number of Twitter followers. Analysis of the experts’ Twitter content was performed.
RESULTS:
Among 59 kidney cancer experts identified, 14 (23.7%) were assistant professors, 24 (40.7%) were associate professors, and 21 (35.6%) were full professors. A total of 5424 tweets were analyzed, 86% of which were medically-related. We identified several differences between academic rank and Twitter variables. Associate professors registered a greater median number of followers subscribed to their Twitter accounts (2360) versus assistant professors (1253) and full professors (934) (p = 0.03) and a greater median number of accounts they themselves followed (752 vs. 290 vs. 235, respectively; p = 0.0009). Use of a more generalized approach (ANCOVA) showed that the most predictive variables for the number of followers are number of tweets, H-index, and percentage of medical tweets (R2 = 0.70).
CONCLUSIONS:
This study supported correlations between metrics of academic and Twitter activity. The generation of a model to predict the number of followers on Twitter is novel – future work will validate this in other disease types.
Renal Cell Carcinoma with Inferior Vena Cava Extension: Can Classification Be Optimized to Predict Perioperative Outcomes?
Abstract
Ambiguity exists regarding the definition of a level III inferior vena cava tumor thrombus (IVC-TT), limiting comparisons between open and minimally-invasive series. We assessed 253 patients who underwent radical nephrectomy with IVC-TT from 2000-2015 and proposed a modified classification based on associations between intraoperative IVC clamp position and need for cardiopulmonary bypass with complications, length of stay, and blood transfusions. Predictive ability of the modified system was not meaningfully improved (AUCs 0.59–0.58; 0.61–0.61; 0.72–0.72). Nevertheless, we advocate for standardization of the border of a level III thrombus at or above the major hepatic veins to facilitate meaningful comparisons between techniques.
