KIDNEY-PAGER: analysis of circulating tumor DNA as a biomarker in renal cancer - an observational trial. Study protocol.

BACKGROUND: Management of localized renal cell carcinoma (RCC) is challenged by inaccurate methods to assess the risk of recurrence and deferred detection of relapse and residual disease after radical or partial nephrectomy. Circulating tumor DNA (ctDNA) has been proposed as a potential biomarker in RCC. PURPOSE: Conduction of an observational study to evaluate the validity of ctDNA as a biomarker of the risk of recurrence and subclinical residual disease to improve postoperative surveillance. MATERIAL AND METHODS: Urine and blood will be prospectively collected before and after surgery of the primary tumor from up to 500 patients until 5 years of follow-up. ctDNA analysis will be performed using shallow whole genome sequencing and cell-free methylated DNA immunoprecipitation sequencing. ctDNA levels in plasma and urine will be correlated to oncological outcomes. Residual blood and urine as well as tissue biopsies will be biobanked for future research. INTERPRETATION: Results will pave the way for future ctDNA-guided clinical trials aiming to improve RCC management.

Multicenter randomized trial of deferred cytoreductive nephrectomy in synchronous metastatic renal cell carcinoma receiving checkpoint inhibitors: the NORDIC-SUN-Trial.

BACKGROUND: Primary tumor removal by cytoreductive nephrectomy in synchronous metastatic renal cell carcinoma patients has been investigated in the context of various treatment regimens. Two randomized controlled trials investigated the role and timing of cytoreductive nephrectomy in the era of targeted therapy and demonstrated that upfront nephrectomy should no longer be performed when patients require systemic therapy. Superiority of checkpoint immunotherapy agents has led to a paradigm change from targeted therapies to immunotherapy-based first-line treatment in patients with primary metastatic disease; thus, deferred cytoreductive nephrectomy needs to be verified in the immunotherapy setting. Furthermore, a need exists for personalizing treatment choices for the individual patient to avoid unnecessary overtreatment. METHODS/DESIGN: To explore the impact of cytoreductive nephrectomy in this patient group receiving checkpoint immunotherapy, we initiated a randomized, controlled trial comparing deferred cytoreductive nephrectomy with no surgery. The trial integrates a comprehensive translational research program with specimen sampling for biomarker analysis. DISCUSSION: The trial aims to show that deferred cytoreductive nephrectomy improves overall survival in patients with synchronous metastatic renal cell carcinoma, and furthermore, to identify relevant biomarkers for personalized renal cancer management. TRIAL REGISTRATION: ClinicalTrials.gov NCT03977571 June 6, 2019.

Management of Renal Cell Carcinoma: Promising Biomarkers and the Challenges to Reach the Clinic.

The incidence of renal cell carcinoma (RCC) is increasing worldwide, yet research within this field is lagging behind other cancers. Despite increased detection of early disease as a consequence of the widespread use of diagnostic CT scans, 25% of patients have disseminated disease at diagnosis. Similarly, around 25% progress to metastatic disease following curatively intended surgery. Surgery is the cornerstone in the treatment of RCC; however, when the disease is disseminated, immunotherapy or immunotherapy in combination with a tyrosine kinase inhibitor is the patient's best option. Immunotherapy is a potent treatment, with durable treatment responses and potential to cure the patient, but only half of the patients benefit from the administered treatment, and there are currently no methods that can identify which patients will respond to immunotherapy. Moreover, there is a need to identify the patients in greatest risk of relapsing after surgery for localized disease and direct adjuvant treatment there. Even though several molecular biomarkers have been published to date, we are still lacking routinely used biomarkers to guide optimal clinical management. The purpose of this review is to highlight some of the most promising biomarkers, discuss the efforts made within this field to date, and describe the barriers needed to be overcome to have reliable and robust predictive and prognostic biomarkers in the clinic for renal cancer.