National clinical study

Analyzing circulating tumor DNA as a marker for response to treatment in the NORDIC-SUN clinical trial

The purpose of this prospective study is to identify if ctDNA can determine whether a given mRCC patient will benefit from and are responding to the immunotherapy administrated for metastatic disease.

ClinicalTrials.gov: NCT03977571

The project received funding in 2023

Abstract

The incidence of renal cell carcinoma (RCC) is increasing worldwide due to lifestyle changes and more widespread use of diagnostic CT. However, despite increased early detection, one third of cases are being diagnosed at an advanced disease stage.

RCC is ‘immune hot’, and immunotherapy has markedly improved the treatment options for metastatic RCC (mRCC). However, treatments are not curative and show overall only modest efficacy. Today physicians rely on only clinical features, such as age and blood chemistry, which is not optimal. Immunotherapy is initiated when the metastases are visible by radiological imaging, but only less than half of the patients benefit from the administered treatment, and there are currently no methods that can identify with certainty which patients will benefit from treatment.

A few studies have proposed circulating cell free DNA (cfDNA)/circulating tumor DNA (ctDNA) as predictive and prognostic markers in RCC. However, the analysis has been challenged in RCC by the trace amounts of ctDNA shedded by RCC tumors. With more sensitive markers and techniques, such as cell-free methylated DNA immunoprecipitation sequencing (cfMeDIP-seq) exploring the cfDNA methylation landscape, it has proven possible to identify ctDNA even in early-stage RCC. Nevertheless, larger studies are needed to fully validate cfDNA and ctDNA as prognostic markers in RCC before clinical trials can be initiated.

The purpose of this prospective study is to identify if ctDNA can determine whether a given mRCC patient will benefit from and are responding to the immunotherapy administrated for metastatic disease. The hypothesis is that measures of tumor burden in mRCC patients by analysis of ctDNA before, during and after treatment will be able to 1) predict which patients that will benefit of treatment, and 2) detect clinical relapses earlier than currently employed surveillance modalities.

Through analysis of DNA methylation enrichment profiles, copy number and fragmental profiles ctDNA levels from 125 patients will be determined and correlated to clinical outcome measures, such as response to therapy, relapse status and survival. This will be the first steps towards performing ctDNA-led clinical trials in renal cancer.

Our results will benefit both patients and the healthcare system; expensive medical treatments should be given in a timely manner but only to patients who need treatment and who are likely to benefit from it.

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