MedicalResearch.com recently showcased NYU Langone Health investigators concerning the topic of Circulating NDA. In this easy to read Q&A format, first and foremost they establish that several studies of metastatic melanoma patients have demonstrated that measuring circulating tumor DNA (ctDNA) associates with their disease burden and survival.
What is ctDNA?
ctDNA is a tumor-derived fragmented DNA in the bloodstream that is not associated with cells. ctDNA should not be confused with cell-free DNA (cfDNA), a broader term which describes DNA that is freely circulating in the bloodstream, but is not necessarily of tumor origin.
Because ctDNA may reflect the entire tumor genome, it has gained traction for its potential clinical utility; liquid biopsies in the form of blood draws may be taken at various time points to monitor tumor progression throughout the treatment regimen.
ctDNA originates directly from the tumor or from circulating tumor cells (CTCs), which describes viable, intact tumor cells that shed from primary tumors and enter the bloodstream or lymphatic system. The precise mechanism of ctDNA release is unclear. The biological processes postulated to be involved in ctDNA release include apoptosis and necrosis from dying cells, or active release from viable tumor cells.
Studies in both human (healthy and cancer patients) and xenografted mice show that size of fragmented cfDNA is predominantly 166bp long, which corresponds to the length of DNA wrapped around a nucleosome plus a linker. Fragmentation of this length is indicative of apoptotic DNA fragmentation, suggesting that apoptosis may be the primary method of ctDNA release.
In healthy tissue, infiltrating phagocytes are responsible for clearance of apoptotic or necrotic cellular debris, which includes cfDNA. Levels of cfDNA in healthy patients is only present at low levels but higher levels of ctDNA in cancer patients can be detected. This possibly occurs due to inefficient immune cell infiltration to tumor sites, which reduces effective clearance of ctDNA from the bloodstream.
ctDNA an Indicator of Cancer Survival
The NYU Langone pair interviewed noted that a general observation evidences those patients with detectable or pre-treatment ctDNA levels and/or detectable ctDNA at various time intervals after initiation of treatment experience shorter survivals than patients with lower pre-treatment or on-treatment ctDNA levels.
The Langone experts observe that ctDNA detection methodology studies have varied, as have the chosen thresholds utilized to categorize a sample as positive or negative not to mention the follow up time point for measurement, if any.
The NYU Langone Study: Combi-D
The ctDNA sample pool was taken from the Combi-D clinical trial: a phase III, randomized, double-blind trial of the BRAF and MEK inhibitors Dabrafenib and Trametinib, which led to FDA approval of the combination therapy for patients with unresectable stage III/IV melanoma. It was only patients with BRAF V600E or V600K mutations identified from tumor genotyping that were enrolled in the Combi-D trial.
First the Langone duo informed MedicalResearch.com that at a 93% ctDNA detection rate of pre-treatment samples, to their knowledge this would be the highest mutation-detection rate in melanoma for these types of studies. Three core findings:
The level of pre-treatment ctDNA was associated with survival
Patients whose ctDNA was detectable prior to treatment and thereafter became undetectable after 4 weeks receiving treatment, generally have longer survival than those who still had detectable ctDNA after 4 weeks of treatment
Achieving undetectable ctDNA in 4 weeks also stratified patients with an elevated baseline lactate dehydrogenase (LDH) into shorter or longer survivals. Baseline LDH is a poor prognostic indicator and a component of the AJCC Melanoma Staging System. The NYU Langone team position that detectable ctDNA after 4 weeks of patient receiving treatment was evidenced of less effective drug treatment, which agreed with the shorter survival of those patients compared to the undetectable group.
MedicalResearch.com reported that NYU Langone representative believes that the study provides solid evidence to support more studies to evaluate more on-treatment blood measurements to continuously improve how we determine how we may be able to truly benefit from these test moving forward. One reasonable hope would be that the continuous monitoring of ctDNA in patients undergoing treatment for metastatic melanoma can provide an early indication of treatment failure, triggering notice to doctors and health team to consider modifying the patient’s treatment or ordering a radiographic scan ahead of the routine schedule.
NYU Langone Interviewees
David Polsky, MD, PhD, Dermatologist and Director of the Digmented Lesion Service
Mahrukh M. Syeda, MS, Research Associate