Is Cell-Free DNA Testing in Pancreatic Ductal Adenocarcinoma Ready for Prime Time?

SIMPLE SUMMARY: Pancreatic cancer is a deadly cancer with limited treatment options. It is often detected in most people at stages where cure is not possible. There is no good test to know if a person will respond to treatment or if there is any disease beyond what can be seen by available imaging tests. Genetic material from the tumor is expected to float in the blood. Studying the alterations in the genetic material could help detect the tumor early, give an idea about its aggressiveness and response to available treatments, and facilitate the discovery of newer therapies. The focus of the studies so far has been on only one kind of genetic aberration, mutations, which has not given us great results. There is a need to explore another type of change known as methylation that could hold answers for managing pancreatic cancers better. ABSTRACT: Cell-free DNA (cfDNA) testing currently does not have a significant role in PDA management: it is insufficient to diagnose PDA, and its use is primarily restricted to identifying targetable mutations (if tissue is insufficient or unavailable). cfDNA testing has the potential to address critical needs in PDA management, such as pre-operative risk stratification (POR), prognostication, and predicting (and monitoring) treatment response. Prior studies have focused primarily on somatic mutations, specifically KRAS variants, and have shown limited success in addressing prognosis and POR. Recent studies have demonstrated the importance of other less prevalent mutations (ERBB2 and TP53), but no studies have provided reliable mutation panels for clinical use. Methylation aberrations in cfDNA (epigenetic markers) in PDA have been relatively less explored. However, early evidence has suggested they offer diagnostic and, to some extent, prognostic value. The inclusion of epigenetic markers of cfDNA adds another dimension to genomic testing and may open new therapeutic avenues beyond addressing critical areas of need in PDA treatment. For cfDNA to substantially influence PDA management, concerted efforts are required to include less frequent mutations and epigenetic markers. Furthermore, relying on KRAS mutations for PDA management will always be inadequate.