Genetic features and therapeutic relevance of emergent circulating tumor DNA alterations in refractory non-colorectal gastrointestinal cancers

Acquired resistance to systemic treatments is inevitable in most cancers, but the genetic basis for this in many cancer types has remained elusive due to constraints in obtaining tissue specimens longitudinally. In the management of gastrointestinal cancers, molecular profiling is conventionally performed at a single time point, although serial evaluations may yield biological insights that inform treatment decisions. We characterize genetic changes in serial liquid biopsies which provide real-time snapshots of tumor genetics and heterogeneity in refractory non-colorectal gastrointestinal cancers, and determine the clinical utility of repeat circulating tumor DNA (ctDNA) testing. In a national cohort of 449 patients with pancreatic, biliary, esophagogastric, and hepatocellular cancers, resistance to conventional therapies is broadly associated with tumor evolution. Emergent ctDNA alterations only detectable at progression occurs in 63% of patients and are frequently associated with treatment actionability. Tumor mutation burden is dynamic in cancers undergoing treatment, but is not associated with time to progression. Objective tumor responses in a case series of patients receiving treatment matched to emergent alterations show that repeat liquid biopsies may have clinical benefit by expanding treatment options in advanced gastrointestinal cancers.