Clinical utility and tissue concordance of circulating tumor DNA in pancreatic ductal adenocarcinoma

BACKGROUND: The utility of circulating tumor DNA (ctDNA) in addressing challenges of molecular tissue profiling and complementing next-generation sequencing is undefined in pancreas ductal adenocarcinoma. The objective of this study was to assess ctDNA detection rates by stage, disease burden, and metastasis patterns; compare overall survival between ctDNA-positive and ctDNA-negative patients cases; and determine concordance between ctDNA and matched-tissue biopsies. METHODS: Patients with pancreas ductal adenocarcinoma who had undergone Next Generation Sequencing by the MSK-ACCESS (Memorial Sloan Kettering - Analysis of Circulating cfDNA to Evaluate Somatic Status) ctDNA assay between 2019 and 2022 were included. Clinical and survival data were abstracted from a prospectively maintained clinical database. RESULTS: A total of 414 patients with pancreas ductal adenocarcinoma: 28% stage I-II, 21% stage III, 51% stage IV. ctDNA detection was highest among patients with advanced disease: 75% stage IV, 38% stage III, 34% stage I-II disease. For stage IV, ctDNA was more frequently detected in patients with at least 2 organs involved vs with less than 2 organs involved (76% vs 38%, P = .025). Higher rates of ctDNA detection were observed in patients with liver metastases vs without (82% vs 52%, P < .001). In the untreated stage IV cohort (n = 120), median overall survival was 10 months for those with detectable ctDNA (95% CI = 6.9 to 14 months) vs 19 months (95% CI = 13 months to not reached) for those with undetectable ctDNA (P = .1). Concordance between ctDNA and matched tissue next-generation sequencing was lower in untreated stage I-III disease, but high for untreated stage IV pancreas ductal adenocarcinoma, including a critical success index of 93.1% of KRAS variants. CONCLUSION: ctDNA is a promising tool in the detection of somatic variants in pancreas ductal adenocarcinoma. Concordance between ctDNA and tissue is high for patients with untreated metastatic disease, notably for detection of KRAS variants.