Prospective Evaluation of Circulating Tumor DNA Using Next-generation Sequencing as a Biomarker During Neoadjuvant Chemotherapy in Localized Pancreatic Cancer

Objective: In this prospective study, we aim to characterize the prognostic value of circulating tumor DNA (ctDNA) by next-generation sequencing (NGS) in patients undergoing neoadjuvant chemotherapy (NAC) for pancreatic ductal adenocarcinoma (PDAC). Background: ctDNA is a promising blood-based biomarker that is prognostic in several malignancies. Detection of ctDNA by NGS may provide insights regarding the mutational profiles in PDAC to help guide clinical decisions for patients in a potentially curative setting. However, the utility of ctDNA as a biomarker in localized PDAC remains unclear. Methods: Patients with localized PDAC were enrolled in a prospective study at Northwestern Medicine between October 2020 and October 2022. Blood samples were collected to perform targeted tumor-agnostic NGS utilizing the Tempus x|F 105 gene panel at 3 timepoints: pretherapy (at diagnosis), post-NAC, and after local therapy, including surgery. The relationship between ctDNA detection and CA19-9 and the prognostic significance of ctDNA detection were analyzed. Results: Fifty-six patients were included in the analysis. ctDNA was detectable in 48% at diagnosis, 33% post-NAC, and 41% after local therapy. After completion of NAC, patients with detectable ctDNA had higher CA19-9 levels versus those without (78.4 vs 30.0; P =0.02). The presence of baseline ctDNA was associated with a CA19-9 response; those without ctDNA had a significant CA19-9 response following NAC (109.0 vs 31.5 U/mL; P =0.01), while those with ctDNA present at diagnosis did not (198.1 vs 113.8 U/mL; P =0.77). In patients treated with NAC, the presence of KRAS ctDNA at diagnosis was associated with and independently predicted worse progression-free survival. Conclusions: This report demonstrates the prognostic value of ctDNA analysis with NGS in localized PDAC. NGS ctDNA is a biomarker of treatment response to NAC. KRAS ctDNA at diagnosis independently predicts worse survival in patients treated with NAC.