Relationship of tumor fraction in circulating tumor DNA (ctDNA) with prognosis in patients with metastatic pancreatic cancer.
Authors: Pathak Priyadarshini , Li Gerald , Quintanilha Julia , Keller Rachel Beth , Pasquina Lincoln , Thierauf Julia , Graf Ryon , Parikh Aparna Raj , Pishvaian Michael J. 
Published: January 2024

621 Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers and is projected to be the 3rd leading cause of cancer related death in the United States in 2023. Most patients are diagnosed at an advanced/metastatic stage and 5-year survival remains dismal at ~12%. While effective regimens are limited, some patients benefit significantly from chemotherapy, while others harbor disease that progresses despite treatment. Unfortunately, it is impossible to predict individual patient outcomes on treatment such that only general prognostic information can be provided to patients and families. Quantification of circulating tumor DNA (ctDNA) is a promising prognostic biomarker and emerging evidence shows that baseline ctDNA tumor fraction (TF) is prognostic in several tumor types. This study represents the largest data set reported to date aimed at evaluating the prognostic value of ctDNA TF in metastatic PDAC (mPDAC). Methods: This study used a cohort of patients from the de-identified nationwide Flatiron Health-Foundation Medicine pancreatic clinico-genomic database who underwent ctDNA testing using FoundationOne Liquid or FoundationOne Liquid CDx as part of routine care. Data originated from approximately 280 US cancer clinics. Patient/disease characteristics, laboratory and treatment data were captured from the electronic health record. Real-world overall survival (rwOS) and time-to-next-treatment (rwTTNT) were evaluated by ctDNA TF while controlling for relevant covariates. In parallel analyses, ctDNA TF cutoffs of ≥1% and ≥10% were evaluated. Exploratory analysis of trichotomized ctDNA TF at 1% and 10% was also performed. Results: 290 patients with mPDAC were included. High ctDNA TF was associated with poor prognostic clinical features regardless of cutpoint. High ctDNA TF also correlated with significantly reduced rwOS in univariable analysis and after correction for covariates, regardless of cutpoint (1%: adj HR 1.33 [0.93-1.90], adj P = 0.12; 10%: adj HR 1.91 [1.28-2.87], adj P = 0.002). The same was observed for rwTTNT (1%: adj HR 1.59 [1.14-2.22], adj P = 0.006; 10%: adj HR 2.18 [1.49-3.19], adj P < 0.001). When ctDNA TF was trichotomized, higher ctDNA TF groups had reduced rwOS and rwTTNT in a stepwise manner in univariable analysis and after correction for covariates (all vs <1%; rwOS: adj HR for 1%-<10% 1.06 [0.71-1.59], adj P = 0.78; adj HR for ≥10% 1.97 [1.26-3.09], adj P = 0.003; rwTTNT: adj HR for 1%-<10% 1.26 [0.87-1.84], adj P = 0.22; adj HR for ≥10% 2.43 [1.60-3.70], adj P < 0.001). Conclusions: ctDNA TF is a prognostic biomarker in mPDAC with potential to inform expected longevity of patients. Uniform cohorts, with regard to treatments given and line of therapy, would help further evaluate the ability of ctDNA TF to identify patients with aggressive disease and inform the design of future studies to personalize therapeutic decision-making.