Relationship of circulating tumor DNA (ctDNA) tumor fraction with prognosis in patients with metastatic pancreatobiliary cancer.
Authors: Pathak Priyadarshini , Li Gerald , Quintanilha Julia , Keller-Evans Rachel B. , Pasquina Lincoln W , Thierauf Julia , Elvin Julia A , Ross Jeffrey S. , Graf Ryon P , Parikh Aparna Raj , Pishvaian Michael J. 
Published: January 2025

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Background:
Carcinomas of the pancreas and biliary tract are among the most lethal cancers. Currently, it is very difficult to predict individual patient outcomes with only general prognostic information available. Emerging evidence shows that baseline ctDNA tumor fraction (TF) is a prognostic factor for many tumor types, including metastatic pancreatic ductal adenocarcinoma (mPDAC). With an additional year of follow-up, we refresh our prior study of the prognostic value of ctDNA TF in mPDAC and extend the analysis to biliary tract cancers (BTC).
Methods:
A genomic dataset comprising patients who underwent ctDNA testing using FoundationOne Liquid or FoundationOne Liquid CDx as part of routine care was used to determine the distribution of ctDNA TF across pancreatobiliary cancer subtypes. A subset of patients was also included in the nationwide (~280 US cancer clinics, ~800 sites of care) de-identified Flatiron Health-Foundation Medicine clinico-genomic database, which was used separately for all other analyses. Clinical data were derived from the electronic health record. Real-world overall survival (rwOS) was evaluated by ctDNA TF while controlling for relevant covariates. In parallel, ctDNA TF cutoffs of ≥1% and ≥10% were evaluated. Exploratory analysis of trichotomized ctDNA TF at 1% and 10% was also performed.
Results:
In 8817 patients with pancreatobiliary carcinoma, 46.1% of PDAC and 41.9% of extra-hepatic cholangiocarcinoma patients had detectable levels of ctDNA TF, while patients with gallbladder carcinomas had the highest levels of ctDNA TF (median 0.8%). 470 patients with mPDAC and 89 patients with BTC were included in the outcomes analysis. High ctDNA TF was associated with clinical features linked to poor prognosis in mPDAC: Stage IV at diagnosis, pretherapy opioid prescriptions, high neutrophil-to-lymphocyte ratio and CA19-9 at baseline, and alterations in
KRAS
,
TP53
,
CDKN2A
, or
SMAD4
. In BTC, high ctDNA TF was associated with Stage IV at diagnosis and cholangiocarcinoma histology. Higher ctDNA TF in mPDAC was associated with significantly reduced rwOS for both cutoffs (1%: HR 1.55 [1.25-1.93], P < 0.001; 10%: HR 1.85 [1.42-2.41], P < 0.001). When ctDNA TF was trichotomized, higher ctDNA TF groups had reduced rwOS stepwise. Similar trends were observed in patients with BTC, but results were not statistically significant.
Conclusions:
ctDNA from pancreatobiliary carcinomas can be frequently detected and characterized in liquid biopsy while also assessing key genomic biomarkers. ctDNA TF was a prognostic biomarker for mPDAC, but not for BTC in this cohort. Detection of ctDNA associated with other clinical factors linked to poor outcomes. Cohorts given uniform treatment could possibly help further evaluate the ability of ctDNA TF to identify patients with more aggressive disease and inform future studies to personalize therapeutic decision-making.