Abstract A142: Circulating tumor DNA as a prognostic biomarker in PDAC: Insights from Real-World Data
Daiane Hemerich Brennan, Nina Kozlova, Gonzalo Lopez, Aparna ChhibberAbstract
Background:
Pancreatic ductal adenocarcinoma (PDAC) carries a dismal prognosis with few validated biomarkers for disease monitoring. Circulating tumor DNA (ctDNA) is a promising liquid biopsy-based biomarker, but its clinical utility remains incompletely defined. While most available data focus on early-stage disease, we evaluated ctDNA in a large real-world PDAC cohort enriched for late-stage metastatic disease to assess its prognostic value at baseline and post-first-line chemotherapy.
Methods:
Patients with PDAC who underwent ctDNA profiling using the Tempus xF liquid biopsy assay were identified from the Tempus Lens database. ctDNA positivity was defined as liquid tumor fraction (LTF) threshold >0.25% or KRAS variant allele fraction (VAF) >0.25%. Molecular subtype (basal-like vs. classical) was derived from transcriptomic profiling. Three complementary analytical frameworks were applied to assess: (1) association between baseline ctDNA and overall survival (OS) (N=1,199) and molecular subtype (N=573); (2) prognostic value of post-treatment ctDNA (N=237); and (3) longitudinal paired ctDNA analyses to explore dynamic changes relative to treatment response (N=41). Claude Code (Anthropic) was used to assist with code development.
Results:
Our study confirms the adverse prognostic impact of ctDNA positivity on OS and treatment outcomes. Baseline ctDNA positivity was independently associated with inferior OS. ctDNA LTF positivity remained significantly associated with shorter OS after adjustment for disease stage (HR=1.39, p=4.59×10-4) and metastatic status (HR=1.37, p=9.39×10-4). Likewise, ctDNA positivity by KRAS VAF similarly predicted inferior survival (stage adjusted HR=1.46, p=2.18×10-5; and metastatic status HR=1.44, p=9.59×10-5). Basal-like tumors showed higher mean LTF levels than classical tumors (5.32% vs. 3.39%; p=4.01×10-7); however, this difference was no longer statistically significant after adjustment for liver metastasis status (p=0.084), suggesting that the higher ctDNA shedding in basal-like tumors is largely explained by late-stage disease and metastatic patterns rather than intrinsic tumor biology. Post treatment, higher ctDNA LTF was associated with worse outcomes (p=0.018), and progressive disease was characterized by higher KRAS VAF (p=7.33×10-5). In longitudinal paired analyses, patients with persistent ctDNA negativity or clearance had the most favorable responses, while persistent positivity was associated with progression (p=0.02).
Conclusions and significance:
These real-world data demonstrate that both LTF and KRAS VAF are independent prognostic biomarkers at baseline and post-treatment. Despite its classification as a low-shedding tumor, ∼80% of late-stage metastatic patients were ctDNA positive by LTF at baseline, suggesting that treatment response in late-stage PDAC could potentially be evaluated using ctDNA dynamics. Prospective studies incorporating both metrics are warranted to further establish ctDNA as a clinical biomarker in PDAC. Microsoft Copilot was used to assist in drafting and refining this abstract.
Citation Format:
Daiane Hemerich Brennan, Nina Kozlova, Gonzalo Lopez, Aparna Chhibber. Circulating tumor DNA as a prognostic biomarker in PDAC: Insights from Real-World Data [abstract]. In: Proceedings of the AACR Conference on Pancreatic Cancer: New Frontiers in Biology and Therapeutic Development; 2026 Sep 25-28; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(18_Suppl_2):Abstract nr A142.