Can Circulating Tumor DNA Reduce the Need for Tissue Biopsy in Pancreatic Cancer?

Sylvester Comprehensive Cancer Center has received a two-year, $225,000 grant from the Pancreatic Cancer Action Network to determine whether a blood-based genetic test can replace tissue biopsy in guiding treatment for metastatic pancreatic cancer. The study arrives at a pivotal moment for the disease, just weeks after the first RAS-targeted therapy reached the U.S. market and as a broader restructuring of the field’s largest adaptive trial platform gets underway.

Key Takeaways

• Sylvester researchers will compare circulating tumor DNA (ctDNA) against standard tissue testing in roughly 490 plasma samples drawn from patients enrolled in PanCAN’s Precision Promise trial network, aiming to show that a blood draw can deliver actionable genetic results in about a week rather than the month tissue sequencing can take.
• The effort follows the August 26, 2026 FDA approval of daraxonrasib (RASONQUE®; Revolution Medicines), the first RAS-targeted therapy for metastatic pancreatic ductal adenocarcinoma (PDAC), raising the practical stakes for fast, reliable molecular profiling in a disease in which nearly 90% of tumors carry a RAS mutation.
• ctDNA’s promise in PDAC is well documented in the literature but remains incompletely realized: published concordance between blood and tissue results has ranged widely, and the technology is generally described as a complement to, rather than a replacement for, tissue biopsy.

A Grant Built Around a Familiar Bottleneck

Pancreatic ductal adenocarcinoma kills most of the patients it is diagnosed in within a year, and by the time metastatic disease is confirmed, clinicians are already racing a clock. Peter Hosein, MD, associate director for clinical research with the Sylvester Pancreatic Cancer Research Institute and professor in the Division of Medical Oncology at the University of Miami Miller School of Medicine, is the study’s principal investigator. Together with co-principal investigator Jashodeep Datta, MD, associate director of translational research at the same institute and associate professor in the Division of Surgical Oncology, Hosein is testing whether a ctDNA assay can shorten that clock without sacrificing accuracy [5].

The bottleneck is straightforward. A tissue biopsy for a pancreatic tumor typically requires endoscopic ultrasound-guided fine-needle aspiration, an invasive procedure that is not always feasible depending on tumor location or a patient’s overall condition, followed by pathology processing and next-generation sequencing that together can take up to a month to return actionable results. A blood draw, by contrast, can be obtained in minutes and, according to Hosein, can return ctDNA results in as little as seven days [5]. For a patient whose window to start an effective first-line regimen is measured in weeks, that difference is not incremental; it can determine whether a patient receives treatment at all.

The new study, funded through the Pancreatic Cancer Action Network’s (PanCAN) research grants program, will analyze ctDNA from approximately 490 plasma samples collected through PanCAN’s Precision Promise adaptive clinical trial, benchmarking the results against tissue-based testing from the same patients on pancreatic cancer-specific biomarkers [5]. Datta framed the effort as a foundational step rather than an endpoint in itself, describing the work as opening avenues that existing technologies have not made possible, with the ultimate goal of establishing ctDNA as an alternative to tissue testing where tissue remains the gold standard, and in the near term as a way to rescue cases where a biopsy sample proves inadequate for molecular analysis, sparing patients a repeat procedure [5].

What Comes Next If ctDNA and Tissue Agree

Beyond simple concordance, the Sylvester team plans to use paired blood samples, collected before treatment and again roughly two months after therapy begins, to examine whether shifts in the proportion of tumor-derived DNA in the blood can flag treatment response or the emergence of resistance before it becomes apparent on imaging [5]. Datta described this as a step toward more nimble treatment switching, in which a change in a patient’s blood-based tumor signal, rather than a new biopsy, could prompt a regimen change [5]. The grant also funds more exploratory work: an investigation into whether pancreatic cancer’s tumor subtypes, a molecular classification system that has proven useful for guiding treatment in other solid tumors but does not yet exist for PDAC, can be defined through blood-based methylation profiling of cell-free DNA [5]. A smaller arm of the study, using roughly 50 blood samples, will test an experimental artificial intelligence platform called Fate-AI, developed by Michele Ceccarelli, PhD, research professor in the Department of Public Health Sciences at the University of Miami, to identify molecular signatures of cancer, including in pancreatic tumors; Sylvester describes this component as an early, proof-of-concept step toward understanding whether the platform can help track treatment response [5].

Why the Timing Matters: A New RAS-Targeted Drug Just Reached the Clinic

The Sylvester grant was announced explicitly against the backdrop of a treatment landscape that changed three weeks earlier. On August 26, 2026, the FDA approved daraxonrasib (RASONQUE®; Revolution Medicines, Inc.), an oral inhibitor of the RAS GTPase family, for adults with metastatic pancreatic adenocarcinoma who have received at least one prior systemic therapy or who are not candidates for multiagent systemic therapy [6,7]. The approval was based on RASolute 302 (NCT06625320), a randomized, open-label, multicenter Phase 3 trial that enrolled 500 patients with metastatic PDAC and disease progression after one prior line of systemic therapy, randomizing them 1:1 to daraxonrasib or physician’s choice of standard chemotherapy, with overall survival and progression-free survival as major efficacy outcomes assessed both in patients with a RAS G12 mutation and in the overall population [6]. Reported results describe a near doubling of survival, with a median overall survival of approximately 13.2 months on daraxonrasib compared with roughly half that on chemotherapy, along with better-tolerated side effects [8,9]. RAS mutations, most commonly in the KRAS gene, are present in roughly 90% of pancreatic adenocarcinomas [9], which is precisely the reason a reliable, fast method of confirming a patient’s RAS mutation status has direct clinical consequence: the same molecular test that could previously only inform prognosis can now inform an approved treatment decision, and doing so faster matters more than it did before this approval existed.

What the Published Literature Already Shows About ctDNA in Pancreatic Cancer

The premise behind the Sylvester study, that a blood test can substitute for or supplement tissue sequencing in PDAC, is not new, and the existing evidence base is both encouraging and genuinely mixed. KRAS is the most frequently altered gene detected in pancreatic cancer ctDNA, present in roughly 90% of PDAC tumors overall, alongside TP53 as the next most common alteration [1,2]. A 2019 analysis from UC San Diego’s Moores Cancer Center that compared ctDNA to tissue-based next-generation sequencing in 112 patients with PDAC found concordance rates between blood and tissue of only 61% for TP53 alterations and 52% for KRAS alterations overall, though concordance for KRAS rose to 72% when ctDNA was compared specifically against tissue from metastatic sites rather than the primary tumor, and the same study found that a higher proportion of ctDNA in a patient’s blood was independently associated with worse survival [1]. A separate cohort study of 104 patients with advanced pancreatic cancer and liver metastasis found detectable ctDNA in half of patients, with TP53 and KRAS again the most commonly altered genes, and reported that ctDNA-positive patients had significantly shorter overall and progression-free survival than ctDNA-negative patients [3].

More recent reviews describe a field that has matured considerably in scope but not yet in standardization. A 2025 review from Northwestern University’s Feinberg School of Medicine catalogs ctDNA’s expanding roles in PDAC, from early detection to disease subtyping, treatment-response monitoring, and minimal residual disease assessment, while explicitly cautioning that many studies report less than 50% concordance between ctDNA and tumor tissue in early-stage disease, a gap the authors attribute in part to intratumoral and intertumoral heterogeneity [2]. That same review notes that ctDNA analysis is not presently a standalone diagnostic solution and continues to require concomitant use with imaging and tissue biopsy, characterizing it as a complementary tool rather than a replacement, a framing that tracks closely with what the Sylvester study is actually designed to test: not whether ctDNA can replace tissue testing outright, but whether it can rescue failed biopsies and accelerate the interval to a usable genetic result [2]. A 2024 systematic review covering 49 studies from 2019 through 2024 reached a similar conclusion, finding that ctDNA analysis, particularly for detecting mutant KRAS, shows diagnostic and prognostic promise but remains limited in early-stage disease, while proteomic approaches, especially when combined with the established biomarker CA 19-9, have so far demonstrated the strongest diagnostic accuracy among the liquid biopsy modalities studied [4].

A Trial Network in Transition

The patient samples underpinning the Sylvester analysis come from PanCAN’s Precision Promise, a multi-arm adaptive registration platform trial (NCT04229004) launched in 2020 to test multiple experimental pancreatic cancer therapies in parallel, an approach PanCAN has said is designed to bring new treatments to patients faster and at lower cost than sequential single-arm trials [10,11]. Precision Promise is itself in the middle of a structural transition. In January 2024, PanCAN announced a strategic alliance with the Global Coalition for Adaptive Research (GCAR) under which PanCAN will continue to treat and follow patients already enrolled in Precision Promise through the study’s completion, while GCAR takes over as sponsor of a next-generation master protocol trial for pancreatic cancer, with PanCAN continuing on as the patient-advocacy partner [11]. Diane Simeone, MD, director of the Pancreatic Cancer Center at NYU Langone Health and chair of the Precision Promise Steering Committee, described the arrangement at the time as a transition to a next phase of growth intended to expand clinical trial options for patients rather than a wind-down of the platform itself [11]. For a companion study like Sylvester’s ctDNA project, which depends on continued access to a well-characterized, prospectively collected patient cohort, that institutional continuity between the two organizations is a practical prerequisite rather than a footnote.

Studies

Sylvester ctDNA validation study. An unregistered ancillary biomarker study funded by a PanCAN research grant, using approximately 490 plasma samples collected through Precision Promise to compare ctDNA against tissue-based genetic testing, evaluate ctDNA kinetics as a marker of treatment response, and pilot blood-based methylation profiling and the Fate-AI computational platform in roughly 50 additional samples [5].

Precision Promise (NCT04229004). A PanCAN-sponsored, adaptive, multi-arm Phase 2/3 registration platform trial in metastatic PDAC, launched in 2020, now transitioning to a GCAR-sponsored master protocol while PanCAN continues to follow currently enrolled patients [10,11].

RASolute 302 (NCT06625320). A randomized, open-label, multicenter Phase 3 trial of daraxonrasib versus physician’s choice chemotherapy in 500 patients with metastatic PDAC previously treated with one line of systemic therapy; the trial supported the August 2026 FDA approval of daraxonrasib [6].

What’s next?

Several questions sit outside what has been announced so far. The Sylvester study is early-stage and ancillary; it is designed to validate a testing approach against an existing gold standard, not to demonstrate that ctDNA-guided treatment selection improves outcomes, and no data from the study itself yet exist. The published literature on ctDNA concordance in PDAC is heterogeneous across assay platforms, gene panels, and disease stages, and the reviews cited here are explicit that no single ctDNA methodology has emerged as clearly superior, leaving open exactly which technical approach the Sylvester team’s benchmarking will ultimately validate.

The Fate-AI proof-of-concept, run in only about 50 samples, is described by Sylvester itself as an early step, and no performance data for the platform in pancreatic cancer have yet been published. Finally, while daraxonrasib’s approval sharpens the clinical argument for faster molecular profiling, that connection is contextual rather than a stated aim of the Sylvester grant; PanCAN’s own announcement frames the study as arriving at a pivotal moment following the drug’s approval without stating that RAS-mutation genotyping for daraxonrasib eligibility is a defined objective of this specific project.

Clinical trials

A Multi-center Trial to Evaluate Multiple Regimens in Metastatic Pancreatic Cancer – ClinicalTrials.gov ID NCT04229004
Phase 3 Study of Daraxonrasib (RMC-6236) in Patients With Previously Treated Metastatic Pancreatic Ductal Adenocarcinoma (PDAC) (RASolute 302) – ClinicalTrials.gov ID NCT06625320

Highlights of Prescribing Information

Daraxonrasib (RASONQUE®; Revolution Medicines)[Prescribing Information]

References

[1] Patel H, Okamura R, Fanta P, Patel C, Lanman RB, Raymond VM, Kato S, Kurzrock R. Clinical correlates of blood-derived circulating tumor DNA in pancreatic cancer. J Hematol Oncol. 2019 Dec 4;12(1):130. doi: 10.1186/s13045-019-0824-4. PMID: 31801585; PMCID: PMC6894333.
[2] Cox M, Vitello D, Chawla A. Translating the multifaceted use of liquid biopsy to management of early disease in pancreatic adenocarcinoma. Front Oncol. 2025 Mar 13;15:1520717. doi: 10.3389/fonc.2025.1520717. PMID: 40182037; PMCID: PMC11966063.
[3] Uesato Y, Sasahira N, Ozaka M, Sasaki T, Takatsuki M, Zembutsu H. Evaluation of circulating tumor DNA as a biomarker in pancreatic cancer with liver metastasis. PLoS One. 2020 Jul 2;15(7):e0235623. doi: 10.1371/journal.pone.0235623. PMID: 32614932; PMCID: PMC7332050.
[4] Munnings R, Gibbs P, Lee B. Evolution of Liquid Biopsies for Detecting Pancreatic Cancer. Cancers (Basel). 2024 Sep 29;16(19):3335. doi: 10.3390/cancers16193335. PMID: 39409954; PMCID: PMC11475855.
[5] University of Miami Miller School of Medicine / Sylvester Comprehensive Cancer Center. Sylvester Explores Blood Test That Could Improve Pancreatic Cancer Treatment. Press release, September 16, 2026.
[6] U.S. Food and Drug Administration. FDA approves daraxonrasib for metastatic pancreatic adenocarcinoma. August 26, 2026. Online. Last accessed on September 16, 2026.
[7] U.S. Food and Drug Administration. FDA Approves First in Class Targeted Therapy for Metastatic Pancreatic Cancer. Press announcement, August 26, 2026. Online. Last accessed on Seoptember 16, 2026.
[8] Lovelace B Jr. FDA approves ‘game-changing’ pancreatic cancer drug. NBC News, August 26, 2026. Online. Last accessed on September 16, 2026.
[9] American Association for Cancer Research. Breaking News: Daraxonrasib Approved for Pancreatic Cancer. AACR Blog, August 26, 2026. Online. Last accessed on September 16, 2026.
[10] ClinicalTrials.gov. Precision Promise: An Adaptive, Multi-Arm Registration Trial in Metastatic Pancreatic Ductal Adenocarcinoma. Identifier NCT04229004.
[11] Pancreatic Cancer Action Network / Global Coalition for Adaptive Research. The Pancreatic Cancer Action Network and the Global Coalition for Adaptive Research Forge a Powerful Alliance to Accelerate Treatment Options for Pancreatic Cancer Patients. Press release, January 9, 2024. Online.  Last accessed on September 16, 2026.

This article is intended for informational purposes for healthcare professionals and does not constitute medical advice.

Featured image: © 2026 CHA/JCO ONC. Used with permission.

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