Liquid Biopsy (ctDNA) Guided Treatment in Localized Pancreatic Cancer: Neoadjuvant CTX vs. Upfront Surgery

Pancreatic ductal adenocarcinoma (PDAC) is characterized by high recurrence rates and poor long-term survival, even following potentially curative surgical resection and modern multimodal treatment. Despite improvements in surgical techniques, perioperative management, and systemic chemotherapy, a substantial proportion of patients with anatomically resectable PDAC experience early disease recurrence, suggesting the presence of occult systemic disease that cannot be adequately identified by conventional staging methods.

Current treatment decisions are primarily based on radiological resectability, clinical performance status, and established biomarkers such as carbohydrate antigen 19-9 (CA19-9). However, these parameters provide limited information about individual tumor biology and the risk of early recurrence. Consequently, patients with apparently favorable anatomical characteristics may still harbor biologically aggressive disease.

Circulating tumor DNA (ctDNA) has emerged as a promising minimally invasive biomarker for assessing tumor biology, monitoring treatment response, and predicting oncological outcomes. In previous studies, the investigators demonstrated that an early decrease in ctDNA levels of at least 42% after two weeks of systemic chemotherapy could predict subsequent radiological treatment response with high sensitivity and specificity, substantially earlier than conventional imaging (Kirchweger et al., Frontiers in Oncology, 2022). Furthermore, pretherapeutic ctDNA positivity in patients with localized PDAC was associated with significantly shorter disease-free survival (3.3 vs. 18.1 months), despite the absence of radiological evidence of advanced or metastatic disease (Kirchweger et al., European Journal of Surgical Oncology, 2021).

These findings suggest that pretherapeutic ctDNA detection may identify patients at increased risk of early recurrence who could potentially benefit from neoadjuvant systemic treatment, even when conventional clinical and radiological criteria favor upfront surgery.

However, a universal neoadjuvant treatment approach for all patients with anatomically resectable PDAC remains controversial. Although neoadjuvant chemotherapy may provide early systemic disease control and reveal aggressive tumor biology, it also exposes patients to treatment-related toxicity, potential deterioration in quality of life, and the risk of losing the opportunity for surgical resection due to disease progression or treatment intolerance. Therefore, a more individualized treatment strategy incorporating biological risk assessment may help optimize treatment sequencing.

The LIQUIPANC study is a prospective, multicenter, randomized clinical trial investigating the prognostic and potential clinical utility of ctDNA-guided treatment strategies in patients with anatomically resectable PDAC.

Eligible patients have localized PDAC without radiological vessel involvement, CA19-9 levels below 500 U/mL, and a multidisciplinary tumor board recommendation for upfront surgical resection based on conventional staging.

Following informed consent, approximately 30 mL of peripheral blood is collected before the initiation of oncological treatment. Plasma-derived ctDNA is analyzed using droplet digital polymerase chain reaction (ddPCR), primarily targeting KRAS G12/G13 mutations, with additional KRAS Q61 testing if the initial analysis is negative.

Treatment allocation is determined as follows:

ctDNA-positive patients: Patients with detectable ctDNA are randomized to one of two treatment strategies:

Neoadjuvant treatment arm: Patients receive neoadjuvant chemotherapy according to current standards of care and the treating physician's choice, followed by surgical resection when clinically feasible and subsequent treatment according to local guidelines.

Standard-of-care arm: Patients undergo upfront surgical resection, followed by adjuvant chemotherapy and further treatment according to current local guidelines and the treating physician's choice.

ctDNA-negative patients: Patients without detectable ctDNA are not randomized and undergo upfront surgical resection in accordance with the multidisciplinary tumor board recommendation and current local standards of care, followed by adjuvant treatment as indicated.

The randomized comparison among ctDNA-positive patients aims to investigate whether neoadjuvant chemotherapy, compared with upfront surgery, improves oncological outcomes in patients with potentially unfavorable tumor biology.

The overall study population will additionally be evaluated to investigate the prognostic significance of baseline ctDNA status and its association with disease recurrence and survival.

The primary endpoint is disease-free survival (DFS). Overall survival (OS) and the prognostic value of ctDNA detection are evaluated as additional outcomes.

LIQUIPANC aims to provide prospective clinical evidence regarding the feasibility and potential value of incorporating liquid biopsy into treatment decision-making for anatomically resectable PDAC. Ultimately, the study seeks to support a more personalized approach to treatment sequencing by identifying patients who may benefit from neoadjuvant systemic therapy while avoiding potentially unnecessary treatment delays and toxicity in others.