Adjuvant Pancreatic Therapy Guided by MRD

In pancreatic cancer, circulating tumor DNA (ctDNA) carries tumor-specific mutations (e.g., KRAS, TP53), which can be tracked using next-generation sequencing (NGS) technology to detect minimal residual disease (MRD) after surgery. Previous observational studies suggest that ctDNA-positive patients have a significantly higher risk of postoperative recurrence. In the MRD window (2-12 weeks post-surgery), the median disease-free survival (DFS) for ctDNA-positive patients was only 6.37 months, compared to 33.31 months for ctDNA-negative patients (HR=5.45), indicating that ctDNA-positive patients may require intensified treatment. Furthermore, patients with persistent ctDNA positivity after completing adjuvant chemotherapy (e.g., gemcitabine) still have a high recurrence rate (70%-90%), suggesting the need for alternative treatment strategies.

In a previous study (NCT05479708) evaluating postoperative MRD detection using plasma ctDNA to assess survival benefits and optimize adjuvant chemotherapy strategies in resectable pancreatic cancer patients, we found that MRD-positive patients at 4-8 weeks post-surgery (Landmark MRD) had a higher risk of recurrence. Analysis from Landmark MRD to 36 weeks post-treatment showed that patients who converted from positive to negative MRD status (MRD clearance) had a significantly lower risk of recurrence compared to those who remained positive and those who converted from negative to positive, and MRD clearance was associated with significantly improved overall survival (OS).

Given the significant trauma of pancreatic surgery and the often poor postoperative physical condition of patients, the optimal adjuvant chemotherapy regimen (single-agent/combination, duration, initiation time, etc.) that balances patient recovery and recurrence control remains unclear. Serum biomarker CA 19-9 is commonly used to assess prognosis in pancreatic cancer but is not a reliable predictor of adjuvant therapy efficacy. Imaging methods such as CT/MRI are often used to assess residual tumor or recurrence risk, but their sensitivity and specificity are limited, making it difficult to accurately evaluate real-time tumor burden. Therefore, we designed a prospective, randomized, interventional clinical trial based on ctDNA MRD to guide adjuvant chemotherapy decisions in patients with radically resected pancreatic cancer. The aim is to evaluate whether a ctDNA-guided treatment approach can reduce the use of adjuvant chemotherapy in low-risk patients without increasing recurrence risk, while intensifying treatment in high-risk patients to improve prognosis.

A ctDNA MRD-guided adjuvant therapy approach can allow patients to receive individualized adjuvant treatment. When ctDNA MRD test results are negative, adjuvant chemotherapy can be stopped with active follow-up. This can ensure that clinical benefits are not compromised while avoiding unnecessary chemotherapy. In cases where ctDNA MRD remains positive, continuing treatment can provide patients with more intensive therapy and potentially lead to better prognoses.

Inclusion criteria

• Capable of providing written informed consent (ICF) and able to understand and agree to comply with the study requirements and assessment schedule
• Male or female aged 18-75 years at the time of ICF signing.
• Histologically confirmed pancreatic ductal adenocarcinoma, Stage I-III, and has undergone R0 resection.
• Time between surgery and randomization ≤ 12 weeks.
• ECOG PS 0-2.
• Fully recovered from surgery and able to receive adjuvant chemotherapy.
• Availability of sufficient tumor tissue for MRD testing.
• Patients with reproductive potential (female patients: must have entered the study after the menstrual period and with a negative pregnancy test) must agree to use two medically acceptable methods of contraception (one used by the patient and one by their partner) during the study and for 4 months (for females) or 6 months (for males) after the last study treatment.

Exclusion criteria

• Other types of non-ductal pancreatic tumors, including neuroendocrine tumors or acinar cell carcinoma, cystadenocarcinoma, and ampullary carcinoma.
• Hepatic or renal dysfunction as follows, or if the investigator considers adjuvant chemotherapy to be clearly contraindicated: a) Moderate/severe renal impairment (GFR < 30 ml/min) calculated using the Cockcroft-Gault equation. b) Absolute neutrophil count < 1.5 × 10^9/L. c) Platelet count < 100 × 10^9/L. d) Hemoglobin < 90 g/L. e) Aspartate aminotransferase (AST) / alanine aminotransferase (ALT) > 2.5 × the upper limit of normal.
• Pregnant or breastfeeding women.
• Any serious or uncontrolled systemic disease, including uncontrolled hypertension, active bleeding, active infection (including hepatitis B, hepatitis C, HIV, etc.), which the investigator deems unsuitable for participation in the study or likely to affect compliance with the study protocol.
• Concurrent presence of another malignancy or a history of malignancy (except for adequately treated carcinoma in situ of the cervix, basal cell carcinoma, or squamous cell carcinoma of the skin)
• Other conditions that the investigator deems unsuitable for participation in the study.