What clinical trials are recommended for localized recurrence of pancreatic ductal adenocarcinoma (PDAC) with known tumor genetic profile?

Clinical Trial Recommendations for Localized Recurrence of PDAC Based on Tumor Genetics

For patients with localized recurrence of pancreatic ductal adenocarcinoma (PDAC), enrollment in a clinical trial is strongly encouraged as the best management option, with trial selection guided by the patient's specific tumor genetic profile.

Diagnostic Evaluation Prior to Trial Selection

• High-quality imaging is essential using specialized pancreatic CT protocol with triphasic cross-sectional imaging and thin slices (3mm) 1
• Comprehensive molecular profiling of the recurrent tumor is critical for matching patients to appropriate targeted therapy trials
• Tumor tissue sample banking along with paired blood and serum samples should be performed for patients enrolling in clinical trials 2

Clinical Trial Selection Based on Genetic Profile

Priority Genetic Alterations to Target:

1. BRCA1/2 Mutations

   • Patients with germline BRCA1/2 mutations should be prioritized for PARP inhibitor trials 2
   • The phase III POLO trial has shown benefit with maintenance olaparib in germline BRCA-mutated PDAC 2
   • For somatic BRCA1/2 mutations, while not yet fully validated in PDAC, consider PARP inhibitor trials based on preliminary evidence 2

2. MSI-High/dMMR Status

   • Patients with microsatellite instability-high (MSI-H) should be directed to immune checkpoint inhibitor trials 2
   • These patients are expected to derive meaningful clinical benefit from immunotherapy 2

3. NTRK Fusions

   • Patients with NTRK fusion-positive tumors should be considered for TRK inhibitor trials 2

4. Other Potentially Actionable Alterations

   • Consider trials targeting KRAS mutations, which may change during disease course 3
   • Evaluate for NRG1, ALK, RET, ROS1 fusions which may be targetable 2
   • PIK3CA, BRAF V600E mutations, MDM2 or ERBB2 amplifications may be relevant for trial selection 2

Treatment Approach While Awaiting Trial Enrollment

• Systemic chemotherapy remains the backbone of treatment with options including:

  • Gemcitabine-based regimens
  • Fluoropyrimidine-based regimens (5-FU, capecitabine)
  • FOLFIRINOX for patients with good performance status 1

• Radiation therapy may be considered after several months of upfront chemotherapy in patients with well-controlled localized disease 2

Practical Considerations for Clinical Trial Participation

• Treatment at or coordinated through a high-volume center is preferred 1
• Phase II and III clinical trials should have a primary endpoint of overall survival 2
• Quality control standards for imaging interpretation and pathologic assessment are critical 2
• Consider trials that incorporate circulating tumor DNA (ctDNA) monitoring, as ctDNA levels correlate with tumor burden and predict outcomes 4

Pitfalls to Avoid

• Avoid trials that don't require comprehensive molecular profiling, as this is essential for matching patients to appropriate targeted therapies
• Be cautious of phase III trials initiated without clinically meaningful efficacy signals in phase II settings 2
• Avoid trials that don't separate patients by disease stage, as outcomes differ significantly between locally advanced and metastatic disease 2
• Re-assessment of molecular biomarkers (especially KRAS) should be performed at disease progression, as biomarker status may change during the course of disease 3

The molecular landscape of PDAC is complex, and clinical trial selection should be guided by the most current and comprehensive tumor genetic profile to maximize potential benefit for patients with localized recurrence.