What is the next best step for a patient with bronchogenic adenocarcinoma and worsening metastatic disease, as indicated by increasing Signatera (circulating tumor DNA test) and Northstar Response (tumor marker), and concerning imaging findings on Computed Tomography (CT) and Positron Emission Tomography/Computed Tomography (PET/CT) scans?

Next Steps for Patient with Bronchogenic Adenocarcinoma and Evidence of Disease Progression

The next best step for this patient with bronchogenic adenocarcinoma showing evidence of disease progression is to obtain a biopsy of one of the enlarging pulmonary nodules to confirm recurrence and perform molecular testing to guide targeted therapy selection.

Assessment of Current Disease Status

The patient shows multiple indicators of disease progression:

• Increasing circulating tumor DNA (Signatera increased from 0.10 to 0.19)
• Rising tumor marker (Northstar Response increased from 36 to 139)
• CT CAP showing enlarging subpleural parenchymal and pleural-based pulmonary nodules
• PET/CT demonstrating multiple hypermetabolic pleural-based paramediastinal nodules and an enlarging FDG-avid right lower lobe nodule

These findings strongly suggest recurrent/progressive metastatic disease, as supported by both anatomical and functional imaging.

Recommended Management Algorithm

1. Tissue Confirmation and Molecular Testing

   • Biopsy the most accessible hypermetabolic lesion (preferably one of the pleural-based nodules)
   • Perform comprehensive molecular testing including:
     • EGFR mutations (exon 19 deletions, exon 21 L858R, T790M)
     • ALK rearrangements
     • ROS1, BRAF, MET, RET, and other actionable mutations

2. Treatment Selection Based on Molecular Profile

   • If EGFR mutation positive: Consider osimertinib (especially if T790M positive) 1
   • If ALK positive: Consider ALK inhibitor therapy such as brigatinib 2
   • If no actionable mutations: Consider platinum-based chemotherapy with or without immunotherapy

3. Monitoring Plan

   • Continue monitoring with Signatera and Northstar Response tests
   • Schedule follow-up imaging (CT or PET/CT) in 2-3 months to assess treatment response

Evidence-Based Rationale

The ESMO guidelines emphasize that "adequate tissue material for histological diagnosis and molecular testing should be obtained to allow individual treatment decisions" and that "re-biopsy at disease progression should be considered" 3. This is particularly important given the availability of targeted therapies for specific molecular alterations.

PET/CT has demonstrated high accuracy in detecting recurrent disease, with studies showing sensitivity of 73-82% and specificity of 89-91% 3. The hypermetabolic nature of the nodules on PET strongly suggests malignancy rather than inflammatory processes.

Important Considerations

• The rising ctDNA (Signatera) is a significant predictor of recurrence. Recent research shows ctDNA detection after definitive treatment is associated with a higher risk of disease recurrence (hazard ratio: 9.94) with 100% specificity and 78% sensitivity 4.

• While PET/CT is valuable for detecting recurrence, it should not be used as a routine surveillance tool but rather for investigation of specific areas of concern 3, which is appropriate in this case given the rising tumor markers and concerning CT findings.

• Molecular testing is crucial as it can identify actionable mutations that may guide therapy selection. For example, osimertinib is indicated for EGFR mutation-positive metastatic NSCLC 1.

• The biopsy should target the most accessible lesion showing FDG avidity on PET/CT to maximize the likelihood of obtaining adequate tissue for both histological confirmation and molecular testing.