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Multi-gene Liquid Biopsy to Detect Resistance to First-line Osimertinib in Patients With EGFR-mutated Lung
Shin Ito1, Kyoji Tsurumi2,3, Norihisa Shindo1
1Division of Molecular and Cellular Oncology, Miyagi Cancer Center Research Institute, Natori, Japan.
Background/Aim:
Osimertinib is currently used as a first-line treatment for EGFR-mutated non-small cell lung cancer, and the emergence of drug resistance poses a substantial challenge. Liquid biopsy with a multi-gene panel can examine both the molecular mechanisms and possibility of early resistance diagnosis.
Patients And Methods:
We used a molecular barcode library construction kit (Archer® LiquidPlex™) that allowed the analysis of multiple cancer-related genes using cell-free DNA from the plasma samples of patients. We collected plasma from 17 consecutive patients with lung adenocarcinoma at our hospital at various time points and cell-free DNA was extracted and subjected to LiquidPlex analysis.
Results:
Plasma DNA concentration was not associated with the presence or absence of resistance to osimertinib. The pathological mutations detected using next-generation sequencing in the resistant specimens were in MAP2K1, PIK3CA, TP53, BRAF, and EGFR. Among the recurrent cases, EGFR mutations identified at the initial diagnosis were detected within 6 months before relapse confirmation in four cases (average 88 days). Many of the recurrent cases without detection of known EGFR mutations in the liquid biopsy showed a longer interval between the detection of relapse and the last blood draw for the liquid biopsy (average 255 days).
Conclusion:
Frequent liquid biopsies are useful for identifying known EGFR mutations as markers for early detection of relapse. Several cancer driver mutations were observed, suggesting a variety of mechanisms of resistance in first-line osimertinib-treated lung adenocarcinoma.
Insights
Frequent liquid biopsies can detect EGFR mutations early, aiding in the relapse detection for non-small cell lung cancer patients treated with osimertinib. This approach also reveals diverse resistance mechanisms.
Area of Science:
- Oncology
- Molecular Diagnostics
- Genetics
Background:
- Osimertinib is a first-line treatment for EGFR-mutated non-small cell lung cancer.
- Drug resistance to osimertinib presents a significant clinical challenge.
- Liquid biopsy offers a non-invasive method for detecting resistance mechanisms and early relapse.
Purpose of the Study:
- To evaluate the utility of liquid biopsy with a multi-gene panel for early resistance diagnosis and monitoring in osimertinib-treated lung adenocarcinoma.
- To identify molecular mechanisms of resistance to first-line osimertinib therapy.
Main Methods:
- Plasma cell-free DNA from 17 lung adenocarcinoma patients was analyzed using the Archer® LiquidPlex™ multi-gene panel.
- Next-generation sequencing was employed to detect mutations in plasma DNA at various time points.
Main Results:
- Plasma DNA concentration did not correlate with osimertinib resistance.
- Mutations in MAP2K1, PIK3CA, TP53, BRAF, and EGFR were identified in resistant specimens.
- EGFR mutations were detected in liquid biopsies an average of 88 days before relapse confirmation in four cases.
Conclusions:
- Frequent liquid biopsies are effective for early relapse detection by identifying known EGFR mutations.
- Observed cancer driver mutations suggest diverse resistance mechanisms in lung adenocarcinoma treated with osimertinib.
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