Background: Leptomeningeal metastases (LM) are much more frequent in patients of
non-small lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations.
Osimertinib, a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFRTKI)
shows promising efficacy for LM.
Objective: The aim of this study was to analyze the concentration of osimertinib and gene variation
of circulating tumor DNA (ctDNA) in human plasma and cerebrospinal fluid (CSF). Furthermore,
we explored whether ctDNA in CSF might be used as a biomarker to predict and monitor therapeutic
Methods: The dynamic paired CSF and blood samples were collected from the NSCLC patient with
LM acquired EGFR-TKI resistance. A method based on ultra-high performance liquid chromatography-
tandem mass spectrometry (UPLC-MS/MS) was developed and validated for detecting
osimertinib in CSF and plasma samples. Gene variations of ctDNA were tested by next-generation
sequencing with a panel of 1021 genes.
Results: The concentrations of osimertinib in CSF were significantly lower than that in plasma
(penetration rate was 1.47 %). Mutations included mTOR, EGFR, CHECK1, ABCC11, and TP53
were explored in ctDNA from plasma and CSF samples. The detected mutation rate of CSF samples
was higher than that of plasma samples (50% vs. 25%). Our data further revealed that the variations
allele frequency (VAF) and molecular tumor burden index (mTBI) of ctDNA derived from CSF exhibited
the negative correlation with efficacy of treatment.
Conclusion: ctDNA from CSF might be a useful biomarker for monitoring the efficacy of treatment
and an effective complement to nuclear magnetic resonance (MRI) for LM
Keywords: Leptomeningeal metastases, Non-small cell lung cancer, Osimertinib,
UPLC-MS/MS, Next-generation sequencing, Cerebrospinal fluid, Plasma.
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