| BackgroundIn recent years,due to the advancement in targeted therapy and immunotherapy,survival of patients with advanced non-small cell lung cancer(NSCLC)has improved dramatically.However,more intense screening and prolonged survival also resulted in the increased rate of diagnosis of central nervous system(CNS)metastases,which had become an important limiting factor for survival.In the era of precision oncology,tumor biopsy and molecular testing is crucial.As CNS is in a special anatomical location and difficult to biopsy,liquid biopsy has become an alternative.Cerebrospinal fluid(CSF)had a direct interaction with the CNS and seems a better media than plasma for CNS metastases.Thus,our study explored the feasibility of CSF to reveal the molecular characteristics and predict prognosis and treatment efficacy for CNS metastases.MethodsWe integrated “performing lumbar puncture for(suspected)CNS metastases diagnosis/progression in advanced NSCLC” into clinical workflow.We collected CSF and matched tumor and plasma for next-generation sequencing of circulating tumor DNA(ct DNA).We also collected patients’ clinical,pathological,radiological and treatment history data and follow up survival.Chi-square or Fisher’s exact test was used for categorical variables for distribution;Kruskal-Wallis test was used to compare ct DNA variant allelic fraction in CSF;Factors that might affect survival outcomes were analyzed with logistic regression model and adjusted by a multivariable Cox model;Survival analysis was performed by log-rank method.All statistical tests were two-sided with P<0.05 for statistical significance.ResultsWe presented the largest number of CSF sample from advanced NSCLC with CNS metastases to date(n=431).We analyzed factors that might influenced the detection of CSF ct DNA and found that ECOG PS score,extracranial control,leptomeningeal metastases(LM)and previous brain radiotherapy were determinants;Besides,leptomeningeal invasion and brain metastatic lesions >10 increased the abundance of ct DNA.Then in order to exam whether CSF could reflect the unique molecular profiles of CNS metastases,we compared CSF with genetic alterations in brain metastases from published articles and presented69-94% concordance rate.We also found that driver gene and resistant mechanisms could be detected by CSF ct DNA in ALK-fusion advancecd NSCLC with LM.Next we explored the prognostic and predictive value of CSF ct DNA.By unsupervised clustered analysis,we defined 5 subgroups of CNS metastases with distinct survival;specific alterations like MYC,CDK4 alterations also affected survival outcomes.As to CSF’s predictive value,EGFR driver subtypes,T790 M mutation and other concurrent alterations detected in CSF distinguished patients with LM who might benefit from osimertinib;T790M-maintained in CSF after progression on osimertinib also indicated better efficacy.Finally,we investigated the use of CSF ct DNA to detect resistant mechanisms to osimertinib and inform LM-specific targeted therapy.For those without resistant alterations detected by CSF,continuation of osimertinib with chemotherapy/ bevacizumab/radiotherapy obtained better control of LM than regimen switch.ConclusionIn advanced NSCLC with CNS metastases,CSF ct DNA detection was determined by clinical,pathological,radiological and treatment factors.Once detected,CSF ct DNA reflected the unique molecular characteristics of CNS metastases,predicted its prognosis and efficacy from targeted therapy and supported CSF-directed site specific treatment.Thus we supported CSF as liquid biopsy of CNS metastases for advanced NSCLC. |
