Dynamic monitoring of cerebrospinal fluid circulating tumor DNA to identify unique genetic profiles of brain metastatic tumors and better predict intracranial tumor responses in non-small cell lung cancer patients with brain metastases: a prospective cohort study (GASTO 1028)
Abstract Background Due to the blood-brain barrier, plasma is not an ideal source to evaluate the genetic characteristics of central nervous system tumors. Thus, cerebrospinal fluid (CSF) is becoming an alternative biopsy type to evaluate the genetic landscape of intracranial tumors. We aimed to exp...
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| Format: | Article |
| Language: | English |
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BMC
2022-11-01
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| Series: | BMC Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12916-022-02595-8 |
| _version_ | 1828094182828277760 |
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| author | Meichen Li Jing Chen Baishen Zhang Juan Yu Na Wang Delan Li Yang Shao Dongqin Zhu Chuqiao Liang Yutong Ma Qiuxiang Ou Xue Hou Likun Chen |
| author_facet | Meichen Li Jing Chen Baishen Zhang Juan Yu Na Wang Delan Li Yang Shao Dongqin Zhu Chuqiao Liang Yutong Ma Qiuxiang Ou Xue Hou Likun Chen |
| author_sort | Meichen Li |
| collection | DOAJ |
| description | Abstract Background Due to the blood-brain barrier, plasma is not an ideal source to evaluate the genetic characteristics of central nervous system tumors. Thus, cerebrospinal fluid (CSF) is becoming an alternative biopsy type to evaluate the genetic landscape of intracranial tumors. We aimed to explore the genetic profiles of CSF-derived circulating tumor DNA (ctDNA) to predict intracranial tumor responses and monitor mutational evolution during the treatment of non-small cell lung cancer (NSCLC) patients with brain metastases. Methods We conducted a prospective study of 92 newly diagnosed NSCLC patients with brain metastases. Paired CSF and plasma samples were collected at baseline, 8 weeks after treatment initiation, and disease progression. All samples underwent next-generation sequencing of 425 cancer-related genes. Results At baseline, the positive detection rates of ctDNA in CSF, plasma, and extracranial tumors were 63.7% (58/91), 91.1% (82/90), and 100% (58/58), respectively. A high level of genetic heterogeneity was observed between paired CSF and plasma, while concordance in driver mutations was also observed. A higher number of unique copy number variations was detected in CSF-ctDNA than in plasma. ctDNA positivity of CSF samples at baseline was associated with poor outcomes (HR=2.565, P=0.003). Moreover, patients with ≥ 50% reductions in the concentrations of CSF ctDNA after 8 weeks of treatment had significantly longer intracranial progression-free survivals (PFS) than patients with < 50% reductions in CSF ctDNA concentrations (13.27 months vs 6.13 months, HR=0.308, P=0.017). A ≥ 50% reduction in CSF ctDNA concentrations had better concordance with radiographic intracranial tumor responses than plasma. A ≥ 50% reduction in plasma ctDNA concentrations was also associated with longer extracranial PFS (11.57 months vs 6.20 months, HR=0.406, P=0.033). Based on clonal evolution analyses, the accumulation of subclonal mutations in CSF ctDNA was observed after 8 weeks of treatment. The clonal mutations that remained in more than 80% in CSF after 8 weeks also predicted shorter intracranial PFS (HR=3.785, P=0.039). Conclusions CSF ctDNA exhibited unique genetic profiles of brain metastases, and dynamic changes in CSF ctDNA could better predict intracranial tumor responses and track clonal evolution during treatment in NSCLC patients with brain metastases. Trial registration ClinicalTrials.gov identifier: NCT 03257735. |
| first_indexed | 2024-04-11T06:55:17Z |
| format | Article |
| id | doaj.art-109e6946d4074b2a935c0d7f3879a6b8 |
| institution | Directory Open Access Journal |
| issn | 1741-7015 |
| language | English |
| last_indexed | 2024-04-11T06:55:17Z |
| publishDate | 2022-11-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Medicine |
| spelling | doaj.art-109e6946d4074b2a935c0d7f3879a6b82022-12-22T04:39:02ZengBMCBMC Medicine1741-70152022-11-0120111210.1186/s12916-022-02595-8Dynamic monitoring of cerebrospinal fluid circulating tumor DNA to identify unique genetic profiles of brain metastatic tumors and better predict intracranial tumor responses in non-small cell lung cancer patients with brain metastases: a prospective cohort study (GASTO 1028)Meichen Li0Jing Chen1Baishen Zhang2Juan Yu3Na Wang4Delan Li5Yang Shao6Dongqin Zhu7Chuqiao Liang8Yutong Ma9Qiuxiang Ou10Xue Hou11Likun Chen12Department of Medical OncologyState Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer CenterDepartment of Medical OncologyState Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer CenterDepartment of Medical OncologyState Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer CenterDepartment of Medical OncologyState Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer CenterDepartment of Oncology, The First Affiliated Hospital of Jinan UniversityChemotherapy Department 2, Zhongshan City People’s HospitalSchool of Public Health, Nanjing Medical UniversityNanjing Geneseeq Technology IncNanjing Geneseeq Technology IncNanjing Geneseeq Technology IncNanjing Geneseeq Technology IncDepartment of Medical OncologyState Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer CenterDepartment of Medical OncologyState Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer CenterAbstract Background Due to the blood-brain barrier, plasma is not an ideal source to evaluate the genetic characteristics of central nervous system tumors. Thus, cerebrospinal fluid (CSF) is becoming an alternative biopsy type to evaluate the genetic landscape of intracranial tumors. We aimed to explore the genetic profiles of CSF-derived circulating tumor DNA (ctDNA) to predict intracranial tumor responses and monitor mutational evolution during the treatment of non-small cell lung cancer (NSCLC) patients with brain metastases. Methods We conducted a prospective study of 92 newly diagnosed NSCLC patients with brain metastases. Paired CSF and plasma samples were collected at baseline, 8 weeks after treatment initiation, and disease progression. All samples underwent next-generation sequencing of 425 cancer-related genes. Results At baseline, the positive detection rates of ctDNA in CSF, plasma, and extracranial tumors were 63.7% (58/91), 91.1% (82/90), and 100% (58/58), respectively. A high level of genetic heterogeneity was observed between paired CSF and plasma, while concordance in driver mutations was also observed. A higher number of unique copy number variations was detected in CSF-ctDNA than in plasma. ctDNA positivity of CSF samples at baseline was associated with poor outcomes (HR=2.565, P=0.003). Moreover, patients with ≥ 50% reductions in the concentrations of CSF ctDNA after 8 weeks of treatment had significantly longer intracranial progression-free survivals (PFS) than patients with < 50% reductions in CSF ctDNA concentrations (13.27 months vs 6.13 months, HR=0.308, P=0.017). A ≥ 50% reduction in CSF ctDNA concentrations had better concordance with radiographic intracranial tumor responses than plasma. A ≥ 50% reduction in plasma ctDNA concentrations was also associated with longer extracranial PFS (11.57 months vs 6.20 months, HR=0.406, P=0.033). Based on clonal evolution analyses, the accumulation of subclonal mutations in CSF ctDNA was observed after 8 weeks of treatment. The clonal mutations that remained in more than 80% in CSF after 8 weeks also predicted shorter intracranial PFS (HR=3.785, P=0.039). Conclusions CSF ctDNA exhibited unique genetic profiles of brain metastases, and dynamic changes in CSF ctDNA could better predict intracranial tumor responses and track clonal evolution during treatment in NSCLC patients with brain metastases. Trial registration ClinicalTrials.gov identifier: NCT 03257735.https://doi.org/10.1186/s12916-022-02595-8Cerebrospinal fluidCirculating tumor DNABrain metastasesIntracranial responseClonal evolution |
| spellingShingle | Meichen Li Jing Chen Baishen Zhang Juan Yu Na Wang Delan Li Yang Shao Dongqin Zhu Chuqiao Liang Yutong Ma Qiuxiang Ou Xue Hou Likun Chen Dynamic monitoring of cerebrospinal fluid circulating tumor DNA to identify unique genetic profiles of brain metastatic tumors and better predict intracranial tumor responses in non-small cell lung cancer patients with brain metastases: a prospective cohort study (GASTO 1028) BMC Medicine Cerebrospinal fluid Circulating tumor DNA Brain metastases Intracranial response Clonal evolution |
| title | Dynamic monitoring of cerebrospinal fluid circulating tumor DNA to identify unique genetic profiles of brain metastatic tumors and better predict intracranial tumor responses in non-small cell lung cancer patients with brain metastases: a prospective cohort study (GASTO 1028) |
| title_full | Dynamic monitoring of cerebrospinal fluid circulating tumor DNA to identify unique genetic profiles of brain metastatic tumors and better predict intracranial tumor responses in non-small cell lung cancer patients with brain metastases: a prospective cohort study (GASTO 1028) |
| title_fullStr | Dynamic monitoring of cerebrospinal fluid circulating tumor DNA to identify unique genetic profiles of brain metastatic tumors and better predict intracranial tumor responses in non-small cell lung cancer patients with brain metastases: a prospective cohort study (GASTO 1028) |
| title_full_unstemmed | Dynamic monitoring of cerebrospinal fluid circulating tumor DNA to identify unique genetic profiles of brain metastatic tumors and better predict intracranial tumor responses in non-small cell lung cancer patients with brain metastases: a prospective cohort study (GASTO 1028) |
| title_short | Dynamic monitoring of cerebrospinal fluid circulating tumor DNA to identify unique genetic profiles of brain metastatic tumors and better predict intracranial tumor responses in non-small cell lung cancer patients with brain metastases: a prospective cohort study (GASTO 1028) |
| title_sort | dynamic monitoring of cerebrospinal fluid circulating tumor dna to identify unique genetic profiles of brain metastatic tumors and better predict intracranial tumor responses in non small cell lung cancer patients with brain metastases a prospective cohort study gasto 1028 |
| topic | Cerebrospinal fluid Circulating tumor DNA Brain metastases Intracranial response Clonal evolution |
| url | https://doi.org/10.1186/s12916-022-02595-8 |
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