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OBJECTIVE: Most recurrent glioblastoma (rGBM) patients do not benefit from immune checkpoint inhibition, emphasizing the necessity for response biomarkers. This study evaluates whether tumor in situ fluid (TISF) circulating tumor DNA (ctDNA) could serve as a biomarker for response to low-dose bevacizumab (Bev) plus anti-PD-1 therapy in rGBM patients, aiming to enhance systemic responses to immunotherapy. METHODS: In this phase II trial, 32 GBM patients with first recurrence after standard therapy were enrolled and then received tislelizumab plus low-dose Bev each cycle. TISF samples were analyzed for ctDNA using a 551-gene panel before each treatment. RESULTS: The median progression-free survival (mPFS) and overall survival (mOS) were 8.2 months (95% CI, 5.2-11.1) and 14.3 months (95% CI, 6.5-22.1), respectively. The 12-month OS was 43.8%, and the objective response rate was 56.3%. Patients with more than 20% reduction in the mutant allele fraction and tumor mutational burden after treatment were significantly associated with better prognosis compared to baseline TISF-ctDNA. Among detectable gene mutations, patients with MUC16 mutation, EGFR mutation & amplification, SRSF2 amplification, and H3F3B amplification were significantly associated with worse prognosis. CONCLUSIONS: Low-dose Bev plus anti-PD-1 therapy significantly improves OS in rGBM patients, offering guiding significance for future individualized treatment strategies. TISF-ctDNA can monitor rGBM patients' response to combination therapy and guide treatment. CLINICAL TRIAL REGISTRATION: This trial is registered with ClinicalTrials.gov, NCT05540275.
Assuntos
Bevacizumab , Neoplasias Encefálicas , DNA Tumoral Circulante , Glioblastoma , Inibidores de Checkpoint Imunológico , Recidiva Local de Neoplasia , Humanos , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Bevacizumab/uso terapêutico , Bevacizumab/administração & dosagem , Feminino , Masculino , Pessoa de Meia-Idade , DNA Tumoral Circulante/genética , DNA Tumoral Circulante/sangue , Inibidores de Checkpoint Imunológico/uso terapêutico , Idoso , Adulto , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/genética , PrognósticoRESUMO
Objective: Tumor in situ fluid (TISF) refers to the fluid within surgical cavities of glioma. Several studies preliminarily proved the value of cell-free tumor DNA (cf-tDNA) from TISF in the dynamic characterization of the glioma genome. Here, we assessed the potential utility of TISF cf-tDNA in broad aspects of tumor evolution under therapeutic pressure. Methods: This study was conducted under an Institutional Review Board-approved protocol at Henan Provincial People's Hospital (China). Cf-tDNA samples were sequenced with a designed 68-gene panel. A total of 205 cf-tDNA samples from 107 patients were studied. The clinical relevance of serial cf-tDNA profiling during the postoperative course was analyzed. Results: At least one tumor mutations were detected in 179/205 (87.3%) TISF cf-tDNA samples. Serial cf-tDNA was complementary to molecular residual disease and to initial tumors. Serial cf-tDNA revealed the selection of pre-existing mismatch repair-deficient cells by temozolomide as a resistant mechanism. Cf-tDNA parameters during treatment were predictive of recurrence, and serial cf-tDNA monitoring had diagnostic value for early recurrence. A total of 223 potentially actionable genomic alterations were assessed in cf-tDNA samples, wherein 78% were not found in any tumor tissue. Conclusions: In conclusion, serial TISF cf-tDNA profiling is valuable in tracking the tumor evolution of glioma during treatment and may be a feasible non-invasive option for monitoring glioma in future prospective studies and clinical practice.
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BACKGROUND: Oligodendroglioma is known for its relatively better prognosis and responsiveness to radiotherapy and chemotherapy. However, little is known about the evolution of genetic changes as oligodendroglioma progresses. METHODS: In this study, we evaluated gene evolution invivo during tumor progression based on deep whole-genome sequencing data (ctDNA). We analyzed longitudinal genomic data from six patients during tumor evolution, of which five patients developed distant recurrence. RESULTS: Whole-exome sequencing demonstrated that the rate of shared mutations between the primary and recurrent samples was relatively low. In two cases, even well-known major driver mutations in CIC and FUBP1 that were detected in primary tumors were not detected in the relapse samples. Among these cases, two patients had a conversion from the IDH mutation in the originating state to the IDH1 wild state during the process of gene evolution under chemotherapy treatment, indicating that the cell phenotype and genetic characteristics of oligodendroglioma may change during tumor evolution. Two patients received long-term temozolomide (TMZ) treatment before the operation, and we found that recurrence tumors harbored mutations in the PI3K/AKT and Sonic hedgehog (SHh) signaling pathways. Hypermutation occurred with mutations in MMR genes in one patient, contributing to the rapid progression of the tumor. CONCLUSION: Oligodendroglioma displayed great spatial and temporal heterogeneity during tumor evolution. The PI3K/AKT and SHh signaling pathways may play an important role in promoting treatment resistance and distant relapse during oligodendroglioma evolution. In addition, there was a tendency to increase the degree of tumor malignancy during evolution. Distant recurrence may be a later event duringoligodendroglioma progression. CLINICALTRIALS: gov, Identifier: NCT05512325.
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Neoplasias Encefálicas , Oligodendroglioma , Humanos , Oligodendroglioma/genética , Oligodendroglioma/terapia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Hedgehog/metabolismo , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Mutação , Genômica , Isocitrato Desidrogenase/genética , Isocitrato Desidrogenase/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a RNA/genéticaRESUMO
The evolutionary trajectories of genomic alterations underlying distant recurrence in glioma remain largely unknown. To elucidate glioma evolution, we analyzed the evolutionary trajectories of matched pairs of primary tumors and relapse tumors or tumor in situ fluid (TISF) based on deep whole-genome sequencing data (ctDNA). We found that MMR gene mutations occurred in the late stage in IDH-mutant glioma during gene evolution, which activates multiple signaling pathways and significantly increases distant recurrence potential. The proneural subtype characterized by PDGFRA amplification was likely prone to hypermutation and distant recurrence following treatment. The classical and mesenchymal subtypes tended to progress locally through subclonal reconstruction, trunk genes transformation, and convergence evolution. EGFR and NOTCH signaling pathways and CDNK2A mutation play an important role in promoting tumor local progression. Glioma subtypes displayed distinct preferred evolutionary patterns. ClinicalTrials.gov, NCT05512325.
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The recurrence of glioma is a difficult problem in clinical treatment. The molecular markers of primary tumors after resection cannot fully represent the characteristics of recurrent tumors. Here, abundant tumor DNA was detected in tumor in situ fluid (TISF). We report that TISF-derived tumor DNA (TISF-DNA) can detect genomic changes in recurrent tumors and facilitate recurrence risk analysis, providing valuable information for diagnosis and prognosis. The tumor DNA in TISF is more representative and sensitive than that in cerebrospinal fluid. It reveals the mutational landscape of minimal residual disease after glioma surgery and the risk of early recurrence, contributing to the clinical management and clinical research of glioma patients.