ACTR-52. CLINICAL IMPACT OF TERT PROMOTER DETECTION IN CIRCULATING CELL-FREE DNA OF PATIENTS WITH GLIOBLASTOMA – A PILOT STUDY

Abstract

BACKGROUND

Detection of circulating cell-free tumor-derived DNA (cfDNA) has been shown to be of clinical value in monitoring cancer treatment. Having in mind that somatic TERT promoter (TERTp) mutations are clonal and frequent in IDH-wild-type glioblastoma (GBM), we conducted a pilot study to assess the clinical impact of TERTp-mutant cfDNA detection in CSF and plasma in GBM patient.

METHODS

A total of 30 GBM patients were prospectively enrolled. Matched plasma and CSF samples were collected before tumor resection in all patients. Using the IonTorrent PGM semiconductor sequencing platform, we analyzed the collected cfDNA and matched tumor DNA samples for hotspot mutations in the promoter region of TERT (C228 and C250). Logistic regression analysis was performed to evaluate the clinical impact of the variant allele frequency (VAF) of TERTp-mutant cfDNA in predicting patients’ overall (OS) and progression-free (PFS) survival.

RESULTS

25 patients had a TERTp-mutant GBM. The matched TERTp-CSF-derived cfDNA was successfully detected with 100% specificity and 92% sensitivity (23 patients). The median VAF of the CSF-cfDNA was 20.3% (0.08%-70.3%). In the plasma, the sensitivity of TERTp-mutant cfDNA detection was far lower (12%). There was a statistically significant linear relationship between the CSF-VAFs and PFS (R² = 0.1615; p=0.0418). Strikingly, in the multivariate analysis, the median VAF for CSF-cfDNA was the best predictor for PFS (p=0.007, HR=4.1, 95% CI: 1.4–11.3) and OS (p=0.013, HR=4.7, 95% CI: 1.3–15.8). In contrast, all other included clinical parameters (age, tumor volume, extent of resection, MGMT promoter methylation status) did not appear as an independent prognostic factor.

CONCLUSIONS

We propose that the detection and accurate quantification of TERTp-mutant CSF-cfDNA in GBM patients is feasible with a high sensitivity and specificity. Additionally, although generated on a small cohort, our findings indicate that pre-resection CSF-derived cfDNA might be a suitable marker to predict survival in TERTp-mutant GBM patients.