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. 2021 Jan 16;3(1):vdab011.
doi: 10.1093/noajnl/vdab011. eCollection 2021 Jan-Dec.

Association of plasma cell-free DNA with survival in patients with IDH wild-type glioblastoma

Stephen J Bagley  1   2   3 , Jacob Till  1 , Aseel Abdalla  1 , Hareena K Sangha  1 , Stephanie S Yee  1 , Jake Freedman  4 , Taylor A Black  1 , Jasmin Hussain  5 , Zev A Binder  2   5 , Steven Brem  2   5 , Arati S Desai  1   2   3 , Donald M O'Rourke  2   5 , Qi Long  6 , Seyed Ali Nabavizadeh  2   7 , Erica L Carpenter  1   2   3
Affiliations

Association of plasma cell-free DNA with survival in patients with IDH wild-type glioblastoma

Stephen J Bagley et al. Neurooncol Adv. .

Abstract

Background: We aimed to determine whether plasma cell-free DNA (cfDNA) concentration is associated with survival in patients with isocitrate dehydrogenase (IDH) wild-type glioblastoma (GBM).

Methods: Pre-operative and post-chemoradiotherapy blood samples were prospectively collected from patients with newly diagnosed IDH wild-type GBM. Patients underwent surgical resection or biopsy and received adjuvant radiotherapy with concomitant temozolomide. Cell-free DNA (cfDNA) was isolated from plasma and quantified using SYBR Green-based q polymerase chain reaction (qPCR).

Results: Sixty-two patients were enrolled and categorized into high vs. low cfDNA groups relative to the pre-operative median value (25.2 ng/mL, range 5.7-153.0 ng/mL). High pre-operative cfDNA concentration was associated with inferior PFS (median progression-free survival (PFS), 3.4 vs. 7.7 months; log-rank P = .004; hazard ratio [HR], 2.19; 95% CI, 1.26-3.81) and overall survival (OS) (median OS, 8.0 vs. 13.9 months; log-rank P = .01; HR, 2.43; 95% CI, 1.19-4.95). After adjusting for risk factors, including O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status, pre-operative cfDNA remained independently associated with PFS (HR, 2.70; 95% CI, 1.50-4.83; P = .001) and OS (HR, 2.65; 95% CI, 1.25-5.59; P = .01). Post-hoc analysis of change in cfDNA post-chemoradiotherapy compared to pre-surgery (n = 24) showed increasing cfDNA concentration was associated with worse PFS (median, 2.7 vs. 6.0 months; log-rank P = .003; HR, 4.92; 95% CI, 1.53-15.84) and OS (median, 3.9 vs. 19.4 months; log-rank P < .001; HR, 7.77; 95% CI, 2.17-27.76).

Conclusions: cfDNA concentration is a promising prognostic biomarker for patients with IDH wild-type GBM. Plasma cfDNA can be obtained noninvasively and may enable more accurate estimates of survival and effective clinical trial stratification.

Keywords: cell-free DNA; glioblastoma; liquid biopsy; overall survival; progression-free survival.

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Figures

Figure 1.
Figure 1.
Pre-operative cfDNA concentration is associated with progression-free and overall survival in GBM. Kaplan–Meier survival curves for progression-free survival (A) and overall survival (B) by pre-operative cfDNA concentration. Low vs. high plasma cfDNA designates patients below or above the median pre-operative cfDNA concentration of 25.2 ng/mL, respectively.
Figure 2.
Figure 2.
Pre-operative cfDNA concentration is associated with survival irrespective of MGMT promoter status. Kaplan–Meier survival curves for progression-free survival (A) and overall survival (B) for 25 MGMT promoter methylation positive patients, and for progression-free survival (C) and overall survival (D) for 37 MGMT negative patients. Low vs. high plasma cfDNA designates patients below or above the median pre-operative cfDNA concentration of 25.2 ng/mL, respectively.
Figure 3.
Figure 3.
Change in cfDNA concentration between the pre-surgery and post-chemoradiotherapy time points is associated with both progression-free and overall survival. Kaplan-Meier survival analyses for a post-hoc cohort of 24 patients demonstrates higher progression-free survival (A) and overall survival (B) for patients who experience decreases in their cfDNA concentration from baseline to the post-chemoradiotherapy time point. Progression-free survival and overall survival are defined from the time of the patient’s first post-chemoradiotherapy MRI.
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