BIOM-31 - Targeted DNA sequencing of recurrent glioblastoma identifies molecular factors associated with clinical outcomes

Friday, November 17, 2023

7:30 PM – 9:30 PM PT

Location: Exhibit Hall A/B

Poster Presenter(s)

Nadeem N. Al-Adli

University of California, San Francisco
San Francisco, United States

Author(s)

William C. Chen

University of California, San Francisco
San Francisco, California, United States
Jacob S. Young

Department of Neurosurgery & Division of Neuro-Oncology, University of California San Francisco
San Francisco, California, United States
Kanish Mirchia

UCSF
San Francisco, California, United States
ZP

Zain Peeran

University of California San Francisco
San Francisco, California, United States
SB

Steve E. Braunstein

University of California San Francisco
San Francisco, California, United States
Arie Perry

University of California, San Francisco
San Francisco, California, United States
John F. de Groot

University of California, San Francisco
San Francisco, California, United States
David R. Raleigh

University of California, San Francisco
San Francisco, California, United States
Joseph F. Costello

University of California, San Francisco
San Francisco, California, United States
MB

Mitchel S. Berger

University of California, San Francisco
San Francisco, California, United States
Harish N. Vasudevan

UCSF
San Francisco, California, United States

Purpose: The goal of our project was to define the molecular features of recurrent glioblastoma (rGBM) and their prognostic significance.

Methods: We retrospectively reviewed 121 consecutive glioblastoma patients who underwent re-resection at a single institution from 2016-2021. Primary treatment in all patients included maximal safe resection followed by radiotherapy with concurrent and adjuvant temozolomide (TMZ). Capture-based targeted DNA sequencing for point mutations and copy number analysis was performed on all re-resection samples. Overall (OS) and progression-free survival (PFS) from re-resection were analyzed with the Kaplan-Meier method and Cox regression analyses.

Results: Median age at first recurrence was 57 years (range, 27-78) and follow up from re-resection was 11 months. Salvage therapy comprised re-irradiation (n=52, 43%), temozolomide (TMZ) (n=39, 32%), lomustine (n=47, 39%), and/or bevacizumab (n=22, 18%). Median OS and PFS were 12.1 and 4.4 months, respectively. Median tumor mutation burden (TMB) was 4 mut/Mb (range, 1-650), average unstable microsatellite sites (MSI) were 1.16% (range, 0-20), and MGMT was methylated in 71 (59%) patients. Longer OS was found after postoperative TMZ (19.1 vs. 9.1), KPS >70 (13.6 vs. 11.1), and/or re-irradiation (12.6 vs. 8.4) (p < .05). On multivariate analysis, TMZ (HR 0.2, 0.079-0.48), re-irradiation (HR 0.27, 0.12-0.58), and mutations in PDGFRA (HR 0.24, 0.067-0.83) or PTEN (HR 2.3, 1.1-4.8) genes were associated with longer OS after re-resection (p < .05). Multivariate predictors of re-irradiation response included MSI > 1.16 (HR 0.25, 0.084-0.75), and mutations in PDGFRA (HR 0.04, 0.005-0.33), TERT (HR 0.16, 0.033-0.78), or PIK3R1 (HR 0.18, 0.041-0.8) genes. In the 46 matched primary/recurrent tumors, 40 (87%%) had a change in a mutation and 9 (20%) demonstrated hypermutation, of which 4 (44%) had mismatch repair deficiencies.

Conclusions: Our study outlines the molecular factors associated with survival and response to re-irradiation in rGBM as well as, the molecular differences between primary/recurrent samples.