CTNI-59 - Rare and novel KIAA1549-BRAF fusion breakpoints predict poor clinical outcome for patients with recurrent or progressive pediatric low-grade glioma: phase II PNOC001 trial results.

Friday, November 17, 2023

7:30 PM – 9:30 PM PT

Location: Exhibit Hall A/B

Poster Presenter(s)

Sebastian M. Waszak

École Polytechnique Fédérale de Lausanne (EPFL)
Lausanne, Vaud, Switzerland

Author(s)

Mariam Aboian

Yale School of Medicine
New Haven, Connecticut, United States
JM

Jane Minturn

Children’s Hospital of Philadelphia
Philadelphia, Pennsylvania, United States
Sarah E. S. Leary

Cancer and Blood Disorders Center, Seattle Children's
Seattle, Washington, United States
MA

Mohamed S. S. Abdelbaki

St. Louis Children's Hospital (NCH)
St. Louis, Missouri, United States
SG

Stewart Goldman

University of Arizona
Phoenix, United States
JE

Jennifer Elster

University of California, San Diego
San Diego, California, United States
AK

Adam Kraya

Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States
ML

Matthew Lueder

Children’s Hospital of Philadelphia
Philadelphia, United States
DR

Divya Ramakrishnan

Department of Radiology and Biomedical Imaging, Yale School of Medicine
New Haven, United States
Mv

Marc von Reppert

Department of Radiology and Biomedical Imaging, Yale School of Medicine
New Haven, United States
KL

Kevin Liu

Brigham and Women's Hospital, Dana-Farber Cancer Institute, Boston Children's Hospital
Boston, United States
AR

Adam Resnick

Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States
David A. Solomon

University of California, San Francisco
San Francisco, California, United States
Annette M. Molinaro

University of California, San Francisco
San Francisco, California, United States
Joanna J. Phillips

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

Michael Prados

University of California, San Francisco
San Francisco, California, United States
Daphne Haas-Kogan

Brigham and Women's Hospital, Dana-Farber Cancer Institute, Boston Children's Hospital
Boston, Massachusetts, United States
Sabine Mueller

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

Objectives: PNOC001 sought to estimate progression-free survival (PFS) associated with everolimus for progressive/recurrent pediatric low-grade glioma (pLGG) and to determine if activated PI3K/AKT/mTOR pathway as measured by positive phosphorylated-ribosomal protein S6 (p-RPS6) was associated with response. A secondary objective was to assess whether somatic drivers influence median PFS.

Methods: Patients, 3-21 years of age, with recurrent/progressive pLGG received everolimus orally at 5 mg/m2 daily. Somatic drivers, when available, were associated with PFS and compared to four independent molecular pLGG cohorts with newly-diagnosed and progressive/recurrent patients.

Results: From 2012 to 2019, 65 subjects enrolled [median age 9.6 years, 3.0-19.9; 46% female]; Median PFS for all-comers was 11.1 months (95%-CI 7.6-19.8, n=64). PFS was not modulated by PI3K/AKT/mTOR pathway activation (median PFS 11.2 vs 9.4 months, P=0.83, n=62). BRAF alterations were identified in 67.8% (40/59) of patients. Rare/novel KIAA1549-BRAF fusion breakpoints were enriched in PNOC001 compared to newly-diagnosed pLGGs in independent cohorts (28.6% vs 2.6%, P=1.4e-4, n=214). In PNOC001, patients with rare/novel KIAA1549-BRAF fusion breakpoints had worse clinical outcomes than patients with common fusion breakpoints (median PFS 6.1 vs 16.7 months, P< 0.05, n=20). Rare/novel KIAA1549-BRAF fusion breakpoints were also enriched in patients with progressive/recurrent disease in independent pLGG cohorts (17.6% vs 2.6%, P=2e-3, n=227). Integration of BRAF alterations and DNA methylation-based tumor subtypes further revealed that rare/novel KIAA1549-BRAF fusion breakpoints are more frequent in supratentorial midline (14.1%) compared to infratentorial (2.0%) pilocytic astrocytomas (P=1e-4). KIAA1549-BRAF fusion breakpoints remained risk factors for progressive/recurrent disease in PNOC001 (P=0.05) and independent pLGG cohorts (P < 0.05) after accounting for tumor location and DNA methylation subtypes.

Conclusions: Rare/novel KIAA1549-BRAF fusion breakpoints are more frequent in supratentorial midline pLGGs and define independent genomic risk factors for disease progression/recurrence. Our results indicate that future clinical trials must interrogate and define KIAA1549-BRAF fusion breakpoints for informative results and conclusions.