Abstract Details

Title Clinical and Molecular Features of a Prospectively-Sequenced Cohort of Glioblastoma Patients with Inherited Disorders in Mismatch Repair

Topic Neuro-oncology

Presentation(s) S16 - Neuro-oncology (4:40 PM-4:48 PM)

Poster/Presentation
Number 005

Background Inherited MMR gene mutations predispose to various cancers including glioma. Heterozygous mutations result in Lynch syndrome (LS) and homozygous mutations cause constitutional mismatch repair deficiency (CMMRD). PDL1 inhibitors are thought to have activity in hypermutated tumors regardless of histology.

Objective To characterize a cohort with glioblastoma and deficiencies in mismatch repair (MMR).

Design/Methods 384 patients with primary CNS tumors were prospectively consented to next generation sequencing (NGS) of their tumor via the MSK-IMPACT platform from 1/2015 to 5/2019. We identified 7 patients (1.8%) with germline inactivating mutations in MSH2, MSH6, MLH1, or PMS2. We separately interrogated a genetic database and identified an additional patient with FoundationOne NGS and another with inadequate tissue for NGS.

Results All patients had glioblastoma (8 IDH-wildtype, 1 IDH-mutant) diagnosed at a median age of 33.6 years in 7 patients with LS and 19.9 years in 2 patients with CMMRD. 6 tumors (75%) were hypermutated (≥10 Mut/Mb) with either microsatellite instability or MMR deficiency by immunohistochemistry. 2 tumors (25%) were non-hypermutated, microsatellite stable, and harbored the constellation of chromosome 7/10 alteration, EGFR amplification, and TERT promoter mutation. These molecular hallmarks of glioblastoma were not found in the hypermutated tumors. One patient’s tumor presented during treatment with nivolumab for ovarian cancer, 3 patients received pembrolizumab for recurrent hypermutated glioblastoma for an average of 2.5 months, and 2 patients received pembrolizumab for recurrent non-hypermutated glioblastoma for an average of 10.1 months. Median survival in the cohort was 39.3 months; there was a higher proportion of long-term survivors (2YS 71%, 5YS 33%, 10YS 33%) compared to a traditional glioblastoma population.

Conclusions Germline defects in mismatch repair account for 1.8% of primary CNS tumors in our cohort; these patients may have better prognoses. Hypermutated glioblastoma exhibiting MMR deficiency were not found to have molecular hallmarks of glioblastoma and had limited benefit from PDL1 blockade.

Authors/Disclosures
Kevin Elmore, MD (Mount Sinai Hospital) PRESENTER	Dr. Elmore has nothing to disclose.
	No disclosure on file
Anna Piotrowski, MD (Memorial Sloan Kettering Cancer Center)	Dr. Piotrowski has nothing to disclose.
Lauren Schaff, MD (Memorial Sloan Kettering Cancer Center)	Dr. Schaff has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Guidepoint. Dr. Schaff has received personal compensation in the range of $500-$4,999 for serving as a Consultant for ONO. Dr. Schaff has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for BTG Pharmaceuticals. Dr. Schaff has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Servier. An immediate family member of Dr. Schaff has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for MichieHamlett Attorneys at Law. The institution of Dr. Schaff has received research support from BTG, plc. The institution of Dr. Schaff has received research support from Merck. The institution of Dr. Schaff has received research support from DebioPharm.
Igor T. Gavrilovic, MD (Memorial Sloan Kettering Cancer Center)	Dr. Gavrilovic has nothing to disclose.
Jacqueline Stone, MD (Memorial Sloan-Kettering Cancer Center)	Dr. Stone has nothing to disclose.
	No disclosure on file
Viviane Tabar	No disclosure on file
Ingo K. Mellinghoff, MD, FACP (Memorial Sloan Kettering Cancer Center)	Dr. Mellinghoff has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Agios. Dr. Mellinghoff has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Black Diamond Therapeutics. Dr. Mellinghoff has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Voyager Therapeutics . Dr. Mellinghoff has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Kazia Therapeutics. Dr. Mellinghoff has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Servier . Dr. Mellinghoff has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Agios. Dr. Mellinghoff has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Black Diamond Therapeutics. Dr. Mellinghoff has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Debiopharm Group. Dr. Mellinghoff has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Puma Biotechnology. Dr. Mellinghoff has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Voyager Therapeutics. Dr. Mellinghoff has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for DC Europa Ltd. Dr. Mellinghoff has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Kazia Therapeutics. Dr. Mellinghoff has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis . Dr. Mellinghoff has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Cardinal Health. Dr. Mellinghoff has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Servier . Dr. Mellinghoff has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for ASCO/JCO. The institution of Dr. Mellinghoff has received research support from Amgen. The institution of Dr. Mellinghoff has received research support from General Electric. The institution of Dr. Mellinghoff has received research support from Lilly. The institution of Dr. Mellinghoff has received research support from Kazia Therapeutics. An immediate family member of Dr. Mellinghoff has received research support from Vigeo Therapeutics. The institution of an immediate family member of Dr. Mellinghoff has received research support from Samus Therapeutics. The institution of Dr. Mellinghoff has received research support from Erasca .
Tejus Bale (MSKCC)	No disclosure on file
Andrew L. Lin, MD (Memorial Sloan Kettering Cancer Center)	The institution of Dr. Lin has received research support from Bristol Myers Squibb. The institution of Dr. Lin has received research support from NantOmics. The institution of Dr. Lin has received research support from Society of Memorial Sloan Kettering Cancer Center.