title: Clinical utility and treatment outcome of comprehensive genomic profiling in high grade glioma patients.
abstract: Genomic research of high grade glioma (HGG) has revealed complex biology with potential for therapeutic impact. However, the utilization of this information and impact upon patient outcome has yet to be assessed. We performed capture-based next generation sequencing (NGS) genomic analysis assay of 236/315 cancer-associated genes, with average depth of over 1000 fold, to guide treatment in HGG patients. We reviewed clinical utility and response rates in correlation to NGS results. Forty-three patients were profiled: 34 glioblastomas, 8 anaplastic astrocytomas, and one patient with anaplastic oligodendroglioma. Twenty-five patients were profiled with the 315 gene panel. The median number of identified genomic alterations (GAs) per patient was 4.5 (range 1-23). In 41 patients (95 %) at least one therapeutically-actionable GA was detected, most commonly in EGFR [17 (40 %)]. Genotype-directed treatments were prescribed in 13 patients, representing a 30 % treatment decision impact. Treatment with targeted agents included everolimus as a single agent and in combination with erlotinib; erlotinib; afatinib; palbociclib; trametinib and BGJ398. Treatments targeted various genomic findings including EGFR alterations, mTOR activation, cell cycle targets and FGFR1 mutations. None of the patients showed response to respective biologic treatments. In this group of patients with HGG, NGS revealed a high frequency of GAs that lead to targeted treatment in 30 % of the patients. The lack of response suggests that further study of mechanisms of resistance in HGG is warranted before routine use of biologically-targeted agents based on NGS results.
authors.affiliation: Division of Oncology, Neuro-Oncology Service, Tel Aviv Sourasky Medical Center, 6 Weizman Street, 64239, Tel Aviv, Israel. deborahblumenthal@gmail.com.|Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. deborahblumenthal@gmail.com.
authors.forename: Deborah T
authors.initials: DT
authors.lastname: Blumenthal
authors.affiliation: Oncotest-Teva Pharmaceuticals, Petah Tikva, Israel.
authors.forename: Addie
authors.initials: A
authors.lastname: Dvir
authors.affiliation: Department of Oncology, Leslie and Michael Gaffin Center for Neuro-Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Alexander
authors.initials: A
authors.lastname: Lossos
authors.affiliation: Department of Oncology, Rambam Health Care Campus, Haifa, Israel.
authors.forename: Tzahala
authors.initials: T
authors.lastname: Tzuk-Shina
authors.affiliation: Oncology Institute, Chaim Sheba Medical Center, Tel Hashomer, Israel.
authors.forename: Tzach
authors.initials: T
authors.lastname: Lior
authors.affiliation: Oncology Institute, Davidoff Center, Rabin Medical Center, Petah Tikva, Israel.
authors.forename: Dror
authors.initials: D
authors.lastname: Limon
authors.affiliation: Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.|Oncology Institute, Davidoff Center, Rabin Medical Center, Petah Tikva, Israel.
authors.forename: Shlomit
authors.initials: S
authors.lastname: Yust-Katz
authors.affiliation: Department of Oncology, Rambam Health Care Campus, Haifa, Israel.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Lokiec
authors.affiliation: Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.|Department of Neurosurgery, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
authors.forename: Zvi
authors.initials: Z
authors.lastname: Ram
authors.affiliation: Foundation Medicine, Cambridge, MA, USA.|Albany Medical College, Albany, NY, USA.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Ross
authors.affiliation: Foundation Medicine, Cambridge, MA, USA.
authors.forename: Siraj M
authors.initials: SM
authors.lastname: Ali
authors.affiliation: Oncotest-Teva Pharmaceuticals, Petah Tikva, Israel.
authors.forename: Roi
authors.initials: R
authors.lastname: Yair
authors.affiliation: Oncotest-Teva Pharmaceuticals, Petah Tikva, Israel.
authors.forename: Lior
authors.initials: L
authors.lastname: Soussan-Gutman
authors.affiliation: Division of Oncology, Neuro-Oncology Service, Tel Aviv Sourasky Medical Center, 6 Weizman Street, 64239, Tel Aviv, Israel.|Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Felix
authors.initials: F
authors.lastname: Bokstein
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics*; D015331:Cohort Studies; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D000069347:Erlotinib Hydrochloride / Q000627:therapeutic use; D000068338:Everolimus / Q000627:therapeutic use; D005260:Female; D023281:Genomics / Q000379:methods*; D005910:Glioma / Q000188:drug therapy / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D015398:Signal Transduction / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D000068338:Everolimus; D000069347:Erlotinib Hydrochloride; C546842:MTOR protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors; D058570:TOR Serine-Threonine Kinases
keywords: Astrocytoma; Glioblastoma; High grade glioma; Massively-parallel sequencing; Targeted molecular therapy