title: Role of Genomic Instability in Immunotherapy with Checkpoint Inhibitors.
abstract: OBJECTIVE
  We evaluated whether tumor genome sequencing to detect the number and type of alterations could be used as a valuable biomarker for judging the potential utility of immune checkpoint inhibitors in patients with advanced cancers.
  
  
  METHODS
  We identified patients with solid tumors who were treated with checkpoint inibitors and had received commercially available next generation sequencing (NGS). Tumors profiled by Caris Life Sciences, Foundation Medicine and Guardant360 between 2013 and 2015. Patients were divided into 5 quintiles based on mutational load (pathogenic mutations plus variants of undetermined significance).
  
  
  RESULTS
  Fifty patients with solid tumors on immunotherapy that had NGS reports available were identified. Top quintile patients had more genomic alterations (median=16.5) than the others (median=2) and had more pathogenic mutations in cell-cycle regulatory genes (100% versus 48%). The overall survival (OS) was significantly superior for patients in the top quintile (722 days) versus the others (432 days). We found no significant difference in progression-free survival (PFS) between the two groups. The objective response rate was numerically higher for the top quintile (50%) vs. others (20%). Programmed cell death protein 1 (PD1) and programmed death-ligand 1 (PDL1) status by immunohistochemistry was not associated with outcomes.
  
  
  CONCLUSIONS
  The use of immune checkpoint blockade in tumors with higher mutational load was associated with improved OS. Our results suggest that the evaluation of tumor genomes may be predictive of immunotherapy benefit.
authors.affiliation: Department of Hematology/Oncology, The West Cancer Center, The University of Tennessee Health Science Center, Memphis, TN, U.S.A. gyaghmour@westclinic.com.
authors.forename: George
authors.initials: G
authors.lastname: Yaghmour
authors.affiliation: Department of Hematology/Oncology, The West Cancer Center, The University of Tennessee Health Science Center, Memphis, TN, U.S.A.
authors.forename: Manjari
authors.initials: M
authors.lastname: Pandey
authors.affiliation: Department of Internal Medicine, The West Cancer Center, The University of Tennessee Health Science Center, Memphis, TN, U.S.A.
authors.forename: Catherine
authors.initials: C
authors.lastname: Ireland
authors.affiliation: Department of Internal Medicine, The West Cancer Center, The University of Tennessee Health Science Center, Memphis, TN, U.S.A.
authors.forename: Kruti
authors.initials: K
authors.lastname: Patel
authors.affiliation: Department of Internal Medicine, The West Cancer Center, The University of Tennessee Health Science Center, Memphis, TN, U.S.A.
authors.forename: Sara
authors.initials: S
authors.lastname: Nunnery
authors.affiliation: Department of Oncologic Radiology, The West Cancer Center, The University of Tennessee Health Science Center, Memphis, TN, U.S.A.
authors.forename: Daniel
authors.initials: D
authors.lastname: Powell
authors.affiliation: Department of Oncologic Radiology, The West Cancer Center, The University of Tennessee Health Science Center, Memphis, TN, U.S.A.
authors.forename: Scott
authors.initials: S
authors.lastname: Baum
authors.affiliation: Department of Hematology/Oncology, The West Cancer Center, The University of Tennessee Health Science Center, Memphis, TN, U.S.A.
authors.forename: Eric
authors.initials: E
authors.lastname: Wiedower
authors.affiliation: Department of Hematology/Oncology, The West Cancer Center, The University of Tennessee Health Science Center, Memphis, TN, U.S.A.
authors.forename: Lee S
authors.initials: LS
authors.lastname: Schwartzberg
authors.affiliation: Department of Hematology/Oncology, The West Cancer Center, The University of Tennessee Health Science Center, Memphis, TN, U.S.A.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Martin
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D060890:B7-H1 Antigen / Q000096:biosynthesis* / Q000235:genetics; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D042822:Genomic Instability / Q000235:genetics / Q000276:immunology; D059014:High-Throughput Nucleotide Sequencing; D000080905:Homeobox A10 Proteins; D018398:Homeodomain Proteins / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D007167:Immunotherapy; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D009369:Neoplasms / Q000235:genetics* / Q000276:immunology* / Q000473:pathology / Q000628:therapy
chemical_list: D060890:B7-H1 Antigen; C423236:CD274 protein, human; D000080905:Homeobox A10 Proteins; D018398:Homeodomain Proteins; D009363:Neoplasm Proteins; C069634:HOXA10 protein, human
keywords: Immunotherapy; PD1; PDL1; genomic instability; next generation sequencing