title: Detection of T790M, the Acquired Resistance EGFR Mutation, by Tumor Biopsy versus Noninvasive Blood-Based Analyses.
abstract: OBJECTIVE
  The T790M gatekeeper mutation in the EGFR is acquired by some EGFR-mutant non-small cell lung cancers (NSCLC) as they become resistant to selective tyrosine kinase inhibitors (TKI). As third-generation EGFR TKIs that overcome T790M-associated resistance become available, noninvasive approaches to T790M detection will become critical to guide management.
  
  
  METHODS
  As part of a multi-institutional Stand-Up-To-Cancer collaboration, we performed an exploratory analysis of 40 patients with EGFR-mutant tumors progressing on EGFR TKI therapy. We compared the T790M genotype from tumor biopsies with analysis of simultaneously collected circulating tumor cells (CTC) and circulating tumor DNA (ctDNA).
  
  
  RESULTS
  T790M genotypes were successfully obtained in 30 (75%) tumor biopsies, 28 (70%) CTC samples, and 32 (80%) ctDNA samples. The resistance-associated mutation was detected in 47% to 50% of patients using each of the genotyping assays, with concordance among them ranging from 57% to 74%. Although CTC- and ctDNA-based genotyping were each unsuccessful in 20% to 30% of cases, the two assays together enabled genotyping in all patients with an available blood sample, and they identified the T790M mutation in 14 (35%) patients in whom the concurrent biopsy was negative or indeterminate.
  
  
  CONCLUSIONS
  Discordant genotypes between tumor biopsy and blood-based analyses may result from technological differences, as well as sampling different tumor cell populations. The use of complementary approaches may provide the most complete assessment of each patient's cancer, which should be validated in predicting response to T790M-targeted inhibitors.
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, Massachusetts. Department of Medicine, Harvard Medical School, Boston, Massachusetts.
authors.forename: Tilak K
authors.initials: TK
authors.lastname: Sundaresan
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, Massachusetts. Department of Medicine, Harvard Medical School, Boston, Massachusetts.
authors.forename: Lecia V
authors.initials: LV
authors.lastname: Sequist
authors.affiliation: Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: John V
authors.initials: JV
authors.lastname: Heymach
authors.affiliation: Department of Medicine, Thoracic Oncology Service, Division of Solid Tumor Oncology, Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College, New York, New York.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Riely
authors.affiliation: Department of Medicine, Harvard Medical School, Boston, Massachusetts. Lowe Center for Thoracic Oncology and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Pasi A
authors.initials: PA
authors.lastname: Jänne
authors.affiliation: Roche Molecular Systems, Inc., Pleasanton, California.
authors.forename: Walter H
authors.initials: WH
authors.lastname: Koch
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, Massachusetts. Department of Medicine, Harvard Medical School, Boston, Massachusetts.
authors.forename: James P
authors.initials: JP
authors.lastname: Sullivan
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, Massachusetts. Department of Medicine, Harvard Medical School, Boston, Massachusetts.
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Fox
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, Massachusetts. Department of Medicine, Harvard Medical School, Boston, Massachusetts.
authors.forename: Robert
authors.initials: R
authors.lastname: Maher
authors.affiliation: MGH Biostatistics Center, Boston, Massachusetts.
authors.forename: Alona
authors.initials: A
authors.lastname: Muzikansky
authors.affiliation: EKF Molecular Diagnostics, Ltd., Cardiff, United Kingdom.
authors.forename: Andrew
authors.initials: A
authors.lastname: Webb
authors.affiliation: Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Hai T
authors.initials: HT
authors.lastname: Tran
authors.affiliation: Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Uma
authors.initials: U
authors.lastname: Giri
authors.affiliation: Clinical Chemistry Service, Department of Laboratory Medicine, Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College, New York, New York.
authors.forename: Martin
authors.initials: M
authors.lastname: Fleisher
authors.affiliation: Department of Medicine, Thoracic Oncology Service, Division of Solid Tumor Oncology, Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College, New York, New York.
authors.forename: Helena A
authors.initials: HA
authors.lastname: Yu
authors.affiliation: Roche Molecular Systems, Inc., Pleasanton, California.
authors.forename: Wen
authors.initials: W
authors.lastname: Wei
authors.affiliation: Department of Medicine, Harvard Medical School, Boston, Massachusetts. Lowe Center for Thoracic Oncology and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Johnson
authors.affiliation: BioMEMS Resource Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Barber
authors.affiliation: BioMEMS Resource Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts.
authors.forename: John R
authors.initials: JR
authors.lastname: Walsh
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, Massachusetts. Department of Medicine, Harvard Medical School, Boston, Massachusetts.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Engelman
authors.affiliation: Department of Medicine, Harvard Medical School, Boston, Massachusetts. BioMEMS Resource Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts.
authors.forename: Shannon L
authors.initials: SL
authors.lastname: Stott
authors.affiliation: BioMEMS Resource Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts.
authors.forename: Ravi
authors.initials: R
authors.lastname: Kapur
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, Massachusetts. Department of Surgery, Harvard Medical School, Boston, Massachusetts.
authors.forename: Shyamala
authors.initials: S
authors.lastname: Maheswaran
authors.affiliation: BioMEMS Resource Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts. Department of Surgery, Harvard Medical School, Boston, Massachusetts.
authors.forename: Mehmet
authors.initials: M
authors.lastname: Toner
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, Massachusetts. Department of Medicine, Harvard Medical School, Boston, Massachusetts. Howard Hughes Medical Institute, Chevy Chase, Maryland. Haber@helix.mgh.harvard.edu.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Haber
mesh_terms: D000328:Adult; D000077716:Afatinib; D000368:Aged; D000369:Aged, 80 and over; D001706:Biopsy; D002289:Carcinoma, Non-Small-Cell Lung / Q000097:blood / Q000235:genetics* / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D066246:ErbB Receptors / Q000097:blood / Q000235:genetics*; D000069347:Erlotinib Hydrochloride / Q000008:administration & dosage; D005260:Female; D000077156:Gefitinib; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009360:Neoplastic Cells, Circulating / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D011799:Quinazolines / Q000008:administration & dosage
chemical_list: D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000077716:Afatinib; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors; D000077156:Gefitinib