title: Mutant allele frequency predicts the efficacy of EGFR-TKIs in lung adenocarcinoma harboring the L858R mutation.
abstract: BACKGROUND
  Whether the mutant allele frequency (MAF) may also have predictive implications for tyrosine kinase inhibitor (TKI) therapy in patients with advanced epidermal growth factor receptor (EGFR)-mutated lung adenocarcinoma (AELAd) remains unknown.
  
  
  METHODS
  Based on a biobanking system in conjunction with our institution, we assessed EGFR mutation status using pyrosequencing (Py) and by outsourcing laboratory tests, such as the Cycleave (Cy) and the Scorpion ARMS (A).
  
  
  RESULTS
  Out of 705 patients enrolled in the Shizuoka Lung Cancer Mutation Study between July 2011 and March 2013, 102 AELAd patients were identified as carrying the L858R mutation (L858Rm) using Py to analyze histological specimens. Of these 102 patients, the EGFR mutation status was assessed using both Py and Cy in 48 patients: the median MAF of L858R (MAFLR) was 18.5% (range: 8%-82%), and 45 patients (94%) were identified as having an L858Rm using both Py and Cy. Three patients (6%) with discrepant L858Rm findings were only identified using Py. The plotting of a receiver operating characteristic curve to identify the discordance in L858Rm findings showed that the area under the curve for MAFLR was 0.967 (95% confidence interval: 0.91-1) and that an MAFLR of 9% resulted in high sensitivity (100%) and specificity (99%). Also, 29 patients with AELAd, excluding those with postoperative recurrences, had their L858R status assessed using Cy or A. The median age, 69 years (range: 47-84 years); male/female, 14 (48%)/15 (52%); smokers/never-smokers 13 (45%)/16 (55%); ECOG PS 0-1/2-3, 26 (90%)/3 (10%); stage IIIB/IV, 4 (14%)/25 (86%); median MAFLR, 18% (range: 8%-63%). Patients with an MAFLR of ≤9% had a significantly shorter progression-free survival (PFS) period after TKI therapy than those with an MAFLR of >9% (mPFS: 92 versus 284 days, P = 0.0027).
  
  
  CONCLUSIONS
  The MAF may be a potential predictive factor of TKI treatment efficacy in patients with AELAd carrying the L858Rm.
authors.affiliation: Division of Thoracic Oncology, Shizuoka Cancer Center, Shizuoka, Japan. Electronic address: a.ono@scchr.jp.
authors.forename: A
authors.initials: A
authors.lastname: Ono
authors.affiliation: Division of Thoracic Oncology, Shizuoka Cancer Center, Shizuoka, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Kenmotsu
authors.affiliation: Division of Drug Discovery and Development, Shizuoka Cancer Center Research Institute, Shizuoka, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Watanabe
authors.affiliation: Division of Drug Discovery and Development, Shizuoka Cancer Center Research Institute, Shizuoka, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Serizawa
authors.affiliation: Clinical Trial Coordination Office, Shizuoka Cancer Center, Shizuoka, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Mori
authors.affiliation: Division of Thoracic Oncology, Shizuoka Cancer Center, Shizuoka, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Imai
authors.affiliation: Division of Thoracic Oncology, Shizuoka Cancer Center, Shizuoka, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Taira
authors.affiliation: Division of Thoracic Oncology, Shizuoka Cancer Center, Shizuoka, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Naito
authors.affiliation: Division of Thoracic Oncology, Shizuoka Cancer Center, Shizuoka, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Murakami
authors.affiliation: Division of Diagnostic Pathology, Shizuoka Cancer Center, Shizuoka, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Nakajima
authors.affiliation: Division of Thoracic Surgery, Shizuoka Cancer Center, Shizuoka, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Ohde
authors.affiliation: Division of Diagnostic Radiology, Shizuoka Cancer Center, Shizuoka, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Endo
authors.affiliation: Third Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Yamamoto
authors.affiliation: Division of Drug Discovery and Development, Shizuoka Cancer Center Research Institute, Shizuoka, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Koh
authors.affiliation: Division of Thoracic Oncology, Shizuoka Cancer Center, Shizuoka, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Takahashi
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000368:Aged; D000369:Aged, 80 and over; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D018740:Genetic Heterogeneity; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects
chemical_list: D047428:Protein Kinase Inhibitors; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: EGFR mutation burden; EGFR-TKI; L858R; lung adenocarcinoma; mutant allele frequency; tumor heterogeneity