Mutant allele frequency predicts the efficacy of EGFR-TKIs in lung adenocarcinoma harboring the L858R mutation

Ann Oncol. 2014 Oct;25(10):1948-1953. doi: 10.1093/annonc/mdu251. Epub 2014 Jul 9.


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.

Patients and 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).

Conclusion: The MAF may be a potential predictive factor of TKI treatment efficacy in patients with AELAd carrying the L858Rm.

Keywords: EGFR mutation burden; EGFR-TKI; L858R; lung adenocarcinoma; mutant allele frequency; tumor heterogeneity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / drug therapy*
  • Adenocarcinoma / genetics*
  • Adenocarcinoma / pathology
  • Adenocarcinoma of Lung
  • Aged
  • Aged, 80 and over
  • Disease-Free Survival
  • ErbB Receptors / genetics*
  • Female
  • Gene Frequency
  • Genetic Heterogeneity
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / pathology
  • Male
  • Middle Aged
  • Mutation
  • Prognosis
  • Protein Kinase Inhibitors / administration & dosage*
  • Protein Kinase Inhibitors / adverse effects


  • Protein Kinase Inhibitors
  • EGFR protein, human
  • ErbB Receptors