title: EGFR mutation detection in circulating cell-free DNA of lung adenocarcinoma patients: analysis of LUX-Lung 3 and 6.
abstract: BACKGROUND
  In the Phase III LUX-Lung 3/6 (LL3/LL6) trials in epidermal growth factor receptor (EGFR) mutation-positive lung adenocarcinoma patients, we evaluated feasibility of EGFR mutation detection using circulating cell-free DNA (cfDNA) and prognostic and predictive utility of cfDNA positivity (cfDNA+).
  
  
  METHODS
  Paired tumour and blood samples were prospectively collected from randomised patients. Mutations were detected using cfDNA from serum (LL3) or plasma (LL6) by a validated allele-specific quantitative real-time PCR kit.
  
  
  RESULTS
  EGFR mutation detection rates in cfDNA were 28.6% (serum) and 60.5% (plasma). Mutation detection in blood was associated with advanced disease characteristics, including higher performance score, number of metastatic sites and bone/liver metastases, and poorer prognosis. In patients with common EGFR mutations, afatinib improved progression-free survival vs chemotherapy in cfDNA+ (LL3: HR, 0.35; P=0.0009; LL6: HR, 0.25; P<0.0001) and cfDNA- (LL3: HR, 0.46; P<0.0001; LL6: HR, 0.12; P<0.0001) cohorts. A trend towards overall survival benefit with afatinib was observed in cfDNA+ patients.
  
  
  CONCLUSIONS
  Plasma cfDNA is a promising alternative to biopsy for EGFR testing. Detectable mutation in blood was associated with more advanced disease and poorer prognosis. Afatinib improved outcomes in EGFR mutation-positive patients regardless of blood mutation status.
authors.affiliation: Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, 106 Zhongshan 2nd Road, Guangzhou 510080, China.
authors.forename: Yi-Long
authors.initials: YL
authors.lastname: Wu
authors.affiliation: Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA.
authors.forename: Lecia V
authors.initials: LV
authors.lastname: Sequist
authors.affiliation: Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan 410018, China.
authors.forename: Cheng-Ping
authors.initials: CP
authors.lastname: Hu
authors.affiliation: Jiangsu Provincial Tumor Hospital, 42 Baiziting, Xuanwu, Nanjing, Jiangsu 210009, China.
authors.forename: Jifeng
authors.initials: J
authors.lastname: Feng
authors.affiliation: Shanghai Lung Tumor Clinical Medical Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, 241 Huaihai West Road, Xuhui, Shanghai 200030, China.
authors.forename: Shun
authors.initials: S
authors.lastname: Lu
authors.affiliation: Yunnan Tumor Hospital (The Third Affiliated Hospital of Kunming Medical University), Xingjie Alley, Xishan, Kunming, Yunnan, China.
authors.forename: Yunchao
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Cancer Center, First Hospital of Jilin University, 71 Xinmin Street, Changchun, 130021, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: West China Hospital, Sichuan University, 24 South Section 1, Yihuan Road, Chengdu, 610065, China.
authors.forename: Mei
authors.initials: M
authors.lastname: Hou
authors.affiliation: West German Cancer Center, University Duisburg-Essen, Hufelandstraße 55, Essen 45147, Germany.|German Cancer Consortium (DKTK), Partner Site University Hospital Essen, Essen 45147, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Schuler
authors.affiliation: The Chinese University of Hong Kong, Shatin, NT, Hong Kong SAR, China.
authors.forename: Tony
authors.initials: T
authors.lastname: Mok
authors.affiliation: Wakayama Medical University, 811-1 Kimiidera, Wakayama, Wakayama Prefecture 641-8509, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Yamamoto
authors.affiliation: Princess Alexandra Hospital and Queensland University of Technology, 199 Ipswich Road, Woolloongabba, QLD 4102, Australia.
authors.forename: Kenneth
authors.initials: K
authors.lastname: O'Byrne
authors.affiliation: McGill University, 845 Rue Sherbrooke O, Montréal, QC H3A 0G4, Canada.
authors.forename: Vera
authors.initials: V
authors.lastname: Hirsh
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Street 65, Biberach 88400, Germany.
authors.forename: Neil
authors.initials: N
authors.lastname: Gibson
authors.affiliation: Boehringer Ingelheim Ltd UK, Ellesfield Avenue, Bracknell, Berkshire RG12 8YS, UK.
authors.forename: Dan
authors.initials: D
authors.lastname: Massey
authors.affiliation: Boehringer Ingelheim GmbH, Binger Street 173, Ingelheim 55216, Germany.
authors.forename: Miyoung
authors.initials: M
authors.lastname: Kim
authors.affiliation: National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei 100, Taiwan.
authors.forename: James Chih-Hsin
authors.initials: JC
authors.lastname: Yang
mesh_terms: D000230:Adenocarcinoma / Q000097:blood* / Q000188:drug therapy / Q000235:genetics / Q000401:mortality; D000077192:Adenocarcinoma of Lung; D000328:Adult; D000077716:Afatinib; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001774:Blood Chemical Analysis / Q000379:methods; D004252:DNA Mutational Analysis / Q000379:methods*; D004273:DNA, Neoplasm / Q000032:analysis / Q000097:blood*; D066246:ErbB Receptors / Q000235:genetics*; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000097:blood* / Q000188:drug therapy / Q000235:genetics / Q000401:mortality; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D011379:Prognosis; D011799:Quinazolines / Q000008:administration & dosage
chemical_list: D004273:DNA, Neoplasm; D011799:Quinazolines; D000077716:Afatinib; C512478:EGFR protein, human; D066246:ErbB Receptors