title: Detection and Dynamic Changes of EGFR Mutations from Circulating Tumor DNA as a Predictor of Survival Outcomes in NSCLC Patients Treated with First-line Intercalated Erlotinib and Chemotherapy.
abstract: OBJECTIVE
  Blood-based circulating-free (cf) tumor DNA may be an alternative to tissue-based EGFR mutation testing in NSCLC. This exploratory analysis compares matched tumor and blood samples from the FASTACT-2 study.
  
  
  METHODS
  Patients were randomized to receive six cycles of gemcitabine/platinum plus sequential erlotinib or placebo. EGFR mutation testing was performed using the cobas tissue test and the cobas blood test (in development). Blood samples at baseline, cycle 3, and progression were assessed for blood test detection rate, sensitivity, and specificity; concordance with matched tumor analysis (n = 238), and correlation with progression-free survival (PFS) and overall survival (OS).
  
  
  RESULTS
  Concordance between tissue and blood tests was 88%, with blood test sensitivity of 75% and a specificity of 96%. Median PFS was 13.1 versus 6.0 months for erlotinib and placebo, respectively, for those with baseline EGFR mut(+) cfDNA [HR, 0.22; 95% confidence intervals (CI), 0.14-0.33, P < 0.0001] and 6.2 versus 6.1 months, respectively, for the EGFR mut(-) cfDNA subgroup (HR, 0.83; 95% CI, 0.65-1.04, P = 0.1076). For patients with EGFR mut(+) cfDNA at baseline, median PFS was 7.2 versus 12.0 months for cycle 3 EGFR mut(+) cfDNA versus cycle 3 EGFR mut(-) patients, respectively (HR, 0.32; 95% CI, 0.21-0.48, P < 0.0001); median OS by cycle 3 status was 18.2 and 31.9 months, respectively (HR, 0.51; 95% CI, 0.31-0.84, P = 0.0066).
  
  
  CONCLUSIONS
  Blood-based EGFR mutation analysis is relatively sensitive and highly specific. Dynamic changes in cfDNA EGFR mutation status relative to baseline may predict clinical outcomes.
authors.affiliation: State Key Laboratory of South China, Hong Kong Cancer Institute, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Tony
authors.initials: T
authors.lastname: Mok
authors.affiliation: Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China. syylwu@live.cn.
authors.forename: Yi-Long
authors.initials: YL
authors.lastname: Wu
authors.affiliation: National Cancer Center, Goyang, Korea.
authors.forename: Jin Soo
authors.initials: JS
authors.lastname: Lee
authors.affiliation: National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Chong-Jen
authors.initials: CJ
authors.lastname: Yu
authors.affiliation: The King Chulalongkorn Memorial Hospital and Chulalongkorn University, Bangkok, Thailand.
authors.forename: Virote
authors.initials: V
authors.lastname: Sriuranpong
authors.affiliation: Philippine General Hospital, Manila, Philippines.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Sandoval-Tan
authors.affiliation: Lung Centre of the Philippines, Quezon City, Philippines.
authors.forename: Guia
authors.initials: G
authors.lastname: Ladrera
authors.affiliation: Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.
authors.forename: Sumitra
authors.initials: S
authors.lastname: Thongprasert
authors.affiliation: Siriraj Hospital, Bangkok, Thailand.
authors.forename: Vichien
authors.initials: V
authors.lastname: Srimuninnimit
authors.affiliation: Shanghai Lung Tumour Clinical Medical Center, Shanghai Chest Hospital, Shanghai, China.
authors.forename: Meilin
authors.initials: M
authors.lastname: Liao
authors.affiliation: Beijing Chest Hospital, Beijing, China.
authors.forename: Yunzhong
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Caicun
authors.initials: C
authors.lastname: Zhou
authors.affiliation: Rizal Medical Center, Pasig City, Philippines.
authors.forename: Fatima
authors.initials: F
authors.lastname: Fuerte
authors.affiliation: Dokter Soetomo Hospital, Surabaya, Indonesia.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Margono
authors.affiliation: Roche Molecular Systems, Inc., Pleasanton, California.
authors.forename: Wei
authors.initials: W
authors.lastname: Wen
authors.affiliation: Roche Molecular Systems, Inc., Pleasanton, California.
authors.forename: Julie
authors.initials: J
authors.lastname: Tsai
authors.affiliation: Roche Products Ltd, Dee Why, Australia.
authors.forename: Matt
authors.initials: M
authors.lastname: Truman
authors.affiliation: F. Hoffmann-La Roche Ltd, Basel, Switzerland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Klughammer
authors.affiliation: Oncology Biomarker Development, Genentech Inc., San Francisco, California.
authors.forename: David S
authors.initials: DS
authors.lastname: Shames
authors.affiliation: Roche Molecular Systems, Inc., Pleasanton, California.
authors.forename: Lin
authors.initials: L
authors.lastname: Wu
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D004252:DNA Mutational Analysis / Q000379:methods*; D004273:DNA, Neoplasm / Q000097:blood*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D018572:Disease-Free Survival; D004311:Double-Blind Method; D000069347:Erlotinib Hydrochloride / Q000008:administration & dosage; D005260:Female; D018773:Genes, erbB-1; D006801:Humans; D007364:Intercalating Agents / Q000008:administration & dosage; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009154:Mutation; D017671:Platinum Compounds / Q000008:administration & dosage; D016896:Treatment Outcome; D000093542:Gemcitabine
chemical_list: D004273:DNA, Neoplasm; D007364:Intercalating Agents; D017671:Platinum Compounds; D003841:Deoxycytidine; D000069347:Erlotinib Hydrochloride; D000093542:Gemcitabine