title: Clinical significance of heterogeneity in response to retreatment with epidermal growth factor receptor tyrosine kinase inhibitors in patients with lung cancer acquiring secondary resistance to the drug.
abstract: BACKGROUND
  In patients with lung cancer acquiring resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), an intrapatient heterogeneity in response to retreatment with EGFR-TKIs remains to be elucidated.
  
  
  METHODS
  Records were retrospectively reviewed for 68 patients with advanced non-small-cell lung cancer who received second EGFR-TKIs after systemic progression that followed durable response to the first EGFR-TKIs. All tumor lesions identified on radiologic images before second EGFR-TKIs were categorized into organs. Tumor response to EGFR-TKIs was assessed per patient and per organ. Mixed response (MR) was defined as the coexistence of at least 2 responsive and progressive organs.
  
  
  RESULTS
  Tumor lesions were detected in 244 organs. The response rate (RR) and median time to progression (TTP) to second EGFR-TKIs for patients were 26.5% and 11.6 weeks (95% CI, 8.5-14.7 weeks), and the RR and median TTP for organs were 38.8% and 17.3 weeks (95% CI, 14.8-19.8 weeks). Of 35 patients categorized to progressive disease, 22 (62.8%) showed MR. Among organs, the RR was highest for the central nervous system (CNS) and lowest for the liver (CNS vs. others vs. liver: 77.8%, 36.9%, 17.6%; P < .001). Multivariate analysis confirmed the organ type and prior drug sensitivity at the time of stopping first EGFR-TKIs as predictors for the risk of progression to second EGFR-TKIs in organs.
  
  
  CONCLUSIONS
  Intrapatient heterogeneity in response to second EGFR-TKIs is not a rare event. The organ type and prior drug sensitivity at the failure time of first EGFR-TKIs may predict the efficacy of second EGFR-TKIs in individual organs.
authors.affiliation: Center for Lung Cancer, National Cancer Center, Goyang, Gyeonggi, South Korea. Electronic address: yjlee@ncc.re.kr.
authors.forename: Youngjoo
authors.initials: Y
authors.lastname: Lee
authors.affiliation: Center for Lung Cancer, National Cancer Center, Goyang, Gyeonggi, South Korea.
authors.forename: Hyae Young
authors.initials: HY
authors.lastname: Kim
authors.affiliation: Center for Lung Cancer, National Cancer Center, Goyang, Gyeonggi, South Korea.
authors.forename: Soo-Hyun
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Center for Lung Cancer, National Cancer Center, Goyang, Gyeonggi, South Korea.
authors.forename: Kun Young
authors.initials: KY
authors.lastname: Lim
authors.affiliation: Center for Lung Cancer, National Cancer Center, Goyang, Gyeonggi, South Korea.
authors.forename: Geon Kook
authors.initials: GK
authors.lastname: Lee
authors.affiliation: Center for Lung Cancer, National Cancer Center, Goyang, Gyeonggi, South Korea.
authors.forename: Tak
authors.initials: T
authors.lastname: Yun
authors.affiliation: Center for Lung Cancer, National Cancer Center, Goyang, Gyeonggi, South Korea.
authors.forename: Ji-Youn
authors.initials: JY
authors.lastname: Han
authors.affiliation: Center for Lung Cancer, National Cancer Center, Goyang, Gyeonggi, South Korea.
authors.forename: Heung Tae
authors.initials: HT
authors.lastname: Kim
authors.affiliation: Center for Lung Cancer, National Cancer Center, Goyang, Gyeonggi, South Korea.
authors.forename: Jin Soo
authors.initials: JS
authors.lastname: Lee
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D000368:Aged; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D008297:Male; D009154:Mutation / Q000235:genetics; D009367:Neoplasm Staging; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D019233:Retreatment; D012189:Retrospective Studies; D015996:Survival Rate
chemical_list: D047428:Protein Kinase Inhibitors; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: Acquired resistance; Drug sensitivity; EGFR tyrosine kinase inhibitor; Non–small-cell lung cancer; Organ