title: Bisphosphonates enhance EGFR-TKIs efficacy in advanced NSCLC patients with EGFR activating mutation: A retrospective study.
abstract: BACKGROUND
  Bisphosphonates have exhibited anti-tumor activity in non-small cell lung cancer (NSCLC). We aimed to evaluate whether the combination of bisphosphonates with tyrosine kinase inhibitors of EGFR (EGFR-TKIs) could obtain a synergistic effect on advanced NSCLC patients with EGFR mutations.
  
  
  METHODS
  Between January 2008 and October 2013, 114 advanced EGFR mutations NSCLC patients who received EGFR-TKIs as first-line therapy were recruited from two cancer centers. Patients were separated into EGFR-TKIs alone or EGFR-TKIs plus bisphosphonates (combination) group. Median progression free survival (mPFS), median overall survival (mOS) distributions and survival curves were analyzed.
  
  
  RESULTS
  Among the 114 patients, 62 had bone metastases (19 patients treated with EGFR-TKIs, 43 patients treated with EGFR-TKIs + bisphosphonates). Median PFS and OS were significantly improved in combination group compared with EGFR-TKIs group (mPFS: 15.0 vs 7.3 months, P = 0.0017; mOS: 25.2 vs 10.4 months, P = 0.0015) in patients with bone metastases. Among the 71 patients (19 patients with bone metastases) treated with EGFR-TKIs alone, patients with bone metastases had poor survival prognosis (mPFS:7.3 vs 12.1 months, P = 0.0434; mOS:10.4 vs 22.0 months, P = 0.0036). The survival of patients with bone metastases who received EGFR-TKIs plus bisphosphonates therapy was non-inferior to patients without bone metastases treated with EGFR-TKIs alone (mPFS: 15.0 vs 12.1 months, p = 0.1871; mOS: 25.2 vs 22.0 months, p = 0.9798).
  
  
  CONCLUSIONS
  Concomitant use of bisphosphonates and EGFR-TKIs improves therapeutic efficacy and brings survival benefits to NSCLC patients with EGFR mutation and bone metastases.
authors.affiliation: Department of Thoracic Oncology, Cancer Center, and State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.|Department of Medical Oncology, Enshi Tujia and Miao Autonomous Prefecture Central Hospital, Hubei Province, China.
authors.forename: Chu-Ying
authors.initials: CY
authors.lastname: Huang
authors.affiliation: Department of Thoracic Oncology, Cancer Center, and State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.|Department of Dermatology, Enshi Tujia and Miao Autonomous Prefecture Central Hospital, Hubei Province, China.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Thoracic Oncology, Cancer Center, and State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: Cheng-Jun
authors.initials: CJ
authors.lastname: Feng
authors.affiliation: Department of Oncology, The Second People's Hospital of Sichuan, Chengdu, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Yu
authors.affiliation: Department of Oncology, The Second People's Hospital of Sichuan, Chengdu, China.
authors.forename: Xiao-Hong
authors.initials: XH
authors.lastname: Cai
authors.affiliation: Department of Oncology, The Second People's Hospital of Sichuan, Chengdu, China.
authors.forename: Wen-Xiu
authors.initials: WX
authors.lastname: Yao
authors.affiliation: Department of Thoracic Oncology, Cancer Center, and State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Thoracic Oncology, Cancer Center, and State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: Xiao-Ke
authors.initials: XK
authors.lastname: Liu
authors.affiliation: Department of Thoracic Oncology, Cancer Center, and State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: Wen-Jiang
authors.initials: WJ
authors.lastname: Zhu
authors.affiliation: Department of Thoracic Oncology, Cancer Center, and State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.|Department of Oncology, The First People's Hospital of Longquanyi District, Chengdu, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Oncology, The Second People's Hospital of Sichuan, Chengdu, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Thoracic Oncology, Cancer Center, and State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: You
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Thoracic Oncology, Cancer Center, and State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: Yong-Sheng
authors.initials: YS
authors.lastname: Wang
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000188:drug therapy / Q000556:secondary; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000401:mortality; D043844:Crown Ethers / Q000008:administration & dosage; D004164:Diphosphonates / Q000008:administration & dosage*; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics; D000069347:Erlotinib Hydrochloride / Q000008:administration & dosage; D005260:Female; D000077156:Gefitinib; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009154:Mutation; D000077268:Pamidronate; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D011799:Quinazolines / Q000008:administration & dosage; D012189:Retrospective Studies; D016896:Treatment Outcome; D000077211:Zoledronic Acid
chemical_list: D043844:Crown Ethers; D004164:Diphosphonates; D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000077211:Zoledronic Acid; C531470:icotinib; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors; D000077268:Pamidronate; D000077156:Gefitinib
keywords: EGFR mutations; EGFR-TKIs; NSCLC; bisphosphonates; bone metastases