title: Interaction of Treatment and Biomarker in Advanced Non-small Cell Lung Cancer.
abstract: There has been a long-standing interest in the investigation of interactions in science. The objective of the study is to evaluate interaction between Epidermal Growth Factor Receptor (EGFR) mutation and treatment from randomized, phase II study of chemotherapy versus chemotherapy plus erlotinib in patients with progressive Non-Small Cell Lung Cancer (NSCLC) following clinical benefit from erlotinib.
  
  
  
  Forty-six patients with advanced stage NSCLC and progression from erlotinib were randomized to receive chemotherapy (pemetrexed or docetaxel) or chemotherapy plus erlotinib between 2008 and 2012. Patient characteristics at baseline including age, gender, tumor stage, race, smoking history and EGFR mutation status along with the clinical outcomes, namely response, Progression- Free Survival (PFS) and Overall Survival (OS) were obtained. The effects of treatment, EGFR mutation and interaction between the two on survival outcomes were evaluated using Cox proportional hazards model with first-order interaction.
  
  
  
  For PFS, there was a significant interaction between treatment (arm B) and EGFR mutation (mutant EGFR+) (p = 0.018), although the main effects of treatment (arm B vs. arm A) and EGFR mutation (mutant vs. wild-type EGFR) were statistically significant (with p = 0.03 and p = 0.088, respectively) favoring arm B and mutant EGFR+. Thus when taking the interaction between treatment and EGFR into account, the hazard ratio comparing arm B to arm A when EGFR is positive was 1.49 (95% CI: 0.72, 3.11); and the hazard ratio comparing arm B to arm A when EGFR is negative was 0.17 (95% CI: 0.04 - 0.84). Similarly, for OS, there was a significant interaction between treatment and EGFR mutation (p = 0.02), with significant main effects of treatment and EGFR favoring arm B and mutant EFGR+. Taking together, the hazard ratio comparing arm B to arm A when EGFR is positive was 1.61 (95% CI: 0.68 - 3.82); and the hazard ratio comparing arm B to arm A when EGFR is negative was 0.16 (95% CI: 0.03 - 0.9).
  
  
  
  The interaction identified by Cox model shows there was an antagonistic effect between chemotherapy + erlotinib and EGFR mutation, a situation that the whole is less than the sum of the parts, despite the prolonging-survival main effect of each factor from Cox model. As a result, the continuing erlotinib beyond progression adds no benefit in survival outcomes but leads to an increase in adverse events.
authors.affiliation: Department of Epidemiology and Biostatistics, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, United States.
authors.forename: Pingfu
authors.initials: P
authors.lastname: Fu
authors.forename: Nathan A
authors.initials: NA
authors.lastname: Pennell
authors.forename: Neelesh
authors.initials: N
authors.lastname: Sharma
authors.forename: Qizhi
authors.initials: Q
authors.lastname: Yi
authors.affiliation: Department of Medicine, University Hospitals Case Medical Center, Case Western Reserve University, 11100 Euclid Avenue, Cleveland, OH 44106, United States.
authors.forename: Afshin
authors.initials: A
authors.lastname: Dowlati
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D018572:Disease-Free Survival; D000077143:Docetaxel; D066246:ErbB Receptors / Q000187:drug effects* / Q000378:metabolism; D000069347:Erlotinib Hydrochloride / Q000008:administration & dosage*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000473:pathology; D009367:Neoplasm Staging; D000068437:Pemetrexed / Q000008:administration & dosage; D016016:Proportional Hazards Models; D011799:Quinazolines / Q000008:administration & dosage; D018570:Risk Assessment; D016019:Survival Analysis; D043823:Taxoids / Q000008:administration & dosage; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; D011799:Quinazolines; D043823:Taxoids; D000068437:Pemetrexed; D000077143:Docetaxel; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: Beyond progression; EGFR TKI; NSCLC; chemotherapy; cox model; interaction