title: Association of Human Papillomavirus and p16 Status With Outcomes in the IMCL-9815 Phase III Registration Trial for Patients With Locoregionally Advanced Oropharyngeal Squamous Cell Carcinoma of the Head and Neck Treated With Radiotherapy With or Without Cetuximab.
abstract: OBJECTIVE
  We conducted a retrospective evaluation of the IMCL-9815 study to examine the association of human papillomavirus (HPV) and p16 protein expression status with outcomes in patients with oropharyngeal carcinoma (OPC) receiving radiotherapy (RT) plus cetuximab or RT alone.
  
  
  METHODS
  In the IMCL-9815 study, patients were randomly allocated to receive RT plus weekly cetuximab or RT alone. A subpopulation of patients with p16-evaluable OPC was retrospectively evaluated on the basis of locoregional control (LRC), overall survival (OS), and progression-free survival (PFS). Evaluable samples from patients with p16-positive OPC were also tested for HPV DNA.
  
  
  RESULTS
  Tumor p16 status was evaluable in 182 patients with OPC enrolled in the IMCL-9815 study; 41% were p16 positive. When treated with RT alone or RT plus cetuximab, p16-positive patients had a longer OS than p16-negative patients (hazard ratio, 0.40; 95% CI, 0.21 to 0.74 and hazard ratio, 0.16; 95% CI, 0.07 to 0.36, respectively). The addition of cetuximab to RT increased LRC, OS, and PFS in both patients with p16-positive OPC and those with p16-negative disease. Interaction tests for LRC, OS, and PFS did not demonstrate any significant interaction between p16 status and treatment effect (P = .087, .085, and .253, respectively). Similar trends were observed when patients with p16-positive/HPV-positive OPC (n = 49) and those with p16-positive/HPV-negative OPC (n = 14) were compared.
  
  
  CONCLUSIONS
  p16 status was strongly prognostic for patients with OPC. The data suggest that the addition of cetuximab to RT improved clinical outcomes regardless of p16 or HPV status versus RT alone.
authors.affiliation: David I. Rosenthal, Diana Bell, and Kian K. Ang, The University of Texas MD Anderson Cancer Center, Houston, TX; Paul M. Harari, University of Wisconsin, Madison, WI; Jordi Giralt, Hospital Vall d'Hebron, Barcelona, Spain; David Raben, University of Colorado School of Medicine, Aurora, CO; Joyce Liu, Merck Serono, Beijing, People's Republic of China; Jeltje Schulten, Merck KGaA, Darmstadt, Germany; and James A. Bonner, University of Alabama at Birmingham Comprehensive Cancer Center, Birmingham, AL.
authors.forename: David I
authors.initials: DI
authors.lastname: Rosenthal
authors.affiliation: David I. Rosenthal, Diana Bell, and Kian K. Ang, The University of Texas MD Anderson Cancer Center, Houston, TX; Paul M. Harari, University of Wisconsin, Madison, WI; Jordi Giralt, Hospital Vall d'Hebron, Barcelona, Spain; David Raben, University of Colorado School of Medicine, Aurora, CO; Joyce Liu, Merck Serono, Beijing, People's Republic of China; Jeltje Schulten, Merck KGaA, Darmstadt, Germany; and James A. Bonner, University of Alabama at Birmingham Comprehensive Cancer Center, Birmingham, AL.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Harari
authors.affiliation: David I. Rosenthal, Diana Bell, and Kian K. Ang, The University of Texas MD Anderson Cancer Center, Houston, TX; Paul M. Harari, University of Wisconsin, Madison, WI; Jordi Giralt, Hospital Vall d'Hebron, Barcelona, Spain; David Raben, University of Colorado School of Medicine, Aurora, CO; Joyce Liu, Merck Serono, Beijing, People's Republic of China; Jeltje Schulten, Merck KGaA, Darmstadt, Germany; and James A. Bonner, University of Alabama at Birmingham Comprehensive Cancer Center, Birmingham, AL.
authors.forename: Jordi
authors.initials: J
authors.lastname: Giralt
authors.affiliation: David I. Rosenthal, Diana Bell, and Kian K. Ang, The University of Texas MD Anderson Cancer Center, Houston, TX; Paul M. Harari, University of Wisconsin, Madison, WI; Jordi Giralt, Hospital Vall d'Hebron, Barcelona, Spain; David Raben, University of Colorado School of Medicine, Aurora, CO; Joyce Liu, Merck Serono, Beijing, People's Republic of China; Jeltje Schulten, Merck KGaA, Darmstadt, Germany; and James A. Bonner, University of Alabama at Birmingham Comprehensive Cancer Center, Birmingham, AL.
authors.forename: Diana
authors.initials: D
authors.lastname: Bell
authors.affiliation: David I. Rosenthal, Diana Bell, and Kian K. Ang, The University of Texas MD Anderson Cancer Center, Houston, TX; Paul M. Harari, University of Wisconsin, Madison, WI; Jordi Giralt, Hospital Vall d'Hebron, Barcelona, Spain; David Raben, University of Colorado School of Medicine, Aurora, CO; Joyce Liu, Merck Serono, Beijing, People's Republic of China; Jeltje Schulten, Merck KGaA, Darmstadt, Germany; and James A. Bonner, University of Alabama at Birmingham Comprehensive Cancer Center, Birmingham, AL.
authors.forename: David
authors.initials: D
authors.lastname: Raben
authors.affiliation: David I. Rosenthal, Diana Bell, and Kian K. Ang, The University of Texas MD Anderson Cancer Center, Houston, TX; Paul M. Harari, University of Wisconsin, Madison, WI; Jordi Giralt, Hospital Vall d'Hebron, Barcelona, Spain; David Raben, University of Colorado School of Medicine, Aurora, CO; Joyce Liu, Merck Serono, Beijing, People's Republic of China; Jeltje Schulten, Merck KGaA, Darmstadt, Germany; and James A. Bonner, University of Alabama at Birmingham Comprehensive Cancer Center, Birmingham, AL.
authors.forename: Joyce
authors.initials: J
authors.lastname: Liu
authors.affiliation: David I. Rosenthal, Diana Bell, and Kian K. Ang, The University of Texas MD Anderson Cancer Center, Houston, TX; Paul M. Harari, University of Wisconsin, Madison, WI; Jordi Giralt, Hospital Vall d'Hebron, Barcelona, Spain; David Raben, University of Colorado School of Medicine, Aurora, CO; Joyce Liu, Merck Serono, Beijing, People's Republic of China; Jeltje Schulten, Merck KGaA, Darmstadt, Germany; and James A. Bonner, University of Alabama at Birmingham Comprehensive Cancer Center, Birmingham, AL.
authors.forename: Jeltje
authors.initials: J
authors.lastname: Schulten
authors.affiliation: David I. Rosenthal, Diana Bell, and Kian K. Ang, The University of Texas MD Anderson Cancer Center, Houston, TX; Paul M. Harari, University of Wisconsin, Madison, WI; Jordi Giralt, Hospital Vall d'Hebron, Barcelona, Spain; David Raben, University of Colorado School of Medicine, Aurora, CO; Joyce Liu, Merck Serono, Beijing, People's Republic of China; Jeltje Schulten, Merck KGaA, Darmstadt, Germany; and James A. Bonner, University of Alabama at Birmingham Comprehensive Cancer Center, Birmingham, AL.
authors.forename: Kian K
authors.initials: KK
authors.lastname: Ang
authors.affiliation: David I. Rosenthal, Diana Bell, and Kian K. Ang, The University of Texas MD Anderson Cancer Center, Houston, TX; Paul M. Harari, University of Wisconsin, Madison, WI; Jordi Giralt, Hospital Vall d'Hebron, Barcelona, Spain; David Raben, University of Colorado School of Medicine, Aurora, CO; Joyce Liu, Merck Serono, Beijing, People's Republic of China; Jeltje Schulten, Merck KGaA, Darmstadt, Germany; and James A. Bonner, University of Alabama at Birmingham Comprehensive Cancer Center, Birmingham, AL. jabonner@uabmc.edu.
authors.forename: James A
authors.initials: JA
authors.lastname: Bonner
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis*; D002294:Carcinoma, Squamous Cell / Q000737:chemistry / Q000401:mortality / Q000473:pathology / Q000628:therapy* / Q000821:virology; D000068818:Cetuximab / Q000009:adverse effects / Q000627:therapeutic use*; D059248:Chemoradiotherapy / Q000009:adverse effects; D017326:Clinical Trials, Phase III as Topic; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000032:analysis*; D004279:DNA, Viral / Q000235:genetics; D018572:Disease-Free Survival; D005260:Female; D006258:Head and Neck Neoplasms / Q000737:chemistry / Q000401:mortality / Q000473:pathology / Q000628:therapy* / Q000821:virology; D061809:Human Papillomavirus DNA Tests; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009959:Oropharyngeal Neoplasms / Q000737:chemistry / Q000401:mortality / Q000473:pathology / Q000628:therapy* / Q000821:virology; D027383:Papillomaviridae / Q000235:genetics / Q000302:isolation & purification*; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D016032:Randomized Controlled Trials as Topic; D012189:Retrospective Studies; D000077195:Squamous Cell Carcinoma of Head and Neck; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004279:DNA, Viral; D000068818:Cetuximab