title: Triaging HPV-positive women with p16/Ki-67 dual-stained cytology: Results from a sub-study nested into the ATHENA trial.
abstract: OBJECTIVE
  In addition to genotyping for HPV16/18, dual-immunostaining for p16/Ki-67 has shown promise as a triage of HPV-positive women. We assessed the performance of p16/Ki-67 dual-stained cytology for triaging HPV-positive women undergoing primary HPV screening.
  
  
  METHODS
  All women ≥25years with valid cervical biopsy and cobas® HPV Test results from the cross-sectional phase of ATHENA who were referred to colposcopy (n=7727) were eligible for enrolment. p16/Ki-67 dual-stained cytology was retrospectively performed on residual cytologic material collected into a second liquid-based cytology vial during the ATHENA enrolment visit. The diagnostic performance of dual-stained cytology, with or without HPV16/18 genotyping, for the detection of biopsy-confirmed cervical intraepithelial neoplasia grade 3 or worse (CIN3+) was determined and compared to Pap cytology. Furthermore, the number of colposcopies required per CIN3+ detected was determined.
  
  
  RESULTS
  Dual-stained cytology was significantly more sensitive than Pap cytology (74.9% vs. 51.9%; p<0.0001) for triaging HPV-positive women, whereas specificity was comparable (74.1% vs. 75.0%; p=0.3198). Referral of all HPV16/18 positive women combined with dual-stained cytology triage of women positive for 12 "other" HPV genotypes provided the highest sensitivity for CIN3+ (86.8%; 95% CI: 81.9-90.8). A similar strategy but using Pap cytology for the triage of women positive for 12 "other" HPV genotypes was less sensitive (78.2%; 95% CI: 72.5-83.2; p=0.0003), but required a similar number of colposcopies per CIN3+ detected.
  
  
  CONCLUSIONS
  p16/Ki-67 dual-stained cytology, either alone or combined with HPV16/18 genotyping, represents a promising approach as a sensitive and efficient triage for colposcopy of HPV-positive women when primary HPV screening is utilized.
authors.affiliation: Columbia University, New York City, NY, USA. Electronic address: tcw1@columbia.edu.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Wright
authors.affiliation: Roche Molecular Systems, Inc., Pleasanton, CA, USA.
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Behrens
authors.affiliation: Ventana Medical Systems, Inc., Tucson, AZ, USA.
authors.forename: James
authors.initials: J
authors.lastname: Ranger-Moore
authors.affiliation: Ventana Medical Systems, Inc., Tucson, AZ, USA; Roche mtm laboratories AG, Mannheim, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Rehm
authors.affiliation: Roche Molecular Systems, Inc., Pleasanton, CA, USA.
authors.forename: Abha
authors.initials: A
authors.lastname: Sharma
authors.affiliation: University of Virginia, Charlottesville, VA, USA.
authors.forename: Mark H
authors.initials: MH
authors.lastname: Stoler
authors.affiliation: Ventana Medical Systems, Inc., Tucson, AZ, USA; Roche mtm laboratories AG, Mannheim, Germany.
authors.forename: Ruediger
authors.initials: R
authors.lastname: Ridder
mesh_terms: D000328:Adult; D001706:Biopsy; D002584:Cervix Uteri / Q000473:pathology; D002986:Clinical Trials as Topic; D003127:Colposcopy; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000032:analysis*; D005260:Female; D005838:Genotype; D006801:Humans; D019394:Ki-67 Antigen / Q000032:analysis*; D065006:Papanicolaou Test; D027383:Papillomaviridae / Q000235:genetics; D030361:Papillomavirus Infections / Q000175:diagnosis / Q000821:virology*; D011237:Predictive Value of Tests; D012017:Referral and Consultation; D012189:Retrospective Studies; D014218:Triage / Q000379:methods*; D002583:Uterine Cervical Neoplasms / Q000737:chemistry* / Q000175:diagnosis / Q000473:pathology* / Q000821:virology; D014626:Vaginal Smears; D002578:Uterine Cervical Dysplasia / Q000737:chemistry* / Q000175:diagnosis / Q000473:pathology* / Q000821:virology
chemical_list: C000614131:CDKN2A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D019394:Ki-67 Antigen
keywords: ATHENA; CINtec PLUS; Cervical cancer screening; Genotyping; HPV; Triage; p16/Ki-67 dual-stained cytology