Evaluation of oncogenic human papillomavirus RNA and DNA tests with liquid-based cytology in primary cervical cancer screening: the FASE study Joseph Monsonego 1 , Michael G. Hudgens 2 , Laurent Zerat 3 , Jean-Claude Zerat 3 , Kari Syrja ¨nen 4 , Philippe Halfon 5 , Fabrice Ruiz 6 and Jennifer S. Smith 7 1 Institute of the Cervix, Federation Mutualiste Parisienne, Paris, France 2 Department of Biostatistics, University of North Carolina, Chapel Hill, NC 3 Laboratoire Lavergne, Paris, France 4 Department of Oncology & Radiotherapy, University Hospital, Turku, Finland 5 Alphabio-CDL, Marseille, France 6 Clinsearch, Bagneux, France 7 Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC The APTIMA V R HPV Assay (AHPV) allows detection of 14 high-risk human papillomavirus (HPV) RNA types in cervical specimens. Until present, the assay has been compared to HPV DNA tests only in triage settings. Herein, we compare AHPV with a DNA assay (Hybrid Capture V R 2; HC2) and liquid-based cytology (LBC; using PreservCyt V R ThinPrep liquid Pap) in a screening setting (French APTIMA screening evaluation [FASE] study). Women (N 5 5,006) aged 20–65 were screened by gynecologists in 17 private practices in Paris, France. One cervical specimen was collected and tested with LBC, AHPV and HC2 assays. Women were referred to colposcopy if they were ASC-US1 in LBC or HPV positive in either HPV assay. To control for verification bias, a random group (14%) with normal LBC and dually HPV negative tests underwent colposcopy. Data from 4,429 women were analyzed. Sensitivity, specificity and predictive values were calculated for the three tests. AHPV and HC2 were highly sensitive for CIN21 (92.0% and 96.7%) and CIN31 (95.7% and 95.3%) detection and much more sensitive than LBC (69.1% for CIN21 and 73.3% for CIN31). Specificity of AHPV was higher than that of HC2, but similar to that of LBC (p < 0.001). Combining LBC with either HPV test slightly increased sensitivity but compromised specificity. AHPV assay is both specific and sensitive for the detection of high-grade precancerous lesions and may be considered as an option for routine cervical cancer screening for women over 20 years of age. Invasive cervical cancer (ICC) is the second most frequent female cancer worldwide, 1 with an estimation of 493,000 cases annually. ICC incidence and mortality rates have dra- matically declined over the past five decades in developed countries, largely due to screening programs based on con- ventional cervical Papanicolaou (Pap) smears. 2,3 Conventional Pap smear screening, however, has limited sensitivity, positive predictive value (PPV) and reproducibility, which limits its use for primary screening. 3,4–7 Liquid-based cytology (LBC) has been shown to be more sensitive than conventional Key words: cervical cancer screening, HPV RNA test, HPV DNA test, liquid-based cytology, high-grade CIN Abbreviations: ACG: atypical glandular lesion; ADC: adenocarcinoma; AHPV: APTIMA V R HPV; ASC-US: atypical cells of undetermined significance; ASC-H: atypical squamous cells: cannot rule out a high grade lesion; CIN: cervical intraepithelial neoplasia; HC2: Hybrid Capture V R 2; HPV: human papillomavirus; HR-HPV: high-risk HPV; HSIL: high-grade cytological abnormalities; ICC: invasive cervical cancer; LBC: liquid-based cytology; LSIL: low-grade cytological abnormalities; NPV: negative predictive value; Pap: Papanicolaou; PPV: positive predictive value; RLU/CO: relative light units to control cut-off; S/CO: signal to cut-off; SIL: squamous intra-epithelial lesion; TZ: transformation zone Conflict of interest: J. Monsonego has received funding to conduct studies related to the FASE study from Gen-Probe Inc. and related to HPV vaccines from Merck and GlaxoSmithKline, and has participated to Steering Committees at Merck and to the Advisory Board of Sanofi Pasteur MSD, Gen-Probe, Qiagen, and Roche Diagnostics. J. Smith has received research grants or contracts, honoraria and consulting fees during the last three years from Qiagen or Genprobe. F. Ruiz is an employee of ClinSearch. K. Syrja ¨nen, M. Hudgens, P. Halfon, L. Zerat and J.C. Zerat have no conflict of interest to report. DOI: 10.1002/ijc.25726 History: Received 23 Jun 2010; Accepted 16 Sep 2010; Online 12 Oct 2010 Correspondence to: Joseph Monsonego, Institute of the Cervix, Federation Mutualiste Parisienne, 174 rue de Courcelles, 75017 Paris, France, Tel.: þ33-1-44-400-120, Fax: þ33-1-47-667-470, E-mail: jmonsonego@wanadoo.fr Early Detection and Diagnosis Int. J. Cancer: 000, 000–000 (2010) V C 2010 UICC International Journal of Cancer IJC