Short Communication Combined CADM1/MAL Methylation and Cytology Testing for Colposcopy Triage of High-Risk HPV-Positive Women

Primary screening for high-risk human papillomavirus (hrHPV) requires a triage protocol. Repeat cytology testing at baseline and after 6 to 12 months has emerged as a reasonable triage approach, but carries the risk of loss to follow-up. Repeat cytology testing may be omitted if cytology is supplemented with another, complementary triage test at baseline. In this study, the performance of combined triage by cytology and DNA methylation analysis was assessed. In hrHPV-positive cervical scrapes (n 1⁄4 250), cytology [threshold: atypical squamous cells of undetermined significance (ASCUS)], bi-markerCADM1/MALmethylation testing (at different assay thresholds), and combinations of both were evaluated for endpoints cervical intraepithelial neoplasia grade 2 or worse (CIN2þ) and grade 3 or worse (CIN3þ). At a predefined methylation threshold of 70% specificity for CIN3þ, combined triage revealed aCIN3þ sensitivity of 86.8% [95%confidence interval (CI), 76.1–97.6] compared with 65.8% (95% CI, 50.7–80.9) for sole cytology triage testing. Corresponding CIN3þ specificity was 64.8% (95% CI, 58.1–71.5) for combined triage and 78.6% (95% CI, 72.8–84.3) for sole cytology triage testing. For CIN2þ, the sensitivity of combined triage testing was 84.5% (95% CI, 75.2–93.8) compared with 65.5% (95%CI, 53.3–77.7) for sole cytology triage, with corresponding specificities of 69.9% (95%CI, 63.1– 76.6) and 83.5% (95% CI, 78.0–89.0), respectively. In conclusion, combined triage reached substantially higher CIN2þ/3þ sensitivities compared with sole cytology at a slight drop in specificity. Therefore, it is an attractive triage strategy for colposcopy of hrHPV-positive women with a high reassurance for cervical cancer and advanced CIN lesions. Cancer Epidemiol Biomarkers Prev; 23(9); 1933–7. 2014 AACR.