A cocktail of p16(INK4a) and Ki-67, p16(INK4a) and minichromosome maintenance protein 2 as triage tests for human papillomavirus primary cervical cancer screening

Most human papillomavirus (HPV) infections are transient and additional triage approaches should be built after HPV-based primary cervical cancer screening. We evaluated the accuracy of p16/Ki-67 and p16/mcm2 dual staining as biomarkers for triaging HPV positive women in China. 4070 participants aged 35 to 64 years attending ongoing cervical cancer screening were enrolled in 2015-2016. Cervical exfoliated cells were collected for HPV DNA analysis and the residual positive specimens were tested for liquid-based cytology and biomarkers. Women infected with HPV 16/18 type or other 12 high-risk HPV types with abnormal cytology results received colposcopy. We found the positive rates of both biomarkers increased significantly with histology severity. p16/Ki-67 positivity in HPV16/18 group, other 12 high-risk HPV group and HPV negative group was 50.0%, 33.7% and 8.9%, respectively. The corresponding p16/mcm2 positivity was 70.0%, 56.3% and 6.7%, respectively. The sensitivity and specificity of p16/Ki-67 for CIN2+ in all HPV-positive women were 91.7% and 63.5%, with a referral rate of 36.2%, while p16/mcm2 were 87.5% and 42.1%, with a referral rate of 58.4%, respectively. The sensitivity of p16/Ki-67 increased to 95.8% for CIN2+ and 100% for CIN3+ when combined with high-grade cytology, without decrease in specificity. Our studies suggest that p16/Ki-67 is an efficient triaging biomarker for HPV-positive women and could reduce colposcopy workload. p16/mcm2 is more sensitive compared with cytology for identifying cervical lesions.