Triage by Methylation Marker Analysis Versus Colposcopy Biopsy in Women who test HPV-Positive or Abnormal LBC Results on Cervical Samples to Triage Cervical Cancer and HSIL for Further Treatment

Study Objective To compare the CareMe-Plus methylation and colposcopy biopsy to triage patients who test HPV-positive or abnormal LBC results for further treatment. Design Prospective observational multi-center study. Setting Academic hospitals. Patients or Participants From November 2017 to March 2019, 4070 patients with HPV-positive or abnormal LBC results in four academic hospitals who underwent colposcopy. Interventions 4070 patients with HPV-positive or abnormal LBC results who underwent colposcopy-examination to identify the grade of cervical lesion, meanwhile the cervical scrapes were tested for CareMe-Plus methylation (based on the human gene EPB41L3 together with HPV16L1, HPV16L2, HPV18L2, HPV31L1 and HPV33L2). 607 women were diagnosed as ≥HSIL via colposcopy-biopsy and then underwent LEEP (Loop Electrosurgical Excision Procedure). The pathology after LEEP as golden standard, the predictive performance of CareMe-Plus and colposcopy-biopsy were compared. The sensitivity and specificity of several alternative methylation tests were analyzed to determine the optimal methylation strategy. Measurements and Main Results The predictive performance of CareMe-plus methylation was significantly greater than colposcopy-biopsy for cervical cancer, CareMe-plus revealed a significant discrimination of women with cervical cancer from those with ≤HSIL (P=0.022). ROC curve analysis showed an AUC of 0.869. The predictive performance of CareMe-plus methylation was significantly greater than colposcopy-biopsy for HSIL+, CareMe-plus methylation analysis revealed a significant discrimination of women with HSIL+ from those with ≤LSIL (P=0.026). ROC curve analysis showed an AUC of 0.800. Of 580 patients, 26 women with cervical cancer were misdiagnosed by colposcopy-biopsy, while that would be decreased to 4 cases when combined with CareMe-Plus methylation. Also, CareMe-plus is superior to other alternative methylation tests including EPB41L3 and QIsure. Conclusion CareMe-plus methylation assay may be applicable to identify HPV-positive or abnormal LBC women with a high-risk of high grade lesion or cervical cancer. It may triage patients for accurate further treatment when combining with colposcopy biopsy.