Human Papillomavirus DNA Methylation Predicts Response to Treatment Using Cidofovir and Imiquimod in Vulval Intraepithelial Neoplasia 3.

Abstract

<b>Purpose:</b> Response rates to treatment of vulval intraepithelial neoplasia (VIN) with imiquimod and cidofovir are approximately 57% and 61%, respectively. Treatment is associated with significant side effects and, if ineffective, risk of malignant progression. Treatment response is not predicted by clinical factors. Identification of a biomarker that could predict response is an attractive prospect. This work investigated HPV DNA methylation as a potential predictive biomarker in this setting.<b>Experimental Design:</b> DNA from 167 cases of VIN 3 from the RT3 VIN clinical trial was assessed. HPV-positive cases were identified using Greiner PapilloCheck and HPV 16 type-specific PCR. HPV DNA methylation status was assessed in three viral regions: <i>E2, L1/L2,</i> and the promoter, using pyrosequencing.<b>Results:</b> Methylation of the HPV <i>E2</i> region was associated with response to treatment. For cidofovir (<i>n</i> = 30), median <i>E2</i> methylation was significantly higher in patients who responded (<i>P</i> ≤ 0.0001); <i>E2</i> methylation >4% predicted response with 88.2% sensitivity and 84.6% specificity. For imiquimod (<i>n</i> = 33), median <i>E2</i> methylation was lower in patients who responded to treatment (<i>P</i> = 0.03; not significant after Bonferroni correction); <i>E2</i> methylation <4% predicted response with 70.6% sensitivity and 62.5% specificity.<b>Conclusions:</b> These data indicate that cidofovir and imiquimod may be effective in two biologically defined groups. HPV <i>E2</i> DNA methylation demonstrated potential as a predictive biomarker for the treatment of VIN with cidofovir and may warrant investigation in a biomarker-guided clinical trial. <i>Clin Cancer Res; 23(18); 5460-8. ©2017 AACR</i>.