Human Papillomavirus DNA methylation predicts response to treatment using cidofovir and imiquimod in Vulval Intraepithelial Neoplasia 3

Purpose <p>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.</p> <p>Experimental design</p> <p>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: E2, L1/L2, and the promoter, using pyrosequencing.</p> <p>Results</p> <p>Methylation of the HPV E2 region was associated with response to treatment. For cidofovir (n=30), median E2 methylation was significantly higher in patients who responded (p = <0.0001); E2 methylation >4% predicted response with 88.2% sensitivity and 84.6% specificity. For imiquimod (n=33), median E2 methylation was lower in patients who responded to treatment (p = 0.03 (not significant after Bonferroni correction)); E2 methylation <4% predicted response with 70.6% sensitivity and 62.5% specificity.</p> <p>Conclusions</p> <p>These data indicate that cidofovir and imiquimod may be effective in two biologically defined groups. HPV E2 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.

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