1. Human Papillomavirus DNA Methylation Predicts Response to Treatment Using Cidofovir and Imiquimod in Vulval Intraepithelial Neoplasia 3
- Author
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Samantha Jayne Hibbitts, Ned George Powell, Alison Nina Fiander, Dean Bryant, Sadie Jones, Amanda Jane Tristram, and Chris Nicholas Hurt
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0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Genes, Viral ,Organophosphonates ,Imiquimod ,Cytosine ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,Promoter Regions, Genetic ,Papillomaviridae ,Neoplasm Staging ,Vulvar Neoplasms ,business.industry ,Papillomavirus Infections ,Methylation ,DNA Methylation ,R1 ,Clinical trial ,Treatment Outcome ,030104 developmental biology ,ROC Curve ,chemistry ,030220 oncology & carcinogenesis ,DNA, Viral ,Immunology ,DNA methylation ,Aminoquinolines ,Pyrosequencing ,Biomarker (medicine) ,Drug Therapy, Combination ,Female ,business ,Biomarkers ,Carcinoma in Situ ,Cidofovir ,DNA ,medicine.drug - Abstract
Purpose: 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.Experimental Design: 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.Results: 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 Conclusions: 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. Clin Cancer Res; 23(18); 5460–8. ©2017 AACR.
- Published
- 2017
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