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Randomized Controlled Trial
. 2022;35(2):143-153.
doi: 10.3233/CBM-210448.

Combined HPV 16 E2 and L1 methylation predict response to treatment with cidofovir and imiquimod in patients with vulval intraepithelial neoplasia

Christopher Nicholas Hurt  1   1 , Belinda Nedjai  2   1 , Carlos Alvarez-Mendoza  3 , Ned Powell  4 , Amanda Tristram  5 , Sadie Jones  6
Affiliations
Randomized Controlled Trial

Combined HPV 16 E2 and L1 methylation predict response to treatment with cidofovir and imiquimod in patients with vulval intraepithelial neoplasia

Christopher Nicholas Hurt et al. Cancer Biomark. 2022.

Abstract

Background: Topical cidofovir and imiquimod can effectively treat approximately 55% of patients with vulval intraepithelial neoplasia (VIN), thus avoiding the need for surgery. Human papillomavirus (HPV) E⁢2 gene methylation predicts response to treatment but a methylation measurement is only obtainable in approximately 50% of patients.

Objective: This work aimed to determine if the applicability and predictive power of the E⁢2 methylation assay could be improved by combining it with the components of a host and viral DNA methylation panel (S5) that has been found to predict disease progression in patients with cervical intraepithelial neoplasia.

Methods: HPV E2 methylation and S5 classifier score were measured in fresh tissue samples collected pre-treatment from 132 patients with biopsy-proven VIN grade 3 who participated in a multicentre clinical trial and were randomised to treatment with cidofovir or imiquimod.

Results: Combining HPV16 E⁢2 and HPV16 L⁢1 methylation provides a biomarker that is both predictive of response to topical treatment and that can produce a clinically applicable result for all patients. Patients with HPV 16 L⁢1^high and HPV 16 E⁢2^high (36/132 (27.3%)) were more likely to respond to treatment with cidofovir (12/15 (80.0%)) than imiquimod (9/21 (42.9%)) (p= 0.026). Patients with HPV 16 L⁢1^low or HPV 16 E⁢2^low (including those with no HPV/unassessable methylation) were more likely to respond to imiquimod: 23/50 (46.0%) vs 31/46 (67.4%) (p= 0.035).

Conclusions: Combined HPV E⁢2 and L⁢1 methylation is a potential predictive marker in treatment for all patients with VIN. These findings justify validation in a prospective trial.

Keywords: HPV; Vulval intraepithelial neoplasia; cidofovir; gene methylation; imiquimod; predictive biomarker.

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Figures

Figure 1.
Figure 1.
HPV16E2 methylation detection by laboratory.
Figure 2.
Figure 2.
Distribution of methylation levels in responders and non-responders by trial arm.
Figure 3.
Figure 3.
Scatter plot of HPV 16 L1 and HPV 16 E2 methylation by treatment group.
See this image and copyright information in PMC

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