Page 196 - Strategies for non-invasive managementof high-grade cervical intraepithelial neoplasia - prognostic biomarkers and immunotherapy Margot Maria Koeneman

Chapter 10
differentiated keratinocytes leading to normalization of the abberant immune response caused by HPV infection, and second, a TLR 7/8 independent pathway that augments pro-inflammatory activity and induces apoptosis as has been described above. Further studies in CIN lesions could unravel the mode of action of imiquimod in regression of high-grade CIN.
Imiquimod in clinical practice
An inventory among Dutch gynecologists shows that clinical application of imiquimod in high- grade CIN is currently very limited. We identified three important reasons for this. First, a limited awareness among physicians of imiquimod as a treatment modality in high-grade CIN. Second, a perceived lack of evidence regarding clinical efficacy and recurrence rates. Third, concerns about clinical applicability, in the sense of side effects and treatment intensity.. The study also revealed a (not unexpected) limited area of indication for imiquimod in high-grade CIN: imiquimod was almost exclusively applied to avoid a secondary LLETZ or primary LLETZ in women with a future pregnancy desire. This perceived area of indication was confirmed in our patient preference study, which clearly indicated that a preference for imiquimod treatment instead of LLETZ is prompted by a future pregnancy desire. Women with a future pregnancy desire accept a lower treatment efficacy and a higher incidence of side effects, in return for a lower risk of obstetric side effects. Nonetheless, a certain minimal treatment efficacy of imiquimod is desired by these women: they prefer imiquimod over LLETZ under the condition that the imiquimod efficacy rate reaches 72%. The only study on imiquimod efficacy by Grimm et al. showed a regression rate of 73% and a remission rate of 49%.[15] Additional evidence on the long-term treatment efficacy of imiquimod treatment should clarify whether a treatment success rate of at least 72% is actually achievable in order to make imiquimod treatment worthwhile for women. When this efficacy rate is not reached in the TOPIC-3 study, we suggest the identification of predictive markers for treatment outcome of imiquimod. This would enable selection of those women in whom an adequate response to imiquimod treatment is expected. Biomarkers for imiquimod treatment outcome should ideally reflect plausible biological processes in pathophysiology and pharmacology. Predictive biomarkers for imiquimod treatment outcome could therefore be identified at the level of patient and lesion characteristics (such as smoking status, CIN grade, HPV genotype and lesion size) or on the level of functional cellular mechanisms in the pathogenesis and regression of CIN and pharmacological effects of imiquimod (such as proliferation markers, genetic markers, TLR-7/8 expression and markers reflecting immune responses). Such predictive biomarkers for treatment outcome were previously studied in VIN. Jones et al. studied HPV DNA methylation as a predictor for clinical response of VIN3 to imiquimod and cidofovir.[59] They hypothesized that HPV infection is likely to be most immunogenic in the context of a productive infection, which are associated with low levels of viral DNA methylation. Indeed, they found that median E2 methylation was lower in patients who responded to imiquimod treatment, but the result was not significant. E2 methylation <4% predicted adequate treatment response with 70.6% sensitivity and 62.5% specificity.[59] As such, E2 methylation does not classify as a valid predictive marker for imiquimod treatment outcome. Markers of the immune response have also been studied with regard to imiquimod treatment outcome. As discussed before, Van Poelgeest et al. found that a preexisting HPV16-specific type 1 T-cell response was associated with a more favorable clinical outcome upon topical imiquimod treatment in VIN in HPV16 positive women.
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