Page 197 - Strategies for non-invasive managementof high-grade cervical intraepithelial neoplasia - prognostic biomarkers and immunotherapy Margot Maria Koeneman

[56] Based on these results, differences in local immune response at baseline could influence the outcome of imiquimod treatment. It has been established that CIN lesions are characterized by an increasing aberrant immune response with increasing disease severity. Hypothetically, a more favorable immune response at baseline may reflect either a less advanced lesion or a more capable immune system, potentially making the lesion more sensitive to immunotherapy. A final example of a potential marker of imiquimod treatment outcome may be TLR7/8 expression. Scott et al. showed that a higher expression of TLR7 in HPV16-positive women was a significant predictor of HPV clearance during follow-up.[55] Halec et al. studied TLR expression in relation to regression of CIN2 lesions and found that women with CIN2 regression showed significantly higher baseline levels of TLR7 compared to women with CIN2 persistence/progression.[60] Increased expression of TLR7/8 may induce a more effective response to imiquimod treatment in high-grade CIN, making TLR7/8 expression a potential predictive marker in this regard. The quest for predictive biomarkers for imiquimod treatment outcome is part of the TOPIC3 study which is currently being conducted.
The TOPIC-3 study
Nearly all gynecologists that responded to our survey indicated that they would be willing to apply imiquimod in high-grade CIN, upon additional evidence on treatment efficacy and clinical applicability. This clearly emphasized the need for further studies on imiquimod as a treatment modality for high-grade CIN. The original TOPIC trial was a randomized controlled trial (RCT), designed to assess short- and long-term treatment efficacy, side effects and quality of life of imiquimod treatment compared to observational management and LLETZ treatment. Additionally, we aimed to identify prognostic biomarkers for spontaneous regression in the observational arm. Inclusion of women was first hampered by the observational arm: most women preferred treatment instead of watchful waiting. After removal of the observational arm, inclusion was further hampered by a strong preference of women for either of the treatment modalities. Consequently, the TOPIC trial was preliminary halted and converted to a non- randomized study, to evaluate the treatment efficacy and clinical applicability of imiquimod cream as compared to LLETZ, in selected populations of women with a preference for either of the two treatment modalities (TOPIC-3 study). The patient inclusions of the TOPIC-3 study have been completed at the time of writing, 4 months prior to the expected completion date.
Conclusion
This thesis discusses alternative strategies in the treatment of high-grade CIN. Based on the available biomarker research and our assessment of HLA types and the 3q26 locus, it is not yet possible to adequately predict the natural history of high-grade CIN lesions in general. In CIN2, simple clinical biomarkers can give an indication of the individual likelihood of disease regression, aiding shared decision-making regarding treatment options. While observational management of CIN2 is considered safe and can be applied, adequate treatment modalities for CIN3 remain vital. Imiquimod as a treatment modality for high-grade CIN may be a suitable alternative to surgical treatment for women who want to refrain from surgery, in order to reduce side effects of surgical excision.
10
Discussion
195