Page 207 - Strategies for non-invasive managementof high-grade cervical intraepithelial neoplasia - prognostic biomarkers and immunotherapy Margot Maria Koeneman

Why is this thesis relevant?
Relevance of non-invasive management of high-grade CIN
High-grade Cervical Intraepithelial Neoplasia (CIN2 and CIN3) is the precursor of cervical cancer. Not all high-grade CIN lesions progress to cervical cancer: this happens in approximately 30% of lesions, while spontaneous regression occurs in 20-40% of cases. Because the natural prognosis of an individual lesion cannot be predicted, high-grade CIN lesions were – until recently – all treated by surgical excision. This obviously results in overtreatment of those lesions that would regress spontaneously. In the Netherlands, approximately 5,000 women are treated for high- grade CIN yearly, most commonly by surgical excision of the cervical transformation zone (Large Loop Excision of the Transformation Zone – LLETZ). This is an effective treatment modality, but it is associated with a twofold increase in the risk of premature birth in subsequent pregnancies, probably due to cervical insufficiency. Premature birth, both early and late, has significant impact on neonatal development and parental quality of life. The risk of premature birth after LLETZ treatment could be avoided by non-invasive management of high grade CIN.
The role of prognostic biomarkers in non-invasive management of high-grade CIN
A first strategy towards non-invasive treatment of high-grade CIN is observational management of those lesions that will show spontaneous regression. This would reduce overtreatment of high-grade CIN lesions. Current histopathological assessment is unable to differentiate between lesions that will progress to cervical cancer and those that will regress spontaneously. Instead, prognostic biomarkers could be applied to this aim. A wide variety of prognostic biomarkers has been studied, but none have reached clinical implementation. This thesis provides an overview of all studied prognostic biomarkers in high-grade CIN, which could serve as a general overview and as a basis for further research. Based on this review and our own biomarker studies, we have formulated several recommendations for future biomarker research, which include the application of the PROBE-criteria and the development of biomarker profiles or prediction models rather than individual markers.
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Valorisation
We developed one such biomarker profile for spontaneous regression of CIN2. Although guidelines recommend observational treatment of CIN2 in younger women, adherence to this recommendation is not optimal. This could be due to fear of disease progression by both the patient and the physician. Our prediction model can be applied in such cases, to provide patients (and physicians) with a more individual risk prediction. This improves individual counseling of women with CIN2 and may reassure women that observational treatment is a good option when the chances of disease regression are high. The model consists of simple clinical parameters, instead of expensive or complicated markers, to make it widely applicable. To improve individual counseling of women with hrHPV positive CIN2, which concerns almost all lesions since the introduction of the new cervical cancer screening program, we identified two prognostic markers in this subgroup of patients. Smoking status and parity influence the natural prognosis of hrHPV positive CIN2 and these factors can now be taken into account when counseling women with regard to treatment options in hrHPV positive CIN2.
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