Page 55 - Strategies for non-invasive managementof high-grade cervical intraepithelial neoplasia - prognostic biomarkers and immunotherapy Margot Maria Koeneman

This review aims to identify potential prognostic biomarkers that predict the natural behaviour
of high-grade CIN. The natural history of high-grade CIN is determined by an interaction of viral
and host factors that influence cellular processes in cervical oncogenesis. Candidate biomarkers 2 should therefore ideally have a clear role in the natural history of CIN, reflecting associated host,
viral and cellular factors. An adequate immune response seems to be of utmost importance in
cervical carcinogenesis, as this should clear HPV infection or cervical precursor lesions before irreversible effects of HPV E6 and E7 on the cell cycle processes have been induced and the
immune system is evaded. This “immunoediting hypothesis” was recently illustrated by Umar,
and assumes sculpting of the tumours’ ability to be recognized by the immune system. This leads
to active immune evasion in later stages of oncogenesis, whereas early stages are recognized
and subsequently cleared by the immune system.(85) In this context, it is not surprizing that methylation assays (as a surrogate marker of the accumulation of genetic and epigenetic changes
as a result of persisting effects of HPV E6 and E7 expression in high-grade CIN) are highly efficient
at detecting advanced high-grade CIN lesions.(21)
Several candidate prognostic biomarkers for the natural history of high-grade CIN were identified in this review. However, none of the studies have been conducted according to the PROBE-criteria. Furthermore, the quality of evidence for those markers that have been associated with disease prognosis is often poor: studies sizes are small and selection criteria and outcome measures show great diversity. Investigation of prognostic biomarkers in high-grade CIN should ideally be performed in prospective follow-up studies on high-grade CIN, to evaluate lesion regression or progression in relation to a biomarker at baseline. The conduction of long-term prospective observational studies is impossible for high-grade CIN patients, due to obvious ethical reasons. One such study was performed, in which women with high-grade CIN were withheld from treatment. Over 30% of these women developed cervical cancer, compared to less than 1% of women receiving treatment.(5) For the identification of candidate prospective biomarkers, we therefore rely largely on short term prospective or retrospective observational studies, in which lesion development in high-grade CIN patients is observed in the time interval between diagnosis and treatment, as was done by Munk and Trimble et al.(6, 8) This seems to be the best alternative for the evaluation of prognostic biomarkers in high-grade CIN. However, such studies should ideally be conducted according to the PROBE-criteria in order to ensure adequate and uniform interpretation of study results.
None of the reviewed candidate prognostic biomarkers is yet approaching application in clinical practice. Nevertheless, several of the identified candidate prognostic biomarkers are of special interest, as they have a clear role in the natural history of high-grade CIN and have been associated with disease regression or progression in one or more studies. These include HLA polymorphisms, markers of the lymphoproliferative response (CD4+, CD8+, CD25 and CD138) and telomerase amplification as host factors, viral genotype and viral DNA methylation as viral factors and cell cycle markers p53, Rb and Ki67. Additional research is needed to evaluate HPV-induced epigenetic effects as prognostic biomarkers, as current evidence is promising but insufficient to draw conclusions. As no single biomarker offers sufficient prognostic value, we believe that prediction of the natural history of CIN will most probably be based on a biomarker profile, consisting of
A review of prognostic biomarkers
53