Page 54 - Strategies for non-invasive managementof high-grade cervical intraepithelial neoplasia - prognostic biomarkers and immunotherapy Margot Maria Koeneman

Chapter 2
Although study results are not always consistent, additional research on markers of the immune response as prognostic biomarkers seems appropriate. After all, HPV and HPV-induced cervical lesions are cleared by the immune system. Telomerase amplification is a well-known contributor to carcinogenesis and expression hTERC (a template in telomere elongation) is associated with CIN grade and with progression of low-grade CIN. No evidence is available on its prognostic value in high-grade CIN, but its established role in carcinogenesis makes it a promising biomarker, in need of additional research. Viral genotype could serve as a prognostic biomarker. Individual differences in oncogenic potential of different HPV-types is well known and HPV16 is associated with a decreased rate of disease regression. Viral DNA methylation of CpG-sites has recently been proven an effective diagnostic biomarker. DNA methylation, as an epigenetic effect, causes altered gene expression and has been associated with many types of cancer. Evidence on the prognostic effects of viral DNA methylation in the natural history of CIN is limited, as this marker was only recently introduced. A first study on low-grade CIN shows promising results, however. Cell cycle factors reflect the cellular processes causing cervical lesions. Lower p53 and pRb was associated with disease persistence in HSIL, probably reflecting in enhanced effect of viral E6 and E7 and increased oncogenic effect. Ki67 reflects cell proliferation as a result of increased E2F, and was associated with progression of CIN 1-2. Its prognostic effect could not be confirmed in high- grade CIN. However, the amount of studies on the prognostic effect of Ki67 is limited and the only study on its role in high-grade CIN was performed in a small patient population. Furthermore, its prognostic value in low-grade CIN was substantial and Ki67 serves has an established role in cervical carcinogenesis. We therefore feel that further research in high-grade CIN seems sensible.
The above mentioned promising biomarkers have all been associated with the natural history of CIN. However, we also advocate further investigation of HPV-induced epigenetic effects. Recently, HPV-induced methylation of host-DNA has been proven a valuable biomarker in CIN diagnostics, as was discussed before. Following on this, its value as a prognostic biomarker should be assessed.
Expert commentary
High-grade CIN is the precursor of cervical carcinoma, one of the most common types of cancers in women worldwide. Prevention of cervical cancer is based on both screening for cervical cancer precursor lesions and adequate treatment of such lesions. Both cervical cancer screening and treatment of high-grade CIN has led to a decreased incidence of cervical cancer, but screening and treatment practices can still be improved. Cervical cancer screening has recently been improved by the introduction of primary HPV-typing. Furthermore, the implementation of biomarkers in cervical cancer screening is being investigated and shows promising results. Treatment of cervical cancer precursor lesions could also be further improved, with the main purpose of reducing overtreatment and under-treatment. Because the natural behaviour of high-grade CIN is still unpredictable, most of such lesions are treated by surgical excision. Approximately 20-40% of all high-grade CIN lesions shows spontaneous regression. Identification of these lesions would make watchful waiting an option in selected patients, especially in those with a future pregnancy wish. Current histopathological assessment is unable to differentiate between high-grade CIN lesions that will regress spontaneously or not. Prognostic biomarkers may be helpful this differentiation.
52