Page 56 - Strategies for non-invasive managementof high-grade cervical intraepithelial neoplasia - prognostic biomarkers and immunotherapy Margot Maria Koeneman

Chapter 2
several markers reflecting host, viral and cellular functions in cervical oncogenesis. Of the currently available composite biomarker profiles, one was developed for the natural history of CIN 1-2. The other composite biomarker profile was developed for high-grade CIN, but could still be improved in terms of predictive value. These two composite biomarker profiles offer a good basis for further development and could be supplemented with other potential prognostic biomarkers.
In conclusion, although several promising biomarkers have been identified for the prediction of the natural history of high-grade CIN, no single biomarker or biomarker profile is currently approaching implementation in clinical practice. Additional clinical trials are necessary to determine their true clinical value. These trials should be carried out in prospective study designs, according to the PROBE criteria.
Five-year view
In concordance with the optimization of HPV and CIN screening and diagnosis, we expect improvement in the field of CIN treatment in the next five years. Medical decision making and treatment of disease is increasingly individualized and based upon individual wishes and characteristics. Currently, all high-grade CIN lesions are treated by LLETZ, as their natural behaviour is unpredictable. As a substantial subset of high-grade CIN lesions regress spontaneously, standard treatment with LLETZ leads to overtreatment. This is particularly disadvantageous for patients with a future pregnancy wish, as they are at increased risk of subfertility and premature birth in subsequent pregnancies. We advocate the development of an adequate biomarker profile in the next five years, by which the behaviour of the individual high-grade CIN lesions can be predicted. This offers the opportunity for an individualized treatment strategy, in which a wait- and-see policy could be applied in those cases in which regression is expected. This is beneficial for both patients, who will be subjected to less overtreatment and associated side effects, and for health care providers, who benefit from less therapeutic colposcopies and probably lower costs.
Aiming to reduce overtreatment of CIN lesions, an increasing number of studies is being conducted on conservative treatment strategies for CIN, including treatment by therapeutic vaccination, topical imiquimod or intralesional interferons. The limited study results show that these treatments may be effective, but only in a subset of patients, making these treatment modalities unfit for application in the general patient population. In line with the development of a biomarker profile for the prediction of the natural history of CIN, a biomarker profile may be developed predicting the response to conservative treatment modalities. This may lead to the differentiation between high-grade CIN patients who will and will not show spontaneous regression and patients who will and will not respond to conservative treatment, leaving only a subset of patients for treatment with LLETZ.
In order to realize these goals, more research on established and potential prognostic biomarkers is necessary. The prognostic value of several viral and host factors, such as viral genotype and markers of lymphoproliferative response, and several well-known cell cycle markers has been established in the past. Other markers have only recently been identified in HPV induced lesions
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