Page 47 - Strategies for non-invasive managementof high-grade cervical intraepithelial neoplasia - prognostic biomarkers and immunotherapy Margot Maria Koeneman

Critical appraisal of candidate biomarkers
All candidate biomarkers were evaluated according to two principles. First, we focus on those 2 biomarkers with a clear role in the natural history of high-grade CIN. Second, their prognostic
value and clinical applicability was evaluated according to established criteria. Pepe et al. have
proposed a design to determine applicability of diagnostic and prognostic candidate biomarkers:
the prospective-specimen-collection, retrospective-blinded-evaluation (PROBE) design.(20) They state that the development of a functional biomarker should go through several stages: discovery of the biomarker, determination of its classification accuracy and finally the validation of its impact on the prediction of clinical outcome. Their design consist of four key components: 1. clinical context and outcome; 2. biomarker performance criteria; 3. biomarker test characteristics and 4. study size. For a more detailed information on their criteria, we refer to their publication on this subject. The majority of potential biomarkers in CIN have been evaluated for diagnostic and not for prognostic purposes.(75) Those studies that were performed on potential prognostic biomarkers in cervical precancerous lesions were mainly conducted in patients with low-grade CIN or cytological abnormalities as opposed to patients with high-grade CIN. Nevertheless, a substantial number of studies have been identified that evaluated biomarkers in the natural history of high-grade CIN and were discussed above. An overview all identified prognostic biomarkers in CIN can be found in table 1, which also provides a concise summary of their evaluation.
None of the studies were performed according to the PROBE criteria for determination of applicability of diagnostic and prognostic candidate biomarkers. Nonetheless, several biomarkers have been identified that show an association with the natural history of histologically proven high-grade CIN or have been identified as promising in this regard: they are associated at least with the natural history of low grade CIN or cytological abnormalities or are recently discovered biomarkers that warrant further investigation in their role as potential prognostic biomarkers. Of special interest are HLA subtypes, markers of the lymphoproliferative response and telomerase amplification (reflecting host factors in the natural history of CIN), viral genotype and viral DNA methylation (reflecting viral factors in the natural history of CIN), and Ki67, p53 and pRb (reflecting cellular factors in the natural history of CIN). HLA subtypes influence the individual immune response and could therefore influence the individual capacity for clearance of HPV and HPV-induced cervical lesions. One HLA subtype was identified in a prospective study, that was associated with decreased disease regression of high-grade CIN. This subtype is carried by approximately half of the population. Individual differences in immune response to HPV infection and cervical precancerous lesions can also be reflected in differences in the lymphoproliferative response. HPV induced lesions are cleared by the cellular immune response. Indeed, markers of a stronger T-cell response have been associated with disease clearance, whereas increased regulatory T-cells (acting as immune suppressors) have been associated with disease persistence.
A review of prognostic biomarkers
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