Surrogate endpoint biomarkers and their modulation in cervical chemoprevention trials

Abstract

BACKGROUND. Surrogate endpoint biomarkers (SEBs) are used as intermediate indicators of a reduction in cancer incidence in chemoprevention studies. SEBs should be expressed differentially in normal and high risk tissue; appear at a well defined stage of carcinogenesis; be studied with reasonable sensitivity, specificity, and accuracy; and be modulated in chemoprevention trials. The concept of SEBs may be useful in the trials of many new therapies. METHODS.The current review includes a comprehensive review of the literature.Many SEBs have been the subject of intense study and include quantitative histopathology and cytology, proliferation markers, regulation markers, differentiation markers, general genomic instability markers, and tissue maintenance markers. Because of the critical biologic and epidemiologic role of the human papillomavirus (HPV) in cervical carcinogenesis, the relation between these markers and HPV should be considered. In addition, biomarkers of HPV infection and its regression should be sought. RESULTS. Several chemoprevention trials have beenpublished that have included the use of SEBs. The biomarkers that appear most promising in these clinical trials can be measured quantitatively and reproducibly: quantitative histology and cytology, proliferating cell nuclear antigen (PCNA), MIB-1, MPM-2, HPV viral load, epidermal growth factor receptor, polyamines, and ploidy. The markers that have been demonstrated to be modulated in chemoprevention trials in the literature are quantitative histology and cytology, PCNA, MPM-2, HPV viral load, and polyamines. CONCLUSIONS.The surrogate endpoint biomarkers of most interest in future research should correlate well with HPV infection, be modulated by several therapeutic agents, and have limited variability and ease in measurement. Cancer 2001;

Spontaneous Regression of High-Grade Cervical Dysplasia: Effects of Human Papillomavirus Type and HLA Phenotype

“…The prevalence of HPV in this cohort was 100% and 98% for high-risk types (16,18,26,31,33,35,39,45, 51, 52, 56, 58, 59, 68, 73, and W13b). HPV16 was found in 68%.…”

The Indicators of Predicting Disease Outcome in HPV Carcinogenesis

“…lrHPV types tend to be associated with polyclonal lesions whereas hrHPV types are associated with monoclonal lesions (Park et al, 1996). Ploidy appears to be a measurable biomarker and a good predictor of the biological behaviour with a better predictive value than the histopathologic characteristics (Follen and Schottenfeld, 2001). It is considered that in advanced dysplastic lesions, aneuploidy precedes HPV integration, further supporting the notion that integration of viral genomes is the consequence and not the cause of chromosomal instability and transformation (Melsheimer et al 2004).…”

“…The risk of progression toward invasive cancer increases with the lesions' grade (Ostor 1993), thus, biomarkers specifically associated with disease progression, allowing for a correct triage must improve the cervical cancer screening www.intechopen.com programs and the early detection of people at risk. Therefore, in order to be useful, the biomarkers must meet the following criteria: (1) they must be differently expressed in normal and high-risk tissues; (2) they should be synthesised in a well defined stage of carcinogenesis; (3) both the marker and its assay must be acceptable sensitive, specific and accurate; (4) they should be easily measured; (5) they should be correlated with a decrease in the cancer incidence rate (Follen and Schottenfeld, 2001). The inherent variability in interpretation between individuals has led to wide ranges in diagnostic precision between practices, but the advent of immunohistochemistry and the more recent discovery of new genes and their functions have resulted in the identification of cellular proteins that are differently expressed in tumours (Nucci et al, 2003).…”

Cervical cancer chemoprevention, vaccines, and surrogate endpoint biomarkers

“…In addition, because the carcinogenic role of the human papillomavirus (HPV) in cervical cancer has been established both in the field of molecular biology and epidemiology, many of these pharmaceuticals have been tested for their ability to suppress the production of viral oncoproteins. 28 A few of these agents have been subjected to rigorous Phase I study design. 3,4 The only agent that has been demonstrated to cause regression of CIN/SILs in a randomized controlled trial in a statistically significant manner in a trial of sufficient sample size is topical all-trans-retinoic acid.…”

“…Classes of surrogate endpoint biomarkers are listed in Table 3. 28 Both vaccines and pharmaceuticals that suppress HPV are of interest. HPV vaccines are being developed following two strategies: preventive and therapeutic.…”