Surrogate endpoint biomarkers and their modulation in cervical chemoprevention trials.

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 been published 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.