Follen M, Schottenfeld D
Department of Gynecologic Oncology, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Cancer. 2001 May 1;91(9):1758-76. doi: 10.1002/1097-0142(20010501)91:9<1758::aid-cncr1195>3.0.co;2-1.
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.
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.
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.
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.
替代终点生物标志物（SEBs）在化学预防研究中用作癌症发病率降低的中间指标。SEBs应在正常组织和高危组织中差异表达；出现在明确的致癌阶段；以合理的敏感性、特异性和准确性进行研究；并在化学预防试验中得到调节。SEBs的概念可能在许多新疗法的试验中有用。
本综述对文献进行了全面回顾。许多SEBs一直是深入研究的对象，包括定量组织病理学和细胞学、增殖标志物、调节标志物、分化标志物、一般基因组不稳定性标志物和组织维持标志物。由于人乳头瘤病毒（HPV）在宫颈癌发生中的关键生物学和流行病学作用，应考虑这些标志物与HPV之间的关系。此外，还应寻找HPV感染及其消退的生物标志物。
已经发表了几项使用SEBs的化学预防试验。在这些临床试验中最有前景的生物标志物可以进行定量和可重复测量：定量组织学和细胞学、增殖细胞核抗原（PCNA）、MIB-1、MPM-2、HPV病毒载量、表皮生长因子受体、多胺和倍性。文献中已证明在化学预防试验中得到调节的标志物是定量组织学和细胞学、PCNA、MPM-2、HPV病毒载量和多胺。
未来研究中最感兴趣的替代终点生物标志物应与HPV感染密切相关，受多种治疗药物调节，变异性有限且易于测量。
