Dhingra K, Vogel V, Sneige N, Sahin A, Aldaz C M, Hortobagyi G N, Hittelman W
University of Texas M.D. Anderson Cancer Center, Department of Breast and Gynecologic Medical Oncology, Houston 77030.
J Cell Biochem Suppl. 1993;17G:37-43. doi: 10.1002/jcb.240531106.
Current chemoprevention trial designs based on epidemiological risk assessment and occurrence of cancer as an endpoint are inefficient and expensive. Novel biomarkers are needed to facilitate the development of chemopreventive interventions. The following four categories of biomarkers may be useful in prevention trials: histologic and morphometric markers; phenotypic markers of dysregulated proliferation, differentiation, and cell loss; specific oncogenes and growth regulators which are qualitatively or quantitatively altered in breast cancers; and markers of genetic and epigenetic instability. Some of these markers will be generally useful regardless of the chemopreventive approach used, whereas others may be uniquely useful in trials of specific chemopreventive agents [e.g., upregulation of progesterone receptor (PR) expression in response to tamoxifen]. The development of these markers requires three phases of study: "Phase I": assessing the prevalence of the putative marker in malignant and premalignant tissue from individuals who have developed breast cancer; "Phase II": assessing in vivo modulation of the biomarker by the proposed chemopreventive agent; and "Phase III": applying the proposed biomarker in larger-scale trials of chemopreventive agent in high-risk populations, either before or after the development of a primary breast malignancy. The use of these biomarkers may also allow identification of novel targets for chemoprevention.
目前基于流行病学风险评估并以癌症发生作为终点的化学预防试验设计效率低下且成本高昂。需要新型生物标志物来促进化学预防干预措施的开发。以下四类生物标志物可能在预防试验中有用：组织学和形态学标志物；增殖、分化和细胞丢失失调的表型标志物；在乳腺癌中发生定性或定量改变的特定癌基因和生长调节因子；以及遗传和表观遗传不稳定性的标志物。无论使用何种化学预防方法，其中一些标志物通常都有用，而其他一些标志物可能在特定化学预防剂的试验中具有独特的用途[例如，他莫昔芬诱导的孕激素受体（PR）表达上调]。这些标志物的开发需要三个阶段的研究：“第一阶段”：评估已患乳腺癌个体的恶性和癌前组织中假定标志物的流行情况；“第二阶段”：评估所提议的化学预防剂对生物标志物的体内调节作用；“第三阶段”：在高危人群中，在原发性乳腺癌发生之前或之后，将所提议的生物标志物应用于化学预防剂的大规模试验中。这些生物标志物的使用还可能有助于确定化学预防的新靶点。
