Crump C, McIntosh M W, Urban N, Anderson G, Karlan B Y
Department of Biostatistics, University of Washington, Seattle 98195, USA.
Cancer Epidemiol Biomarkers Prev. 2000 Oct;9(10):1107-11.
Ovarian cancer screening protocols generally have been limited by inadequate recognition of the normal behavior of tumor markers in women at risk of ovarian cancer. We have characterized the behavior of five serum tumor markers in a large cohort of healthy women and examined the implications for screening. Serial measurements of CA125, HER-2/neu, urinary gonadotropin peptide, lipid-associated sialic acid, and Dianon marker 70/K were obtained during 6 years of follow-up of 1257 healthy women at high risk of ovarian cancer. We analyzed individual-specific tumor marker behavior and explored methods that can exploit this information to develop individual-specific screening rules. These five tumor markers behaved approximately independently. Substantial heterogeneity was observed among women in the behavior of each tumor marker, particularly CA125. Intraclass correlation (ICC), or the proportion of total variability that occurs between individuals, was approximately 0.6 for log-transformed CA125 and urinary gonadotropin peptide, and less than 0.4 for the other markers. This degree of tumor marker heterogeneity among healthy women, and the relative independence of these markers, has important implications for screening and diagnostic tests. Independence of markers results in the clinically useful fact that the combined false positive rate from screening with multiple markers may be estimated by the sum of individual false positive rates. Heterogeneity of tumor marker patterns in healthy women implies that a fixed screening cutoff level is suboptimal to a degree that depends strongly on ICC. Using information on longitudinal measurements and ICC, individual-specific screening rules may be developed with the potential to improve early detection of ovarian cancer.
卵巢癌筛查方案通常受到限制，原因是对卵巢癌高危女性体内肿瘤标志物正常行为的认识不足。我们已对一大群健康女性体内五种血清肿瘤标志物的行为进行了特征描述，并研究了其对筛查的意义。在对1257名卵巢癌高危健康女性进行6年随访期间，对CA125、HER-2/neu、尿促性腺激素肽、脂质相关唾液酸和Dianon标志物70/K进行了系列测量。我们分析了个体特异性肿瘤标志物的行为，并探索了利用这些信息制定个体特异性筛查规则的方法。这五种肿瘤标志物的行为大致独立。在每种肿瘤标志物的行为方面，女性之间观察到了显著的异质性，尤其是CA125。对于对数转换后的CA125和尿促性腺激素肽，组内相关系数（ICC），即个体间总变异性的比例约为0.6，而其他标志物则小于0.4。健康女性中这种程度的肿瘤标志物异质性以及这些标志物的相对独立性，对筛查和诊断测试具有重要意义。标志物的独立性导致了一个临床上有用的事实，即通过多种标志物进行筛查时的联合假阳性率可通过个体假阳性率之和来估计。健康女性中肿瘤标志物模式的异质性意味着固定的筛查临界值在一定程度上是次优的，这在很大程度上取决于ICC。利用纵向测量和ICC的信息，可以制定个体特异性筛查规则，有可能改善卵巢癌的早期检测。
