Combining CA 125 and SMR serum markers for diagnosis and early detection of ovarian carcinoma
Introduction
CA 125 can identify 85% of clinically advanced ovarian carcinomas [1], [2], [3], and several studies have shown that deviations in CA 125 may occur 18 months or more before clinical diagnosis [4], [5]. Thus, monitoring CA 125 could lead to identifying ovarian cancer long before it is clinically apparent. Moreover, the ability of CA 125 to detect cancer early in a screening program is supported by the observation that individual women have temporally stable levels of CA 125 [6], suggesting that specially tailored screening algorithms could lead to detecting the disease based on very small deviations in CA 125 levels [7], [8], [9], [10]. Presently, a large randomized trial evaluating longitudinal change in CA 125 for ovarian cancer early detection is underway in the United Kingdom [11].
Although CA 125 is the best available single marker for ovarian cancer, its sensitivity and specificity may not be sufficient for screening average-risk postmenopausal women. In particular, it is elevated above reference levels in only 50% of clinically detectable early stage disease [1], [2], [3] and is not infrequently elevated in patients with benign ovarian tumors. Adding one or several markers to CA 125 for use as a composite marker (CM) would improve diagnostic performance if sensitivity were improved with no loss in specificity.
Proposals to combine other markers with CA 125 have been made previously, and investigators have evaluated the ability of some established markers to improve the identification of clinical disease [12], [13]. Here, we evaluate the performance of a composite marker (CM) consisting of CA 125 and a novel marker SMR [14]. We report and compare the ability of CA 125, SMR, and the CM to distinguish the serum of women with clinically detected ovarian cancer from that of women with benign ovarian tumors and healthy women. In addition, we report the temporal stability of the three markers to assess whether each can improve their sensitivity when used in a longitudinal algorithm [6], [15]. We use receiver operating characteristic (ROC) methods to show that the CM has higher sensitivity than either marker used alone, maintaining overall specificity with respect to benign ovarian tumors as well as a healthy screening population. We use correlation analysis to demonstrate that the CM maintains the high temporal stability of CA 125, which implies that its superiority over CA 125 may also hold when used in a longitudinal screening algorithm.
Section snippets
SMR ELISA assay
SMR was measured by a sandwich ELISA [14] that uses monoclonal antibodies (MAbs) to two different epitopes expressed on molecules expressed by the mesothelin [16], [17] and megakaryocyte potentiating factor (MPF) [18] family, including a recently described soluble molecule that has an 82-bp insert in the membrane-associated part of mesothelin and MPF [14]. These molecules are overexpressed in >95% of ovarian carcinomas according to immunohistology, while their expression in normal tissues,
Marker behavior in healthy subjects
For CA 125, SMR, and the CM, we found no statistically significant differences in marker levels with respect to age, hormone replacement therapy (HRT) use, and race. Menopausal status approached statistical significance for CA 125 (P = 0.08), but not for SMR (P = 0.37) nor for the CM (P = 0.67). Table 4 summarizes the levels of CA 125 and SMR for healthy subjects and for women with benign ovarian tumors by menopausal status, and for ovarian cancer cases by stage of disease at diagnosis. The
Discussion
We evaluated the performance of two markers, CA 125 and SMR, and their composite marker (CM) for several performance characteristics relevant to their potential use in diagnosis and early detection. The best individual marker for diagnosis was found to be CA 125, which performed as published. However, a CM combining CA 125 with SMR was superior to using CA 125 alone to diagnose cancer, and our results suggest that the improvement in sensitivity to cancer may occur in the range of specificity
Acknowledgments
We thank Dr. Nancy Kiviat for characterization of specimens, Mrs Pernilla Wintzell and Mr. John Raycraft for performing ELISA assays, Suepattra May for management of specimens, Alicia Sato for assistance in data analysis, and Edyta Bojanowska for manuscript editing. The work was supported by NCI grants CA 85780 (I. Hellstrom and K.E. Hellstrom), R01 CA75494 (McIntosh, Urban, and Drescher), and P50 CA83636 (all authors) and by DOD grant DAMD-17-98-1-8649 (Urban and Drescher).
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