Assessing lead time of selected ovarian cancer biomarkers: a nested case-control study

Abstract

Background: CA125, human epididymis protein 4 (HE4), mesothelin, B7-H4, decoy receptor 3 (DcR3), and spondin-2 have been identified as potential ovarian cancer biomarkers. Except for CA125, their behavior in the prediagnostic period has not been evaluated.

Methods: Immunoassays were used to determine concentrations of CA125, HE4, mesothelin, B7-H4, DcR3, and spondin-2 proteins in prediagnostic serum specimens (1-11 samples per participant) that were contributed 0-18 years before ovarian cancer diagnosis from 34 patients with ovarian cancer (15 with advanced-stage serous carcinoma) and during a comparable time interval before the reference date from 70 matched control subjects who were participating in the Carotene and Retinol Efficacy Trial. Lowess curves were fit to biomarker levels in cancer patients and control subjects separately to summarize mean levels over time. Receiver operating characteristic curves were plotted, and area-under-the curve (AUC) statistics were computed to summarize the discrimination ability of these biomarkers by time before diagnosis.

Results: Smoothed mean concentrations of CA125, HE4, and mesothelin (but not of B7-H4, DcR3, and spondin-2) began to increase (visually) in cancer patients relative to control subjects approximately 3 years before diagnosis but reached detectable elevations only within the final year before diagnosis. In descriptive receiver operating characteristic analyses, the discriminatory power of these biomarkers was limited (AUC statistics range = 0.56-0.75) but showed increasing accuracy with time approaching diagnosis (eg, AUC statistics for CA125 were 0.57, 0.68, and 0.74 for > or = 4, 2-4, and <2 years before diagnosis, respectively).

Conclusion: Serum concentrations of CA125, HE4, and mesothelin may provide evidence of ovarian cancer 3 years before clinical diagnosis, but the likely lead time associated with these markers appears to be less than 1 year.

Figure 1

Times of blood collections and ovarian cancer diagnosis among women who developed ovarian cancer during the Carotene and Retinol Efficacy Trial. Open circles = times of blood collections; solid circles = time of ovarian cancer diagnosis.

Figure 2

Lowess curves of standardized marker levels by time before diagnosis or reference date. Standardized marker levels were rescaled to have a mean of 0 and a SD of 1 among control subjects. A) CA125. One cancer patient and one control subject had standardized CA125 levels that were greater than 6 and so were excluded from the graph. B) Human epididymis protein 4. C) Mesothelin. D) B7-H4. E) Decoy receptor 3. F) Spondin-2. Dx = diagnosis.

Figure 3

Receiver operating characteristics curves by time before diagnosis. Standardized biomarker levels were used for this analysis and were rescaled to have a mean of 0 and a SD of 1 among control subjects. A) CA125. B) Human epididymis protein 4. C) Mesothelin. D) B7-H4. E) Decoy receptor 3. F) Spondin-2. AUC = area under the curve.

Figure 4

Lowess curves of standardized marker levels by time before diagnosis or reference date (A–D) and corresponding receiver operating characteristic curves by time before diagnosis (E–H) for composite markers. A and E) Composite marker 1 (defined for each observation on each woman as the sum of her CA125, human epididymis protein 4 [HE4], and mesothelin levels). B and F) Composite marker 2 (similarly defined as the sum of levels of all markers). One cancer patient had a value for composite marker 2 that was greater than 12 and so was excluded from the graph in (B). C and G) Composite marker 3 (defined for each observation on each woman as the maximum of her standardized CA125, HE4, or mesothelin levels). D and H) Composite marker 4 (similarly defined as the maximum of all marker levels). One cancer patient and one control subject had values for composite markers 3 and 4 that were greater than 6 and so were excluded from the graphs in (C) and (D). Dx = diagnosis; AUC = area under the curve.