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


CONCLUSIONS
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.
Anderson
Garnet L
GL
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, PO Box 19024, M3-A410, Seattle, WA 98109-1024, USA. garnet@whi.org
McIntosh
Martin
M
Wu
Lieling
L
Barnett
Matt
M
Goodman
Gary
G
Thorpe
Jason D
JD
Bergan
Lindsay
L
Thornquist
Mark D
MD
Scholler
Nathalie
N
Kim
Nam
N
O'Briant
Kathy
K
Drescher
Charles
C
Urban
Nicole
N
D000328:Adult; D000368:Aged; D019540:Area Under Curve; D018122:B7-1 Antigen / Q000097:blood; D014408:Biomarkers, Tumor / Q000097:blood*; D018394:CA-125 Antigen / Q000097:blood*; D016022:Case-Control Studies; D030501:Epididymal Secretory Proteins / Q000378:metabolism*; D016326:Extracellular Matrix Proteins / Q000097:blood; D005260:Female; D058851:GPI-Linked Proteins; D006801:Humans; D007118:Immunoassay; D008562:Membrane Glycoproteins / Q000097:blood*; D000090204:Mesothelin; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000097:blood; D010051:Ovarian Neoplasms / Q000097:blood* / Q000175:diagnosis*; D011237:Predictive Value of Tests; D012372:ROC Curve; D053323:Receptors, Tumor Necrosis Factor, Member 6b / Q000097:blood; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D060907:V-Set Domain-Containing T-Cell Activation Inhibitor 1; D023083:beta-Defensins
D018122:B7-1 Antigen; D014408:Biomarkers, Tumor; D018394:CA-125 Antigen; C426184:DEFB126 protein, human; D030501:Epididymal Secretory Proteins; D016326:Extracellular Matrix Proteins; D058851:GPI-Linked Proteins; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D053323:Receptors, Tumor Necrosis Factor, Member 6b; C122166:SPON2 protein, human; C505911:TNFRSF6B protein, human; D060907:V-Set Domain-Containing T-Cell Activation Inhibitor 1; C475826:VTCN1 protein, human; D023083:beta-Defensins; D000090204:Mesothelin