title: Interpretation of single and serial measures of HE4 and CA125 in asymptomatic women at high risk for ovarian cancer.
abstract: BACKGROUND
  Human epididymis protein 4 (HE4) is approved for clinical use with CA125 to predict epithelial ovarian cancer in women with a pelvic mass or in remission after chemotherapy. Previously reported reference ranges for HE4 are inconsistent.
  
  
  METHODS
  We report positivity thresholds yielding 90%, 95%, 98%, and 99% specificity for age-defined populations of healthy women for HE4, CA125, and Risk of Ovarian Malignancy Algorithm (ROMA), a weighted average of HE4 and CA125. HE4 and CA125 were measured in 1,780 samples from 778 healthy women aged >25 years with a documented deleterious mutation, or aged >35 years with a significant family history. Effects on marker levels of a woman's age, ethnicity, and epidemiologic characteristics were estimated, as were the population-specific means, variances, and within- and between-woman variances used to generate longitudinal screening algorithms for these markers.
  
  
  RESULTS
  CA125 levels were lower with Black ethnicity (P = 0.008). Smoking was associated with higher HE4 (P = 0.007) and ROMA (P < 0.019). Continuous oral contraceptive use decreased levels of CA125 (P = 0.041), and ROMA (P = 0.12). CA125 was lower in women age ≥55, and HE4 increased with age (P < 0.01), particularly among women age ≥55.
  
  
  CONCLUSIONS
  Because of the strong effect of age on HE4, thresholds for HE4 are best defined for women of specific ages. Age-specific population thresholds for HE4 for 95% specificity ranged from 41.4 pmol/L for women age 30 to 82.1 pmol/L for women age 80.
  
  
  CONCLUSIONS
  Incorporation of serial marker values from screening history reduces personalized thresholds for CA125 and HE4 but is inappropriate for ROMA.
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, M2-B230, P.O. Box 19024, Seattle, WA 98109, USA. nurban@fhcrc.org.
authors.forename: Nicole
authors.initials: N
authors.lastname: Urban
authors.forename: Jason
authors.initials: J
authors.lastname: Thorpe
authors.forename: Beth Y
authors.initials: BY
authors.lastname: Karlan
authors.forename: Martin W
authors.initials: MW
authors.lastname: McIntosh
authors.forename: Melanie R
authors.initials: MR
authors.lastname: Palomares
authors.forename: Mary B
authors.initials: MB
authors.lastname: Daly
authors.forename: Pamela
authors.initials: P
authors.lastname: Paley
authors.forename: Charles W
authors.initials: CW
authors.lastname: Drescher
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000465:Algorithms; D018394:CA-125 Antigen / Q000378:metabolism*; D000077216:Carcinoma, Ovarian Epithelial; D005260:Female; D006801:Humans; D016014:Linear Models; D008137:Longitudinal Studies; D008875:Middle Aged; D009375:Neoplasms, Glandular and Epithelial / Q000378:metabolism* / Q000473:pathology; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000473:pathology; D011506:Proteins / Q000378:metabolism*; D012307:Risk Factors; D000081102:WAP Four-Disulfide Core Domain Protein 2
chemical_list: D018394:CA-125 Antigen; D011506:Proteins; D000081102:WAP Four-Disulfide Core Domain Protein 2; C569698:WFDC2 protein, human