Use of CA125 and HE4 serum markers to predict ovarian cancer in elevated-risk women.
BACKGROUND
Serum markers are used before pelvic imaging to improve specificity and positive predictive value (PPV) of ovarian cancer multimodal screening strategies.


METHODS
We conducted a randomized controlled pilot trial to estimate surgical PPV of a "2 of 3 tests positive" screening rule, and to compare use of HE4 as a first-line (Arm 1) versus a second-line (Arm 2) screen, in women at high and elevated risk for epithelial ovarian cancer (EOC) at five study sites. Semiannual screening was offered to 208 women ages 25 to 80 years with deleterious BRCA germline mutations and to 834 women ages 35 to 80 years with pedigrees suggesting inherited susceptibility. Annual screening was offered to 130 women ages 45 to 80 years (Risk Group 3) with epidemiologic and serum marker risk factors. Rising marker levels were identified using the parametric empirical Bayes algorithm.


RESULTS
Both strategies yielded surgical PPV above 25%. Protocol-indicated surgery was performed in 6 women, identifying two ovarian malignancies and yielding a surgical PPV in both arms combined of 33% (95% confidence interval: 4%-78%), 25% in Arm 1 and 50% in Arm 2. Surgical consultation was recommended for 37 women (26 in Arm 1 and 11 in Arm 2). On the basis of 12 women with at least 2 of 3 tests positive (CA125, HE4, or imaging), an intent-to-treat analysis yielded PPV of 14% in Arm 1 and 20% in Arm 2.


CONCLUSIONS
Positive screens were more frequent when HE4 was included in the primary screen.


CONCLUSIONS
HE4 may be useful as a confirmatory screen when rising CA125 is used alone as a primary screen.
Authors' Affiliations: Cedars-Sinai Medical Center, Los Angeles; Beth.Karlan@cshs.org.
Beth Y
BY
Karlan
Fred Hutchinson Cancer Research Center;
Jason
J
Thorpe
Fred Hutchinson Cancer Research Center;
Kate
K
Watabayashi
Fred Hutchinson Cancer Research Center; Pacific Gynecology Specialists, Seattle, Washington;
Charles W
CW
Drescher
City of Hope Comprehensive Cancer Center, Duarte;
Melanie
M
Palomares
Fox Chase Cancer Center, Philadelphia, Pennsylvania; and.
Mary B
MB
Daly
Pacific Gynecology Specialists, Seattle, Washington;
Pam
P
Paley
Stanford University, Palo Alto, California;
Paula
P
Hillard
Fred Hutchinson Cancer Research Center;
M Robyn
MR
Andersen
Fred Hutchinson Cancer Research Center;
Garnet
G
Anderson
Dana Farber Cancer Center, Boston, Massachusetts.
Ronny
R
Drapkin
Fred Hutchinson Cancer Research Center;
Nicole
N
Urban
D000368:Aged; D000369:Aged, 80 and over; D000465:Algorithms; D014408:Biomarkers, Tumor / Q000097:blood*; D018394:CA-125 Antigen / Q000097:blood*; D000077216:Carcinoma, Ovarian Epithelial; D055088:Early Detection of Cancer / Q000379:methods*; D005260:Female; D019398:Genes, BRCA1; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D008565:Membrane Proteins / Q000097:blood*; D008875:Middle Aged; D009375:Neoplasms, Glandular and Epithelial / Q000097:blood* / Q000235:genetics; D010051:Ovarian Neoplasms / Q000097:blood* / Q000235:genetics; D010865:Pilot Projects; D011237:Predictive Value of Tests; D011506:Proteins / Q000032:analysis*; D012372:ROC Curve; D012680:Sensitivity and Specificity; D000081102:WAP Four-Disulfide Core Domain Protein 2
D014408:Biomarkers, Tumor; D018394:CA-125 Antigen; C451759:MUC16 protein, human; D008565:Membrane Proteins; D011506:Proteins; D000081102:WAP Four-Disulfide Core Domain Protein 2; C569698:WFDC2 protein, human