Identifying post-menopausal women at elevated risk for epithelial ovarian cancer.
OBJECTIVE
We developed and validated a hybrid risk classifier combining serum markers and epidemiologic risk factors to identify post-menopausal women at elevated risk for invasive fallopian tube, primary peritoneal, and ovarian epithelial carcinoma.


METHODS
To select epidemiologic risk factors for use in the classifier, Cox proportional hazards analyses were conducted using 74,786 Women's Health Initiative (WHI) Observational Study (OS) participants. To construct a combination classifier, 210 WHI OS cases and 536 matched controls with serum marker measurements were analyzed; validation employed 143 cases and 725 matched controls from the WHI Clinical Trial (CT) with similar data.


RESULTS
Analyses identified a combination risk classifier composed of two elevated-risk groups: 1) women with CA125 or HE4 exceeding a 98% specificity threshold; and 2) women with intact fallopian tubes, prior use of menopausal hormone therapy for at least two years, and either a first degree relative with breast or ovarian cancer or a personal history of breast cancer. In the WHI OS population, it classified 13% of women as elevated risk, identifying 30% of ovarian cancers diagnosed up to 7.8years post-enrollment (Hazard Ratio [HR]=2.6, p<0.001). In the WHI CT validation population, it classified 8% of women as elevated risk, identifying 31% of cancers diagnosed within 7years of enrollment (HR=4.6, p<0.001).


CONCLUSIONS
CA125 and HE4 contributed significantly to a risk prediction classifier combining serum markers with epidemiologic risk factors. The hybrid risk classifier may be useful to identify post-menopausal women who would benefit from timely surgical intervention to prevent epithelial ovarian cancer.
Fred Hutchinson Cancer Research Center, Seattle, WA, United States. Electronic address: nurban@fhcrc.org.
Nicole
N
Urban
Fred Hutchinson Cancer Research Center, Seattle, WA, United States.
Sarah
S
Hawley
Fred Hutchinson Cancer Research Center, Seattle, WA, United States.
Holly
H
Janes
Cedars-Sinai Medical Center, Los Angeles, CA, United States.
Beth Y
BY
Karlan
Johns Hopkins Medicine, Baltimore, MD, United States.
Christine D
CD
Berg
Fred Hutchinson Cancer Research Center, Seattle, WA, United States.
Charles W
CW
Drescher
Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States.
JoAnn E
JE
Manson
Cancer Prevention, Inc., Las Vegas NV and Keck School of Medicine, University of Southern California, Los Angeles, CA, United States.
Melanie R
MR
Palomares
Fox Chase Cancer Center, Philadelphia PA, United States.
Mary B
MB
Daly
University at Buffalo, SUNY, Buffalo, NY, United States.
Jean
J
Wactawski-Wende
University of Miami, Miami, FL, United States.
Mary J
MJ
O'Sullivan
Fred Hutchinson Cancer Research Center, Seattle, WA, United States.
Jason
J
Thorpe
University of Texas Health Science Center, San Antonio TX, United States.
Randal D
RD
Robinson
Stony Brook University, Stony Brook, NY, United States.
Dorothy
D
Lane
Fred Hutchinson Cancer Research Center, Seattle, WA, United States.
Christopher I
CI
Li
Fred Hutchinson Cancer Research Center, Seattle, WA, United States.
Garnet L
GL
Anderson
D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001942:Breast Feeding / Q000706:statistics & numerical data*; D001943:Breast Neoplasms / Q000453:epidemiology*; D018394:CA-125 Antigen / Q000378:metabolism; D000077216:Carcinoma, Ovarian Epithelial; D016022:Case-Control Studies; D003278:Contraceptives, Oral, Hormonal / Q000627:therapeutic use*; D015914:Estrogen Replacement Therapy / Q000706:statistics & numerical data*; D005260:Female; D006801:Humans; D008875:Middle Aged; D009375:Neoplasms, Glandular and Epithelial / Q000453:epidemiology* / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000453:epidemiology* / Q000378:metabolism; D010298:Parity; D017698:Postmenopause; D016016:Proportional Hazards Models; D011506:Proteins / Q000378:metabolism; D018570:Risk Assessment; D012307:Risk Factors; D013246:Sterilization, Tubal / Q000706:statistics & numerical data*; D013627:Talc / Q000627:therapeutic use; D000081102:WAP Four-Disulfide Core Domain Protein 2
D014408:Biomarkers, Tumor; D018394:CA-125 Antigen; D003278:Contraceptives, Oral, Hormonal; D011506:Proteins; D000081102:WAP Four-Disulfide Core Domain Protein 2; C569698:WFDC2 protein, human; D013627:Talc
CA125; HE4; Ovarian cancer; Risk prediction