Correlates of circulating ovarian cancer early detection markers and their contribution to discrimination of early detection models: results from the EPIC cohort.
BACKGROUND
Ovarian cancer early detection markers CA125, CA15.3, HE4, and CA72.4 vary between healthy women, limiting their utility for screening.


METHODS
We evaluated cross-sectional relationships between lifestyle and reproductive factors and these markers among controls (n = 1910) from a nested case-control study in the European Prospective Investigation into Cancer and Nutrition (EPIC). Improvements in discrimination of prediction models adjusting for correlates of the markers were evaluated among postmenopausal women in the nested case-control study (n = 590 cases). Generalized linear models were used to calculate geometric means of CA125, CA15.3, and HE4. CA72.4 above vs. below limit of detection was evaluated using logistic regression. Early detection prediction was modeled using conditional logistic regression.


RESULTS
CA125 concentrations were lower, and CA15.3 higher, in post- vs. premenopausal women (p ≤ 0.02). Among postmenopausal women, CA125 was higher among women with higher parity and older age at menopause (ptrend≤ 0.02), but lower among women reporting oophorectomy, hysterectomy, ever use of estrogen-only hormone therapy, or current smoking (p < 0.01). CA15.3 concentrations were higher among heavier women and in former smokers (p ≤ 0.03). HE4 was higher with older age at blood collection and in current smokers, and inversely associated with OC use duration, parity, and older age at menopause (≤ 0.02). No associations were observed with CA72.4. Adjusting for correlates of the markers in prediction models did not improve the discrimination.


CONCLUSIONS
This study provides insights into sources of variation in ovarian cancer early detection markers in healthy women and informs about the utility of individualizing marker cutpoints based on epidemiologic factors.
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, 69120, Germany. r.fortner@dkfz.de.
Renée T
RT
Fortner
Ob/Gyn Epidemiology Center, Brigham and Women's Hospital, Boston, MA, USA.
Allison F
AF
Vitonis
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, 69120, Germany.
Helena
H
Schock
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, 69120, Germany.
Anika
A
Hüsing
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, 69120, Germany.
Theron
T
Johnson
Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School, Boston, MA, USA.|Laboratory of Genital Tract Biology, Brigham and Women's Hospital, Boston, MA, USA.
Raina N
RN
Fichorova
Laboratory of Genital Tract Biology, Brigham and Women's Hospital, Boston, MA, USA.
Titilayo
T
Fashemi
Laboratory of Genital Tract Biology, Brigham and Women's Hospital, Boston, MA, USA.
Hidemi S
HS
Yamamoto
Unit of Diet, Genes and Environment, Danish Cancer Society Research Center, Copenhagen, Denmark.
Anne
A
Tjønneland
Unit of Diet, Genes and Environment, Danish Cancer Society Research Center, Copenhagen, Denmark.
Louise
L
Hansen
Department of Public Health, Section for Epidemiology, Aarhus University, Aarhus, Denmark.
Kim
K
Overvad
INSERM, Centre for Research in Epidemiology and Population Health (CESP), U1018, Nutrition, Hormones and Women's Health team, Villejuif, F-94805, France.|Université Paris Sud, UMRS 1018, Villejuif, F-94805, France.|Gustave Roussy, Villejuif, F-94805, France.
Marie-Christine
MC
Boutron-Ruault
INSERM, Centre for Research in Epidemiology and Population Health (CESP), U1018, Nutrition, Hormones and Women's Health team, Villejuif, F-94805, France.|Université Paris Sud, UMRS 1018, Villejuif, F-94805, France.|Gustave Roussy, Villejuif, F-94805, France.
Marina
M
Kvaskoff
INSERM, Centre for Research in Epidemiology and Population Health (CESP), U1018, Nutrition, Hormones and Women's Health team, Villejuif, F-94805, France.|Université Paris Sud, UMRS 1018, Villejuif, F-94805, France.|Gustave Roussy, Villejuif, F-94805, France.|Human Genetics Foundation (HuGeF), Torino, Italy.
Gianluca
G
Severi
Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany.
Heiner
H
Boeing
Hellenic Health Foundation, Athens, Greece.|WHO Collaborating Center for Nutrition and Health, Unit of Nutritional Epidemiology and Nutrition in Public Health, Dept. of Hygiene, Epidemiology and Medical Statistics, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.
Antonia
A
Trichopoulou
Hellenic Health Foundation, Athens, Greece.|WHO Collaborating Center for Nutrition and Health, Unit of Nutritional Epidemiology and Nutrition in Public Health, Dept. of Hygiene, Epidemiology and Medical Statistics, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.
Vassiliki
V
Benetou
Hellenic Health Foundation, Athens, Greece.|Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy.
Carlo
C
La Vecchia
Cancer Risk Factors and Life-Style Epidemiology Unit, Cancer Research and Prevention Institute - ISPO, Florence, Italy.
Domenico
D
Palli
Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Sabina
S
Sieri
Cancer Registry and Histopathology Unit, "Civic - M.P-Arezzo" Hospital, ASP, Ragusa, Italy.
Rosario
R
Tumino
Department of Medical Sciences, University of Torino and Human Genetics Foundation - HuGeF, Torino, Italy.
Giuseppe
G
Matullo
Dipartimeno di Medicina Clinica e Chirurgia, Federico II University, Naples, Italy.
Amalia
A
Mattiello
Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, Netherlands.
N Charlotte
NC
Onland-Moret
Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, Netherlands.|MRC-PHE Centre for Environment and Health, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College, London, UK.
Petra H
PH
Peeters
Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, The Arctic University of Norway, Tromsø, Norway.|Department of Research, Cancer Registry of Norway, Institute of Population-Based Cancer Research, Oslo, Norway.|Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.|Genetic Epidemiology Group, Folkhälsan Research Center, Helsinki, Finland.
Elisabete
E
Weiderpass
Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, The Arctic University of Norway, Tromsø, Norway.
Inger Torhild
IT
Gram
Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, The Arctic University of Norway, Tromsø, Norway.
Mie
M
Jareid
Public Health Directorate, Asturias, Spain.
J Ramón
JR
Quirós
Cancer Epidemiology Research Program, Bellvitge Biomedical Research Institute (IDIBELL), Catalan Institute of Oncology (ICO), Barcelona, Spain.
Eric J
EJ
Duell
Escuela Andaluza de Salud Pública, Instituto de Investigación Biosanitaria ibs.GRANADA, Hospitales Universitarios de Granada/Universidad de Granada, Granada, Spain.|CIBER de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.
Maria-Jose
MJ
Sánchez
Department of Epidemiology/Murcia Health Authority, Murcia, Spain.|IMIB-Arrixaca, Murcia University, CIBERESP, Murcia, Spain.
María Dolores
MD
Chirlaque
CIBER de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.|Navarra Public Health Institute, Pamplona, Spain.|IdiSNA, Navarra Institute for Health Research, Pamplona, Spain.
Eva
E
Ardanaz
Public Health Division and BioDonostia Research Institute and CIBERESP, Basque Regional Health Department, San Sebastian, Spain.
Nerea
N
Larrañaga
Department of Clinical Sciences, Lund University, Lund, Sweden.
Björn
B
Nodin
Department of Clinical Sciences, Lund University, Lund, Sweden.|Division of Surgery, Skåne University Hospital, Lund, Sweden.
Jenny
J
Brändstedt
Department of Clinical Sciences, Obstetrics and Gynecology, Umeå University, Umeå, Sweden.
Annika
A
Idahl
Cancer Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom.
Kay-Tee
KT
Khaw
Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
Naomi
N
Allen
International Agency for Research on Cancer, Lyon, France.
Marc
M
Gunter
International Agency for Research on Cancer, Lyon, France.
Mattias
M
Johansson
International Agency for Research on Cancer, Lyon, France.
Laure
L
Dossus
Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.
Melissa A
MA
Merritt
Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.
Elio
E
Riboli
Ob/Gyn Epidemiology Center, Brigham and Women's Hospital, Boston, MA, USA.|Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School, Boston, MA, USA.
Daniel W
DW
Cramer
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, 69120, Germany.
Rudolf
R
Kaaks
Ob/Gyn Epidemiology Center, Brigham and Women's Hospital, Boston, MA, USA.|Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School, Boston, MA, USA.
Kathryn L
KL
Terry
D000328:Adult; D000368:Aged; D019540:Area Under Curve; D014408:Biomarkers, Tumor; D016022:Case-Control Studies; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D055088:Early Detection of Cancer; D005060:Europe / Q000453:epidemiology; D005260:Female; D006801:Humans; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000097:blood* / Q000175:diagnosis* / Q000453:epidemiology / Q000628:therapy; D011159:Population Surveillance; D012307:Risk Factors
D014408:Biomarkers, Tumor
CA125; CA15.3; Early detection markers; HE4; Ovarian cancer