Correlates of circulating ovarian cancer early detection markers and their contribution to discrimination of early detection models: results from the EPIC cohort

Renée T. Fortner, Allison F. Vitonis, Helena Schock, Anika Hüsing, Theron Johnson, Raina N. Fichorova, Titilayo Fashemi, Hidemi S. Yamamoto, Anne Tjønneland, Louise Hansen, Kim Overvad, Marie-Christine Boutron-Ruault, Marina Kvaskoff, Gianluca Severi, Heiner Boeing, Antonia Trichopoulou, Vassiliki Benetou, Carlo La Vecchia, Domenico Palli, Sabina Sieri, Rosario Tumino, Giuseppe Matullo, Amalia Mattiello, N. Charlotte Onland-Moret, Petra H. Peeters, Elisabete Weiderpass, Inger Torhild Gram, Mie Jareid, J. Ramón Quirós, Eric J. Duell, Maria-Jose Sánchez, María Dolores Chirlaque, Eva Ardanaz, Nerea Larrañaga, Björn Nodin, Jenny Brändstedt, Annika Idahl, Kay-Tee Khaw, Naomi Allen, Marc Gunter, Mattias Johansson, Laure Dossus, Melissa A. Merritt, Elio Riboli, Daniel W. Cramer, Rudolf Kaaks, Kathryn L. Terry

Ovarian cancer early detection markers CA125, CA15.3, HE4, and CA72.4 vary between healthy women, limiting their utility for screening. 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. 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. 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.