Abstract B2: Sex steroid hormones and epithelial ovarian cancer: A nested case-control study in two maternity cohorts
Authors: Schock Helena , Lundin Eva , Zeleniuch-Jacquotte Anne , Grankvist Kjell , Lakso Hans-Åke , Pukkala Eero , Lehtinen Matti , Toniolo Paolo , Surcel Heljä-Marja , Lukanova Annekatrin 
Published: August 2014

Abstract
Sex steroid hormones are thought to be involved in the etiology of epithelial ovarian cancer (EOC). At present, only the association of prediagnostic endogenous androgen concentrations with risk of EOC has been investigated and the results were unremarkable. The relatively small number of cases included in the previous studies precluded analyses by histological subtypes, despite growing evidence that the associations of risk factors differ by histological subtype and invasiveness of EOC.
We nested a case-control study within the Finnish Maternity Cohort and the Northern Sweden Maternity Cohort. Study subjects were selected among cohort members with singleton pregnancies, who donated a blood sample during the first trimester of a pregnancy leading to childbirth, and who were free of invasive cancer (except for non-melanoma skin cancer) and/or borderline ovarian cancer up to the relevant index date. Through linkages with the nationwide cancer registries, we identified 1,052 EOC cases among cohort members diagnosed after blood collection and before March 2011. The sample from the pregnancy that led to the birth of the last child before diagnosis was selected for the study. Up to three controls were matched to each case by cohort, age at and date of blood donation as well as parity at the index pregnancy and cancer diagnosis (n=2,692). Concentrations of progesterone, 17-hydroxyprogesterone (17-OHP), androgens (testosterone and androstenedione), and estradiol were measured by high-performance liquid chromatography tandem mass spectrometry. Odds ratios (OR) and 95% confidence intervals [CI] across tertiles of hormone concentrations were estimated by conditional logistic regression and adjusted for gestational age at blood donation (except for androgens), maternal age at first birth, smoking and family history of breast and/or ovarian cancer.
The majority of the cases were diagnosed with invasive EOC (n=642, 61%). Of these, 283 (44%) were serous, 150 (23%) mucinous, and 128 (20%) endometrioid or clear cell. Among the borderline tumors (n=410, 39%), 194 (47%) were serous and 206 (50%) mucinous. Median age at EOC diagnosis was 44 years and on average 12 years elapsed between blood donation and diagnosis.
Associations of hormones with EOC differed by tumor histology and invasiveness. None of the hormones were associated with risk of invasive serous tumors. For borderline serous tumors, we observed positive associations with testosterone (1.85 [1.16-2.95]) and 17-OHP (1.75 [1.06-2.89]) comparing extreme tertiles of hormone concentrations. Risk of both invasive and borderline mucinous tumors significantly increased with androgen concentrations (about 75% risk increase in the top tertiles of each hormone for each subtype). Risk of endometrioid and clear cell tumors increased with rising estradiol concentrations (2.33 [0.95-5.72], ptrend=0.07). Similar associations were observed in subgroup analyses by time between blood donation and cancer diagnosis or ages at diagnosis or blood donation.
In this large prospective study elevated early pregnancy androgen concentrations were associated with risk of borderline serous, and borderline and invasive mucinous EOC, whereas elevated estradiol concentrations were associated with risk of endometrioid and clear cell EOC. These results support a role of sex steroid hormones in the etiology of EOC arising in the ovaries. In contrast, sex steroid concentrations were not related to invasive serous tumors, which are presumed to originate in the fallopian tubes. First trimester progesterone concentrations were not associated with maternal risk of EOC, but it would be of interest to explore if the peak concentrations during the third trimester are etiologically important.
Citation Format: Helena Schock, Eva Lundin, Anne Zeleniuch-Jacquotte, Kjell Grankvist, Hans-Åke Lakso, Eero Pukkala, Matti Lehtinen, Paolo Toniolo, Heljä-Marja Surcel, Annekatrin Lukanova. Sex steroid hormones and epithelial ovarian cancer: A nested case-control study in two maternity cohorts. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr B2.