Background: Intrahepatic cholangiocarcinoma (ICC) arises from cholangiocytes in the intrahepatic bile duct and is the second most common type of liver cancer. Cholangiocytes express both oestrogen receptor-α and -β, and oestrogens positively modulate cholangiocyte proliferation. Studies in women and men have reported higher circulating oestradiol is associated with increased ICC risk, further supporting a hormonal aetiology. However, no observational studies have examined the associations between exogenous hormone use and reproductive factors, as proxies of endogenous hormone levels, and risk of ICC. Methods: We harmonised data from 1,107,498 women who enroled in 12 North American-based cohort studies (in the Liver Cancer Pooling Project, LCPP) and the UK Biobank between 1980–1998 and 2006–2010, respectively. Cox proportional hazards regression models were used to generate hazard ratios (HR) and 95% confidence internals (CI). Then, meta-analytic techniques were used to combine the estimates from the LCPP (n = 180 cases) and the UK Biobank (n = 57 cases). Results: Hysterectomy was associated with a doubling of ICC risk (HR = 1.98, 95% CI: 1.27–3.09), compared to women aged 50–54 at natural menopause. Long-term oral contraceptive use (9+ years) was associated with a 62% increased ICC risk (HR = 1.62, 95% CI: 1.03–2.55). There was no association between ICC risk and other exogenous hormone use or reproductive factors. Conclusions: This study suggests that hysterectomy and long-term oral contraceptive use may be associated with an increased ICC risk.
Bibliographical noteFunding Information:
For the Black Women’s Health Study, pathology data were obtained from several of the following state cancer registries (AZ, CA, CO, CT, DE, DC, FL, GA, IL, IN, KY, LA, MD, MA, MI, NJ, NY, NC, OK, PA, SC, TN, TX, VA), and results reported do not necessarily represent their views. For the Nurses’ Health Study and the Health Professionals Follow-up Study, we would like to thank the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, WY. We assume full responsibility for analyses and interpretation of these data. For NIH-AARP, the acknowledgement can be found at the following website: https://dietandhealth. cancer.gov/acknowledgement.html. For the Women’s Health Initiative, the full list of investigators that have contributed can be found on the following website: https:// www.whi.org/researchers/Documents%20%20Write%20a%20Paper/WHI% 20Investigator%20Long%20List.pdf. The American Cancer Society funds the creation, maintenance, and updating of the Cancer Prevention Study-II cohort. The authors express sincere appreciation to all Cancer Prevention Study-II participants, and to each member of the study and biospecimen management group. We would like to acknowledge the contribution to this study from central cancer registries supported through the Centers for Disease Control and Prevention’s National Program of Cancer Registries and cancer registries supported by the National Cancer Institute’s Surveillance Epidemiology and End Results Program.
Funding infromation Access to the UK Biobank was funded by a Cancer Research UK Population Research Postdoctoral Fellowship (Ú.C.M.). NIH Intramural Research Program, National Cancer Institute (J.L.P., A.A.F., L.E.B.F., J.N.H., C.M.K., N.D.F., B.I.G., J.K., L.M.L., M.S.L., M.P.P., C.S., R.S., K.A.M.). National Institutes of Health grants CA047988 (I. L., J.E.B.), CA182913 (I.L., J.E.B.), HL043851 (I.L., J.E.B.), HL080467 (I.L., J.E.B.), HL099355 (I.L., J.E.B.), K07 CA188126 (X.Z.), DK098311 (A.T.C.), CA186107 (A.T.C.), CA87969 (A.T. C.), CA167552 (A.T.C.), P30 CA016087 (A.Z-J.), P30 ES000260 (A.Z-J.), UM1 CA164974 (L Rosenberg, JR Palmer), R01 CA058420 (L.R., J.R.P.), and R01 CA39742 (K.R., J.N.P.). American Cancer Society Research Scholar Grant RSG NEC-130476 (X.Z.). The WHI program (J.W-W., T.E.R., Y.L., J.W.B.) is funded by the National Institutes of Health contracts HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C and HHSN268201600004C. The HPFS and NHS programs (X. Z.) were support by the National Cancer Institute, National Institutes of Health grant numbers UM1CA186107, P50CA127003, P01CA87969 and UM1CA167552.
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