Exogenous hormone use, reproductive factors and risk of intrahepatic cholangiocarcinoma among women: results from cohort studies in the Liver Cancer Pooling Project and the UK Biobank.
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA. jpetrick@bu.edu.
- Centre for Public Health, Queen's University Belfast, Belfast, Northern Ireland, UK.
- Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA.
- Department of Population Health, New York University School of Medicine, New York, NY, USA.
- Department of Epidemiology and Environmental Health, University at Buffalo, Buffalo, NY, USA.
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
- Slone Epidemiology Center, Boston University, Boston, MA, USA.
- Department of Epidemiology & Population Health, Albert Einstein College of Medicine, Bronx, NY, USA.
- Department of Exercise and Nutrition Sciences, Milken Institute School of Public Health, George Washington University, Washington, DC, USA.
- Division of Pediatric Epidemiology and Clinical Research and Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
- Department of Population Health and Disease Prevention, Program in Public Health, University of California, Irvine, Irvine, CA, USA.
- Epidemiology Division, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.
- Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
- Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, GA, USA.
- Division of Medical Oncology, National Cancer Centre, Singapore, Singapore.
- Department of Medicine, University of Arizona, Tucson, AZ, USA.
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.