Associations between reproductive factors and biliary tract cancers in women from the Biliary Tract Cancers Pooling Project

Abstract

Background & aims: Gallbladder cancer (GBC) is known to have a female predominance while other biliary tract cancers (BTCs) have a male predominance. However, the role of female reproductive factors in BTC etiology remains unclear.

Methods: We pooled data from 19 studies of >1.5 million women participating in the Biliary Tract Cancers Pooling Project to examine the associations of parity, age at menarche, reproductive years, and age at menopause with BTC. Associations for age at menarche and reproductive years with BTC were analyzed separately for Asian and non-Asian women. Hazard ratios (HRs) and 95% CIs were estimated using Cox proportional hazards models, stratified by study.

Results: During 21,681,798 person-years of follow-up, 875 cases of GBC, 379 of intrahepatic bile duct cancer (IHBDC), 450 of extrahepatic bile duct cancer (EHBDC), and 261 of ampulla of Vater cancer (AVC) occurred. High parity was associated with risk of GBC (HR ≥5 vs. 0 births 1.72; 95% CI 1.25-2.38). Age at menarche (HR per year increase 1.15; 95% CI 1.06-1.24) was associated with GBC risk in Asian women while reproductive years were associated with GBC risk (HR per 5 years 1.13; 95% CI 1.04-1.22) in non-Asian women. Later age at menarche was associated with IHBDC (HR 1.19; 95% CI 1.09-1.31) and EHBDC (HR 1.11; 95% CI 1.01-1.22) in Asian women only.

Conclusion: We observed an increased risk of GBC with increasing parity. Among Asian women, older age at menarche was associated with increased risk for GBC, IHBDC, and EHBDC, while increasing reproductive years was associated with GBC in non-Asian women. These results suggest that sex hormones have distinct effects on cancers across the biliary tract that vary by geography.

Lay summary: Our findings show that the risk of gallbladder cancer is increased among women who have given birth (especially women with 5 or more children). In women from Asian countries, later age at menarche increases the risk of gallbladder cancer, intrahepatic bile duct cancer and extrahepatic bile duct cancer. We did not see this same association in women from Western countries. Age at menopause was not associated with the risk of any biliary tract cancers.

Keywords: Biliary tract cancer; Gallbladder cancer; Parity; Reproductive factors.

Figure 1.

Hazard ratios and 95% confidence intervals for the relationship between biliary tract cancer site and A) parity and B) age at menopause. Abbreviations: AVC, ampulla of Vater cancer; CI, confidence interval; EHBDC, extrahepatic bile duct cancer; IHBDC, intrahepatic bile duct cancer; and GBC, gallbladder cancer. Cox proportional hazard models for parity as a continuous predictor used age as the time scale and were adjusted for participant birth year, use of oral contraceptives (ever/never), age at menarche, race (white, black, Asian/Pacific Islander, other), education (2 for non-Asian women and <18.5, 18.5 – <23, 23 – <27.5, ≥27.5 kg/m² for Asian women), and the baseline hazard was stratified by study. *P-interaction = 0.001; **P-interaction = 0.002

Figure 2.

Hazard ratios and 95% confidence intervals for the relationship between biliary tract cancer site and A) age of menarche and B) reproductive years by geographic region. Abbreviations: AVC, ampulla of Vater cancer; CI, confidence interval; EHBDC, extrahepatic bile duct cancer; IHBDC, intrahepatic bile duct cancer; and GBC, gallbladder cancer. Cox proportional hazard models for age of menarche as a continuous predictor used age as the time scale and were adjusted for participant birth year, education (2 for non-Asian women and <18.5, 18.5 – <23, 23 – <27.5, ≥27.5 kg/m² for Asian women), and the baseline hazard was stratified by study. *P-interaction = 0.001; **P-interaction = 0.002