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

Highlights

• We pooled data from 19 longitudinal studies to estimate the associations between female reproductive factors and BTC.

• The risk of GBC was increased with increasing number of live births in all women.

• The risk of GBC, IHBDC, and EHBDC were increased with later age of menarche among women from Asian countries only.

• Age of menopause was not associated with an increased risk of any BTC.

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.

Introduction

Rare but lethal, biliary tract cancers (BTCs) include cancers of the gallbladder (GBC), intrahepatic bile duct (IHBDC), extrahepatic bile duct (EHBDC), and ampulla of Vater (AVC). GBC has a female predominance with a worldwide female-to-male incidence rate ratio of 2:1.^1,2 However, this ratio varies greatly by geography, ranging from 1:1 in the Far East to 4:1 in Spain.² Conversely, incidence rates of IHBDC, EHBDC, and AVC are higher in men worldwide.^2,3

This sex ratio suggests that sex hormones may be involved in gallbladder carcinogenesis. High parity is associated with gallstones, often the precursor to gallbladder dysplasia.⁴ During pregnancy gallbladder volume increases and bile flow decreases.[5], [6], [7] Elevated estrogen levels during pregnancy lead to an increase in cholesterol saturation of the bile.^6,8,9 Progesterone, also elevated during pregnancy, contributes to biliary stasis by impairing the smooth muscle contractility of the biliary tract, leading to the formation of cholesterol gallstones.^6,[8], [9], [10] Gallstones are also risk factors for cholangiocarcinoma and evidence suggests that estrogen promotes tumor growth in the biliary tract.^11,12 However, because the pronounced female predominance is absent for these cancers, the role of female reproductive factors in carcinogenesis across the biliary tract is unclear. Further, given that the sex ratio of gallbladder cancer in East Asia is closer to 1, the role of female sex hormones may vary by geographic region.¹³

The rarity of BTCs make conducting large prospective studies on their etiology difficult, and much of the evidence to date is obtained from studies with small sample sizes that lack geographic variability.[14], [15], [16], [17] Few studies have examined female reproductive factors in the development of these cancers separately by site, other than the gallbladder.^18,19 Further, many studies lacked information on important covariates, such as use of oral contraceptives and age at menarche.^14,16 To address these shortcomings, we examined the associations of parity, age at menarche, reproductive years, and age at menopause with BTC risk using a large pooling project.