Jill Koshiol

Ph.D, MPH

National Cancer Institute

Senior Investigator

PLCO (Learn more about this study)

2021-0010

Jul 13, 2021

Association of sex steroid hormones and biliary tract cancers in men and women

Biliary tract cancers include gallbladder (GBC), intrahepatic bile duct (IHBDC), extrahepatic bile duct (EHBDC). GBC has a female predominance with a worldwide female‐to‐male incidence rate ratio of 2:1. Conversely, incidence rates of IHBDC and EHBDC are higher in men. These sex disparities suggest that sex hormones may be involved in carcinogenesis. Indeed, high parity, oral contraceptives, and menopausal hormone therapy among women have been associated with an increased risk of gallstones, GBC, and IHBDC.1-8 Further, Petrick et al. have found that higher levels of estradiol were associated with an increased risk of IHBDC in women.9 No prior work has been done to examine the association between sex hormone levels and GBC

Due to their rarity, little is known about the etiology of EHBDC. In addition to gallstones, other risk factors that have been observed for EHBDC include smoking and excess body weight, though hormonal pathways have not been elucidated. Because gallstones and gallbladder disease are risk factors for GBC and other cancers of the biliary tract, the male predominance EHBDC is peculiar. Direct measurement of sex hormones would provide insight into EHBDC etiology and provide a good contrast with GBC, which shows a female predominance. With one of the largest collection of biliary tract cancer cases, the Biliary Tract Cancers Pooling Project (BiTCaPP) presents a unique opportunity to examine the associations between sex steroid hormones and cancer across the biliary tract separately in men and women.

We will employ a nested case-control study design to match GBC and EHBDC cases to non-cancer controls nested within the BiTCaPP. Eligible cases will be selected from BiTCaPP cohort participants (including PLCO) aged ≥50 with first primary invasive cancer diagnosis ICD-O-3 topography codes for cancers of the gallbladder (C23) and extrahepatic bile duct (C24), with an available baseline blood sample. Women who are postmenopausal using menopausal hormone therapy or who are premenopausal at blood draw will be excluded. Cases will be individually matched to 2 controls using incidence-density sampling based on sex, study, age (within 1 year), race/ethnicity, year of blood draw (within 1 year), and time (AM/PM) of blood draw. Controls for GBC should not have evidence of having had a cholecystectomy. The total sample size will include 316 GBC cases with 720 matched controls and 252 EHBDC cases e matched to 504 controls. From PLCO, we are requesting 45 GBC cases with 90 matched controls and 49 EHBDC cases with 98 matched controls.

A total of 0.5 ml heparinized plasma or serum, or EDTA plasma will be required from participants at baseline for the measurement of sex steroid hormones, including 0.4 ml plasma or serum to measure sex hormones (progesterone, dehydroepiandrosterone, androstenedione, dihydrotestosterone, testosterone, estrone, and estradiol) and 0.1 ml plasma or serum for the measurement of SHBG. All samples will be analyzed at a single expert laboratory for liquid chromatography-tandem mass spectrometry-based hormone measurements, the Cancer Research Technology Program, Leidos-Biomedical Research, Inc., Frederick National Laboratory for Cancer Research.

Aim 1. To examine the associations between sex-steroid hormones (estradiol, estrone, progesterone, testosterone, DHEA, androstenedione, DHT, and SHBG) levels and GBC in older men and postmenopausal women (≥50 years of age), separately.

Aim 2. To examine the associations between sex-steroid hormones (estradiol, estrone, testosterone, DHEA, androstenedione, DHT, and SHBG) levels and EHBDC in older men and postmenopausal women (≥50 years of age), separately.