Family History of Cancer and Risk of Biliary Tract Cancers: Results from the Biliary Tract Cancers Pooling Project

Biliary tract cancers (BTCs), including gallbladder (GBC), intrahepatic (IHBDC) and extrahepatic (EHBDC) bile duct, and ampulla of Vater (AVC) cancers, have a poor prognosis (1). Previous studies found associations of familial cancer syndromes (familial adenomatous polyposis, Lynch syndrome, neurofibromatosis type 1) with BTC risk, suggesting they may have a heritable component (2).

Although some studies suggest a higher risk of BTCs among individuals with a family history of cancer (FHC) compared with people without a FHC, most studies examined BTCs combined (3) or only at one anatomic site (4–6) or had small numbers of cases (3, 5–8). Also, it is unknown whether family history of gastrointestinal or hormonally dependent cancers is associated with BTCs. We investigated associations of type of FHC with risk of BTC by anatomic site.

The Biliary Tract Cancers Pooling Project (BiTCaPP) combines data from 28 prospective studies involving over 2.8 million people. The National Cancer Institute has Office of Human Subjects Research Protection exemption for BiTCaPP. Contributing studies received institutional review board approval prior to data collection; participants gave written informed consent.

FHC was available from 12 BiTCaPP studies (Table 1) and was harmonized as: any FHC, first degree FHC, cancer history in a female relative, cancer history in a male relative, family history of gastrointestinal cancers (colorectum, esophagus, small intestine, stomach, liver, biliary tract, pancreas), and family history of hormonally related cancers (breast, ovarian, prostate, endometrial/uterine). Exclusions were prevalent disease at baseline, missing person time, age at baseline, or case/non-case status and age <18 years at baseline.

Relationships between FHC and baseline characteristics were examined using χ² tests for categorical variables and t tests for continuous variables. We used Cox proportional hazards regression models with age as the time scale and left truncation at recruitment to estimate HRs and 95% confidence intervals (CIs) for associations between FHC and BTCs, adjusting for sex and race/ethnicity, with baseline hazard stratified by study. Analyses were repeated restricting to studies reporting cholecystectomy and to people without a history of cholecystectomy. To address concerns that FHC may be associated with history of cholecystectomy, and thereby bias results toward the null, we evaluated these relationships using logistic regression adjusting for baseline age, sex, and race/ethnicity. All tests were two-sided (α = 0.05) and conducted using SAS software (Version 9.3).

Data were available for over 1.5 million people (58% of BiTCaPP) and 21,706,107 person-years (Table 1). Participants averaged 60 years-old at baseline and were mostly non-Hispanic white with slightly more women than men (Table 1). Compared with people without a FHC, people with a FHC were more likely to be women (59% vs. 53%, P < 0.0001) and non-Hispanic white (87% vs. 79%, P < 0.0001) and to have a college education (68% vs. 60%, P < 0.0001). Differences in baseline age [mean (standard deviation) for with FHC vs. without FHC, P-value: 61 (8) vs. 60 (9), <0.0001] and history of diabetes or gallstones (with FHC vs. without FHC, P-value: 8% vs. 9%, <0.0001 for diabetes and 10% vs. 9%, <0.0001 for gallstones) between people with and without any FHC were statistically significant, but too small to be clinically meaningful. People with any FHC more frequently reported a cholecystectomy history [odds ratio (95% CI): 1.20 (1.18–1.21)].

FHC was not associated with IHBDC or EHBDC (Table 2). FHC was marginally, inversely associated with overall GBC, but the association was null after restricting to people who had not had a cholecystectomy. Having a relative with a hormonally related cancer was marginally and inversely associated with AVC risk.

In the largest study to date, we examined associations of FHC and BTC risk by anatomic site. We observed no association of FHC with IHBDC or EHBDC and marginal, inverse associations with GBC and with AVC. To address the concern that associations of FHC with GBC may reflect informative censoring by cholecystectomy rather than a true association, we restricted FHC-GBC analyses to studies reporting cholecystectomy and to people not reporting a history of a cholecystectomy, which drove associations between FHC and GBC to the null. The association between family history of hormonally related cancer (upper CI of 0.99) and AVC may represent a false-positive finding among many comparisons.

Although most previous studies reported FHC associated with higher risk of BTCs overall (3), GBC (4, 5, 7), EHBDC or IHBDC (6, 7), or AVC (7), one study using FHC from the Utah pedigree database reported statistically nonsignificant, lower risks of BTCs with FHC (8). BiTCaPP was also predominantly comprised of non-Hispanic whites from the United States. It is possible that the association of FHC with BTC risk may vary by population. Thus, FHC still may be an important predictor of BTC risk outside of the United States. Misclassification of self-reported FHC is possible but likely nondifferential.

In the largest prospective study, we found no associations between FHC and BTC risk. These results provide no support to the hypothesis that having a FHC is associated with higher BTC risk. As we were unable to examine associations of family history of BTCs with BTCs, the results do not preclude this potential association.

No potential conflicts of interest were disclosed.

Conception and design: A.L. Van Dyke, G.G. Giles, J.L. Petrick, P.T. Campbell, J. Koshiol

Development of methodology: A.L. Van Dyke, B. Zhu, J.L. Petrick, J. Koshiol

Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): A.L. Van Dyke, D. Albanes, G. Andreotti, L.E. Beane Freeman, A.T. Chan, N.D. Freedman, G.G. Giles, F. Grodstein, R.L. Milne, K.R. Monroe, M.L. Neuhouser, JM.P. Purdue, K. Robien, C. Schairer, R. Sinha, S. Weinstein, X. Zhang, J.L. Petrick, J. Koshiol

Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): A.L. Van Dyke, M.S. Langhamer, B. Zhu, R.M. Pfeiffer, G. Andreotti, A.T. Chan, K. Robien, S. Weinstein, X. Zhang, J.L. Petrick, J.L. Petrick, J. Koshiol

Writing, review, and/or revision of the manuscript: A.L. Van Dyke, M.S. Langhamer, B. Zhu, R.M. Pfeiffer, D. Albanes, G. Andreotti, L.E. Beane Freeman, A.T. Chan, N.D. Freedman, S.M. Gapstur, G.G. Giles, F. Grodstein, L.M. Liao, J. Luo, R.L. Milne, K.R. Monroe, M.L. Neuhouser, J.N. Poynter, M.P. Purdue, K. Robien, C. Schairer, R. Sinha, S. Weinstein, X. Zhang, J.L. Petrick, K.A. McGlynn, J.L. Petrick, J. Koshiol

Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): A.L. Van Dyke, D. Albanes, G. Andreotti, L.E. Beane Freeman, N.D. Freedman, F. Grodstein, K.R. Monroe, M.L. Neuhouser

Study supervision: A.L. Van Dyke, J. Koshiol

This work and the following coauthors were supported by the Intramural Research Program (IRP) of the National Institutes of Health (NIH), National Cancer Institute (NCI), Division of Cancer Epidemiology and Genetics (DCEG; A.L. Van Dyke, M.S. Langhamer, B. Zhu, R.M. Pfeiffer, D. Albanes, G. Andreotti, L.E. Beane Freeman, N.D. Freedman, L. Liao, M.P. Purdue, C. Schairer, R. Sinha, S. Weinstein, J.L. Petrick, K.A. McGlynn, J. Koshiol). The Agricultural Health Study is funded by the IRP of the NIH, NCI (Z01 P010119). The NIH-AARP Diet and Health Study is supported by the IRP of DCEG at NCI, part of the NIH. The Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study is supported by the Intramural Research Program of the U.S. NCI, NIH, and by U.S. Public Health Service contract HHSN261201500005C from the NCI, Department of Health and Human Services. The Breast Cancer Detection and Demonstration Project is supported by the IRP of NCI, NIH and the American Cancer Society. The American Cancer Society funded the Cancer Prevention Studies (CPS), including the CPS-II Nutrition Cohort, as well as S.G. Gapstur and P.T. Campbell. The Health Professionals Follow-up Study: Prospective Studies of Diet and Cancer in Men and Women, A.T. Chan, and X. Zhang were supported by the Epidemiology and Genomics Research Program (EGRP), Division of Cancer Control and Population Sciences (DCCPS) NCI (CA055075). The Iowa Women's Health Study, K. Robien, and J. Poynter were funded through the EGRP, DCCPS, at NCI (CA039742). The Melbourne Collaborative Cohort Study, G. Giles, and R. Milne were funded by Vic-Health, Cancer Council Victoria, and by Australian National Health and Medical Research Council grants 209057 and 396414. Cases and their vital status were ascertained through the Victorian Cancer Registry and the Australian Institute of Health and Welfare, including the National Death Index and the Australian Cancer Database. Understanding Ethnic Differences in Cancer: The Multiethnic Cohort Study and K.R. Monroe received funding from the NCI (U01 CA164973). The Nurses' Health Study I: Dietary and Hormonal Determinants of Cancer in Women and F. Grodstein received funding through the EGRP, DCCPS, NCI (CA087969 and CA049449). NCI funded the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial through contracts. The Women's Health Initiative, M.L. Neuhouser, and J. Luo are funded by the National Heart, Lung, and Blood Institute, NCI, NIH, U.S. Department of Health and Human Services through contracts HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, and HHSN268201600004C. A.T. Chan also received funding from the National Institute of Diabetes and Digestive and Kidney Diseases, NIH (K24 DK098311) and from NCI, NIH (R01 CA137178, R01 CA202704, and R01 CA176272).

The authors thank the participants, investigators, study coordinators, data managers, and other research staff of the studies contributing family history of cancer data to BiTCaPP. We also thank Eric Boyd with Information Management Services (Calverton, Maryland) for his contribution to data harmonization.

The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

For NIH-AARP, the acknowledgement statement is on the following website: https://dietandhealth.cancer.gov/acknowledgement.html.

The Melbourne Collaborative Cohort Study was made possible by the contributions of many people, including the original investigators, the recruiting teams, and the many thousands of Melbourne residents who participated in the study.

We would like to thank the participants and staff of the Nurses' Health Study and the Health Professionals Follow-up Study for their valuable contributions as well as 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. The authors assume full responsibility for analyses and interpretation of these data.

For a list of the investigators who have contributed to the Women's Health Initiative science, please visit the following website: http://www.whi.org/researchers/Documents%20%20Write%20a%20Paper/WHI%20Investigator%20Short%20List.pdf.

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