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Supplementary Table S1. Cohorts Participating in the Liver Cancer Pooling Project with Information on Aspirin Use. Supplementary Table S2. Assessment of aspirin and ibuprofen use, Liver Cancer Pooling Project. Supplemental Table S3. Adjusted* Hazard Ratios (HR) and 95% Confidence Intervals (CI) for Associations Between NSAID Use and Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma Incidence by Sex, Cigarette Use, Alcohol Consumption, and Ibuprofen Use, Liver Cancer Pooling Project. Supplemental Table S4. Adjusted* Hazard Ratios (HR) and 95% Confidence Intervals (CI) for Associations Between NSAID Use and Confirmed or Suspected Hepatocellular Carcinoma, Liver Cancer Pooling Project.

Chronic inflammation plays a pivotal role in the pathogenesis of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), the two most common types of liver cancer. A number of prior experimental studies have suggested that nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin and ibuprofen, may potentially protect against liver cancer. However, no observational study has examined the association between aspirin duration and dose or other over-the-counter non-aspirin NSAIDs, such as ibuprofen, and liver cancer incidence. Furthermore, the association between NSAID use and risk of ICC is unclear. As part of the Liver Cancer Pooling Project, we harmonized data on 1,084,133 individuals (HCC = 679, ICC = 225) from 10 U.S.-based prospective cohort studies. Cox proportional hazards regression models were used to evaluate multivariable-adjusted HRs and 95% confidence intervals (CI). Current aspirin use, versus nonuse, was inversely associated with HCC (HR, 0.68; 95% CI, 0.57–0.81), which persisted when restricted to individuals not using non-aspirin NSAIDs and in a 5- and 10-year lag analysis. The association between aspirin use and HCC risk was stronger for users who reported daily use, longer duration use, and lower dosage. Ibuprofen use was not associated with HCC risk. Aspirin use was associated with a reduced ICC risk in men (HR, 0.64; 95% CI, 0.42–0.98) but not women (HR, 1.34; 95% CI, 0.89–2.01; Pinteraction = 0.01). The observed inverse association between aspirin use and liver cancer in our study, together with previous data, suggests the merit of future intervention studies of aspirin and other agents that affect chronic inflammatory pathways for HCC and possibly ICC. Cancer Prev Res; 8(12); 1156–62. ©2015 AACR.

Background: Thyroid cancer incidence has risen dramatically in the United States since the early 1980s. Although the prevalence of obesity has doubled during this time period, the relationship between obesity and thyroid cancer is uncertain.Methods: We examined the association between body mass index (BMI) and thyroid cancer risk in a pooled analysis of five prospective U.S. studies, including 413,979 women and 434,953 men. Proportional hazards models with attained age as the time metric were adjusted for education, race, marital status, smoking, alcohol intake, and (where appropriate) cohort and sex.Results: Over follow-up (mean = 10.3 years), 768 women and 388 men were diagnosed with thyroid cancer. The risk of thyroid cancer was greater with increasing BMI [per 5 kg/m2: HR in women, 1.16 (95% CI, 1.08–1.24); HR in men, 1.21 (95% CI, 0.97–1.49)]. There was no significant heterogeneity between studies (both P > 0.05). For women and men combined, the HRs for overweight (25.0–29.9 kg/m2) and obesity (≥30 kg/m2) compared with normal-weight (18.5–24.9 kg/m2) were 1.20 (95% CI, 1.04–1.38) and 1.53 (95% CI, 1.31–1.79), respectively. We found no significant effect modification by other factors, and the results did not differ significantly by histologic type. A significant positive association for BMI in young adulthood (ages 18–20) with thyroid cancer risk was also observed [per 5-kg/m2 increase: HR, 1.18 (95% CI, 1.03–1.35)].Conclusion: BMI was positively associated with thyroid cancer risk in both men and women.Impact: Our study provides strong evidence that obesity is an independent risk factor for thyroid cancer. Cancer Epidemiol Biomarkers Prev; 20(3); 464–72. ©2011 AACR.

Associations between continuous total lifetime number of ovulatory cycles and ovarian cancer by tumor aggressiveness considering mutual adjustment for LOC component factors: duration of oral contraceptive use and pregnancies, Ovarian Cancer Cohort Consortium (OC3).

This file contains Supplementary Figure 1, parts A - D, and the figure description.

Background: Coffee consumption has been reported to be inversely associated with hepatocellular carcinoma (HCC), the most common type of liver cancer. Caffeine has chemopreventive properties, but whether caffeine is responsible for the coffee–HCC association is not well studied. In addition, few studies have examined the relationship by sex, and no studies have examined whether there is an association between coffee and intrahepatic cholangiocarcinoma (ICC), the second most common type of liver cancer.Methods: In the Liver Cancer Pooling Project, a consortium of U.S.-based cohort studies, data from 1,212,893 individuals (HCC, n = 860; ICC, n = 260) in nine cohorts were pooled. Multivariable-adjusted hazard ratios (HR) and 95% confidence intervals (CI) were estimated using proportional hazards regression.Results: Higher coffee consumption was associated with lower risk of HCC (HR>3 cups/day vs. non-drinker, 0.73; 95% CI, 0.53–0.99; Ptrend cups/day = Pinteraction = 0.07). Women who consumed more than three cups of coffee per day were at a 54% lower risk of HCC (HR, 0.46; 95% CI, 0.26–0.81), whereas men had more modest reduced risk of HCC (HR, 0.93; 95% CI, 0.63–1.37). The associations were stronger for caffeinated coffee (HR>3 cups/day vs. non-drinker, 0.71; 95% CI, 0.50–1.01) than decaffeinated coffee (HR, 0.92; 95% CI, 0.55–1.54). There was no association between coffee consumption and ICC.Conclusions: These findings suggest that, in a U.S. population, coffee consumption is associated with reduced risk of HCC.Impact: Further research into specific coffee compounds and mechanisms that may account for these associations is needed. Cancer Epidemiol Biomarkers Prev; 24(9); 1398–406. ©2015 AACR.

Repeated exposure to the acute proinflammatory environment that follows ovulation at the ovarian surface and distal fallopian tube over a woman's reproductive years may increase ovarian cancer risk. To address this, analyses included individual-level data from 558,709 naturally menopausal women across 20 prospective cohorts, among whom 3,246 developed invasive epithelial ovarian cancer (2,045 serous, 319 endometrioid, 184 mucinous, 121 clear cell, 577 other/unknown). Cox models were used to estimate multivariable-adjusted HRs between lifetime ovulatory cycles (LOC) and its components and ovarian cancer risk overall and by histotype. Women in the 90th percentile of LOC (>514 cycles) were almost twice as likely to be diagnosed with ovarian cancer than women in the 10th percentile (Significance:Although ovarian cancer is rare, risk of most ovarian cancers doubles as the number of lifetime ovulatory cycles increases from approximately 300 to 500. Thus, identifying an important area for cancer prevention research.

Supplementary Table 1 from Obesity and Thyroid Cancer Risk among U.S. Men and Women: A Pooled Analysis of Five Prospective Studies

This file contains Supplementary tables 1 - 7 and the text for Supplementary Figure 1A-D.

figure legends for supp. figures 1, 2, and 3

Descriptive table or cohorts and results from sensitivity analyses

Biliary tract cancers are rare but highly fatal with poorly understood etiology. Identifying potentially modifiable risk factors for these cancers is essential for prevention. Here we estimated the relationship between adiposity and cancer across the biliary tract, including cancers of the gallbladder (GBC), intrahepatic bile ducts (IHBDC), extrahepatic bile ducts (EHBDC), and the ampulla of Vater (AVC). We pooled data from 27 prospective cohorts with over 2.7 million adults. Adiposity was measured using baseline body mass index (BMI), waist circumference, hip circumference, waist-to-hip, and waist-to-height ratios. HRs and 95% confidence intervals (95% CI) were estimated using Cox proportional hazards models adjusted for sex, education, race, smoking, and alcohol consumption with age as the time metric and the baseline hazard stratified by study. During 37,883,648 person-years of follow-up, 1,343 GBC cases, 1,194 EHBDC cases, 784 IHBDC cases, and 623 AVC cases occurred. For each 5 kg/m2 increase in BMI, there were risk increases for GBC (HR = 1.27; 95% CI, 1.19–1.36), IHBDC (HR = 1.32; 95% CI, 1.21–1.45), and EHBDC (HR = 1.13; 95% CI, 1.03–1.23), but not AVC (HR = 0.99; 95% CI, 0.88–1.11). Increasing waist circumference, hip circumference, waist-to-hip ratio, and waist-to-height ratio were associated with GBC and IHBDC but not EHBDC or AVC. These results indicate that adult adiposity is associated with an increased risk of biliary tract cancer, particularly GBC and IHBDC. Moreover, they provide evidence for recommending weight maintenance programs to reduce the risk of developing these cancers.Significance:These findings identify a correlation between adiposity and biliary tract cancers, indicating that weight management programs may help minimize the risk of these diseases.

Summary of 20 Ovarian Cancer Cohort Consortium (OC3) cohorts included in analysis of lifetime ovulatory cycles (LOC) and incident ovarian cancer.

Supplementary Table 1A: The Pearson correlation coefficient of untransformed metabolite levels was estimated between each pair of metabolites within each of the four studies. Supplementary Table 1B: The Pearson correlation coefficient of untransformed metabolite levels was estimated between each of the metabolic pathway groups within each of the four studies. Supplementary Table 2A.: We evaluated the odds ratio (OR) of breast cancer in women with estrogen levels in the 2nd, 3rd, 4th, and 5th quintiles of each study, as compared to women in the lowest quintile, using analyses that did not adjust for any other estrogen variable. Supplementary Table 2B.: We evaluated the OR of breast cancer in women with analyte/path:Total ratios in the 2nd, 3rd, 4th, and 5th quintiles of each study, as compared to women in the lowest quintile, using analyses that adjusted for total estrogen level. Supplementary Table 3: Inter-decile odds ratios (ORs) and 95% confidence intervals from each study contributing to the meta-analysis of all studies for analyte:total ratios from models adjusted for total estrogen level. Supplementary Table 4: Inter-decile odds ratios (ORs) and 95% confidence intervals from each study contributing to the meta-analysis of all studies for analyte:total ratios from models adjusted for total estrogen level. Supplementary Table 5: Inter-decile odds ratios (ORs) and 95% confidence intervals (CIs) from random effects meta-analysis of all studies for estrogen levels, unadjusted for total estrogen levels, and inter-decile ORs and 95% CIs from random effects meta-analysis for analyte:total ratios from models adjusted for total estrogen level. Supplementary Table 6: Inter-decile odds ratios (ORs) for Path2:Path16 ratio within subgroups of individuals using models adjusted for total estrogen level. Supplementary Table 7: We classified women into 9 groups, defined by tertiles of total estrogen level and tertiles of Path-2:Path-16 ratio. Supplementary Table 8: We measured the association between the Path-2:Path-16 ratio (dependent variable) and each of the covariates listed in the first column (independent variable). Supplementary Figure 1: The Path-2:Path-16 ratio is plotted as a function of the log of the total estrogen level within each study. Supplementary Figure 2: Odds ratios and 95% confidence intervals comparing the risk of breast cancer in individuals with a higher analyte or pathway concentration (90th percentile) to individuals with a lower concentration (10th percentile). Supplementary Figure 3: Odds ratios and 95% confidence intervals comparing the risk of breast cancer in individuals with a higher analyte:total or pathway:total ratio (90th percentile) to individuals with a lower ratio (10th percentile).

Results from individual participant meta-analysis of WC. Footnote to Supplementary Figure 2. Multivariable models include age, sex, study, alcohol, smoking, race and body mass index.

Supplementary Table S1: Cohorts participating in analysis of coffee variables, Liver Cancer Pooling Project. Supplementary Table S2: Assessment of coffee consumption, Liver Cancer Pooling Project. Supplementary Table S3: Characteristics of participants in the Liver Cancer Pooling Project by coffee drinking. Supplementary Table S4: Adjusted Hazard Ratios (HR) and 95% Confidence Intervals (CI) for Associations Between Coffee Consumption and Intrahepatic Cholangiocarcinoma Incidence by Sex, Smoking Status, Body Mass Index, and Diabetes, Liver Cancer Pooling Project. Supplementary Table S5: Adjusted Hazard Ratios (HR) and 95% Confidence Intervals (CI) for Associations Between Coffee Consumption and Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma Incidence by Caffeine Content; Sensitivity Analysis Excluding WHI and Jointly Modeling Caffeine Content and Drinking Intensity, Liver Cancer Pooling Project. Supplementary Table S6: Adjusted Hazard Ratios (HR) and 95% Confidence Intervals (CI) for Associations Between Coffee Consumption and Suspected Hepatocellular Carcinoma Incidence by Caffeine Content, Liver Cancer Pooling Project. Supplementary Table S7: Adjusted Hazard Ratios (HR) and 95% Confidence Intervals (CI) for Associations Between Coffee Consumption and Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma Incidence by Caffeine Content in the AARP Study, Liver Cancer Pooling Project. Supplementary Table S8: Adjusted Hazard Ratios (HR) and 95% Confidence Intervals (CI) for Associations Between Coffee Consumption and Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma Incidence by Sex in the AARP Study, Liver Cancer Pooling Project. Supplementary Table S9: Adjusted Hazard Ratios (HR) and 95% Confidence Intervals (CI) for Associations Between Coffee Consumption and Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma Incidence by Caffeine Content excluding the AARP Study, Liver Cancer Pooling Project. Supplementary Table S10: Adjusted Hazard Ratios (HR) and 95% Confidence Intervals (CI) for Associations Between Coffee Consumption and Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma Incidence by Sex excluding the AARP Study, Liver Cancer Pooling Project. Supplementary Figure S1: Meta-influence Graph of the Influence of Individuals Studies for Associations between Coffee Consumption versus No Consumption and Hepatocellular Carcinoma, Liver Cancer Pooling Project.

Results from individual participant meta-analysis of diabetes. Multivariable models include age, sex, study, alcohol, smoking, race and body mass index.

Endogenous estradiol and estrone are linked causally to increased risks of breast cancer. In this study, we evaluated multiple competing hypotheses for how metabolism of these parent estrogens may influence risk. Prediagnostic concentrations of estradiol, estrone, and 13 metabolites were measured in 1,298 postmenopausal cases of breast cancer and 1,524 matched controls in four separate patient cohorts. The median time between sample collection and diagnosis was 4.4 to 12.7 years across the cohorts. Estrogen analytes were measured in serum or urine by liquid chromatography-tandem mass spectrometry. Total estrogen levels (summing all 15 estrogens/estrogen metabolites) were associated strongly and positively with breast cancer risk. Normalizing total estrogen levels, we also found that a relative increase in levels of 2-hydroxylation pathway metabolites, or in the ratio of 2-hydroxylation:16-hydroxylation pathway metabolites, were associated inversely with breast cancer risk. These associations varied by total estrogen levels, with the largest risk reductions occurring in women in the highest tertile. With appropriate validation, these findings suggest opportunities for breast cancer prevention by modifying individual estrogen metabolism profiles through either lifestyle alterations or chemopreventive strategies. Cancer Res; 77(4); 918–25. ©2017 AACR.

Supplemental Table 1 has selected results by estrogen receptor status and Supplemental Table 2 shows the number of cases for results presented in Supplemental Table 1

Background: Obesity has been associated with substantially higher risk of inflammatory breast cancer (IBC) than other breast cancer. Here, we assess whether comorbidities of obesity, namely diabetes, abnormal glucose, dyslipidemia, and hypertension, are differentially related to risk of IBC and other breast cancers by tumor stage at diagnosis (localized/regional/distant/unstaged).Methods: We used linked SEER-Medicare data, with female breast cancer cases ages 66+ years identified by SEER registries (years 1992–2011). We divided first breast cancers into IBC (N = 2,306), locally advanced non-IBC (LABC; N = 10,347), and other (N = 197,276). We selected female controls (N = 200,000) from a stratified 5% random sample of Medicare recipients alive and breast cancer free. We assessed exposures until 12 months before diagnosis/selection using Medicare claims data. We estimated odds ratios (OR) and 99.9% confidence intervals (CI) using unconditional logistic regression.Results: Diabetes was associated with increased risk of distant IBC (98.5% of IBC cases; OR 1.44; 99.9% CI 1.21–1.71), distant (OR 1.24; 99.9% CI, 1.09–1.40) and regional (OR 1.29 (99.9% CI, 1.14–1.45) LABC, and distant (OR 1.23; 99.9% CI, 1.10–1.39) and unstaged (OR 1.32; 99.9% CI, 1.18–1.47) other breast cancers. Dyslipidemia was associated with reduced risk of IBC (OR 0.80; 95% CI, 0.67–0.94) and other breast cancers except localized disease. Results were similar by tumor estrogen receptor status. Abnormal glucose levels and hypertension had little association with risk of any tumor type.Conclusions: Associations with diabetes and dyslipidemia were similar for distant stage IBC and other advanced tumors.Impact: If confirmed, such findings could suggest avenues for prevention. Cancer Epidemiol Biomarkers Prev; 26(6); 862–8. ©2017 AACR.

Results from individual participant meta-analysis of BMI. Multivariable models include age, sex, study, alcohol, smoking, and race.

PURPOSE: Inflammatory breast cancer (IBC) is a rare, poorly understood and aggressive tumor. We extended prior findings linking high body mass index (BMI) to substantial increased IBC risk by examining BMI associations before and after adjustment for well-characterized comorbidities using medical record data for diabetes, insulin resistance, and disturbances of cholesterol metabolism in a general community healthcare setting. METHODS: We identified 247 incident IBC cases diagnosed at Kaiser Permanente Northern California between 2005–2017 and 2470 controls matched 10:1 on birth year and geographic area and with ≥13 months of continuous enrollment prior to diagnosis/index date. We assessed exposures from 6 years up to one year prior to the diagnosis/index date, using logistic regression to calculate odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: Before adjustment for comorbidities, ORs (95% CIs) for BMI of 25

Obesity is known to be associated with primary liver cancer (PLC), but the separate effects of excess abdominal and gluteofemoral size are unclear. Thus, we examined the association between waist and hip circumference with risk of PLC overall and by histologic type-hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). The Liver Cancer Pooling Project is a consortium of prospective cohort studies that include data from 1,167,244 individuals (PLC n = 2,208, HCC n = 1,154, ICC n = 335). Multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CI) were estimated using proportional hazards regression. Waist circumference, per 5 cm increase, was associated with an 11% increased PLC risk (HR = 1.11, 95%CI: 1.09-1.14), including when adjusted for hip circumference (HR = 1.12, 95%CI: 1.08-1.17) and also when restricted to individuals in a normal body mass index (BMI) range (18.5 to

Biliary tract cancers are rare but highly fatal with poorly understood etiology. Identifying potentially modifiable risk factors for these cancers is essential for prevention. Here we estimated the relationship between adiposity and cancer across the biliary tract, including cancers of the gallbladder (GBC), intrahepatic bile ducts (IHBDC), extrahepatic bile ducts (EHBDC), and the ampulla of Vater (AVC). We pooled data from 27 prospective cohorts with over 2.7 million adults. Adiposity was measured using baseline body mass index (BMI), waist circumference, hip circumference, waist-to-hip, and waist-to-height ratios. HRs and 95% confidence intervals (95% CI) were estimated using Cox proportional hazards models adjusted for sex, education, race, smoking, and alcohol consumption with age as the time metric and the baseline hazard stratified by study. During 37,883,648 person-years of follow-up, 1,343 GBC cases, 1,194 EHBDC cases, 784 IHBDC cases, and 623 AVC cases occurred. For each 5 kg/m2 increase in BMI, there were risk increases for GBC (HR = 1.27; 95% CI, 1.19–1.36), IHBDC (HR = 1.32; 95% CI, 1.21–1.45), and EHBDC (HR = 1.13; 95% CI, 1.03–1.23), but not AVC (HR = 0.99; 95% CI, 0.88–1.11). Increasing waist circumference, hip circumference, waist-to-hip ratio, and waist-to-height ratio were associated with GBC and IHBDC but not EHBDC or AVC. These results indicate that adult adiposity is associated with an increased risk of biliary tract cancer, particularly GBC and IHBDC. Moreover, they provide evidence for recommending weight maintenance programs to reduce the risk of developing these cancers. Significance: These findings identify a correlation between adiposity and biliary tract cancers, indicating that weight management programs may help minimize the risk of these diseases.

PURPOSE: Inflammatory breast cancer (IBC) rates increased in the United States before the turn of the 21(st) century. We examine trends by estrogen-receptor (ER) status since then. METHODS: Using data from the Surveillance, Epidemiology and End Results (SEER) program for years 2001-2015, we calculated age-adjusted incidence rates for IBC (defined by AJCC TNM category T4d, extent of disease codes, and morphology code 8530) by ER status, which was imputed if unknown, among women aged 25-84 years. For comparison, we included other locally advanced breast cancer and other breast cancers partitioned into localized and regional/distant/unstaged. We fit joinpoint log-linear models to annual rates to calculate annual percentage change (APC) and average annual percentage change (AAPC). RESULTS: Slight increases in ER+ IBC rates among women aged 25-44 (AAPC = 0.5) were similar to other advanced tumor types, but declines among women aged 45-84 (AAPC=−2.2) were greater. Declines in ER− IBC rates for women aged 25-84 (AAPC=−3.7) were greater than for other tumor types. CONCLUSIONS: Our results show a reversal of the rising rates of IBC overall reported at the end of the 20(th) century. Direction of trends for IBC are consistent with other breast cancer types, except for ER+ localized breast cancer in older women. Decreasing parity and rising prevalence of older age at first birth may contribute to declining rates of ER− IBC. Otherwise, patterns of changing risk factors are inconsistent with the trends we observed. Further studies of IBC are necessary to identify additional risk factors and possible preventive strategies.

Background: White blood cell (WBC) DNA may contain methylation patterns that are associated with subsequent breast cancer risk. Using a high-throughput array and samples collected, on average, 1.3 years prior to diagnosis, a case–cohort analysis nested in the prospective Sister Study identified 250 individual CpG sites that were differentially methylated between breast cancer cases and noncases. We examined five of the top 40 CpG sites in a case–control study nested in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) Cohort. Methods: We investigated the associations between prediagnostic WBC DNA methylation in 297 breast cancer cases and 297 frequency-matched controls. Two WBC DNA specimens from each participant were used: a proximate sample collected 1 to 2.9 years and a distant sample collected 4.2–7.3 years prior to diagnosis in cases or the comparable timepoints in controls. WBC DNA methylation level was measured using targeted bisulfite amplification sequencing. We used logistic regression to obtain ORs and 95% confidence intervals (CI). Results: A one-unit increase in percent methylation in ERCC1 in proximate WBC DNA was associated with increased breast cancer risk (adjusted OR = 1.29; 95% CI, 1.06–1.57). However, a one-unit increase in percent methylation in ERCC1 in distant WBC DNA was inversely associated with breast cancer risk (adjusted OR = 0.83; 95% CI, 0.69–0.98). None of the other ORs met the threshold for statistical significance. Conclusions: There was no convincing pattern between percent methylation in the five CpG sites and breast cancer risk. Impact: The link between prediagnostic WBC DNA methylation marks and breast cancer, if any, is poorly understood.

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.

Repeated exposure to the acute proinflammatory environment that follows ovulation at the ovarian surface and distal fallopian tube over a woman's reproductive years may increase ovarian cancer risk. To address this, analyses included individual-level data from 558,709 naturally menopausal women across 20 prospective cohorts, among whom 3,246 developed invasive epithelial ovarian cancer (2,045 serous, 319 endometrioid, 184 mucinous, 121 clear cell, 577 other/unknown). Cox models were used to estimate multivariable-adjusted HRs between lifetime ovulatory cycles (LOC) and its components and ovarian cancer risk overall and by histotype. Women in the 90th percentile of LOC (>514 cycles) were almost twice as likely to be diagnosed with ovarian cancer than women in the 10th percentile ( Significance: Although ovarian cancer is rare, risk of most ovarian cancers doubles as the number of lifetime ovulatory cycles increases from approximately 300 to 500. Thus, identifying an important area for cancer prevention research.

Background - Regular use of aspirin has been associated with a reduced risk of cancer at several sites but the data for endometrial cancer are conflicting. Evidence regarding use of other analgesics is limited. Patients and methods - We pooled individual-level data from seven cohort and five case–control studies participating in the Epidemiology of Endometrial Cancer Consortium including 7120 women with endometrial cancer and 16 069 controls. For overall analyses, study-specific odds ratios (ORs) and 95% confidence intervals (CI) were estimated using logistic regression and combined using random-effects meta-analysis; for stratified analyses, we used mixed-effects logistic regression with study as a random effect. Results - At least weekly use of aspirin and non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) was associated with an approximately 15% reduced risk of endometrial cancer among both overweight and obese women (OR = 0.86 [95% CI 0.76–0.98] and 0.86 [95% CI 0.76–0.97], respectively, for aspirin; 0.87 [95% CI 0.76–1.00] and 0.84 [0.74–0.96], respectively, for non-aspirin NSAIDs). There was no association among women of normal weight (body mass index 2, Pheterogeneity = 0.04 for aspirin, Pheterogeneity = 0.003 for NSAIDs). Among overweight and obese women, the inverse association with aspirin was stronger for use 2–6 times/week (OR = 0.81, 95% CI 0.68–0.96) than for daily use (0.91, 0.80–1.03), possibly because a high proportion of daily users use low-dose formulations. There was no clear association with use of acetaminophen. Conclusion - Our pooled analysis provides further evidence that use of standard-dose aspirin or other NSAIDs may reduce risk of endometrial cancer among overweight and obese women.

Studies of the etiology of inflammatory breast cancer (IBC), a rare but aggressive breast cancer, have been hampered by limited risk factor information. We extend previous studies by evaluating a broader range of risk factors. Between 2009 and 2015, we conducted a case–control study of IBC at six centers in Egypt, Tunisia, and Morocco; enrolled were 267 IBC cases and for comparison 274 non-IBC cases and 275 controls, both matched on age and geographic area to the IBC cases. We administered questionnaires and collected anthropometric measurements for all study subjects. We used multiple imputation methods to account for missing values and calculated odds ratios (ORs) and 95% confidence intervals (CIs) using polytomous logistic regression comparing each of the two case groups to the controls, with statistical tests for the difference between the coefficients for the two case groups. After multivariable adjustment, a livebirth within the previous 2 years (OR 4.6; 95% CI 1.8 to 11.7) and diabetes (OR 1.8; 95% CI 1.1 to 3.0) were associated with increased risk of IBC, but not non-IBC (OR 0.9; 95% CI 0.3 to 2.5 and OR 0.9; 95% CI 0.5 to 1.6 for livebirth and diabetes, respectively). A family history of breast cancer, inflammatory-like breast problems, breast trauma, and low socioeconomic status were associated with increased risk of both tumor types. We identified novel risk factors for IBC and non-IBC, some of which preferentially increased risk of IBC compared to non-IBC. Upon confirmation, these findings could help illuminate the etiology and aid in prevention of this aggressive cancer.

Objectives and Methods: Using pooled multivariable-adjusted rate ratios (RR), we explored relationships between prediagnostic body-mass-index (BMI), waist-to-hip-ratio (WHR), and weight-gain during adulthood, and ALS in 419,894 women and 148,166 men from 10 community-based cohorts in USA, Europe, and Australia; 428 ALS deaths were documented in women and 204 in men. Results: Higher mid-to-later adulthood BMI was associated with lower ALS mortality. For 5kg/m(2) increased BMI, the rate was 15% lower (95% confidence interval [CI]: 4-24%;p=0.005). Although a clear linear trend was not evident for WHR at enrollment (p=0.099) individuals in the highest cohort-specific quartile had 27% (95%CI: 0-47%; p=0.053) lower ALS compared to those in the lowest. BMI in early adulthood did not predict ALS; fewer than 10% of participants had early adulthood BMI >25kg/m(2), limiting power. Weight-gain during adulthood was strongly associated with lower ALS; for an additional 1kg gain in weight/year, the RR=0.43 (95%CI: 0.28-0.65; p

Background While tobacco and alcohol are established risk factors for hepatocellular carcinoma (HCC), the most common type of primary liver cancer, it is unknown whether they also increase the risk of intrahepatic cholangiocarcinoma (ICC). Thus, we examined the association between tobacco and alcohol use by primary liver cancer type. Methods The Liver Cancer Pooling Project is a consortium of 14 US-based prospective cohort studies that includes data from 1,518,741 individuals (HCC n = 1423, ICC n = 410). Multivariable-adjusted hazards ratios (HRs) and 95% confidence intervals (CI) were estimated using proportional hazards regression. Results Current smokers at baseline had an increased risk of HCC (hazard ratio (HR) = 1.86, 95% confidence interval (CI): 1.57–2.20) and ICC (HR = 1.47, 95% CI: 1.07–2.02). Among individuals who quit smoking >30 years ago, HCC risk was almost equivalent to never smokers (HR = 1.09, 95% CI: 0.74–1.61). Compared to non-drinkers, heavy alcohol consumption was associated with an 87% increased HCC risk (HR≥7 drinks/day = 1.87, 95% CI: 1.41–2.47) and a 68% increased ICC risk (HR≥5 drinks/day = 1.68, 95% CI: 0.99–2.86). However, light-to-moderate alcohol consumption of 0–0.5–

Background: Although some familial cancer syndromes include biliary tract cancers (BTCs; cancers of the gallbladder, intrahepatic and extrahepatic bile ducts, and ampulla of Vater), the few studies that have examined the relationships between family history of cancer (FHC) and BTCs have reported inconclusive findings. The objective of this study was to investigate the associations of FHC with risk of BTC in the Biliary Tract Cancers Pooling Project (BiTCaPP). Methods: We used Cox proportional hazards regressions models to estimate HRs and 95% confidence intervals for associations between FHC (any, first-degree, in female relative, in male relative, relative with gastrointestinal cancer, and relative with hormonally related cancer) and BTC risk by anatomic site within the biliary tract, adjusting for sex and race/ethnicity. Sensitivity analyses were conducted that restricted to studies reporting cholecystectomy data and to people without a history of cholecystectomy. Results: Data on FHC were available from 12 prospective studies within BiTCaPP, which collectively contributed 2,246 cases (729 gallbladder, 345 intrahepatic and 615 extrahepatic bile duct, and 385 ampulla of Vater cancers) with 21,706,107 person-years of follow-up. A marginal, inverse association between FHC and gallbladder cancer was driven to the null when analysis was restricted to studies reporting cholecystectomy data and to people without a history of cholecystectomy. FHC was not associated with risk of BTC at the other anatomic sites. Conclusions: These findings do not support an association between FHC and BTCs. Impact: In a study of 1.5 million people, FHC is not a risk factor for BTCs. Cancer Epidemiol Biomarkers Prev; 27(3); 348–51. ©2018 AACR.

The female preponderance of many autoimmune diseases suggests a possible hormonal etiology. Little research exists on systemic and organ-specific autoimmune diseases and risk of breast cancer by tumor estrogen receptor (ER)- and progesterone receptor (PR)- status. Here we evaluate associations between selected systemic and organ-specific autoimmune diseases and breast cancer risk overall and by tumor ER- and PR-status. We used linked Surveillance, Epidemiology and End Results (SEER)-Medicare data, with first female breast cancer cases ages ≥66 years identified by SEER registries (years 1992-2011) (N = 209,929). We selected female controls (N = 200,000) from a stratified 5% random sample of Medicare recipients who were alive and breast cancer-free. We assessed exposures until 12 months before breast cancer diagnosis/selection using Medicare claims data. We estimated odds ratios (OR) and 99.9% confidence intervals (CI) using unconditional and multinomial logistic regression. We found reduced breast cancer risk among those with rheumatoid arthritis (OR=0.84; 99.9% CI 0.79-0.89), systemic lupus erythematosus (OR=0.82; 99.9% CI 0.70-0.97), and pernicious anemia (OR=0.90; 99.9% CI 0.83-0.97), and increased risk among those with psoriasis (OR=1.16; 99.9% CI 1.06-1.27). Statistically significant alterations in risk for rheumatoid arthritis were limited to ER-positive (+) breast cancer, whereas those for the other three conditions were further limited to ER+/PR+ breast cancer. However, only differences for rheumatoid arthritis by ER-status were statistically significant (p-heterogeneity=.0001). The reasons for these associations need to be investigated in future studies accounting for host characteristics and autoimmune disease treatment. This article is protected by copyright. All rights reserved.

Background Several studies have suggested that global DNA methylation in circulating white blood cells (WBC) is associated with breast cancer risk. Methods To address conflicting results and concerns that the findings for WBC DNA methylation in some prior studies may reflect disease effects, we evaluated the relationship between global levels of WBC DNA methylation in white blood cells and breast cancer risk in a case-control study nested within the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO) cohort. A total of 428 invasive breast cancer cases and 419 controls, frequency matched on age at entry (55–59, 60–64, 65–69, ≥70 years), year of entry (on/before September 30, 1997, on/after October 1, 1997) and period of DNA extraction (previously extracted, newly extracted) were included. The ratio of 5-methyl-2’ deoxycytidine [5-mdC] to 2’-deoxyguanine [dG], assuming [dG] = [5-mdC] + [2’-deoxycytidine [dC]] (%5-mdC), was determined by liquid chromatography-electrospray ionization-tandem mass spectrometry, an especially accurate method for assessing total genomic DNA methylation. Results Odds ratio (OR) estimates and 95% confidence intervals (CI) for breast cancer risk adjusted for age at entry, year of entry, and period of DNA extraction, were 1.0 (referent), 0.89 (95% CI, 0.6–1.3), 0.88 (95% CI, 0.6–1.3), and 0.84 (95% CI, 0.6–1.2) for women in the highest compared to lowest quartile levels of %5md-C (p for trend = .39). Effects did not meaningfully vary by time elapsed from WBC collection to diagnosis. Discussion These results do not support the hypothesis that global DNA hypomethylation in WBC DNA is associated with increased breast cancer risk prior to the appearance of clinical disease.

Background: Obesity has been associated with substantially higher risk of inflammatory breast cancer (IBC) than other breast cancer. Here, we assess whether comorbidities of obesity, namely diabetes, abnormal glucose, dyslipidemia, and hypertension, are differentially related to risk of IBC and other breast cancers by tumor stage at diagnosis (localized/regional/distant/unstaged). Methods: We used linked SEER-Medicare data, with female breast cancer cases ages 66+ years identified by SEER registries (years 1992–2011). We divided first breast cancers into IBC (N = 2,306), locally advanced non-IBC (LABC; N = 10,347), and other (N = 197,276). We selected female controls (N = 200,000) from a stratified 5% random sample of Medicare recipients alive and breast cancer free. We assessed exposures until 12 months before diagnosis/selection using Medicare claims data. We estimated odds ratios (OR) and 99.9% confidence intervals (CI) using unconditional logistic regression. Results: Diabetes was associated with increased risk of distant IBC (98.5% of IBC cases; OR 1.44; 99.9% CI 1.21–1.71), distant (OR 1.24; 99.9% CI, 1.09–1.40) and regional (OR 1.29 (99.9% CI, 1.14–1.45) LABC, and distant (OR 1.23; 99.9% CI, 1.10–1.39) and unstaged (OR 1.32; 99.9% CI, 1.18–1.47) other breast cancers. Dyslipidemia was associated with reduced risk of IBC (OR 0.80; 95% CI, 0.67–0.94) and other breast cancers except localized disease. Results were similar by tumor estrogen receptor status. Abnormal glucose levels and hypertension had little association with risk of any tumor type. Conclusions: Associations with diabetes and dyslipidemia were similar for distant stage IBC and other advanced tumors. Impact: If confirmed, such findings could suggest avenues for prevention. Cancer Epidemiol Biomarkers Prev; 26(6); 862–8. ©2017 AACR.

Background In almost all countries, incidence rates of liver cancer are 100-200% higher in males than in females. However, this difference is predominantly driven by hepatocellular carcinoma (HCC), which accounts for 75% of liver cancer cases. Intrahepatic cholangiocarcinoma (ICC) accounts for 12% of cases and has rates only 30% higher in males. Hormones are hypothesized to underlie observed sex differences. We investigated whether prediagnostic circulating hormone and sex hormone binding globulin (SHBG) levels were associated with liver cancer risk, overall and by histology, by leveraging resources from five prospective cohorts. Methods Seven sex steroid hormones and SHBG were quantitated using gas chromatography-tandem mass spectrometry (GC-MS/MS) and competitive electrochemiluminescence immunoassay, respectively, from baseline serum/plasma samples of 191 post-menopausal female liver cancer cases (HCC n=83, ICC n=56) and 426 controls, matched on sex, cohort, age, race/ethnicity, and blood collection date. Odds ratios (ORs) and 95% confidence intervals (CIs) for associations between a one-unit increase in log2 hormone value (approximate doubling of circulating concentration) and liver cancer were calculated using multivariable-adjusted conditional logistic regression. Results A doubling in the concentration of 4-androstenedione was associated with a 50% decreased liver cancer risk (OR=0.50,95%CI=0.30-0.82), while SHBG was associated with a 31% increased risk (OR=1.31,95%CI=1.05-1.63). Examining histology, a doubling of estradiol was associated with a 40% increased risk of ICC (OR=1.40,95%CI=1.05-1.89), but not HCC (OR=1.12,95%CI=0.81-1.54). Conclusions This study provides the first evidence that higher levels of 4-androstenedione may be associated with lower, and SHBG with higher, liver cancer risk in women. However, this study does not support the hypothesis that higher estrogen levels decrease liver cancer risk. Indeed, estradiol may be associated with an increased ICC risk.

PURPOSE: We describe the clinico-pathologic and mammographic characteristics of inflammatory breast cancer (IBC) and non-IBC cases enrolled in a case-control study. Because IBC is a clinico-pathologic entity with rapid appearance of erythema and other signs, its diagnosis is based on clinical observation and thus, by necessity, subjective. Therefore, we evaluate our cases by photographic review by outside expert clinicians and by degree of adherence to the two most recent definitions of IBC: the international expert panel consensus statement and American Joint Committee on Cancer (AJCC) 8(th) edition (we used the slightly less restrictive 7(th) edition definition for our study). METHODS: We enrolled 267 IBC and 274 age- and geographically-matched non-IBC cases at 6 sites in Egypt, Tunisia, and Morocco in a case-control study of IBC conducted between 2009–2015. We collected clinic-pathologic and mammographic data and standardized medical photographs of the breast. RESULTS: We identified many differences between IBC and non-IBC cases; 54.5% versus 68.8% were estrogen receptor-positive, 39.9% versus 14.8% human epidermal growth factor receptor 2-positive, 91% versus 4% exhibited erythema, 63% versus 97% had a mass, and 57% versus 10% had mammographic evidence of skin thickening, Seventy-six percent of IBC cases adhered to the expert panel consensus statement and 36% to the AJCC definition; 86 percent were confirmed as IBC by either photographic review or adherence to the consensus statement. CONCLUSIONS: We successfully identified distinct groups of IBC and non-IBC cases; the reliability of IBC diagnosis would benefit from expert review of standardized medical photographs and associated clinical information.

Background Tobacco and alcohol are well-established risk factors for numerous cancers, yet their relationship to biliary tract cancers remains unclear. Methods We pooled data from 26 prospective studies to evaluate associations of cigarette smoking and alcohol consumption with biliary tract cancer risk. Study-specific hazard ratios (HRs) and 95% confidence intervals (CIs) for associations with smoking and alcohol consumption were calculated. Random-effects meta-analysis produced summary estimates. All statistical tests were two-sided. Results Over a period of 38 369 156 person-years of follow-up, 1391 gallbladder, 758 intrahepatic bile duct, 1208 extrahepatic bile duct, and 623 ampulla of Vater cancer cases were identified. Ever, former, and current smoking were associated with increased extrahepatic bile duct and ampulla of Vater cancers risk (eg, current vs never smokers HR = 1.69, 95% CI = 1.34 to 2.13 and 2.22, 95% CI = 1.69 to 2.92, respectively), with dose-response effects for smoking pack-years, duration, and intensity (all Ptrend 40 cigarettes per day vs never smokers HR = 2.15, 95 % CI = 1.15 to 4.00; Ptrend = .001). No convincing association was observed between smoking and gallbladder cancer. Alcohol consumption was only associated with intrahepatic bile duct cancer, with increased risk for individuals consuming five or more vs zero drinks per day (HR = 2.35, 95%CI = 1.46 to 3.78; Ptrend = .04). There was evidence of statistical heterogeneity among several cancer sites, particularly between gallbladder cancer and the other biliary tract cancers. Conclusions Smoking appears to increase the risk of developing all biliary tract cancers except gallbladder cancer. Alcohol may increase the risk of intrahepatic bile duct cancer. Findings highlight etiologic heterogeneity across the biliary tract.

Incidence rates for liver cancer have increased 3-fold since the mid-1970s in the United States in parallel with increasing trends for obesity and type II diabetes mellitus. We conducted an analysis of baseline body mass index (BMI), waist circumference (WC), and type II diabetes mellitus with risk of liver cancer. The Liver Cancer Pooling Project maintains harmonized data from 1.57 million adults enrolled in 14 U.S.-based prospective studies. Cox regression estimated HRs and 95% confidence intervals (CI) adjusted for age, sex, study center, alcohol, smoking, race, and BMI (for WC and type II diabetes mellitus). Stratified analyses assessed whether the BMI–liver cancer associations differed by hepatitis sera-positivity in nested analyses for a subset of cases (n = 220) and controls (n = 547). After enrollment, 2,162 incident liver cancer diagnoses were identified. BMI, per 5 kg/m2, was associated with higher risks of liver cancer, more so for men (HR = 1.38; 95% CI, 1.30–1.46) than women (HR = 1.25; 95% CI, 1.17–1.35; Pinteraction = 0.02). WC, per 5 cm, was associated with higher risks of liver cancer, approximately equally by sex (overall, HR = 1.08; 95% CI, 1.04–1.13). Type II diabetes mellitus was associated with higher risk of liver cancer (HR = 2.61; 95% CI, 2.34–2.91). In stratified analyses, there was a null association between BMI and liver cancer risk for participants who were sera-positive for hepatitis. This study suggests that high BMI, high WC, and type II diabetes mellitus are associated with higher risks of liver cancer and that the association may differ by status of viral hepatitis infection. Cancer Res; 76(20); 6076–83. ©2016 AACR.

Background: Higher body mass index (BMI) and circulating estrogen levels each increase postmenopausal breast cancer risk, particularly estrogen receptor–positive (ER+) tumors. Higher BMI also increases estrogen production. Methods: We estimated the proportion of the BMI-ER+ breast cancer association mediated through estrogen in a case–control study nested within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Participants included 143 women with invasive ER+ breast cancer and 268 matched controls, all postmenopausal and never having used hormone therapy at baseline. We used liquid chromatography-tandem mass spectrometry to measure 15 estrogens and estrogen metabolites in baseline serum. We calculated BMI from self-reported height and weight at baseline. We estimated the mediating effect of unconjugated estradiol on the BMI-ER+ breast cancer association using Aalen additive hazards and Cox regression models. Results: All estrogens and estrogen metabolites were statistically significantly correlated with BMI, with unconjugated estradiol most strongly correlated [Pearson correlation (r) = 0.45]. Approximately 7% to 10% of the effect of overweight, 12% to 15% of the effect of obesity, and 19% to 20% of the effect of a 5 kg/m2 BMI increase on ER+ breast cancer risk was mediated through unconjugated estradiol. The BMI–breast cancer association, once adjusted for unconjugated estradiol, was not modified by further adjustment for two metabolic ratios statistically significantly associated with both breast cancer and BMI. Conclusion: Circulating unconjugated estradiol levels partially mediate the BMI–breast cancer association, but other potentially important estrogen mediators (e.g., bioavailable estradiol) were not evaluated. Impact: Further research is required to identify mechanisms underlying the BMI–breast cancer association. Cancer Epidemiol Biomarkers Prev; 25(1); 105–13. ©2015 AACR.

Ovarian cancer risk factors differ by histotype; however, within subtype, there is substantial variability in outcomes. We hypothesized that risk factor profiles may influence tumor aggressiveness, defined by time between diagnosis and death, independent of histology. Among 1.3 million women from 21 prospective cohorts, 4,584 invasive epithelial ovarian cancers were identified and classified as highly aggressive (death in

PURPOSE: We sought to disentangle the effects of statins and other lipid-lowering drugs and the underlying dyslipidemia for which they are prescribed on breast cancer risk. METHODS: We conducted a case-control study within the linked Surveillance, Epidemiology, and End Results (SEER)-Medicare data. Cases were women with invasive breast cancer aged 66+ years (N=30,004) identified by SEER registries (years 2007–2011). Controls were women (N=198,969) identified from a 5% random sample of Medicare recipients alive and breast cancer free in year of selection. Participants had a minimum of 13 months of Part A, Part B non-health maintenance organization Medicare and Part D Medicare coverage at least 13 months preceding cancer diagnosis/selection. Exposures were assessed until 12 months before diagnosis/control selection. Odds ratios (OR) and 99.9% confidence intervals (CI) were estimated using adjusted unconditional and multinomial logistic regression. RESULTS: ORs of invasive breast cancer associated with dyslipidemia, statins, and non-statin lipid-lowering drugs were 0.86 (99.9% CI 0.81–0.90), 1.07 (99.9% CI 1.03–1.13) and 1.03 (99.9% CI 0.95–1.11), respectively. Risk reductions with dyslipidemia were slightly greater when untreated than treated and did not vary much by time between dyslipidemia and breast cancer diagnosis. Whether treated or untreated, dyslipidemia was associated with greater reductions in risk for later stage than earlier stage breast cancer (p-heterogeneity

OBJECTIVE: Obesity and diabetes are associated with an increased liver cancer risk. However, most studies have examined all primary liver cancers or hepatocellular carcinoma, with few studies evaluating intrahepatic cholangiocarcinoma (ICC), the second most common type of liver cancer. Thus, we examined the association between obesity and diabetes and ICC risk in a pooled analysis and conducted a systematic review/meta-analysis of the literature. DESIGN: For the pooled analysis, we utilized the Liver Cancer Pooling Project, a consortium of 13 US-based, prospective cohort studies with data from 1,541,143 individuals (ICC cases n=414). In our systematic review, we identified 14 additional studies. We then conducted a meta-analysis, combining the results from LCPP with results from the 5 prospective studies identified through September 2017. RESULTS: In the LCPP, obesity and diabetes were associated with a 62% [Hazard Ratio (HR)=1.62, 95% Confidence Interval (CI): 1.24–2.12] and an 81% (HR=1.81, 95%CI: 1.33–2.46) increased ICC risk, respectively. In the meta-analysis of prospectively ascertained cohorts and nested case-control studies, obesity was associated with a 49% increased ICC risk [Relative Risk (RR)=1.49, 95%CI: 1.32–1.70; n=4 studies; I(2)=0%]. Diabetes was associated with a 53% increased ICC risk (RR=1.53, 95%CI: 1.31–1.78; n=6 studies). While we noted heterogeneity between studies (I(2)=67%) for diabetes, results were consistent in subgroup analyses. Results from hospital-based case-control studies (n=9) were mostly consistent, but these studies are potentially subject to reverse causation. CONCLUSIONS: These findings suggest that obesity and diabetes are associated with increased ICC risk, highlighting similar etiologies of hepatocellular carcinoma and intrahepatic cholangiocarcinoma. However, additional prospective studies are needed to verify these associations.