Fiber and whole grain intakes in relation to liver cancer risk: An analysis in 2 prospective cohorts and systematic review and meta-analysis of prospective studies.

BACKGROUND AND AIMS: The association between fiber or whole grain intakes and the risk of liver cancer remains unclear. We assessed the associations between fiber or whole grain intakes and liver cancer risk among 2 prospective studies, and systematically reviewed and meta-analyzed these results with published prospective studies. APPROACH AND RESULTS: A total of 111,396 participants from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) and 26,085 men from the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study were included. Intakes of total fiber and whole grains were estimated from validated food frequency questionnaires. Study-specific HRs and 95% CI with liver cancer risk were estimated using multivariable-adjusted Cox regression. We systematically reviewed existing literature, and studies were combined in a dose-response meta-analysis. A total of 277 (median follow-up = 15.6 y) and 165 (median follow-up = 16.0 y) cases of liver cancer were observed in Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial and Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, respectively. Dietary fiber was inversely associated with liver cancer risk in Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (HR 10g/day : 0.69; 95% CI: 0.55-0.86). No significant associations were observed between whole grain intakes and liver cancer risk in either study. Our meta-analysis included 2383 incident liver cancer cases (7 prospective cohorts) for fiber intake and 1523 cases (5 prospective cohorts) for whole grain intake; combined HRs for liver cancer risk were 0.83 (0.76-0.91) per 10 g/day of fiber and 0.92 (0.85-0.99) per 16 g/day (1 serving) of whole grains. CONCLUSIONS: Dietary fiber and whole grains were inversely associated with liver cancer risk. Further research exploring potential mechanisms and different fiber types is needed.

Helicobacter hepaticus and Helicobacter bilis in liver and biliary cancers from ATBC and PLCO.

BACKGROUND: Helicobacter species (spp.) have been detected in human bile and hepatobiliary tissue Helicobacter spp. promote gallstone formation and hepatobiliary tumors in laboratory studies, though it remains unclear whether Helicobacter spp. contribute to these cancers in humans. We used a multiplex panel to assess whether seropositivity to Helicobacter (H.) hepaticus or H. bilis proteins was associated with the development of hepatobiliary cancers in the Finnish Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study, and US-based Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO). METHODS: We included 62 biliary and 121 liver cancers, and 190 age-matched controls from ATBC and 74 biliary and 105 liver cancers, and 364 age- and sex-matched controls from PLCO. Seropositivity to 14 H. hepaticus and H. bilis antigens was measured using a multiplex assay. Odds ratios (ORs) and 95% confidence intervals (CIs) were adjusted for major hepatobiliary cancer risk factors and Helicobacter pylori serostatus. RESULTS: Seropositivity to the H. bilis antigen, P167D, was associated with more than a twofold higher risk of liver cancer (OR: 2.38; 95% CI: 1.06, 5.36) and seropositivity to the H. hepaticus antigens HH0407 or HH1201, or H. bilis antigen, HRAG 01470 were associated with higher risk of biliary cancer (OR: 5.01; 95% CI: 1.53, 16.40; OR: 2.40; 95% CI: 1.00, 5.76; OR: 3.27; 95% CI: 1.14, 9.34, respectively) within PLCO. No associations for any of the H. hepaticus or H. bilis antigens were noted for liver or biliary cancers within ATBC. CONCLUSIONS: Further investigations in cohort studies should examine the role of Helicobacter spp. in the etiology of liver and biliary cancers.

Enterohepatic Shunt-Driven Cholemia Predisposes to Liver Cancer.

BACKGROUND & AIMS: Pathogenesis of hepatocellular carcinoma (HCC), which kills millions annually, is poorly understood. Identification of risk factors and modifiable determinants and mechanistic understanding of how they impact HCC are urgently needed. METHODS: We sought early prognostic indicators of HCC in C57BL/6 mice, which we found were prone to developing this disease when fed a fermentable fiber-enriched diet. Such markers were used to phenotype and interrogate stages of HCC development. Their human relevance was tested using serum collected prospectively from an HCC/case-control cohort. RESULTS: HCC proneness in mice was dictated by the presence of congenitally present portosystemic shunt (PSS), which resulted in markedly elevated serum bile acids (BAs). Approximately 10% of mice from various sources exhibited PSS/cholemia, but lacked an overt phenotype when fed standard chow. However, PSS/cholemic mice fed compositionally defined diets, developed BA- and cyclooxygenase-dependent liver injury, which was exacerbated and uniformly progressed to HCC when diets were enriched with the fermentable fiber inulin. Such progression to cholestatic HCC associated with exacerbated cholemia and an immunosuppressive milieu, both of which were required in that HCC was prevented by impeding BA biosynthesis or neutralizing interleukin-10 or programmed death protein 1. Analysis of human sera revealed that elevated BA was associated with future development of HCC. CONCLUSIONS: PSS is relatively common in C57BL/6 mice and causes silent cholemia, which predisposes to liver injury and HCC, particularly when fed a fermentable fiber-enriched diet. Incidence of silent PSS/cholemia in humans awaits investigation. Regardless, measuring serum BA may aid HCC risk assessment, potentially alerting select individuals to consider dietary or BA interventions.

Racial/ethnic disparities in hepatocellular carcinoma incidence and mortality rates in the United States, 1992-2018.

BACKGROUND AND AIMS: HCC is characterized by racial/ethnic disparities in rates. Recent USA reports suggest that incidence has begun to decline, but it is not clear whether the declines have occurred among all groups, nor whether mortality has declined. Thus, the current study examined USA incidence and mortality between 1992 and 2018. APPROACH & RESULTS: HCC incidence and incidence-based mortality data from the Surveillance, Epidemiology, and End Results program were used to calculate age-standardized rates by race/ethnicity, sex, and age. Trends were analyzed using joinpoint regression to estimate annual percent change (APC). Age-period-cohort models assessed the effects on trends of age, calendar period, and birth cohort. Overall, HCC incidence significantly declined between 2015 and 2018 (APC, -5.6%). Whereas most groups experienced incidence declines, the trends were most evident among Asians/Pacific Islanders, women, and persons <50 years old. Exceptions were the rates among non-Hispanic Black persons, which did not significantly decline (APC, -0.7), and among American Indians/Alaska Natives, which significantly increased (APC, +4.3%). Age-period-cohort modeling found that birth cohort had a greater effect on rates than calendar period. Among the baby boom cohorts, the 1950-1954 cohort had the highest rates. Similar to the overall incidence decline, HCC mortality rates declined between 2013 and 2018 (APC, -2.2%). CONCLUSIONS: HCC incidence and mortality rates began to decline for most groups in 2015, but persistent differences in rates continued to exist. Rates among non-Hispanic Black persons did not decline significantly, and rates among American Indians/Alaska Natives significantly increased, suggesting that greater effort is needed to reduce the HCC burden among these vulnerable groups.

Association of high-evidence gastric cancer susceptibility loci and somatic gene expression levels with survival.

Eleven high-evidence single-nucleotide polymorphisms (SNPs) at nine loci for gastric cancer (GC) risk were reported, but their associations with survival remain unknown. In this study, we examined associations between SNP and GC survival by anatomic location and histology among 1147 incident cases from the Shanxi Upper Gastrointestinal Genetics Project. We further examined whether SNPs were expression quantitative trait loci in normal and tumor gastric tissues, and whether tumor versus normal somatic mRNA differences in 126 cases were associated with survival. No SNPs were associated with GC survival overall. However, subtype-specific associations were observed for gastric cardia adenocarcinomas at MUC1/TRIM46/1q22 rs2070803 [HRAA versus GA+GG = 2.16; 95% confidence interval (CI) = 1.24-3.78; P = 0.0068] and LTA/TNF/6p21.33 rs1799724 (HRTT+CT versus CC = 1.30; 95% CI = 1.07-1.57; P = 0.0077), and for diffuse-type GC at PSCA/8q24.3 rs2294008 (HRTT versus CT+CC = 1.99; 95% CI = 1.33-2.97; P = 7.8E-04). Rs2294008T was a cis-expression quantitative trait loci for PSCA, upregulating mRNA in normal gastric (ß = 0.60; P = 5.7E-21) and GC (ß = 0.30; P = 0.0089) tissues. Cases in the highest quartile (the smallest downregulation of tumor PSCA) had shortest survival than cases with the most downregulated PSCA (median survival of 0.47 years in the highest quartile versus 3.73 years in the lowest quartile; hazard ratio = 9.70; 95% CI = 2.46-38.4; P = 0.0012). Less striking effects for mRNA levels were observed for MTX1 at 1q22 in gastric cardia adenocarcinoma and for JRK at 8q24.3 in diffuse GC. Our results suggest three high-evidence GC risk loci have prognostic importance in GC subtypes. Future studies in well-characterized independent populations are warranted to validate our findings and further investigate the clinical utility of these variants in predicting GC prognosis.

Association of seropositivity to Helicobacter species and biliary tract cancer in the ATBC study.

UNLABELLED: Helicobacter have been detected in human bile and hepatobiliary tissue. Despite evidence that Helicobacter species promote gallstone formation and hepatobiliary tumors in laboratory studies, it remains unclear whether Helicobacter species contribute to these cancers in humans. We used a multiplex panel to assess whether seropositivity to 15 Helicobacter pylori proteins was associated with subsequent incidence of hepatobiliary cancers in the Finnish Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. We included 64 biliary cancers, 122 liver cancers, and 224 age-matched controls which occurred over the course of 22 years. Helicobacter pylori seropositivity was defined as those positive to ≥ 4 antigens. Odds ratios (OR) and 95% confidence intervals were adjusted for major hepatobiliary cancer risk factors. Among the controls, 88% were seropositive to H. pylori at baseline. Among those who subsequently developed hepatobiliary cancer, the prevalence of seropositivity was higher: 100% for gallbladder cancer, 97% of extrahepatic bile duct cancer, 91% of ampula of Vater cancer, 96% of intrahepatic bile duct cancer, and 94% of hepatocellular carcinoma. Although the OR for gallbladder cancer could not be calculated, the OR for the other sites were 7.01 (95% confidence interval [CI]: 0.79-62.33), 2.21 (0.19-25.52), 10.67 (0.76-150.08), and 1.20 (0.42-3.45), respectively, with an OR of 5.47 (95% CI: 1.17-25.65) observed for the biliary tract cancers combined. ORs above 1 were observed for many of the investigated antigens, although most of these associations were not statistically significant. CONCLUSION: Seropositivity to H. pylori proteins was associated with an increased risk of biliary tract cancers in ATBC. Further studies are needed to confirm our findings and to determine how H. pylori might influence the risk of biliary tract cancer.

Serum metabolomic profile of hair dye use.

The International Agency for Research on Cancer reported that some chemicals in hair dyes are probably carcinogenic to those exposed to them occupationally. Biological mechanisms through which hair dye use may be related to human metabolism and cancer risk are not well-established. We conducted the first serum metabolomic examination comparing hair dye users and nonusers in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. Metabolite assays were conducted using ultrahigh performance liquid chromatography-tandem mass spectrometry. The association between metabolite levels and hair dye use was estimated using linear regression, adjusting for age, body mass index, smoking, and multiple comparisons. Among the 1,401 detected metabolites, 11 compounds differed significantly between the two groups, including four amino acids and three xenobiotics. Redox-related glutathione metabolism was heavily represented, with L-cysteinylglycine disulfide showing the strongest association with hair dye (effect size (ß) = - 0.263; FDR adjusted p-value = 0.0311), along with cysteineglutathione disulfide (ß = - 0.685; FDR adjusted p-value = 0.0312). 5alpha-Androstan-3alpha,17beta-diol disulfate was reduced in hair dye users (ß = - 0.492; FDR adjusted p-value = 0.077). Several compounds related to antioxidation/ROS and other pathways differed significantly between hair dye users and nonusers, including metabolites previously associated with prostate cancer. Our findings suggest possible biological mechanisms through which the use of hair dye could be associated with human metabolism and cancer risk.

Yoghurt Intake and Gastric Cancer: A Pooled Analysis of 16 Studies of the StoP Consortium.

BACKGROUND: Yoghurt can modify gastrointestinal disease risk, possibly acting on gut microbiota. Our study aimed at exploring the under-investigated association between yoghurt and gastric cancer (GC). METHODS: We pooled data from 16 studies from the Stomach Cancer Pooling (StoP) Project. Total yoghurt intake was derived from food frequency questionnaires. We calculated study-specific odds ratios (ORs) of GC and the corresponding 95% confidence intervals (CIs) for increasing categories of yoghurt consumption using univariate and multivariable unconditional logistic regression models. A two-stage analysis, with a meta-analysis of the pooled adjusted data, was conducted. RESULTS: The analysis included 6278 GC cases and 14,181 controls, including 1179 cardia and 3463 non-cardia, 1191 diffuse and 1717 intestinal cases. The overall meta-analysis revealed no association between increasing portions of yoghurt intake (continuous) and GC (OR = 0.98, 95% CI = 0.94-1.02). When restricting to cohort studies, a borderline inverse relationship was found (OR = 0.93, 95% CI = 0.88-0.99). The adjusted and unadjusted OR were 0.92 (95% CI = 0.85-0.99) and 0.78 (95% CI = 0.73-0.84) for any vs. no yoghurt consumption and GC risk. The OR for 1 category of increase in yoghurt intake was 0.96 (95% CI = 0.91-1.02) for cardia, 1.03 (95% CI = 1.00-1.07) for non-cardia, 1.12 (95% CI = 1.07-1.19) for diffuse and 1.02 (95% CI = 0.97-1.06) for intestinal GC. No effect was seen within hospital-based and population-based studies, nor in men or women. CONCLUSIONS: We found no association between yoghurt and GC in the main adjusted models, despite sensitivity analyses suggesting a protective effect. Additional studies should further address this association.

Circulating bile acid concentrations and non-alcoholic fatty liver disease in Guatemala.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a major liver disease worldwide. Bile acid dysregulation may be a key feature in its pathogenesis and progression. AIMS: To characterise the relationship between bile acid levels and NAFLD at the population level METHODS: We conducted a cross-sectional study in Guatemala in 2016 to examine the prevalence of NAFLD. Participants (n = 415) completed questionnaires, donated blood samples and had a brief medical exam. NAFLD was determined by calculation of the fatty liver index. The levels of 15 circulating bile acids were determined by LC-MS/MS. Adjusted prevalence odds ratios (PORadj ) and 95% CI were calculated to examine the relationships between bile acid levels (in tertiles) and NAFLD. RESULTS: Persons with NAFLD had significantly higher levels of the conjugated primary bile acids glycocholic acid (GCA) (PORadj T3 vs T1  = 1.85), taurocholic acid (TCA) (PORadj T3 vs T1  = 2.45) and taurochenodeoxycholic acid (TCDCA) (PORadj T3 vs T1  = 2.10), as well as significantly higher levels the unconjugated secondary bile acid, deoxycholic acid (DCA) (PORadj T3 vs T1  = 1.78) and its conjugated form, taurodeoxycholic acid (TDCA) (PORadj T3 vs T1  = 1.81). CONCLUSIONS: The bile acid levels of persons with and without NAFLD differed significantly. Among persons with NAFLD, higher levels of the conjugated forms of CA (i.e. GCA, TCA) and the secondary bile acids that derive from CA (i.e. DCA, TDCA) may indicate there is hepatic overproduction of CA, which may affect the liver via aberrant signalling mediated by the bile acids.

A population-based investigation of the association between alcohol intake and serum total ghrelin concentrations among cigarette-smoking, non-alcohol-dependent male individuals.

BACKGROUND: Ghrelin plays significant roles in regulating appetite, food intake, and metabolism. Furthermore, the ghrelin system is increasingly being studied in relation to alcohol seeking behaviors. To this end, it is important to understand the possible effects of alcohol intake on the ghrelin system. The aim of the present study was to investigate the association between alcohol drinking and circulating ghrelin levels in a large sample of cigarette-smoking, non-alcohol-dependent male individuals. METHODS: We utilized data from two nested case-control studies (study A, n = 807; study B, n = 976) based within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) trial. Data on alcohol consumption (grams of pure alcohol consumed per day) were obtained via a food frequency questionnaire. Blood samples were also collected (after 12 h of fasting), and serum concentrations of total ghrelin were measured by radioimmunoassay. RESULTS: Dichotomous comparison between alcohol drinkers (>0 g/day of alcohol intake) and non-drinkers (0 g/day of alcohol intake) found higher total ghrelin levels among individuals who drank alcohol than those who did not, with statistically significant results in study A [F (1, 798) = 4.32, P = 0.03] and less robust results in study B [F (1, 966) = 2.62, P = 0.10], controlling for a list of factors that may influence ghrelin levels and/or differ between drinkers and non-drinkers. Bivariate correlational analysis among drinkers found no association between the quantity of daily alcohol intake and blood total ghrelin concentrations. CONCLUSION: These results indicate elevated ghrelin levels among alcohol drinkers and provide additional/relevant information on the complex interaction between alcohol use and the ghrelin system.

Circulating 25-hydroxyvitamin D and the risk of rarer cancers: Design and methods of the Cohort Consortium Vitamin D Pooling Project of Rarer Cancers.

The Cohort Consortium Vitamin D Pooling Project of Rarer Cancers (VDPP), a consortium of 10 prospective cohort studies from the United States, Finland, and China, was formed to examine the associations between circulating 25-hydroxyvitamin D (25(OH)D) concentrations and the risk of rarer cancers. Cases (total n = 5,491) included incident primary endometrial (n = 830), kidney (n = 775), ovarian (n = 516), pancreatic (n = 952), and upper gastrointestinal tract (n = 1,065) cancers and non-Hodgkin lymphoma (n = 1,353) diagnosed in the participating cohorts. At least 1 control was matched to each case on age, date of blood collection (1974-2006), sex, and race/ethnicity (n = 6,714). Covariate data were obtained from each cohort in a standardized manner. The majority of the serum or plasma samples were assayed in a central laboratory using a direct, competitive chemiluminescence immunoassay on the DiaSorin LIAISON platform (DiaSorin, Inc., Stillwater, Minnesota). Masked quality control samples included serum standards from the US National Institute of Standards and Technology. Conditional logistic regression analyses were conducted using clinically defined cutpoints, with 50-<75 nmol/L as the reference category. Meta-analyses were also conducted using inverse-variance weights in random-effects models. This consortium approach permits estimation of the association between 25(OH)D and several rarer cancers with high accuracy and precision across a wide range of 25(OH)D concentrations.

Vitamin D-Binding Protein and Risk of Renal Cell Carcinoma in the Cancer Prevention Study-II Cohort.

Background: Kidney cancer has several well-established risk factors, including smoking, obesity, and hypertension. These factors do not, however, completely account for its etiology. One previous study of vitamin D-binding protein (DBP) and risk of renal cell carcinoma found a striking inverse association that warranted replication.Methods: We conducted a nested case-control study in the American Cancer Society Cancer Prevention Study-II Nutrition Cohort to prospectively examine circulating DBP concentration and renal cell carcinoma risk. Cases (n = 87) were matched 1:1 to controls on gender, race, age (±5 years), and date of blood collection (±30 days). ORs and 95% confidence intervals (CIs) were estimated for quartiles of DBP using conditional logistic regression.Results: There was a statistically significant inverse trend across quartiles of DBP such that participants with higher DBP had a markedly decreased risk of renal cell carcinoma (vs. Q1: Q2 OR, 0.93; 95% CI, 0.41-2.11; Q3 OR, 0.42; 95% CI, 0.15-1.15; Q4 OR, 0.33; 95% CI, 0.10-1.06; P trend = 0.03).Conclusions: Our findings demonstrate a strong inverse association between circulating DBP and risk of renal cell carcinoma, supporting the findings from previous research.Impact: This is only the second study to examine DBP and risk of kidney cancer, and one of only a handful of studies to examine circulating DBP and risk of cancer at any site. Our findings support emerging evidence for an etiologic role of DBP in cancer and may provide insights into the etiology of kidney and other cancers. Cancer Epidemiol Biomarkers Prev; 27(10); 1203-7. ©2018 AACR.

Association of 25-Hydroxyvitamin D with Liver Cancer Incidence and Chronic Liver Disease Mortality in Finnish Male Smokers of the ATBC Study.

Background: Although circulating 25-hydroxyvitamin D [25(OH)D] concentrations were linked to liver cancer and chronic liver disease (CLD) in laboratory studies, few epidemiologic studies have addressed the associations.Methods: Within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, we measured 25(OH)D in baseline serum of 202 incident liver cancer cases and 225 CLD deaths that occurred during nearly 25 years of follow-up, and 427 controls. ORs and 95% confidence intervals (CIs) were estimated using unconditional logistic regression. We examined predetermined clinically defined cut-points, and season-specific and season-standardized quartiles.Results: Low serum 25(OH)D concentrations were associated with higher risk of liver cancer (<25 nmol/L vs. ≥50 nmol/L: 1.98; 95% CI, 1.22-3.20; Ptrend across categories = 0.003) and CLD mortality (1.93; 95% CI, 1.23-3.03; Ptrend = 0.006) in models adjusted for age and date of blood draw. After additional adjustment for body mass index, diabetes, smoking, and other potential confounders, the association remained statistically significant for liver cancer (1.91; 95% CI, 1.16-3.15; Ptrend = 0.008), but was somewhat attenuated for CLD mortality (1.67; 95% CI, 1.02-2.75; Ptrend = 0.05). Associations were similar for analyses using season-specific and season-standardized quartiles, and after excluding participants with diabetes, or hepatitis B or C.Conclusions: Our results suggest a possible preventive role for vitamin D against liver cancer and CLD, although the importance of the liver for vitamin D metabolism and the lack of information about underlying liver disease makes reverse causality a concern.Impact: Future studies are needed to evaluate associations of vitamin D with liver cancer and liver disease in other populations, particularly those with a different constellation of risk factors. Cancer Epidemiol Biomarkers Prev; 27(9); 1075-82. ©2018 AACR.

Prediagnostic Sex Steroid Hormones in Relation to Male Breast Cancer Risk.

PURPOSE: Although previous studies have implicated a variety of hormone-related risk factors in the etiology of male breast cancers, no previous studies have examined the effects of endogenous hormones. PATIENTS AND METHODS: Within the Male Breast Cancer Pooling Project, an international consortium comprising 21 case-control and cohort investigations, a subset of seven prospective cohort studies were able to contribute prediagnostic serum or plasma samples for hormone quantitation. Using a nested case-control design, multivariable unconditional logistic regression analyses estimated odds ratios and 95% CIs for associations between male breast cancer risk and 11 individual estrogens and androgens, as well as selected ratios of these analytes. RESULTS: Data from 101 cases and 217 matched controls were analyzed. After adjustment for age and date of blood draw, race, and body mass index, androgens were found to be largely unrelated to risk, but circulating estradiol levels showed a significant association. Men in the highest quartile had an odds ratio of 2.47 (95% CI, 1.10 to 5.58) compared with those in the lowest quartile (trend P = .06). Assessment of estradiol as a ratio to various individual androgens or sum of androgens showed no further enhancement of risk. These relations were not significantly modified by either age or body mass index, although estradiol was slightly more strongly related to breast cancers occurring among younger (age < 67 years) than older men. CONCLUSION: Our results support the notion of an important role for estradiol in the etiology of male breast cancers, similar to female breast cancers.

Tobacco and alcohol in relation to male breast cancer: an analysis of the male breast cancer pooling project consortium.

BACKGROUND: The etiology of male breast cancer is poorly understood, partly due to its relative rarity. Although tobacco and alcohol exposures are known carcinogens, their association with male breast cancer risk remains ill-defined. METHODS: The Male Breast Cancer Pooling Project consortium provided 2,378 cases and 51,959 controls for analysis from 10 case-control and 10 cohort studies. Individual participant data were harmonized and pooled. Unconditional logistic regression was used to estimate study design-specific (case-control/cohort) ORs and 95% confidence intervals (CI), which were then combined using fixed-effects meta-analysis. RESULTS: Cigarette smoking status, smoking pack-years, duration, intensity, and age at initiation were not associated with male breast cancer risk. Relations with cigar and pipe smoking, tobacco chewing, and snuff use were also null. Recent alcohol consumption and average grams of alcohol consumed per day were also not associated with risk; only one subanalysis of very high recent alcohol consumption (>60 g/day) was tentatively associated with male breast cancer (ORunexposed referent = 1.29; 95% CI, 0.97-1.71; OR>0-<7 g/day referent = 1.36; 95% CI, 1.04-1.77). Specific alcoholic beverage types were not associated with male breast cancer. Relations were not altered when stratified by age or body mass index. CONCLUSIONS: In this analysis of the Male Breast Cancer Pooling Project, we found little evidence that tobacco and alcohol exposures were associated with risk of male breast cancer. IMPACT: Tobacco and alcohol do not appear to be carcinogenic for male breast cancer. Future studies should aim to assess these exposures in relation to subtypes of male breast cancer.

Anthropometric and hormonal risk factors for male breast cancer: male breast cancer pooling project results.

BACKGROUND: The etiology of male breast cancer is poorly understood, partly because of its relative rarity. Although genetic factors are involved, less is known regarding the role of anthropometric and hormonally related risk factors. METHODS: In the Male Breast Cancer Pooling Project, a consortium of 11 case-control and 10 cohort investigations involving 2405 case patients (n = 1190 from case-control and n = 1215 from cohort studies) and 52013 control subjects, individual participant data were harmonized and pooled. Unconditional logistic regression generated study design-specific (case-control/cohort) odds ratios (ORs) and 95% confidence intervals (CIs), with exposure estimates combined using fixed effects meta-analysis. All statistical tests were two-sided. RESULTS: Risk was statistically significantly associated with weight (highest/lowest tertile: OR = 1.36; 95% CI = 1.18 to 1.57), height (OR = 1.18; 95% CI = 1.01 to 1.38), and body mass index (BMI; OR = 1.30; 95% CI = 1.12 to 1.51), with evidence that recent rather than distant BMI was the strongest predictor. Klinefelter syndrome (OR = 24.7; 95% CI = 8.94 to 68.4) and gynecomastia (OR = 9.78; 95% CI = 7.52 to 12.7) were also statistically significantly associated with risk, relations that were independent of BMI. Diabetes also emerged as an independent risk factor (OR = 1.19; 95% CI = 1.04 to 1.37). There were also suggestive relations with cryptorchidism (OR = 2.18; 95% CI = 0.96 to 4.94) and orchitis (OR = 1.43; 95% CI = 1.02 to 1.99). Although age at onset of puberty and histories of infertility were unrelated to risk, never having had children was statistically significantly related (OR = 1.29; 95% CI = 1.01 to 1.66). Among individuals diagnosed at older ages, a history of fractures was statistically significantly related (OR = 1.41; 95% CI = 1.07 to 1.86). CONCLUSIONS: Consistent findings across case-control and cohort investigations, complemented by pooled analyses, indicated important roles for anthropometric and hormonal risk factors in the etiology of male breast cancer. Further investigation should focus on potential roles of endogenous hormones.