Imaging Modalities in Inflammatory Breast Cancer (IBC) Diagnosis: A Computer-Aided Diagnosis System Using Bilateral Mammography Images.

Inflammatory breast cancer (IBC) is an aggressive type of breast cancer. It leads to a significantly shorter survival than other types of breast cancer in the U.S. The American Joint Committee on Cancer (AJCC) defines the diagnosis based on specific criteria. However, the clinical presentation of IBC in North Africa (Egypt, Morocco, and Tunisia) does not agree, in many cases, with the AJCC criteria. Healthcare providers with expertise in IBC diagnosis are limited because of the rare nature of the disease. This paper reviewed current imaging modalities for IBC diagnosis and proposed a computer-aided diagnosis system using bilateral mammograms for early and improved diagnosis. The National Institute of Cancer in Egypt provided the image dataset consisting of IBC and non-IBC cancer cases. Type 1 and Type 2 fuzzy logic classifiers use the IBC markers that the expert team identified and extracted carefully. As this research is a pioneering work in its field, we focused on breast skin thickening, its percentage, the level of nipple retraction, bilateral breast density asymmetry, and the ratio of the breast density of both breasts in bilateral digital mammogram images. Granulomatous mastitis cases are not included in the dataset. The system's performance is evaluated according to the accuracy, recall, precision, F1 score, and area under the curve. The system achieved accuracy in the range of 92.3-100%.

Prediagnostic White Blood Cell DNA Methylation and Risk of Breast Cancer in the Prostate Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) Cohort.

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.

Risk factors for inflammatory and non-inflammatory breast cancer in North Africa.

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Obesity and related conditions and risk of inflammatory breast cancer: a nested case-control study.

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 and 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-< 30, 30-< 35, and ≥ 35 compared to < 25 kg/m2 were 1.5 (0.9-2.3), 2.0 (1.2-3.1), and 2.5 (1.4-4.4), respectively. After adjustment for pre-diabetes/diabetes, HDL-C and triglyceride levels, and dyslipidemia, corresponding ORs were 1.3 (0.8-2.1), 1.6 (0.9-2.9), and 1.9 (1.0-3.5). The OR for HDL-C levels < 50 mg/dL compared to ≥ 65 mg/dL was 2.0 (1.2-3.3) in the adjusted model. In a separate model the OR for a triglyceride/HDL-C ratio ≥ 2.50 compared to < 1.62 was 1.7 (1.1-2.8) after adjustment for BMI, pre-diabetes/diabetes, and dyslipidemia. Results did not differ significantly by estrogen receptor status. CONCLUSIONS: Obesity and measures of insulin resistance independently increased IBC risk as did obesity and low HDL-C levels. These findings, if confirmed, have implications for IBC prevention.

Exogenous hormone use, reproductive factors and risk of intrahepatic cholangiocarcinoma among women: results from cohort studies in the Liver Cancer Pooling Project and the UK Biobank.

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 -ß, 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.

The Risk of Ovarian Cancer Increases with an Increase in the Lifetime Number of Ovulatory Cycles: An Analysis from the Ovarian Cancer Cohort Consortium (OC3).

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 (<294) [HR (95% confidence interval): 1.92 (1.60-2.30)]. Risk increased 14% per 5-year increase in LOC (60 cycles) [(1.10-1.17)]; this association remained after adjustment for LOC components: number of pregnancies and oral contraceptive use [1.08 (1.04-1.12)]. The association varied by histotype, with increased risk of serous [1.13 (1.09-1.17)], endometrioid [1.20 (1.10-1.32)], and clear cell [1.37 (1.18-1.58)], but not mucinous [0.99 (0.88-1.10), P-heterogeneity = 0.01] tumors. Heterogeneity across histotypes was reduced [P-heterogeneity = 0.15] with adjustment for LOC components [1.08 serous, 1.11 endometrioid, 1.26 clear cell, 0.94 mucinous]. Although the 10-year absolute risk of ovarian cancer is small, it roughly doubles as the number of LOC rises from approximately 300 to 500. The consistency and linearity of effects strongly support the hypothesis that each ovulation leads to small increases in the risk of most ovarian cancers, a risk that cumulates through life, suggesting this as an important area for identifying intervention strategies. 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.

Abdominal and gluteofemoral size and risk of liver cancer: The liver cancer pooling project.

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 <25 kg/m2 ; HR = 1.14, 95%CI: 1.07-1.21). Hip circumference, per 5 cm increase, was associated with a 9% increased PLC risk (HR = 1.09, 95%CI: 1.06-1.12), but no association remained after adjustment for waist circumference (HR = 0.99, 95%CI: 0.94-1.03). HCC and ICC results were similar. These findings suggest that excess abdominal size is associated with an increased risk of liver cancer, even among individuals considered to have a normal BMI. However, excess gluteofemoral size alone confers no increased risk. Our findings extend prior analyses, which found an association between excess adiposity and risk of liver cancer, by disentangling the separate effects of excess abdominal and gluteofemoral size through utilization of both waist and hip circumference measurements.

Associations Between Prediagnostic Concentrations of Circulating Sex Steroid Hormones and Liver Cancer Among Postmenopausal Women.

BACKGROUND AND AIMS: In almost all countries, incidence rates of liver cancer (LC) are 100%-200% higher in males than in females. However, this difference is predominantly driven by hepatocellular carcinoma (HCC), which accounts for 75% of LC 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 LC risk, overall and by histology, by leveraging resources from five prospective cohorts. APPROACH AND RESULTS: Seven sex steroid hormones and SHBG were quantitated using gas chromatography/tandem mass spectrometry and competitive electrochemiluminescence immunoassay, respectively, from baseline serum/plasma samples of 191 postmenopausal female LC 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 LC were calculated using multivariable-adjusted conditional logistic regression. A doubling in the concentration of 4-androstenedione (4-dione) was associated with a 50% decreased LC risk (OR = 0.50; 95% CI = 0.30-0.82), whereas 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 evidence that higher levels of 4-dione may be associated with lower, and SHBG with higher, LC risk in women. However, this study does not support the hypothesis that higher estrogen levels decrease LC risk. Indeed, estradiol may be associated with an increased ICC risk.

Smoking, Alcohol, and Biliary Tract Cancer Risk: A Pooling Project of 26 Prospective Studies.

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 < .01). Current smoking and smoking intensity were also associated with intrahepatic bile duct cancer (eg, >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.

Anthropometric Risk Factors for Cancers of the Biliary Tract in the Biliary Tract Cancers Pooling Project.

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.

Clinico-pathologic and mammographic characteristics of inflammatory and non-inflammatory breast cancer at six centers in North Africa.

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) 8th edition (we used the slightly less restrictive 7th 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 and 2015. We collected clinico-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.

Inflammatory and other breast cancer incidence rate trends by estrogen receptor status in the Surveillance, Epidemiology, and End Results database (2001-2015).

PURPOSE: Inflammatory breast cancer (IBC) rates increased in the United States before the turn of the twenty-first 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: The rate of increase in ER+ IBC rates among women aged 25-44 (AAPC = 0.5) was similar to other advanced tumor types, but declines among women aged 45-84 (AAPC = - 2.2) were more rapid. Declines in ER- IBC rates for women aged 25-84 (AAPC = - 3.7) were more rapid than for other tumor types. CONCLUSIONS: Our results show a reversal of the rising rates of IBC overall reported at the end of the twentieth century. Direction of trends for IBC is 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.

Ovarian cancer risk factors by tumor aggressiveness: An analysis from the Ovarian Cancer Cohort Consortium.

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 <1 year, n = 864), very aggressive (death in 1 to < 3 years, n = 1,390), moderately aggressive (death in 3 to < 5 years, n = 639), and less aggressive (lived 5+ years, n = 1,691). Using competing risks Cox proportional hazards regression, we assessed heterogeneity of associations by tumor aggressiveness for all cases and among serous and endometrioid/clear cell tumors. Associations between parity (phet = 0.01), family history of ovarian cancer (phet = 0.02), body mass index (BMI; phet ≤ 0.04) and smoking (phet < 0.01) and ovarian cancer risk differed by aggressiveness. A first/single pregnancy, relative to nulliparity, was inversely associated with highly aggressive disease (HR: 0.72; 95% CI [0.58-0.88]), no association was observed for subsequent pregnancies (per pregnancy, 0.97 [0.92-1.02]). In contrast, first and subsequent pregnancies were similarly associated with less aggressive disease (0.87 for both). Family history of ovarian cancer was only associated with risk of less aggressive disease (1.94 [1.47-2.55]). High BMI (≥35 vs. 20 to < 25 kg/m2 , 1.93 [1.46-2.56] and current smoking (vs. never, 1.30 [1.07-1.57]) were associated with increased risk of highly aggressive disease. Results were similar within histotypes. Ovarian cancer risk factors may be directly associated with subtypes defined by tumor aggressiveness, rather than through differential effects on histology. Studies to assess biological pathways are warranted.

Body Mass Index, Diabetes and Intrahepatic Cholangiocarcinoma Risk: The Liver Cancer Pooling Project and Meta-analysis.

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; I2 = 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 (I2 = 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.

Prediagnostic body size and risk of amyotrophic lateral sclerosis death in 10 studies.

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 5 kg/m2 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 >25 kg/m2, 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 < 0.001). Associations persisted when adjusted for diabetes at enrollment, restricted to never-smokers, and ALS deaths in the 5 years after enrollment were excluded (accounting for recent weight loss). CONCLUSIONS: These findings confirm somewhat conflicting, underpowered evidence that adiposity is inversely associated with ALS. We newly demonstrate that weight-gain during adulthood is strongly predictive of lower ALS risk.

Tobacco, alcohol use and risk of hepatocellular carcinoma and intrahepatic cholangiocarcinoma: The Liver Cancer Pooling Project.

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 <3 drinks/day appeared to be inversely associated with HCC risk (HR>0-<0.5 drinks/day = 0.77, 95% CI: 0.67-0.89; HR>0.5-<1 drinks/day = 0.57, 95% CI: 0.44-0.73; HR1-<3 drinks/day = 0.71, 95% CI: 0.58-0.87), but not ICC. CONCLUSIONS: These findings suggest that, in this relatively healthy population, smoking cessation and light-to-moderate drinking may reduce the risk of HCC.

Lipid-lowering drugs, dyslipidemia, and breast cancer risk in a Medicare population.

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 < 0.0001). CONCLUSIONS: Lipid-lowering drugs did not account for the lower breast cancer risk associated with dyslipidemia. Our data do not support using statins or other lipid-lowering drugs to prevent breast cancer.

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

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.

Autoimmune diseases and breast cancer risk by tumor hormone-receptor status among elderly women.

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 = 0.0001). The reasons for these associations need to be investigated in future studies accounting for host characteristics and autoimmune disease treatment.

White blood cell DNA methylation and risk of breast cancer in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO).

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.