Publications by authors named "Catherine Schairer"

108 Publications

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

Cancer Epidemiol Biomarkers Prev 2021 Aug 9;30(8):1575-1581. Epub 2021 Jun 9.

Department of Veterinary and Animal Sciences, University of Massachusetts, Amherst, Massachusetts.

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 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 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.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1717DOI Listing
August 2021

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

Breast Cancer Res Treat 2020 Nov 2;184(2):543-558. Epub 2020 Sep 2.

Medical School of the City University of New York, New York, USA.

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.
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http://dx.doi.org/10.1007/s10549-020-05864-3DOI Listing
November 2020

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

Breast Cancer Res Treat 2020 Sep 20;183(2):467-478. Epub 2020 Jul 20.

Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA.

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/m 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.
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http://dx.doi.org/10.1007/s10549-020-05785-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8257005PMC
September 2020

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.

Br J Cancer 2020 07 7;123(2):316-324. Epub 2020 May 7.

Division of Medical Oncology, National Cancer Centre, Singapore, Singapore.

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.
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http://dx.doi.org/10.1038/s41416-020-0835-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7374167PMC
July 2020

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).

Cancer Res 2020 03 13;80(5):1210-1218. Epub 2020 Jan 13.

Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, University Utrecht, Utrecht, the Netherlands.

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.
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http://dx.doi.org/10.1158/0008-5472.CAN-19-2850DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7056529PMC
March 2020

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

Hepatology 2020 08;72(2):535-547

Division of Medical Oncology, National Cancer Centre Singapore, Singapore.

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 log 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.
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http://dx.doi.org/10.1002/hep.31057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7391790PMC
August 2020

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

Int J Cancer 2020 08 23;147(3):675-685. Epub 2019 Dec 23.

Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, GA.

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/m ; 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.
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http://dx.doi.org/10.1002/ijc.32760DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7391795PMC
August 2020

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

J Natl Cancer Inst 2019 12;111(12):1263-1278

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.
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http://dx.doi.org/10.1093/jnci/djz103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6910180PMC
December 2019

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

Cancer Res 2019 08 21;79(15):3973-3982. Epub 2019 May 21.

Department of Epidemiology and Biostatistics, School of Public Health, Indiana University Bloomington, Bloomington, Indiana.

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/m 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.
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http://dx.doi.org/10.1158/0008-5472.CAN-19-0459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6759233PMC
August 2019

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

Breast Cancer Res Treat 2019 Jul 22;176(2):407-417. Epub 2019 Apr 22.

Medical School of the City University of New York, New York, NY, USA.

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.
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http://dx.doi.org/10.1007/s10549-019-05237-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6705400PMC
July 2019

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

Breast Cancer Res Treat 2019 Jun 26;175(3):755-764. Epub 2019 Mar 26.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD, USA.

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.
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http://dx.doi.org/10.1007/s10549-019-05193-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7737397PMC
June 2019

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

Int J Cancer 2019 07 14;145(1):58-69. Epub 2019 Jan 14.

City of Hope, Duarte, CA.

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 (p = 0.01), family history of ovarian cancer (p = 0.02), body mass index (BMI; p ≤ 0.04) and smoking (p < 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/m , 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.
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http://dx.doi.org/10.1002/ijc.32075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6488363PMC
July 2019

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

Am J Gastroenterol 2018 10 3;113(10):1494-1505. Epub 2018 Sep 3.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA. Department of Population Health, New York University School of Medicine, New York, NY, USA. Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA. Department of Epidemiology and Environmental Health, University at Buffalo, Buffalo, NY, USA. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA. Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA. Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA. Slone Epidemiology Center at Boston University, Boston, MA, USA. Department of Epidemiology & Population Health, Albert Einstein College of Medicine, Bronx, NY, USA. Department of Exercise and Nutrition Sciences, Milken Institute School of Public Health, George Washington University, Washington, DC, USA. Division of Pediatric Epidemiology and Clinical Research and Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA. Epidemiology Research Program, American Cancer Society, Atlanta, GA, USA. VA Boston Healthcare System, Boston, MA, USA. Division of Medical Oncology, National Cancer Centre, Singapore, Singapore. Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

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 = 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 = 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.
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http://dx.doi.org/10.1038/s41395-018-0207-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6521884PMC
October 2018

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

Amyotroph Lateral Scler Frontotemporal Degener 2018 08 16;19(5-6):396-406. Epub 2018 Apr 16.

a Department of Nutrition , Harvard T.H. Chan School of Public Health , Boston , MA , USA.

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/m 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/m, 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.
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http://dx.doi.org/10.1080/21678421.2018.1452944DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6423444PMC
August 2018

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

Br J Cancer 2018 04 9;118(7):1005-1012. Epub 2018 Mar 9.

Department of Population Health, New York University School of Medicine, New York, NY, USA.

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 = 1.87, 95% CI: 1.41-2.47) and a 68% increased ICC risk (HR = 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 = 0.77, 95% CI: 0.67-0.89; HR = 0.57, 95% CI: 0.44-0.73; HR = 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.
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http://dx.doi.org/10.1038/s41416-018-0007-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5931109PMC
April 2018

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

Breast Cancer Res Treat 2018 Jun 15;169(3):607-614. Epub 2018 Feb 15.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

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.
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http://dx.doi.org/10.1007/s10549-018-4680-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6705395PMC
June 2018

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

Cancer Epidemiol Biomarkers Prev 2018 03 16;27(3):348-351. Epub 2018 Jan 16.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland.

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). 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. 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. These findings do not support an association between FHC and BTCs. In a study of 1.5 million people, FHC is not a risk factor for BTCs. .
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http://dx.doi.org/10.1158/1055-9965.EPI-17-1003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5835211PMC
March 2018

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

Int J Cancer 2018 03 24;142(6):1202-1208. Epub 2017 Nov 24.

National Cancer Institute, Division of Cancer Epidemiology and Genetics, National Institutes of Health, Bethesda, MD.

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.
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http://dx.doi.org/10.1002/ijc.31148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5773407PMC
March 2018

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

Breast Cancer Res 2017 Aug 18;19(1):94. Epub 2017 Aug 18.

Department of Civil and Environmental Engineering, University of Massachusetts, Amherst, MA, 01003, USA.

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.
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http://dx.doi.org/10.1186/s13058-017-0886-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5563066PMC
August 2017

Body Size Indicators and Risk of Gallbladder Cancer: Pooled Analysis of Individual-Level Data from 19 Prospective Cohort Studies.

Cancer Epidemiol Biomarkers Prev 2017 04 17;26(4):597-606. Epub 2017 Mar 17.

Epidemiology Research Program, American Cancer Society, Atlanta, Georgia.

There are few established risk factors for gallbladder cancer beyond gallstones. Recent studies suggest a higher risk with high body mass index (BMI), an indicator of general heaviness, but evidence from other body size measures is lacking. Associations of adult BMI, young adult BMI, height, adult weight gain, waist circumference (WC), waist-height ratio (WHtR), hip circumference (HC), and waist-hip ratio (WHR) with gallbladder cancer risk were evaluated. Individual-level data from 1,878,801 participants in 19 prospective cohort studies (14 studies had circumference measures) were harmonized and included in this analysis. Multivariable Cox proportional hazards regression estimated hazard ratios (HR) and 95% confidence intervals (CI). After enrollment, 567 gallbladder cancer cases were identified during 20.1 million person-years of observation, including 361 cases with WC measures. Higher adult BMI (per 5 kg/m, HR: 1.24; 95% CI, 1.13-1.35), young adult BMI (per 5 kg/m, HR: 1.12; 95% CI, 1.00-1.26), adult weight gain (per 5 kg, HR: 1.07; 95% CI, 1.02-1.12), height (per 5 cm, HR: 1.10; 95% CI, 1.03-1.17), WC (per 5 cm, HR: 1.09; 95% CI, 1.02-1.17), WHtR (per 0.1 unit, HR: 1.24; 95% CI, 1.00-1.54), and HC (per 5 cm, HR: 1.13; 95% CI, 1.04-1.22), but not WHR (per 0.1 unit, HR: 1.03; 95% CI, 0.87-1.22), were associated with higher risks of gallbladder cancer, and results did not differ meaningfully by sex or other demographic/lifestyle factors. These findings indicate that measures of overall and central excess body weight are associated with higher gallbladder cancer risks. Excess body weight is an important, and potentially preventable, gallbladder cancer risk factor. .
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http://dx.doi.org/10.1158/1055-9965.EPI-16-0796DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5380577PMC
April 2017

Reliability of medical records in diagnosing inflammatory breast cancer in Egypt.

BMC Res Notes 2017 Mar 16;10(1):126. Epub 2017 Mar 16.

Department of Epidemiology, College of Public Health, University of Nebraska Medical Center, 984395 Nebraska Medical Center, Omaha, NE, 68198-4395, USA.

Background: Inflammatory breast cancer (IBC) is a rare, aggressive breast cancer diagnosed clinically by the presence of diffuse erythema, peau d'orange, and edema that arise quickly in the affected breast. This study evaluated the validity of medical records in Gharbiah, Egypt in identifying clinical signs/symptoms of IBC. For 34 IBC cases enrolled in a case-control study at the Gharbiah Cancer Society and Tanta Cancer Center, Egypt (2009-2010), we compared signs/symptoms of IBC noted in medical records to those recorded on a standardized form at the time of IBC diagnosis by clinicians participating in the case-control study. We calculated the sensitivity and specificity of medical records as compared to the case-control study for recording these signs/symptoms. We also performed McNemar's tests.

Results: In the case-control study, 32 (94.1%) IBC cases presented with peau d'orange, 30 (88.2%) with erythema, and 31 (91.2%) with edema. The sensitivities of the medical records as compared to the case-control study were 0.8, 0.5, and 0.2 for peau d'orange, erythema, and edema, respectively. Corresponding specificities were 1.0, 0.5, and 1.0. p values for McNemar's test were <0.05 for all signs. Medical records had data on the extent and duration of signs for at most 27% of cases for which this information was recorded in the case-control study. Twenty-three of the 34 cases (67.6%) had confirmed diagnosis of IBC in their medical records.

Conclusion: Medical records lacked information on signs/symptoms of IBC, especially erythema and edema, when compared to the case-control study. Deficient medical records could have implications for diagnosis and treatment of IBC and proper documentation of cases in cancer registries.
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http://dx.doi.org/10.1186/s13104-017-2433-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5356360PMC
March 2017

Diabetes, Abnormal Glucose, Dyslipidemia, Hypertension, and Risk of Inflammatory and Other Breast Cancer.

Cancer Epidemiol Biomarkers Prev 2017 06 13;26(6):862-868. Epub 2017 Jan 13.

National Cancer Institute, Division of Cancer Epidemiology and Genetics, NIH, Bethesda, Maryland.

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). 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 ( = 2,306), locally advanced non-IBC (LABC; = 10,347), and other ( = 197,276). We selected female controls ( = 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. 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. Associations with diabetes and dyslipidemia were similar for distant stage IBC and other advanced tumors. If confirmed, such findings could suggest avenues for prevention. .
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http://dx.doi.org/10.1158/1055-9965.EPI-16-0647DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5575736PMC
June 2017

Association of Estrogen Metabolism with Breast Cancer Risk in Different Cohorts of Postmenopausal Women.

Cancer Res 2017 02 23;77(4):918-925. Epub 2016 Dec 23.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland.

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. .
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http://dx.doi.org/10.1158/0008-5472.CAN-16-1717DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5313342PMC
February 2017

Body Mass Index, Waist Circumference, Diabetes, and Risk of Liver Cancer for U.S. Adults.

Cancer Res 2016 10;76(20):6076-6083

Department of Epidemiology and Environmental Health, University at Buffalo, Buffalo, New York.

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/m, 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; P = 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.
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http://dx.doi.org/10.1158/0008-5472.CAN-16-0787DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5141518PMC
October 2016

Ovarian Cancer Risk Factors by Histologic Subtype: An Analysis From the Ovarian Cancer Cohort Consortium.

J Clin Oncol 2016 08 20;34(24):2888-98. Epub 2016 Jun 20.

Nicolas Wentzensen, Britton Trabert, Amanda Black, Louise A. Brinton, Patricia Hartge, Catherine Schairer, and Hannah P. Yang, National Cancer Institute; Dale P. Sandler, National Institute of Environmental Health Science, Bethesda, MD; Elizabeth M. Poole, Julie Buring, I-Min Lee, and Shelley S. Tworoger, Brigham and Women's Hospital; Elizabeth M. Poole, Hans-Olov Adami, Julie Buring, I-Min Lee, and Shelley S. Tworoger, Harvard University, Boston, MA; Emily White and Ulrike Peters, Fred Hutchinson Cancer Research Center, Seattle, WA; Alan A. Arslan, Tess V. Clendenen, and Anne Zeleniuch-Jacquotte, New York University School of Medicine; Thomas Rohan, Albert Einstein College of Medicine, New York, NY; Alpa V. Patel, Susan M. Gapstur, and Mia M. Gaudet, American Cancer Society, Atlanta, GA; V. Wendy Setiawan, University of Southern California, Los Angeles; Leslie Bernstein and James V. Lacey Jr, City of Hope, Duarte, CA; Kala Visvanathan and Judith Hoffman-Bolton, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD; Elisabete Weiderpass and Inger T. Gram, University of Tromsø-The Arctic University of Norway, Tromsø; Elisabete Weiderpass, Cancer Registry of Norway, Oslo, Norway; Elisabete Weiderpass, Hans-Olov Adami, Louise K. Sjöholm, and Alicja Wolk, Karolinska Institute; Stockholm; Annika Idahl and Eva Lundin, Umeå University, Umeå, Sweden; Elisabete Weiderpass, Folkhälsan Research Center, Helsinki, Finland; Lesley M. Butler, University of Pittsburgh, Pittsburgh, PA; Saioa Chamosa, BioDonostia Research Institute, San Sebastian, Spain; Laure Dossus, French Institute of Health and Medical Research, Paris; Sabina Rinaldi, International Agency for Research on Cancer, Lyon, France; Renee Fortner and Rudolf Kaaks, German Cancer Research Center, Heidelberg, Germany; Michael Jones and Anthony Swerdlow, The Institute of Cancer Research; Melissa A. Merritt, Imperial College of London, London; Ruth Travis, University of Oxford, Oxford, United Kingdom; Victoria

Purpose: An understanding of the etiologic heterogeneity of ovarian cancer is important for improving prevention, early detection, and therapeutic approaches. We evaluated 14 hormonal, reproductive, and lifestyle factors by histologic subtype in the Ovarian Cancer Cohort Consortium (OC3).

Patients And Methods: Among 1.3 million women from 21 studies, 5,584 invasive epithelial ovarian cancers were identified (3,378 serous, 606 endometrioid, 331 mucinous, 269 clear cell, 1,000 other). By using competing-risks Cox proportional hazards regression stratified by study and birth year and adjusted for age, parity, and oral contraceptive use, we assessed associations for all invasive cancers by histology. Heterogeneity was evaluated by likelihood ratio test.

Results: Most risk factors exhibited significant heterogeneity by histology. Higher parity was most strongly associated with endometrioid (relative risk [RR] per birth, 0.78; 95% CI, 0.74 to 0.83) and clear cell (RR, 0.68; 95% CI, 0.61 to 0.76) carcinomas (P value for heterogeneity [P-het] < .001). Similarly, age at menopause, endometriosis, and tubal ligation were only associated with endometrioid and clear cell tumors (P-het ≤ .01). Family history of breast cancer (P-het = .008) had modest heterogeneity. Smoking was associated with an increased risk of mucinous (RR per 20 pack-years, 1.26; 95% CI, 1.08 to 1.46) but a decreased risk of clear cell (RR, 0.72; 95% CI, 0.55 to 0.94) tumors (P-het = .004). Unsupervised clustering by risk factors separated endometrioid, clear cell, and low-grade serous carcinomas from high-grade serous and mucinous carcinomas.

Conclusion: The heterogeneous associations of risk factors with ovarian cancer subtypes emphasize the importance of conducting etiologic studies by ovarian cancer subtypes. Most established risk factors were more strongly associated with nonserous carcinomas, which demonstrate challenges for risk prediction of serous cancers, the most fatal subtype.
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http://dx.doi.org/10.1200/JCO.2016.66.8178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5012665PMC
August 2016

Association of Leisure-Time Physical Activity With Risk of 26 Types of Cancer in 1.44 Million Adults.

JAMA Intern Med 2016 06;176(6):816-25

Unit of Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden.

Importance: Leisure-time physical activity has been associated with lower risk of heart-disease and all-cause mortality, but its association with risk of cancer is not well understood.

Objective: To determine the association of leisure-time physical activity with incidence of common types of cancer and whether associations vary by body size and/or smoking.

Design, Setting, And Participants: We pooled data from 12 prospective US and European cohorts with self-reported physical activity (baseline, 1987-2004). We used multivariable Cox regression to estimate hazard ratios (HRs) and 95% confidence intervals for associations of leisure-time physical activity with incidence of 26 types of cancer. Leisure-time physical activity levels were modeled as cohort-specific percentiles on a continuous basis and cohort-specific results were synthesized by random-effects meta-analysis. Hazard ratios for high vs low levels of activity are based on a comparison of risk at the 90th vs 10th percentiles of activity. The data analysis was performed from January 1, 2014, to June 1, 2015.

Exposures: Leisure-time physical activity of a moderate to vigorous intensity.

Main Outcomes And Measures: Incident cancer during follow-up.

Results: A total of 1.44 million participants (median [range] age, 59 [19-98] years; 57% female) and 186 932 cancers were included. High vs low levels of leisure-time physical activity were associated with lower risks of 13 cancers: esophageal adenocarcinoma (HR, 0.58; 95% CI, 0.37-0.89), liver (HR, 0.73; 95% CI, 0.55-0.98), lung (HR, 0.74; 95% CI, 0.71-0.77), kidney (HR, 0.77; 95% CI, 0.70-0.85), gastric cardia (HR, 0.78; 95% CI, 0.64-0.95), endometrial (HR, 0.79; 95% CI, 0.68-0.92), myeloid leukemia (HR, 0.80; 95% CI, 0.70-0.92), myeloma (HR, 0.83; 95% CI, 0.72-0.95), colon (HR, 0.84; 95% CI, 0.77-0.91), head and neck (HR, 0.85; 95% CI, 0.78-0.93), rectal (HR, 0.87; 95% CI, 0.80-0.95), bladder (HR, 0.87; 95% CI, 0.82-0.92), and breast (HR, 0.90; 95% CI, 0.87-0.93). Body mass index adjustment modestly attenuated associations for several cancers, but 10 of 13 inverse associations remained statistically significant after this adjustment. Leisure-time physical activity was associated with higher risks of malignant melanoma (HR, 1.27; 95% CI, 1.16-1.40) and prostate cancer (HR, 1.05; 95% CI, 1.03-1.08). Associations were generally similar between overweight/obese and normal-weight individuals. Smoking status modified the association for lung cancer but not other smoking-related cancers.

Conclusions And Relevance: Leisure-time physical activity was associated with lower risks of many cancer types. Health care professionals counseling inactive adults should emphasize that most of these associations were evident regardless of body size or smoking history, supporting broad generalizability of findings.
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http://dx.doi.org/10.1001/jamainternmed.2016.1548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5812009PMC
June 2016

Anthropometric Factors and Thyroid Cancer Risk by Histological Subtype: Pooled Analysis of 22 Prospective Studies.

Thyroid 2016 02;26(2):306-18

14 Epidemiology Branch, National Institute of Environmental Health Sciences , Research Triangle Park, North Carolina.

Background: Greater height and body mass index (BMI) have been associated with an increased risk of thyroid cancer, particularly papillary carcinoma, the most common and least aggressive subtype. Few studies have evaluated these associations in relation to other, more aggressive histologic types or thyroid cancer-specific mortality.

Methods: This large pooled analysis of 22 prospective studies (833,176 men and 1,260,871 women) investigated thyroid cancer incidence associated with greater height, BMI at baseline and young adulthood, and adulthood BMI gain (difference between young-adult and baseline BMI), overall and separately by sex and histological subtype using multivariable Cox proportional hazards regression models. Associations with thyroid cancer mortality were investigated in a subset of cohorts (578,922 men and 774,373 women) that contributed cause of death information.

Results: During follow-up, 2996 incident thyroid cancers and 104 thyroid cancer deaths were identified. All anthropometric factors were positively associated with thyroid cancer incidence: hazard ratios (HR) [confidence intervals (CIs)] for height (per 5 cm) = 1.07 [1.04-1.10], BMI (per 5 kg/m2) = 1.06 [1.02-1.10], waist circumference (per 5 cm) = 1.03 [1.01-1.05], young-adult BMI (per 5 kg/m2) = 1.13 [1.02-1.25], and adulthood BMI gain (per 5 kg/m2) = 1.07 [1.00-1.15]. Associations for baseline BMI and waist circumference were attenuated after mutual adjustment. Baseline BMI was more strongly associated with risk in men compared with women (p = 0.04). Positive associations were observed for papillary, follicular, and anaplastic, but not medullary, thyroid carcinomas. Similar, but stronger, associations were observed for thyroid cancer mortality.

Conclusion: The results suggest that greater height and excess adiposity throughout adulthood are associated with higher incidence of most major types of thyroid cancer, including the least common but most aggressive form, anaplastic carcinoma, and higher thyroid cancer mortality. Potential underlying biological mechanisms should be explored in future studies.
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http://dx.doi.org/10.1089/thy.2015.0319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4754509PMC
February 2016

Quantifying the Role of Circulating Unconjugated Estradiol in Mediating the Body Mass Index-Breast Cancer Association.

Cancer Epidemiol Biomarkers Prev 2016 Jan 4;25(1):105-13. Epub 2015 Dec 4.

Epidemiology and Biostatistics Program, Division of Cancer Epidemiology and Genetics, NCI, Bethesda, Maryland.

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/m(2) 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.
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http://dx.doi.org/10.1158/1055-9965.EPI-15-0687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5555590PMC
January 2016

Breast cancer by age at diagnosis in the Gharbiah, Egypt, population-based registry compared to the United States Surveillance, Epidemiology, and End Results Program, 2004-2008.

Biomed Res Int 2015 1;2015:381574. Epub 2015 Oct 1.

Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI 48109, USA ; Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA.

Objective: Although breast cancers (BCs) in young women often display more aggressive features, younger women are generally not screened for early detection. It is important to understand the characteristics of young onset breast cancer to increase awareness in this population. This analysis includes all ages, with emphasis placed on younger onset BC in Egypt as compared to the United States.

Methods: BC cases in the Gharbiah cancer registry (GCR), Egypt, were compared to those in the Surveillance, Epidemiology, and End Results (SEER) database. This analysis included 3,819 cases from the GCR and 273,019 from SEER diagnosed 2004-2008.

Results: GCR cases were diagnosed at later stages, with <5% diagnosed at Stage I and 12% diagnosed at Stage IV. 48% of all SEER cases were diagnosed at Stage I, dropping to 30% among those ≤40. Significant differences in age, tumor grade, hormone receptor status, histology, and stage exist between GCR and SEER BCs. After adjustment, GCR cases were nearly 45 times more likely to be diagnosed at stage III and 16 times more likely to be diagnosed at stage IV than SEER cases.

Conclusions: Future research should examine ways to increase literacy about early detection and prompt therapy in young cases.
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http://dx.doi.org/10.1155/2015/381574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4606134PMC
August 2016

NSAID Use and Risk of Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma: The Liver Cancer Pooling Project.

Cancer Prev Res (Phila) 2015 Dec 21;8(12):1156-62. Epub 2015 Sep 21.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland.

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; P(interaction) = 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.
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http://dx.doi.org/10.1158/1940-6207.CAPR-15-0126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4704448PMC
December 2015
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