Background

We investigated risk factors for inflammatory breast cancer (IBC), a rare, aggressive, and poorly understood breast cancer that is characterized by diffuse breast skin erythema and edema.

Methods

We included 617 IBC case subjects in a nested case-control study from the Breast Cancer Surveillance Consortium database (1994-2009). We also included 1151 noninflammatory, locally advanced, invasive breast cancers with chest wall/breast skin involvement (LABC), 7600 noninflammatory invasive case subjects without chest wall/breast skin involvement (BC), and 93 654 control subjects matched to case subjects on age and year at diagnosis and mammography registry. We present estimates of rate ratios (RRs) and 95% confidence intervals (CI) from conditional logistic regression analyses for each case group vs control subjects based on multiply imputed datasets.

Results

First-degree family history of breast cancer and high mammographic breast density increased risk of IBC, LABC, and BC. High body mass index (BMI) increased IBC risk irrespective of menopausal status and estrogen receptor (ER) expression; rate ratios for BMI 30 and greater vs BMI less than 25 were 3.90 (95% CI = 1.50 to 10.14) in premenopausal women and 3.70 (95% CI = 1.98 to 6.94) in peri/postmenopausal women not currently using hormones. BMI 30 and greater slightly increased risk of ER-positive BC (RR = 1.40; 95% CI = 1.11 to 1.76). Statistically significant reductions in risk of ER-negative IBC with older age at first birth and of ER-positive IBC with higher education were not seen for LABC and BC of the same ER status.

Conclusions

Different associations with BMI, age at first birth, and education between IBC and/or LABC and BC suggest a distinct etiology for IBC.

Background

Women with elevated mammographic density have an increased risk of developing breast cancer. However, among women diagnosed with breast cancer, it is unclear whether higher density portends reduced survival, independent of other factors.

Methods

We evaluated relationships between mammographic density and risk of death from breast cancer and all causes within the US Breast Cancer Surveillance Consortium. We studied 9232 women diagnosed with primary invasive breast carcinoma during 1996-2005, with a mean follow-up of 6.6 years. Mammographic density was assessed using the Breast Imaging Reporting and Data System (BI-RADS) density classification. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated by Cox proportional hazards regression; women with scattered fibroglandular densities (BI-RADS 2) were the referent group. All statistical tests were two-sided.

Results

A total of 1795 women died, of whom 889 died of breast cancer. In multivariable analyses (adjusted for site, age at and year of diagnosis, American Joint Committee on Cancer stage, body mass index, mode of detection, treatment, and income), high density (BI-RADS 4) was not related to risk of death from breast cancer (HR = 0.92, 95% CI = 0.71 to 1.19) or death from all causes (HR = 0.83, 95% CI = 0.68 to 1.02). Analyses stratified by stage and other prognostic factors yielded similar results, except for an increased risk of breast cancer death among women with low density (BI-RADS 1) who were either obese (HR = 2.02, 95% CI = 1.37 to 2.97) or had tumors of at least 2.0 cm (HR = 1.55, 95% CI = 1.14 to 2.09).

Conclusions

High mammographic breast density was not associated with risk of death from breast cancer or death from any cause after accounting for other patient and tumor characteristics. Thus, risk factors for the development of breast cancer may not necessarily be the same as factors influencing the risk of death after breast cancer has developed.

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

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.

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.

Background

The prevalence of class III obesity (body mass index [BMI]≥40 kg/m2) has increased dramatically in several countries and currently affects 6% of adults in the US, with uncertain impact on the risks of illness and death. Using data from a large pooled study, we evaluated the risk of death, overall and due to a wide range of causes, and years of life expectancy lost associated with class III obesity.

Methods and findings

In a pooled analysis of 20 prospective studies from the United States, Sweden, and Australia, we estimated sex- and age-adjusted total and cause-specific mortality rates (deaths per 100,000 persons per year) and multivariable-adjusted hazard ratios for adults, aged 19-83 y at baseline, classified as obese class III (BMI 40.0-59.9 kg/m2) compared with those classified as normal weight (BMI 18.5-24.9 kg/m2). Participants reporting ever smoking cigarettes or a history of chronic disease (heart disease, cancer, stroke, or emphysema) on baseline questionnaires were excluded. Among 9,564 class III obesity participants, mortality rates were 856.0 in men and 663.0 in women during the study period (1976-2009). Among 304,011 normal-weight participants, rates were 346.7 and 280.5 in men and women, respectively. Deaths from heart disease contributed largely to the excess rates in the class III obesity group (rate differences = 238.9 and 132.8 in men and women, respectively), followed by deaths from cancer (rate differences = 36.7 and 62.3 in men and women, respectively) and diabetes (rate differences = 51.2 and 29.2 in men and women, respectively). Within the class III obesity range, multivariable-adjusted hazard ratios for total deaths and deaths due to heart disease, cancer, diabetes, nephritis/nephrotic syndrome/nephrosis, chronic lower respiratory disease, and influenza/pneumonia increased with increasing BMI. Compared with normal-weight BMI, a BMI of 40-44.9, 45-49.9, 50-54.9, and 55-59.9 kg/m2 was associated with an estimated 6.5 (95% CI: 5.7-7.3), 8.9 (95% CI: 7.4-10.4), 9.8 (95% CI: 7.4-12.2), and 13.7 (95% CI: 10.5-16.9) y of life lost. A limitation was that BMI was mainly ascertained by self-report.

Conclusions

Class III obesity is associated with substantially elevated rates of total mortality, with most of the excess deaths due to heart disease, cancer, and diabetes, and major reductions in life expectancy compared with normal weight. Please see later in the article for the Editors' Summary.