Dataset Information

A Metabolomics Analysis of Body Mass Index and Postmenopausal Breast Cancer Risk.

ABSTRACT: Background:Elevated body mass index (BMI) is associated with increased risk of postmenopausal breast cancer. The underlying mechanisms, however, remain elusive. Methods:In a nested case-control study of 621 postmenopausal breast cancer case participants and 621 matched control participants, we measured 617 metabolites in prediagnostic serum. We calculated partial Pearson correlations between metabolites and BMI, and then evaluated BMI-associated metabolites (Bonferroni-corrected ? level for 617 statistical tests = P < 8.10?×?10-5) in relation to invasive breast cancer. Odds ratios (ORs) of breast cancer comparing the 90th vs 10th percentile (modeled on a continuous basis) were estimated using conditional logistic regression while controlling for breast cancer risk factors, including BMI. Metabolites with the lowest P values (false discovery rate < 0.2) were mutually adjusted for one another to determine those independently associated with breast cancer risk. Results:Of 67 BMI-associated metabolites, two were independently associated with invasive breast cancer risk: 16a-hydroxy-DHEA-3-sulfate (OR?=?1.65, 95% confidence interval [CI] = 1.22 to 2.22) and 3-methylglutarylcarnitine (OR?=?1.67, 95% CI?=?1.21 to 2.30). Four metabolites were independently associated with estrogen receptor-positive (ER+) breast cancer risk: 16a-hydroxy-DHEA-3-sulfate (OR?=?1.84, 95% CI?=?1.27 to 2.67), 3-methylglutarylcarnitine (OR?=?1.91, 95% CI?=?1.23 to 2.96), allo-isoleucine (OR?=?1.76, 95% CI?=?1.23 to 2.51), and 2-methylbutyrylcarnitine (OR?=?1.89, 95% CI?=?1.22 to 2.91). In a model without metabolites, each 5 kg/m2 increase in BMI was associated with a 14% higher risk of breast cancer (OR?=?1.14, 95% CI?=?1.01 to 1.28), but adding 16a-hydroxy-DHEA-3-sulfate and 3-methylglutarylcarnitine weakened this association (OR?=?1.06, 95% CI?=?0.93 to 1.20), with the logOR attenuating by 57.6% (95% CI?=?21.8% to 100.0+%). Conclusion:These four metabolites may signal metabolic pathways that contribute to breast carcinogenesis and that underlie the association of BMI with increased postmenopausal breast cancer risk. These findings warrant further replication efforts.

SUBMITTER: Moore SC

PROVIDER: S-EPMC6279273 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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A Metabolomics Analysis of Body Mass Index and Postmenopausal Breast Cancer Risk.

Moore Steven C SC Playdon Mary C MC Sampson Joshua N JN Hoover Robert N RN Trabert Britton B Matthews Charles E CE Ziegler Regina G RG

Journal of the National Cancer Institute 20180601 6

<h4>Background</h4>Elevated body mass index (BMI) is associated with increased risk of postmenopausal breast cancer. The underlying mechanisms, however, remain elusive.<h4>Methods</h4>In a nested case-control study of 621 postmenopausal breast cancer case participants and 621 matched control participants, we measured 617 metabolites in prediagnostic serum. We calculated partial Pearson correlations between metabolites and BMI, and then evaluated BMI-associated metabolites (Bonferroni-corrected α ...[more]

PMID: 29325144

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Project description:BackgroundBody fatness is a dynamic exposure throughout life. To provide more insight into the association between body mass index (BMI) and postmenopausal breast cancer, we aimed to examine the age at onset, duration, intensity, and trajectories of body fatness in adulthood in relation to risk of breast cancer subtypes.MethodsBased on self-reported anthropometry in the prospective Norwegian Women and Cancer Study, we calculated the age at onset, duration, and intensity of overweight and obesity using linear mixed-effects models. BMI trajectories in adulthood were modeled using group-based trajectory modeling. We used Cox proportional hazards models to calculate hazard ratios (HRs) with 95% confidence intervals (CIs) for the associations between BMI exposures and breast cancer subtypes in 148,866 postmenopausal women.ResultsA total of 7223 incident invasive postmenopausal breast cancer cases occurred during follow-up. Increased overweight duration and age at the onset of overweight or obesity were associated with luminal A-like breast cancer. Significant heterogeneity was observed in the association between age at overweight and overweight duration and the intrinsic-like subtypes (pheterogeneity 0.03). Compared with women who remained at normal weight throughout adulthood, women with a descending BMI trajectory had a reduced risk of luminal A-like breast cancer (HR 0.54, 95% CI 0.33-0.90), whereas women with ascending BMI trajectories were at increased risk (HR 1.09; 95% CI 1.01-1.17 for "Normal-overweight"; HR 1.20; 95% CI 1.07-1.33 for "Normal-obesity"). Overweight duration and weighted cumulative years of overweight and obesity were inversely associated with luminal B-like breast cancer.ConclusionsIn this exploratory analysis, decreasing body fatness from obesity in adulthood was inversely associated with overall, hormone receptor-positive and luminal A-like breast cancer in postmenopausal women. This study highlights the potential health benefits of reducing weight in adulthood and the health risks associated with increasing weight throughout adult life. Moreover, our data provide evidence of intrinsic-like tumor heterogeneity with regard to age at onset and duration of overweight.

Project description:ImportanceObesity is associated with an increased risk of breast cancer, including the estrogen receptor (ER)-positive subtype in postmenopausal women. Whether excess adiposity is associated with increased risk in women with a normal body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) is unknown.ObjectiveTo investigate the association between body fat and breast cancer risk in women with normal BMI.Design, setting, and participantsThis ad hoc secondary analysis of the Women's Health Initiative (WHI) clinical trial and observational study cohorts was restricted to postmenopausal participants with a BMI ranging from 18.5 to 24.9. Women aged 50 to 79 years were enrolled from October 1, 1993, through December 31, 1998. Of these, 3460 participants underwent body fat measurement with dual-energy x-ray absorptiometry (DXA) at 3 US designated centers with follow-up. At a median follow-up of 16 years (range, 9-20 years), 182 incident breast cancers had been ascertained, and 146 were ER positive. Follow-up was complete on September 30, 2016, and data from October 1, 1993, through September 30, 2016, was analyzed August 2, 2017, through August 21, 2018.Main outcomes and measuresBody fat levels were measured at baseline and years 1, 3, 6, and 9 using DXA. Information on demographic data, medical history, and lifestyle factors was collected at baseline. Invasive breast cancers were confirmed via central review of medical records by physician adjudicators. Blood analyte levels were measured in subsets of participants.ResultsAmong the 3460 women included in the analysis (mean [SD] age, 63.6 [7.6] years), multivariable-adjusted hazard ratios for the risk of invasive breast cancer were 1.89 (95% CI, 1.21-2.95) for the highest quartile of whole-body fat and 1.88 (95% CI, 1.18-2.98) for the highest quartile of trunk fat mass. The corresponding adjusted hazard ratios for ER-positive breast cancer were 2.21 (95% CI, 1.23-3.67) and 1.98 (95% CI, 1.18-3.31), respectively. Similar positive associations were observed for serial DXA measurements in time-dependent covariate analyses. Circulating levels of insulin, C-reactive protein, interleukin 6, leptin, and triglycerides were higher, whereas levels of high-density lipoprotein cholesterol and sex hormone-binding globulin were lower in those in the uppermost vs lowest quartiles of trunk fat mass.Conclusions and relevanceIn postmenopausal women with normal BMI, relatively high body fat levels were associated with an elevated risk of invasive breast cancer and altered levels of circulating metabolic and inflammatory factors. Normal BMI categorization may be an inadequate proxy for the risk of breast cancer in postmenopausal women.Trial registrationClinicalTrials.gov identifier: NCT00000611.

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Dataset Information

A Metabolomics Analysis of Body Mass Index and Postmenopausal Breast Cancer Risk.

Publications

A Metabolomics Analysis of Body Mass Index and Postmenopausal Breast Cancer Risk.

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