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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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Project description:Importance:Obesity 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. Objective:To investigate the association between body fat and breast cancer risk in women with normal BMI. Design, Setting, and Participants:This 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 Measures:Body 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. Results:Among 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 Relevance:In 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 Registration:ClinicalTrials.gov identifier: NCT00000611.

Project description:BackgroundObesity and elevated breast density are common risk factors for breast cancer, and their effects may vary by estrogen receptor (ER) subtype. However, their joint effects on ER subtype-specific risk are unknown. Understanding this relationship could enhance risk stratification for screening and prevention. Thus, we assessed the association between breast density and ER subtype according to body mass index (BMI) and menopausal status.MethodsWe conducted a case-control study nested within two mammography screening cohorts, the Mayo Mammography Health Study and the San Francisco Bay Area Breast Cancer SPORE/San Francisco Mammography Registry. Our pooled analysis contained 1538 ER-positive and 285 ER-negative invasive breast cancer cases and 4720 controls matched on age, menopausal status at time of mammogram, and year of mammogram. Percent density was measured on digitized film mammograms using computer-assisted techniques. We used polytomous logistic regression to evaluate the association between percent density and ER subtype by BMI subgroup (normal/underweight, < 25 kg/m2 versus overweight/obese, ≥ 25 kg/m2). We used Wald chi-squared tests to assess for interactions between percent density and BMI. Our analysis was stratified by menopausal status and hormone therapy usage at the time of index mammogram.ResultsPercent density was associated with increased risk of overall breast cancer regardless of menopausal status or BMI. However, when analyzing breast cancer across ER subtype, we found a statistically significant (p = 0.008) interaction between percent density and BMI in premenopausal women only. Specifically, elevated percent density was associated with a higher risk of ER-negative than ER-positive cancer in overweight/obese premenopausal women [OR per standard deviation increment 2.17 (95% CI 1.50-3.16) vs 1.33 (95% CI 1.11-1.61) respectively, Pheterogeneity = 0.01]. In postmenopausal women, elevated percent density was associated with similar risk of ER-positive and ER-negative cancers, and no substantive differences were seen after accounting for BMI or hormone therapy usage.ConclusionsThe combination of overweight/obesity and elevated breast density in premenopausal women is associated with a higher risk of ER-negative compared with ER-positive cancer. Eighteen percent of premenopausal women in the USA have elevated BMI and breast density and may benefit from lifestyle modifications involving weight loss and exercise.

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

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