• Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD.

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 α 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.