The association of prediagnostic circulating levels of cardiometabolic markers, testosterone and sex hormone‐binding globulin with risk of breast cancer among normal weight postmenopausal women in the UK Biobank

Abstract

Emerging evidence suggests that normal weight postmenopausal women with a relative excess of body fat are at increased breast cancer risk. However, little is known about the associations between obesity‐related blood markers and risk of breast cancer among these individuals. In this prospective study comprising 58 629 normal weight postmenopausal women (body mass index between 18.5 kg/m2 and 24.9 kg/m2) who were enrolled in the UK Biobank cohort between 2006 and 2010, we examined the associations of glycated hemoglobin, triglycerides, high‐density lipoprotein cholesterol, C‐reactive protein (CRP), testosterone and sex hormone‐binding globulin (SHBG) with risk of breast cancer. A total of 1268 postmenopausal breast cancer cases were ascertained during a median follow‐up period of 7 years. Women with CRP, total testosterone and free testosterone (FT) levels in the highest quintile had increased risk of breast cancer compared to those in the lowest quintile (HRQ5 vs Q1: 1.35, 95% confidence interval [CI]: 1.12‐1.63, HR Q5 vs Q1: 1.47, 95% CI: 1.20‐1.80 and HR Q5 vs Q1: 1.53, 95% CI: 1.23‐1.90, respectively), whereas those with SHBG in the highest quintile had reduced risk (HR Q5 vs Q1: 0.70, 95% CI: 0.56‐0.88). These associations were attenuated but persisted after additional adjustment for BMI, fat mass index (whole body fat mass [kg]/height [m2]) or waist circumference and after mutual adjustment for testosterone, CRP and/or SHBG. Our study suggests that the risk of postmenopausal breast cancer among normal weight women is increased in association with relatively high levels of CRP and testosterone and with relatively low levels of SHBG.

Biomarkers and Disease Trajectories Influencing Women’s Health: Results from the UK Biobank Cohort

“…The association between circulating estradiol and breast cancer was supported by previous studies in premenopausal as well as post-menopausal women (Endogenous Hormones and Breast Cancer Collaborative Group et al 2013 ; Fuhrman et al 2012 ). We further confirmed that high circulating testosterone and low SHBG levels were associated with an increased risk of breast cancer in our study, likely due to aromatase activity in fat tissues for testosterone (de Jong et al 2001 ) and the binding effect of SHBG with estrogen (Arthur et al 2021 ; Missmer et al 2004 ). Additionally, a Mendelian randomization study also suggested SHBG as a causal factor for breast cancer (Dimou et al 2019 ).…”

Effect of Serum Lipid Profile on the Risk of Breast Cancer: Systematic Review and Meta-Analysis of 1,628,871 Women

“…Of the 93 eligible full articles, 26 prospective studies met the inclusion criteria; their key characteristics are shown in Table 1 . Among these studies, 21/26 were cohort studies [ 8 , 9 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 ] and 5/26 were nested case control studies [ 33 , 34 , 35 , 36 , 37 ]. Study sample sizes ranged from 594 to 288,057 persons aged >20 years.…”

“…The mean follow up period was 12.41 years (range 7 to 26 years). Sixteen of the studies were conducted in European countries [ 8 , 9 , 14 , 15 , 16 , 18 , 24 , 25 , 26 , 28 , 29 , 30 , 32 , 34 , 35 , 36 ], 7 in the USA [ 17 , 19 , 20 , 27 , 31 , 33 , 37 ], 2 in Japan [ 22 , 23 ] and 1 in Korea [ 21 ]. Overall, 1,628,871 women were included in the present meta-analysis, of whom 36,590 were diagnosed with breast cancer during the follow-up period.…”

“…The full text versions of studies meeting the inclusion criteria were retrieved and screened to determine their eligibility by two reviewers (S.G and A.R.J). A study quality assessment was performed according to the Newcastle-Ottawa Scale (NOS, Table 1 [ 8 , 9 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 ]) as bias-assessment scores without an effect on selection [ 38 ]. By evaluating the selection, comparability and outcome of each study, the rating system scored studies from 0 (highest degree of bias) to 9 (lowest degree of bias).…”

Increased trunk fat is associated with altered gene expression in breast tissue of normal weight women

“…Circulating levels of C-reactive protein, insulin, leptin, and triglycerides were higher, whereas levels of sex hormone-binding globulin and high-density lipoprotein cholesterol were lower in those in the highest vs. lowest quartiles of trunk fat mass 8 . More recently, we found that high levels of blood C-reactive protein and testosterone or low blood levels of sex hormone-binding globulin were associated with an elevated risk of postmenopausal breast cancer among normal BMI women 9 .…”