Adiposity, hormone replacement therapy use and breast cancer risk by age and hormone receptor status: a large prospective cohort study

Abstract

IntroductionAssociations of hormone-receptor positive breast cancer with excess adiposity are reasonably well characterized; however, uncertainty remains regarding the association of body mass index (BMI) with hormone-receptor negative malignancies, and possible interactions by hormone replacement therapy (HRT) use.MethodsWithin the European EPIC cohort, Cox proportional hazards models were used to describe the relationship of BMI, waist and hip circumferences with risk of estrogen-receptor (ER) negative and progesterone-receptor (PR) negative (n = 1,021) and ER+PR+ (n = 3,586) breast tumors within five-year age bands. Among postmenopausal women, the joint effects of BMI and HRT use were analyzed.ResultsFor risk of ER-PR- tumors, there was no association of BMI across the age bands. However, when analyses were restricted to postmenopausal HRT never users, a positive risk association with BMI (third versus first tertile HR = 1.47 (1.01 to 2.15)) was observed. BMI was inversely associated with ER+PR+ tumors among women aged ≤49 years (per 5 kg/m2 increase, HR = 0.79 (95%CI 0.68 to 0.91)), and positively associated with risk among women ≥65 years (HR = 1.25 (1.16 to 1.34)). Adjusting for BMI, waist and hip circumferences showed no further associations with risks of breast cancer subtypes. Current use of HRT was significantly associated with an increased risk of receptor-negative (HRT current use compared to HRT never use HR: 1.30 (1.05 to 1.62)) and positive tumors (HR: 1.74 (1.56 to 1.95)), although this risk increase was weaker for ER-PR- disease (Phet = 0.035). The association of HRT was significantly stronger in the leaner women (BMI ≤22.5 kg/m2) than for more overweight women (BMI ≥25.9 kg/m2) for, both, ER-PR- (HR: 1.74 (1.15 to 2.63)) and ER+PR+ (HR: 2.33 (1.84 to 2.92)) breast cancer and was not restricted to any particular HRT regime.ConclusionsAn elevated BMI may be positively associated with risk of ER-PR- tumors among postmenopausal women who never used HRT. Furthermore, postmenopausal HRT users were at an increased risk of ER-PR- as well as ER+PR+ tumors, especially among leaner women. For hormone-receptor positive tumors, but not for hormone-receptor negative tumors, our study confirms an inverse association of risk with BMI among young women of premenopausal age. Our data provide evidence for a possible role of sex hormones in the etiology of hormone-receptor negative tumors.

Adiposity and breast cancer risk in postmenopausal women: Results from the UK Biobank prospective cohort

“…These findings are consistent with those from two previous large prospective studies which found that the positive association between adiposity and postmenopausal breast cancer risk was more marked in women aged 65 or older6 and in women who had experienced menopause ≥15 years previously 22…”

Impact of Body Mass Index on Prognostically Relevant Breast Cancer Tumor Characteristics

“…Our observed associations with age are in accordance with the findings in the literature for Caucasian women [39]. At a higher age, tumors are more often ER positive [39,40,41,42]. In the study by Parise et al [39], the increase in the percentage of the ER + /PR + /HER2 - subtype with increasing age almost mirrored the increasing proportion of BC cases in white women [39].…”

Body fatness as a cause of cancer: epidemiologic clues to biologic mechanisms

“…Further support of that hypothesis comes from comparing the BMI-breast cancer association among the two major subtypes of breast cancer -those that express estrogen receptors (ER-positive) and those that do not (ER-negative). Excess adiposity has been associated with increased breast cancer risk for ER-positive breast cancers but not for ER-negative breast cancers in most studies, although in a large cohort, the risk for postmenopausal ER-negative breast cancer was also marginally increased by obesity among women who had never used hormone replacement therapy (Ritte et al 2012). Overall, the epidemiologic evidence is compelling that among postmenopausal women, the BMI-breast cancer relationship is driven mostly by the production of endogenous estrogens by aromatase activity in adipose tissues.…”

“…After menopause, when adipose tissue becomes the primary source of circulating estrogens, the association between excess adiposity and breast cancer risk becomes strongly positive, with progressively increasing risk with increasing BMI (Key et al 2003, Ritte et al 2012. Serum estrogen levels have been shown to be positively associated with breast cancer risk in prospective cohort studies, and postmenopausal hormone replacement therapy increases breast cancer risk, so estrogens and progestins clearly play roles in breast cancer etiology (Key et al 2003, Anderson et al 2004, Endogenous Hormones and Breast Cancer Collaborative Group 2011, Ritte et al 2012.…”

“…Serum estrogen levels have been shown to be positively associated with breast cancer risk in prospective cohort studies, and postmenopausal hormone replacement therapy increases breast cancer risk, so estrogens and progestins clearly play roles in breast cancer etiology (Key et al 2003, Anderson et al 2004, Endogenous Hormones and Breast Cancer Collaborative Group 2011, Ritte et al 2012. The observation that obesity does not appear to be a risk factor among women who are using hormone replacement therapy suggests that elevated estrogen levels, regardless of whether they come from endogenous or exogenous sources, increase breast cancer risk, and those effects are not additive.…”