Introduction: Associations 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 hormonereceptor
negative malignancies, and possible interactions by hormone replacement therapy (HRT) use.
Methods: Within 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 progesteronereceptor
(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.
Results: For 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.
Conclusions: An 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 hormonereceptor
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 hormonereceptor
negative tumors.