Adiposity, hormone replacement therapy use and breast cancer risk by age and hormone receptor status: a large prospective cohort study
Authors: Ritte Rebecca , Lukanova Annekatrin , Berrino Franco , Dossus Laure , Tjønneland Anne , Olsen Anja , Overvad Thure Filskov , Overvad Kim , Clavel-Chapelon Françoise , Fournier Agnès , Fagherazzi Guy , Rohrmann Sabine , Teucher Birgit , Boeing Heiner , Aleksandrova Krasimira , Trichopoulou Antonia , Lagiou Pagona , Trichopoulos Dimitrios , Palli Domenico , Sieri Sabina , Panico Salvatore , Tumino Rosario , Vineis Paolo , Quirós José Ramón , Buckland Genevieve , Sánchez Maria-José , Amiano Pilar , Chirlaque María-Dolores , Ardanaz Eva , Sund Malin , Lenner Per , Bueno-de-Mesquita Bas , van Gils Carla H , Peeters Petra HM , Krum-Hansen Sanda , Gram Inger Torhild , Lund Eiliv , Khaw Kay-Tee , Wareham Nick , Allen Naomi E , Key Timothy J , Romieu Isabelle , Rinaldi Sabina , Siddiq Afshan , Cox David , Riboli Elio , Kaaks Rudolf 
Published: May 2012

Abstract
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 hormone-receptor 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 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.

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 (P
het = 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 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.