TY - JOUR

T1 - Mediation analysis of the alcohol-postmenopausal breast cancer relationship by sex hormones in the EPIC cohort

AU - Assi, Nada

AU - Rinaldi, Sabina

AU - Viallon, Vivian

AU - Dashti, S. Ghazaleh

AU - Dossus, Laure

AU - Fournier, Agnes

AU - Cervenka, Iris

AU - Kvaskoff, Marina

AU - Turzanski-Fortner, Renee

AU - Bergmann, Manuela

AU - Boeing, Heiner

AU - Panico, Salvatore

AU - Ricceri, Fulvio

AU - Palli, Domenico

AU - Tumino, Rosario

AU - Grioni, Sara

AU - Sanchez Perez, Maria Jose

AU - Chirlaque, Maria-Dolores

AU - Bonet, Catalina

AU - Barricarte Gurrea, Aurelio

AU - Amiano Etxezarreta, Pilar

AU - Merino, Susana

AU - de Mesquita, H. Bas Bueno

AU - van Gils, Carla H.

AU - Onland-Moret, Charlotte

AU - Tjonneland, Anne

AU - Overvad, Kim

AU - Trichopoulou, Antonia

AU - Martimianaki, Georgia

AU - Karakatsani, Anna

AU - Key, Tim

AU - Christakoudi, Sofia

AU - Ellingjord-Dale, Merete

AU - Tsilidis, Kostas

AU - Riboli, Elio

AU - Kaaks, Rudolf

AU - Gunter, Marc J.

AU - Ferrari, Pietro

PY - 2020

Y1 - 2020

N2 - Alcohol consumption is associated with higher risk of breast cancer (BC); however, the biological mechanisms underlying this association are not fully elucidated, particularly the extent to which this relationship is mediated by sex hormone levels. Circulating concentrations of estradiol, testosterone, their free fractions and sex-hormone binding globulin (SHBG), were examined in 430 incident BC cases and 645 matched controls among alcohol-consuming postmenopausal women nested within the European Prospective Investigation into Cancer and Nutrition. Mediation analysis was applied to assess whether individual hormone levels mediated the relationship between alcohol intake and BC risk. An alcohol-related hormonal signature, obtained by partial least square (PLS) regression, was evaluated as a potential mediator. Total (TE), natural direct and natural indirect effects (NIE) were estimated. Alcohol intake was positively associated with overall BC risk and specifically with estrogen receptor-positive tumors with respectively TE = 1.17(95%CI: 1.01,1.35) and 1.36(1.08,1.70) for a 1-standard deviation (1-SD) increase of intake. There was no evidence of mediation by sex steroids or SHBG separately except for a weak indirect effect through free estradiol where NIE = 1.03(1.00,1.06). However, an alcohol-related hormonal signature negatively associated with SHBG and positively with estradiol and testosterone was associated with BC risk (odds ratio [OR] = 1.25 [1.07,1.47]) for a 1-SD higher PLS score, and had a statistically significant NIE accounting for a mediated proportion of 24%. There was limited evidence of mediation of the alcohol-BC association by individual sex hormones. However, a hormonal signature, reflecting lower levels of SHBG and higher levels of sex steroids, mediated a substantial proportion of the association.

AB - Alcohol consumption is associated with higher risk of breast cancer (BC); however, the biological mechanisms underlying this association are not fully elucidated, particularly the extent to which this relationship is mediated by sex hormone levels. Circulating concentrations of estradiol, testosterone, their free fractions and sex-hormone binding globulin (SHBG), were examined in 430 incident BC cases and 645 matched controls among alcohol-consuming postmenopausal women nested within the European Prospective Investigation into Cancer and Nutrition. Mediation analysis was applied to assess whether individual hormone levels mediated the relationship between alcohol intake and BC risk. An alcohol-related hormonal signature, obtained by partial least square (PLS) regression, was evaluated as a potential mediator. Total (TE), natural direct and natural indirect effects (NIE) were estimated. Alcohol intake was positively associated with overall BC risk and specifically with estrogen receptor-positive tumors with respectively TE = 1.17(95%CI: 1.01,1.35) and 1.36(1.08,1.70) for a 1-standard deviation (1-SD) increase of intake. There was no evidence of mediation by sex steroids or SHBG separately except for a weak indirect effect through free estradiol where NIE = 1.03(1.00,1.06). However, an alcohol-related hormonal signature negatively associated with SHBG and positively with estradiol and testosterone was associated with BC risk (odds ratio [OR] = 1.25 [1.07,1.47]) for a 1-SD higher PLS score, and had a statistically significant NIE accounting for a mediated proportion of 24%. There was limited evidence of mediation of the alcohol-BC association by individual sex hormones. However, a hormonal signature, reflecting lower levels of SHBG and higher levels of sex steroids, mediated a substantial proportion of the association.

KW - sex steroids

KW - alcohol

KW - breast cancer

KW - mediation analysis

KW - hormonal signature

KW - EPIC

U2 - 10.1002/ijc.32324

DO - 10.1002/ijc.32324

M3 - Journal article

C2 - 30968961

VL - 146

SP - 759

EP - 768

JO - International Journal of Cancer

JF - International Journal of Cancer

SN - 0020-7136

IS - 3

ER -