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Int J Cancer. 2019 Apr 10. doi: 10.1002/ijc.32324. [Epub ahead of print]

Mediation analysis of the alcohol-postmenopausal breast cancer relationship by sex hormones in the EPIC Cohort.

Author information

1
Nutritional Methodology and Biostatistics Group, International Agency for Research on Cancer (IARC), 150 cours Albert Thomas, 69008 Lyon, France.
2
Biomarkers Group, International Agency for Research on Cancer (IARC), 150 cours Albert Thomas, 69008 Lyon, France.
3
Center for Epidemiology and Biostatistics, The University of Melbourne School of Population and Global Health, Parkville, VIC, Australia.
4
CESP, Fac. de médecine - Univ. Paris-Sud, Fac. de médecine - UVSQ, INSERM, Université Paris-Saclay, 94805, Villejuif, France.
5
Gustave Roussy, F-94805, Villejuif, France.
6
Nutritional Epidemiology Group, International Agency for Research on Cancer (IARC), 150 cours Albert Thomas, 69008 Lyon, France.
7
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
8
Department of Epidemiology, German Institute of Human Nutrition, Potsdam-Rehbruecke, 14558 Nuthetal, Germany.
9
Dipartimento di Medicina Clinica e Chirurgia, Federico II University, Naples, Italy.
10
Department of Clinical and Biological Sciences, University of Turin, Italy.
11
Unit of Epidemiology, Regional Health Service ASL TO3, Grugliasco (TO), Italy.
12
Cancer Risk Factors and Life-Style Epidemiology Unit, Institute for Cancer Research, Prevention and Clinical Network - ISPRO, Florence, Italy.
13
Cancer Registry and Histopathology Department, "Civic -M.P.Arezzo" Hospital, ASP, Ragusa, Italy.
14
Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Via Venezian 1, 20133, Milan, Italy.
15
CIBER de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.
16
Escuela Andaluza de Salud Pública. Instituto de Investigación Biosanitaria, IBS GRANADA, Universidad de Granada. Granada, Spain.
17
Department of Epidemiology, Regional Health Council, IMIB-Arrixaca, Murcia, Spain.
18
Department of Health and Social Sciences, Universidad de Murcia, Murcia, Spain.
19
Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, Institut Català d'Oncologia, Av. Granvia de L'Hospitalet 199-203, 08908 L'Hospitalet de Llobregat, Spain.
20
Navarra Public Health Institute, Pamplona, Spain.
21
Navarra Institute for Health Research (IdiSNA), Pamplona, Spain.
22
Public Health Division of Gipuzkoa, BioDonostia Research Institue, San Sebastian, Spain.
23
Public Health Directorate, Asturias, Spain.
24
Department. for Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), PO Box 1, 3720 BA Bilthoven,, The Netherlands.
25
Department of Gastroenterology and Hepatology, University Medical Centre, Utrecht, The Netherlands.
26
Department of Epidemiology and Biostatistics, MRC-HPA Centre for Environment and Health, School of Public Health, Imperial College London, Norfolk Place W2 1PG London, UK.
27
Department of Social & Preventive Medicine, Faculty of Medicine, University of Malaya, Pantai Valley, 50603, Kuala Lumpur, Malaysia.
28
Julius Center for Health Sciences and Primary Care, Cancer Epidemiology University Medical Center Utrecht, 3508 GA, Utrecht, The Netherlands.
29
Danish Cancer Society Research Center, Strandboulevarden 49, DK 2100 Copenhagen, Denmark.
30
Department of Public Health, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
31
The Department of Epidemiology, School of Public Health, Aarhus University, Aarhus, Denmark.
32
Hellenic Health Foundation, Athens, Greece.
33
Pulmonary Medicine Department, School of Medicine, National and Kapodistrian University of Athens, "ATTIKON" University Hospital, Haidari, Greece.
34
Cancer Epidemiology Unit, University of Oxford, Oxford, United Kingdom.
35
MRC Centre for Transplantation, King's College London, Great Maze Pond, London SE1 9RT, United Kingdom.
36
Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece.

Abstract

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 (NDE) and natural indirect effects (NIE) were estimated. Alcohol intake was positively associated with overall BC risk and specifically with estrogen receptor positive tumours with respectively TE=1.17(95%CI: 1.01,1.35) and 1.36(1.08,1.70) for a 1-SD deviation 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 (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. This article is protected by copyright. All rights reserved.

KEYWORDS:

EPIC; alcohol; breast cancer; hormonal signature; mediation analysis; sex steroids

PMID:
30968961
DOI:
10.1002/ijc.32324

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