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

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  • Nada Assi, Nutritional Methodology and Biostatistics Group, International Agency for Research on Cancer (IARC), 150 cours Albert Thomas, 69008 Lyon, France., France
  • Sabina Rinaldi, Biomarkers Group, International Agency for Research on Cancer (IARC), 150 cours Albert Thomas, 69008 Lyon, France., France
  • Vivian Viallon, Nutritional Methodology and Biostatistics Group, International Agency for Research on Cancer (IARC), 150 cours Albert Thomas, 69008 Lyon, France., France
  • S Ghazaleh Dashti, Center for Epidemiology and Biostatistics, The University of Melbourne School of Population and Global Health, Parkville, VIC, Australia., Nutritional Methodology and Biostatistics Group, International Agency for Research on Cancer (IARC), 150 cours Albert Thomas, 69008 Lyon, France., Australia
  • Laure Dossus, Nutritional Methodology and Biostatistics Group, International Agency for Research on Cancer (IARC), 150 cours Albert Thomas, 69008 Lyon, France., France
  • Agnès Fournier, Nutritional Epidemiology Group, International Agency for Research on Cancer (IARC), 150 cours Albert Thomas, 69008 Lyon, France., Gustave Roussy, Universite Paris-Saclay, France
  • Iris Cervenka, Gustave Roussy, Universite Paris-Saclay, France
  • Marina Kvaskoff, Gustave Roussy, Universite Paris-Saclay, France
  • Renée Turzanski-Fortner, German Cancer Research Center, Germany
  • Manuela Bergmann, Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), Nuthetal, 14558, Germany., Germany
  • Heiner Boeing, Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), Nuthetal, 14558, Germany., Germany
  • Salvatore Panico, Dipartimento di Medicina Clinica e Chirurgia, Università degli Studi di Federico II University, Naples, Italy., Italy
  • Fulvio Ricceri, Unit of Epidemiology, Regional Health Service ASL TO3, Grugliasco (TO), Turin, Italy., University of Turin, Italy
  • Domenico Palli, Cancer Risk Factors and Life-Style Epidemiology Unit. Institute for Cancer Research, Prevention and Clinical Network - ISPRO, 50141, Florence, Italy., Italy
  • Rosario Tumino, Cancer Registry and Histopathology Department, Civic-M.P.Arezzo Hospital, ASP, 97100 Ragusa, Italy. rtumino@tin.it., Italy
  • Sara Grioni, Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Via Venezian 1, 20133, Milan, Italy., Italy
  • María José Sánchez Pérez, Escuela Andaluza de Salud Pública, Instituto de Investigación Biosanitaria ibs, Granada Hospitales Universitarios de Granada/Universidad de Granada, Granada, Spain., CIBER Epidemiología y Salud Pública (CIBERESP), Spain., Spain
  • María-Dolores Chirlaque, CIBER Epidemiología y Salud Pública (CIBERESP), Spain., Universidad de Murcía, IMIB-Arrixaca, Spain
  • Catalina Bonet, 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., Spain
  • Aurelio Barricarte Gurrea, IdiSNA, Navarra Institute for Health Research, Pamplona, Spain., CIBER Epidemiología y Salud Pública (CIBERESP), Spain., Public Health Institute of Navarra, Spain
  • Pilar Amiano Etxezarreta, Public Health Division of Gipuzkoa, BioDonostia Research Institue, San Sebastian, Spain., CIBER Epidemiología y Salud Pública (CIBERESP), Spain., Spain
  • Susana Merino, Public Health Directorate, Asturias, Spain., Spain
  • Bas Bueno de Mesquita, National Institute for Public Health and the Environment (RIVM), University Medical Centre Utrecht, Imperial College London, University of Malaya, Malaysia
  • Carla H van Gils, Julius Center for Health Sciences and Primary Care, Cancer Epidemiology University Medical Center Utrecht, 3508 GA, Utrecht, The Netherlands., Netherlands
  • Charlotte Onland-Moret, Julius Center for Health Sciences and Primary Care, Cancer Epidemiology University Medical Center Utrecht, 3508 GA, Utrecht, The Netherlands., Netherlands
  • Anne Tjønneland, Danish Cancer Society, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
  • Kim Overvad
  • Antonia Trichopoulou, Hellenic Health Foundation, Athens, Greece., Greece
  • Georgia Martimianaki, Hellenic Health Foundation, Athens, Greece., Greece
  • Anna Karakatsani, National and Kapodistrian University of Athens, Hellenic Health Foundation., Greece
  • Tim Key, Cancer Epidemiology Unit, University of Oxford, Oxford, United Kingdom., United Kingdom
  • Sofia Chistakoudi, Imperial College London, King's College London, United Kingdom
  • Merete Ellingjord-Dale, Imperial College London, United Kingdom
  • Kostas Tsilidis, Imperial College London, University of Ioannina School of Medicine, Greece
  • Elio Riboli, Imperial College London, United Kingdom
  • Rudolf Kaaks, German Cancer Research Center, Germany
  • Marc J Gunter, International Agency for Research on Cancer (IARC-WHO), Lyon, France., France
  • Pietro Ferrari, International Agency for Research on Cancer (IARC-WHO), Lyon, France., France

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.

Original languageEnglish
JournalInternational Journal of Cancer
Volume146
Issue3
Pages (from-to)759-768
Number of pages10
ISSN0020-7136
DOIs
Publication statusPublished - Feb 2020

    Research areas

  • EPIC, alcohol, breast cancer, hormonal signature, mediation analysis, sex steroids

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