Mediation analysis of the alcohol-postmenopausal breast cancer relationship by sex hormones in the EPIC cohort
Assi, Nada; Rinaldi, Sabina; Viallon, Vivian; Dashti, S. Ghazaleh; Dossus, Laure; Fournier, Agnès; Cervenka, Iris; Kvaskoff, Marina; Turzanski-Fortner, Renée; Bergmann, Manuela; Boeing, Heiner; Panico, Salvatore; Ricceri, Fulvio; Palli, Domenico; Tumino, Rosario; Grioni, Sara; Sánchez Pérez, María José; Chirlaque, María Dolores; Bonet, Catalina; Gurrea, Aurelio Barricarte; Amiano Etxezarreta, Pilar; Merino, Susana; Bueno de Mesquita, H. Bas; van Gils, Carla H.; Onland-Moret, Charlotte; Tjønneland, Anne; Overvad, Kim; Trichopoulou, Antonia; Martimianaki, Georgia; Karakatsani, Anna; Key, Tim; Christakoudi, Sofia; Ellingjord-Dale, Merete; Tsilidis, Kostas; Riboli, Elio; Kaaks, Rudolf; Gunter, Marc J.; Ferrari, Pietro
(2020) International Journal of Cancer, volume 146, issue 3, pp. 759 - 768
(Article)
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
... read more
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.
show less
Download/Full Text
The full text of this publication is not available.
Keywords: alcohol, breast cancer, EPIC, hormonal signature, mediation analysis, sex steroids, Oncology, Cancer Research, Journal Article
ISSN: 0020-7136
Publisher: Wiley-Liss Inc.
Note: Funding Information: Key words: sex steroids, alcohol, breast cancer, mediation analysis, hormonal signature, EPIC Abbreviations: 1-SD: one standard deviation; 95%CI: 95% confidence intervals; BC: breast cancer; BMI: body mass index; DKFZ: German Cancer Research Center; EPIC: European Prospective Investigation into Cancer and nutrition; ER(+ or −): estrogen receptor (positive or negative); IARC: International Agency for Research on Cancer; NDE: natural direct effect; NIE: natural indirect effect; OR: odds ratio; PLS: partial least squares; RD: risk difference; SHBG: sex hormone binding globulin; TE: total effect; WCRF: World Cancer Research Fund Additional Supporting Information may be found in the online version of this article. Conflict of interest: The authors declare no potential conflicts of interest. Grant sponsor: Associazione Italiana per la Ricerca sul Cancro; Grant sponsor: Bundesministerium für Bildung und Forschung; Grant sponsor: Cancer Research UK; Grant numbers: 14136, C570/A16491, C8221/A19170; Grant sponsor: Cancerfonden; Grant sponsor: Centre International de Recherche sur le Cancer; Grant sponsor: Consiglio Nazionale delle Ricerche; Grant sponsor: County Council of Skåne; Grant sponsor: County Council of Västerbotten ; Grant sponsor: Deutsche Forschungsgemeinschaft; Grant number: Graduiertenkolleg 793: Epidemiology of communicabl; Grant sponsor: Deutsche Krebshilfe; Grant sponsor: Deutsches Krebsforschungszentrum; Grant sponsor: Directorate-General for Health and Food Safety; Grant sponsor: Dutch Prevention Funds; Grant sponsor: Fondation de France; Grant number: 00069254; Grant sponsor: Health Research Fund (FIS); Grant number: PI13/00061; Grant sponsor: Hellenic Health Foundation; Grant sponsor: Institut Gustave Roussy; Grant sponsor: Institut National de la Santé et de la Recherche Médicale; Grant sponsor: ISCIII RETIC; Grant number: RD06/0020; Grant sponsor: Kræftens Bekæmpelse; Grant sponsor: Ligue Contre le Cancer; Grant sponsor: LK Research Funds; Grant sponsor: Medical Research Council; Grant numbers: 1000143, MR/M012190/1; Grant sponsor: Ministerie van Volksgezondheid, Welzijn en Sport; Grant sponsor: Mutuelle Générale de l’Education Nationale; Grant sponsor: National Cancer Institute; Grant number: 1U01CA98216-01; Grant sponsor: Netherlands Cancer Registry; Grant sponsor: Nordic Centre of Excellence programme on Food, Nutrition and Health Norway; Grant sponsor: Regional Government of Andalucía; Grant sponsor: Regional Government of Asturias; Grant sponsor: Regional Government of Basque Country; Grant sponsor: Regional Government of Murcia; Grant number: 6236; Grant sponsor: Regional Government of Navarra; Grant sponsor: Statistics Netherlands; Grant sponsor: Swedish Scientific Council; Grant sponsor: World Cancer Research Fund; Grant sponsor: Zorg Onderzoek Nederland DOI: 10.1002/ijc.32324 History: Received 8 Jan 2019; Accepted 13 Mar 2019; Online 10 Apr 2019 Correspondence to: Pietro Ferrari, International Agency for Research on Cancer, 150 Cours Albert Thomas, 69372 Lyon Cedex 08, France, Tel: +33-472-73-8031, Fax: +33-472-73-8361, E-mail: ferrarip@iarc.fr Funding Information: N. Assi was financially supported by a grant from the Fondation de France (FdF) supporting her postdoctoral research (grant number: 00069254). T. Key was funded through a grant from Cancer Research UK (grant number: CRUK C8221/A19170). The steroids measurements used in our study were (partly) funded by a grant from the German Research Foundation, Graduiertenkolleg 793: Epidemiology of communicable and chronic noncommunicable diseases and their interrelationships and through financial support from the National Cancer Institute (USA) (grant no. 1U01CA98216-01). The coordination of EPIC is financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer. The national cohorts are supported by Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l’Education Nationale, Institut National de la Santé et de la Recherche Médicale (INSERM) (France); Deutsche Krebshilfe, Deutsches Krebsforschungszentrum and Federal Ministry of Education and Research (Germany); the Hellenic Health Foundation (Greece); Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands); Nordic Center of Excellence Program on Food, Nutrition and Health. (Norway); Health Research Fund (FIS), PI13/00061 to Granada), Regional Governments of Andalucía, Asturias, Basque Country, Murcia (no. 6236) and Navarra, ISCIII RETIC (RD06/0020) (Spain); Swedish Cancer Society, Swedish Scientific Council and County Councils of Skåne and Västerbotten (Sweden); Cancer Research UK (14136 to EPIC-Norfolk; C570/A16491 and C8221/A19170 to EPIC-Oxford), Medical Research Council (1000143 to EPIC-Norfolk and MR/M012190/1 to EPIC-Oxford) (United Kingdom). Our study was done independently and with no input from the funders. The funders were not involved in the design, implementation, analysis or interpretation of the data. Publisher Copyright: © 2019 UICC
(Peer reviewed)