Coffee consumption and breast cancer risk among BRCA1 and BRCA2 mutation carriers Andr e Nkondjock 1,2 , Parviz Ghadirian 1 , Joanne Kotsopoulos 3 , Jan Lubinski 4 , Henry Lynch 5 , Charmaine Kim-Sing 6 , Douglas Horsman 6 , Barry Rosen 7 , Claudine Isaacs 8 , Barbara Weber 9 , William Foulkes 10 , Peter Ainsworth 11 , Nadine Tung 12 , Andrea Eisen 13 , Eitan Friedman 14 , Charis Eng 15 , Ping Sun 3 and Steven A. Narod 3 * 1 Epidemiology Research Unit, Research Centre, Centre Hospitalier de ’Universitaire de Montr eal, CHUM Hoˆtel-Dieu, Montr eal, Canada 2 McLaughlin Centre for Population Health Risk Assessment, Institute of Population Health, University of Ottawa, Ottawa, Canada 3 Centre for Research in Women’s Health, Women’s College Hospital, University of Toronto, Toronto, Canada 4 Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland 5 Department of Preventive Medicine and Public Health, Creighton University School of Medicine, Omaha, NE, USA 6 British Columbia Cancer Agency, Vancouver, Canada 7 Familial Ovarian Cancer Clinic, Princess Margaret Hospital, Toronto, Canada 8 Lombardi Cancer Center, Georgetown University Medical Center, Washington, DC, USA 9 Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, USA 10 Departments of Medicine, Human Genetics and Oncology, McGill University, Montr eal, Canada 11 London Regional Cancer Program, LHSC, London, Canada 12 Department of Oncology, Beth Israel Deaconess Hospital, Boston, MA, USA 13 Toronto-Sunnybrook Regional Cancer, Toronto, Canada 14 The Suzanne Levy Gertner Oncogenetics Unit, The Chaim Sheba Medical Center, Tel-Hashomer, Israel 15 Clinical Cancer Genetics Program, Comprehensive Cancer Center, Division of Human Genetics, Department of Internal Medicine, The Ohio State University, Columbus OH, USA Although there are several plausible biologic mechanisms whereby coffee consumption might influence the risk of breast cancer, epidemiologic evidence is limited. We assessed the associa- tion between coffee consumption and breast cancer risk among high-risk women who carry BRCA mutations. We performed a matched case-control analysis on 1,690 women with a BRCA1 or BRCA2 mutation from 40 centers in 4 countries. Average lifetime coffee consumption was estimated via a self-administered ques- tionnaire. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using conditional logistic regression. After adjust- ment for potential confounders, the ORs for breast cancer in BRCA carriers who habitually drank 0, 1–3, 4–5 and 6 or more cups of coffee were 1.00, 0.90 (95% CI 0.72–1.12), 0.75 (95% CI 0.47–1.19) and 0.31 (95% CI 0.13–0.71; p-trend 5 0.02). The effect was limited to the consumption of caffeinated coffee. These results suggest that among women with BRCA gene mutation, coffee con- sumption is unlikely to be harmful and that high levels of con- sumption may in fact be related to reduced breast cancer risk. ' 2005 Wiley-Liss, Inc. Key words: BRCA1; BRCA2; breast cancer; coffee; case-control study Coffee is among the most widely consumed beverages in the world and is a major source of dietary caffeine. Over the last 2 decades, coffee and caffeine have been studied with regard to their potential role in breast cancer etiology. A number of animal stud- ies have reported caffeine to both stimulate and to suppress breast tumors, depending upon the species and the phase of administra- tion. 1 Coffee consumption (or caffeine intake) has been directly associated with plasma estradiol, estrone and sex hormone-binding globulin levels, and inversely associated with testosterone. 2,3 Cof- fee consumption also induces cell differentiation 4 and may inhibit mitosis. 5 These effects suggest that coffee consumption may affect breast cancer risk, but epidemiologic evidence supporting the association between coffee consumption and breast cancer risk is scant. A decrease in breast cancer risk in women with high levels of coffee consumption has been reported in several studies, 6,7 but other investigators have detected no relationship between coffee consumption and breast cancer risk. 1,8 It has been estimated that the risk of developing breast cancer among women with a mutation in BRCA1 or BRCA2 is as high as 80% by the age of 70. 9 Whether or not coffee affects BRCA- related breast cancer risk is currently unknown. To address this issue, we examined the association between coffee consumption and the risk of breast cancer among women with BRCA1 and BRCA2 gene mutations from 40 participating centers in 4 countries. Material and methods Study population and design The study population has been described elsewhere. 10 Briefly, eligible study subjects included women who were currently alive and were known to be carriers of deleterious mutations of the BRCA1 or BRCA2 gene. These women were identified from 40 participating clinical cancer genetics centers in 4 countries and were participants in prior and ongoing clinical research protocols at the host institutions. All study subjects received counseling and provided written informed consent for genetic testing. Our study was approved by the institutional review boards of the host institutions. In most cases, testing was initially offered to women who had been affected with breast or ovarian cancer. When a BRCA1 or BRCA2 mutation was identified in a proband or relative, genetic testing was offered to other at-risk women in the family. In a few families (<10% of the total), only unaffected car- riers were identified. Mutation detection was performed using a range of techniques, but all nucleotide sequences were confirmed by direct sequencing of DNA. A woman was eligible for the cur- rent study when the molecular analysis established that she was a carrier of a pathogenic mutation. Most (>95%) of the mutations identified in the study subjects were nonsense mutations, dele- tions, insertions or small frameshifts. There was information on cancer history and mutation carrier status for a total of 6,053 women who carried BRCA1 or BRCA2 *Correspondence to: Centre for Research in Women’s Health, 790 Bay Street, 7th Floor, Toronto, Ontario, M5G 1N8, Canada. Fax: 1416-351-3767. E-mail: steven.narod@sw.ca Received 6 January 2005; Accepted after revision 8 April 2005 DOI 10.1002/ijc.21296 Published online 19 July 2005 in Wiley InterScience (www.interscience. wiley.com). Int. J. Cancer: 118, 103–107 (2006) ' 2005 Wiley-Liss, Inc. Publication of the International Union Against Cancer