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Exogenous hormones, tumor intrinsic subtypes, and breast cancer

Le Cornet, C.
; 
Jung, A. Y.
; 
Behrens, S.
; 
Middha, P.
; 
Truong, T.
; 
Jernström, H.
; 
Bolla, M. K.
; 
Wang, Q.
; 
Southey, M. C.
; 
Beane Freeman, L. E.
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Abstract
IMPORTANCE: Etiologic heterogeneity in breast carcinogenesis needs to be well characterized for targeted prevention. Associations between menopausal hormonal therapy (MHT) and oral contraceptive (OC) use and breast cancer intrinsic-like subtypes are not well understood. OBJECTIVE: To examine whether exogenous hormone use is differentially associated with breast cancer subtypes and to evaluate heterogeneity by intrinsic-like subtypes. DESIGN, SETTING, AND PARTICIPANTS: This study pooled data from 31 nested and population-based case-control studies involved in the Breast Cancer Association Consortium. The study population included individuals with breast cancer and control participants from 13 case-control studies nested in prospective cohorts (recruited between 1982 and 2011) and 18 population-based case-control studies (recruited between 1990 and 2013). Data analysis was performed in June 2024. EXPOSURE: MHT use (estrogen-progestin therapy [EPT] or estrogen-only therapy [ET]) in postmenopausal women and OC use in premenopausal women (never, past use, or current use). MAIN OUTCOMES AND MEASURES: Breast cancer intrinsic-like subtypes (luminal A-like, luminal B-like, luminal B-ERBB2 [formerly HER2 or HER2/neu]-like, ERBB2 enriched-like, or triple-negative) were determined by immunohistochemistry of tumor sections. Polytomous logistic regression was performed to estimate the association between exogenous hormones and risk of breast cancer by intrinsic-like subtypes. Analyses by subtypes were stratified by body mass index (BMI [calculated as weight in kilograms divided by height in meters squared]; healthy weight, 18.5-<25; overweight, 25-<30; or obesity, ≥30). RESULTS: This study included 42 269 individuals with breast cancer (11 901 [28.2%] premenopausal and 30 368 [71.8%] postmenopausal; 23 353 [55.2%] had a known intrinsic-like subtype) and 71 072 control participants. The mean (SD) age of all participants was 57.9 (10.9) years. In postmenopausal women, associations between current MHT use (EPT or ET) and breast cancer differed by subtype. Current EPT users with healthy weight were more likely to be diagnosed with luminal A-like (odds ratio [OR], 2.51 [95% CI, 2.26-2.80]) or luminal B-ERBB2-like (OR, 1.95 [95% CI, 1.61-2.37]) subtypes. These associations were attenuated but remained for individuals with overweight (OR, 1.40 [95% CI, 1.02-1.92]) or obesity (OR, 1.68 [95% CI, 1.01-2.78]). EPT use increased the odds of being diagnosed with luminal B-like tumors solely in women with healthy weight (OR, 1.47 [95% CI, 1.17-1.86]). Current ET use was positively associated with luminal A-like disease in women with healthy weight only (OR, 1.16 [95% CI, 1.01-1.32]), showing inverse associations with higher BMI (obesity: OR, 0.65 [95% CI, 0.50-0.85]). In premenopausal women, recent OC use was associated with luminal B-ERBB2-like (OR, 1.50 [95% CI, 1.09-2.08]), ERBB2 enriched-like (OR, 2.33 [95% CI, 1.55-3.51]), and triple-negative (OR, 1.75 [95% CI, 1.33-2.29]; P < .04 for heterogeneity) tumors. CONCLUSIONS AND RELEVANCE: In this study, clear differences were observed in associations between current EPT use and luminal-like breast cancer subtypes and other subtypes. EPT users with healthy weight were more likely to be diagnosed with luminal-like breast cancer compared with nonusers. Subtype heterogeneity was less apparent in associations of OC and ET use. Future studies on contemporary formulations, patterns of use, and routes of administration of exogenous hormone usage are warranted.
Authors
Le Cornet, C.
Jung, A. Y.
Behrens, S.
Middha, P.
Truong, T.
Jernström, H.
Bolla, M. K.
Wang, Q.
Southey, M. C.
Beane Freeman, L. E.
Koutros, S.
Stone, J.
Rennert, G.
Shulman, K.
Aronson, K. J.
Murphy, R. A.
Guénel, P.
Patel, A. V.
Bodelon, C.
Teras, L. R.
Shahi, S.
Lacey, J. V.
Dossus, L.
Kaaks, R.
Holleczek, B.
Brenner, H.
Brauch, H.
Hoppe, R.
Czene, K.
Hall, P. F. L.
Mannermaa, A.
Wu, A. H.
Obi, N.
Michailidou, K.
Panayiotidis, M. I.
McLean, C.
Haiman, C. A.
Augustinsson, A.
Zheng, W.
Shu, X. O.
Perou, C. M.
Troester, M. A.
Van Alsten, S.
Eliassen, A. H.
Abubakar, M.
Kraft, P.
Ahearn, T. U.
Evans, D. G.
Wolk, A.
Milne, R. L.
Easton, D. F.
Pharoah, P. D. P.
Schmidt, M. K.
García-Closas, M.
Vachon, C. M.
Fortner, R. T.
Chang-Claude, J.
Affiliation
Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany. Division of General Internal Medicine, Department of Medicine, University of California, San Francisco. Paris-Saclay University, Université de Versailles Saint-Quentin-en-Yvelines, Institut National de la Santé et de la Recherche Médicale, Gustave Roussy, Centre for Epidemiology and Population Health, Villejuif, France. Division of Oncology, Department of Clinical Sciences, Lund University, Lund, Sweden. Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, United Kingdom. Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia. Department of Clinical Pathology, University of Melbourne, Melbourne, Victoria, Australia. Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia. Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, US Department of Health and Human Services, Bethesda, Maryland. Genetic Epidemiology Group, School of Population and Global Health, University of Western Australia, Perth, Western Australia, Australia. Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Victoria, Australia. Technion-Israel Institute of Technology-Association for Promotion of Research in Precision Medicine, Faculty of Medicine, Haifa, Israel. Oncology Department, Clalit Health Services, Haifa and Western Galilee District, Israel. Department of Public Health Sciences, Cancer Research Institute, Queen's University, Kingston, Ontario, Canada. School of Population and Public Health, University of British Columbia, Vancouver, British Columbia, Canada. Cancer Control Research, BC Cancer Agency, Vancouver, British Columbia, Canada. Department of Population Science, American Cancer Society, Atlanta, Georgia. Department of Computational and Quantitative Medicine, City of Hope, Duarte, California. City of Hope Comprehensive Cancer Center, City of Hope, Duarte, California. Nutrition and Metabolism Branch, International Agency for Research on Cancer, Lyon, France. Saarland Cancer Registry, Saarbrücken, Germany. Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany. German Cancer Research Center, German Cancer Consortium, Heidelberg, Germany. Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany. iFIT (Image-Guided and Functionally Instructed Tumor Therapies) Cluster of Excellence, University of Tübingen, Tübingen, Germany. German Cancer Consortium and German Cancer Research Center Partner Site Tübingen, Tübingen, Germany. University of Tübingen, Tübingen, Germany. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. Department of Oncology, Södersjukhuset, Stockholm, Sweden. Translational Cancer Research Area, University of Eastern Finland, Kuopio, Finland. Pathology and Forensic Medicine, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland. Biobank of Eastern Finland, Kuopio University Hospital, Kuopio, Finland. Department of Population Health and Public Health Sciences, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles. Institute for Occupational and Maritime Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Institute for Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Biostatistics Unit, Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus. Department of Cancer Genetics, Therapeutics, and Ultrastructural Pathology, Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus. Now with Department of Comparative Biomedical Sciences, College of Veterinary Medicine, Mississippi State University, Starkville. Anatomical Pathology Unit, Alfred Hospital, Melbourne, Victoria, Australia. Department of Population and Public Health Sciences, Center for Genetic Epidemiology, Keck School of Medicine, University of Southern California, Los Angeles. Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee. Department of Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill. Department of Epidemiology, Gillings School of Global Public Health, UNC Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill. Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts. Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, Massachusetts. Division of Evolution and Genomic Sciences, Faculty of Biology, Medicine, and Health, Manchester Academic Health Science Centre, School of Biological Sciences, University of Manchester, Manchester, United Kingdom. North West Genomics Laboratory Hub, St Mary's Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester Centre for Genomic Medicine, Manchester, United Kingdom. Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden. Department of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, United Kingdom. Department of Computational Biomedicine, Cedars-Sinai Medical Center, West Hollywood, California. Division of Molecular Pathology, Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands. Division of Psychosocial Research and Epidemiology, Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands. Department of Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands. Division of Genetics and Epidemiology, Institute of Cancer Research, London, United Kingdom. Division of Epidemiology, Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota. Department of Research, Cancer Registry of Norway, Norwegian Institute of Public Health, Oslo, Norway. Cancer Epidemiology Group, University Medical Center Hamburg-Eppendorf, University Cancer Center Hamburg, Hamburg, Germany.
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2025
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All Paterson Institute for Cancer Research
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Le Cornet C, Jung AY, Behrens S, Middha P, Truong T, Jernström H, et al. Exogenous Hormones, Tumor Intrinsic Subtypes, and Breast Cancer. JAMA network open. 2025 Jul 1;8(7):e2519236. PubMed PMID: 40622713. Pubmed Central PMCID: PMC12235495 Fisher Scientific during the conduct of the study. Dr Jernström reported receiving grants from the Fru Berta Kamprad Foundation and from Cancerfonden during the conduct of the study. Dr Murphy reported receiving consulting fees from Pharmavite outside the submitted work. Dr Shu reported receiving grants from the National Institutes of Health (NIH) during the conduct of the study. Dr Perou reported receiving grants from the National Cancer Institute (NCI) Breast Specialized Program of Research Excellence during the conduct of the study. In addition, Dr Perou reported holding stock in and receiving royalties for US Patent No. 12,995,459 from Bioclassifier LLC outside the submitted work. Dr Eliassen reported receiving grants from the NIH during the conduct of the study. Dr Ahearn reported being employed by the NCI during the conduct of the study. Dr Milne reported receiving grants from the National Health and Medical Research Council of Australia during the conduct of the study. Dr Easton reported receiving grants (paid to University of Cambridge) from Cancer Research UK, the European Union, Genome Canada, and the Canadian Institutes of Health Research during the conduct of the study. Dr Pharoah reported receiving grants from Cancer Research UK during the conduct of the study. Dr Schmidt reported receiving grants from the European Union (Breast Cancer Stratification Project [B-CAST]) during the conduct of the study. Dr Vachon reported receiving grants from the NCI during the conduct of the study. No other disclosures were reported. Epub 2025/07/07. eng.
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https://christie.openrepository.com/handle/10541/627732
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