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Original research
Physical activity, sedentary time and breast cancer risk: a Mendelian randomisation study
  1. Suzanne C Dixon-Suen1,
  2. Sarah J Lewis2,3,
  3. Richard M Martin2,3,4,
  4. Dallas R English1,5,
  5. Terry Boyle6,7,
  6. Graham G Giles1,5,8,
  7. Kyriaki Michailidou9,10,
  8. Manjeet K Bolla11,
  9. Qin Wang11,
  10. Joe Dennis11,
  11. Michael Lush11,
  12. ABCTB Investigators12,
  13. Thomas U Ahearn13,
  14. Christine B Ambrosone14,
  15. Irene L Andrulis15,16,
  16. Hoda Anton-Culver17,
  17. Volker Arndt18,
  18. Kristan J Aronson19,
  19. Annelie Augustinsson20,
  20. Päivi Auvinen21,22,
  21. Laura E Beane Freeman13,
  22. Heiko Becher23,
  23. Matthias W Beckmann24,
  24. Sabine Behrens25,
  25. Marina Bermisheva26,
  26. Carl Blomqvist27,28,
  27. Natalia V Bogdanova29,30,
  28. Stig E Bojesen31,32,
  29. Bernardo Bonanni33,
  30. Hermann Brenner18,34,
  31. Thomas Brüning35,
  32. Saundra S Buys36,
  33. Nicola J Camp36,
  34. Daniele Campa25,37,
  35. Federico Canzian38,
  36. Jose E Castelao39,
  37. Melissa H Cessna40,41,
  38. Jenny Chang-Claude25,42,
  39. Stephen J Chanock13,
  40. Christine L Clarke43,
  41. Don M Conroy44,
  42. Fergus J Couch45,
  43. Angela Cox46,
  44. Simon S Cross47,
  45. Kamila Czene48,
  46. Mary B Daly49,
  47. Peter Devilee50,51,
  48. Thilo Dörk30,
  49. Miriam Dwek52,
  50. Diana M Eccles53,
  51. A. Heather Eliassen54,55,
  52. Christoph Engel56,57,
  53. Mikael Eriksson48,
  54. D. Gareth Evans58,59,
  55. Peter A Fasching24,60,
  56. Olivia Fletcher61,
  57. Henrik Flyger62,
  58. Lin Fritschi63,
  59. Marike Gabrielson48,
  60. Manuela Gago-Dominguez64,65,
  61. Montserrat García-Closas13,
  62. José A García-Sáenz66,
  63. Mark S Goldberg67,68,
  64. Pascal Guénel69,
  65. Melanie Gündert70,71,
  66. Eric Hahnen72,73,
  67. Christopher A Haiman74,
  68. Lothar Häberle24,
  69. Niclas Håkansson75,
  70. Per Hall48,76,
  71. Ute Hamann77,
  72. Steven N Hart78,
  73. Michelle Harvie79,
  74. Peter Hillemanns30,
  75. Antoinette Hollestelle80,
  76. Maartje J Hooning80,
  77. Reiner Hoppe81,82,
  78. John Hopper5,
  79. Anthony Howell83,
  80. David J Hunter55,84,
  81. Anna Jakubowska85,86,
  82. Wolfgang Janni87,
  83. Esther M John88,89,
  84. Audrey Jung25,
  85. Rudolf Kaaks25,
  86. Renske Keeman90,
  87. Cari M Kitahara91,
  88. Stella Koutros13,
  89. Peter Kraft55,92,
  90. Vessela N Kristensen93,94,
  91. Katerina Kubelka-Sabit95,
  92. Allison W Kurian88,89,
  93. James V Lacey96,97,
  94. Diether Lambrechts98,99,
  95. Loic Le Marchand100,
  96. Annika Lindblom101,102,
  97. Sibylle Loibl103,
  98. Jan Lubiński85,
  99. Arto Mannermaa104,105,
  100. Mehdi Manoochehri77,
  101. Sara Margolin76,106,
  102. Maria Elena Martinez65,107,
  103. Dimitrios Mavroudis108,
  104. Usha Menon109,
  105. Anna Marie Mulligan110,111,
  106. Rachel A Murphy112,113,
  107. NBCS Collaborators93,94,
  108. Heli Nevanlinna114,
  109. Ines Nevelsteen115,
  110. William G Newman58,59,
  111. Kenneth Offit116,117,
  112. Andrew F Olshan118,
  113. Håkan Olsson20,
  114. Nick Orr119,
  115. Alpa Patel120,
  116. Julian Peto121,
  117. Dijana Plaseska-Karanfilska122,
  118. Nadege Presneau52,
  119. Brigitte Rack87,
  120. Paolo Radice123,
  121. Erika Rees-Punia120,
  122. Gad Rennert124,
  123. Hedy S Rennert124,
  124. Atocha Romero125,
  125. Emmanouil Saloustros126,
  126. Dale P Sandler127,
  127. Marjanka K Schmidt90,128,
  128. Rita K Schmutzler72,73,
  129. Lukas Schwentner87,
  130. Christopher Scott78,
  131. Mitul Shah44,
  132. Xiao-Ou Shu129,
  133. Jacques Simard130,
  134. Melissa C Southey1,8,
  135. Jennifer Stone5,131,
  136. Harald Surowy70,71,
  137. Anthony J Swerdlow132,133,
  138. Rulla M Tamimi55,134,
  139. William J Tapper53,
  140. Jack A Taylor127,135,
  141. Mary Beth Terry136,
  142. Rob A E M Tollenaar137,
  143. Melissa A Troester118,
  144. Thérèse Truong69,
  145. Michael Untch138,
  146. Celine M Vachon139,
  147. Vijai Joseph116,
  148. Barbara Wappenschmidt72,73,
  149. Clarice R Weinberg140,
  150. Alicja Wolk75,141,
  151. Drakoulis Yannoukakos142,
  152. Wei Zheng129,
  153. Argyrios Ziogas17,
  154. Alison M Dunning44,
  155. Paul D P Pharoah11,44,
  156. Douglas F Easton11,44,
  157. Roger L Milne1,5,8,
  158. Brigid M Lynch1,5,143
  159. on behalf of the Breast Cancer Association Consortium
  1. 1 Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia
  2. 2 Bristol Medical School, Department of Population Health Sciences, University of Bristol, Bristol, UK
  3. 3 MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK
  4. 4 NIHR Biomedical Research Centre, University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol, Bristol, UK
  5. 5 Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia
  6. 6 Allied Health and Human Performance, University of South Australia, Adelaide, South Australia, Australia
  7. 7 Australian Centre for Precision Health, University of South Australia Cancer Research Institute, Adelaide, South Australia, Australia
  8. 8 Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia
  9. 9 Biostatistics Unit, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
  10. 10 Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
  11. 11 Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
  12. 12 Australian Breast Cancer Tissue Bank, Westmead Institute for Medical Research, The University of Sydney, Sydney, New South Wales, Australia
  13. 13 Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
  14. 14 Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
  15. 15 Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada
  16. 16 Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
  17. 17 Department of Medicine, Genetic Epidemiology Research Institute, University of California Irvine, Irvine, California, USA
  18. 18 Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
  19. 19 Department of Public Health Sciences, and Cancer Research Institute, Queen’s University, Kingston, Ontario, Canada
  20. 20 Department of Cancer Epidemiology, Clinical Sciences, Lund University, Lund, Sweden
  21. 21 Department of Oncology, Cancer Center, Kuopio University Hospital, Kuopio, Finland
  22. 22 Institute of Clinical Medicine, Oncology, University of Eastern Finland, Kuopio, Finland
  23. 23 Institute of Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  24. 24 Department of Gynecology and Obstetrics, Comprehensive Cancer Center ER-EMN, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
  25. 25 Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
  26. 26 Institute of Biochemistry and Genetics, FSBSI Ufa Federal Research Centre of the Russian Academy of Sciences, Ufa, Russian Federation
  27. 27 Department of Oncology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
  28. 28 Department of Oncology, Örebro University Hospital, Örebro, Sweden
  29. 29 Department of Radiation Oncology, Hannover Medical School, Hannover, Germany
  30. 30 Gynaecology Research Unit, Hannover Medical School, Hannover, Germany
  31. 31 Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
  32. 32 Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
  33. 33 Division of Cancer Prevention and Genetics, European Institute of Oncology IRCCS, Milan, Italy
  34. 34 Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany
  35. 35 Institute for Prevention and Occupational Medicine of the German Social Accident Insurance (IPA), Institute of the Ruhr University Bochum, Bochum, Germany
  36. 36 Department of Internal Medicine and Huntsman Cancer Institute, The University of Utah, Salt Lake City, Utah, USA
  37. 37 Department of Biology, University of Pisa, Pisa, Italy
  38. 38 Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany
  39. 39 Oncology and Genetics Unit, Instituto de Investigación Sanitaria Galicia Sur (IISGS), Xerencia de Xestion Integrada de Vigo-SERGAS, Vigo, Spain
  40. 40 Department of Pathology, Intermountain Medical Center, Intermountain Healthcare, Salt Lake City, Utah, USA
  41. 41 Intermountain Biorepository, Intermountain Healthcare, Salt Lake City, Utah, USA
  42. 42 Cancer Epidemiology Group, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  43. 43 Westmead Institute for Medical Research, The University of Sydney, Sydney, New South Wales, Australia
  44. 44 Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK
  45. 45 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
  46. 46 Sheffield Institute for Nucleic Acids (SInFoNiA), Department of Oncology and Metabolism, The University of Sheffield, Sheffield, UK
  47. 47 Academic Unit of Pathology, Department of Neuroscience, The University of Sheffield, Sheffield, UK
  48. 48 Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
  49. 49 Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA
  50. 50 Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands
  51. 51 Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands
  52. 52 School of Life Sciences, University of Westminster, London, UK
  53. 53 Faculty of Medicine, University of Southampton, Southampton, UK
  54. 54 Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
  55. 55 Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
  56. 56 Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany
  57. 57 LIFE - Leipzig Research Centre for Civilization Diseases, University of Leipzig, Leipzig, Germany
  58. 58 Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
  59. 59 North West Genomics Laboratory Hub, Manchester Centre for Genomic Medicine, St Mary’s Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK
  60. 60 David Geffen School of Medicine, Department of Medicine Division of Hematology and Oncology, University of California Los Angeles, Los Angeles, California, USA
  61. 61 The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK
  62. 62 Department of Breast Surgery, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
  63. 63 School of Population Health, Curtin University, Perth, Western Australia, Australia
  64. 64 Genomic Medicine Group, International Cancer Genetics and Epidemiology Group, Fundación Pública Galega de Medicina Xenómica, Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago, SERGAS, Santiago de Compostela, Spain
  65. 65 Moores Cancer Center, University of California San Diego, La Jolla, California, USA
  66. 66 Medical Oncology Department, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria San Carlos (IdISSC), Centro de Investigación Biomédica en Red de Cáncer, Madrid, Spain
  67. 67 Department of Medicine, McGill University, Montréal, Québec, Canada
  68. 68 Division of Clinical Epidemiology, Royal Victoria Hospital, McGill University, Montréal, Québec, Canada
  69. 69 Team ‘Exposome and Heredity’, Center for Research in Epidemiology and Population Health (CESP), Gustave Roussy, INSERM, University Paris-Saclay, Villejuif, France
  70. 70 Molecular Epidemiology Group, C080, German Cancer Research Center (DKFZ), Heidelberg, Germany
  71. 71 Molecular Biology of Breast Cancer, University Womens Clinic Heidelberg, University of Heidelberg, Heidelberg, Germany
  72. 72 Center for Familial Breast and Ovarian Cancer, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
  73. 73 Center for Integrated Oncology (CIO), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
  74. 74 Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
  75. 75 Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
  76. 76 Department of Oncology, Södersjukhuset, Stockholm, Sweden
  77. 77 Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
  78. 78 Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA
  79. 79 Prevent Breast Cancer Research Unit, Manchester University Hospital Foundation NHS Trust, Manchester, UK
  80. 80 Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
  81. 81 Dr Margarete Fischer Bosch Institute of Clinical Pharmacology, Stuttgart, Germany
  82. 82 University of Tübingen, Tübingen, Germany
  83. 83 Division of Cancer Sciences, The University of Manchester, Manchester, UK
  84. 84 Nuffield Department of Population Health, University of Oxford, Oxford, UK
  85. 85 Department of Genetics and Pathology, Pomeranian Medical University in Szczecin, Szczecin, Poland
  86. 86 Independent Laboratory of Molecular Biology and Genetic Diagnostics, Pomeranian Medical University in Szczecin, Szczecin, Poland
  87. 87 Department of Gynaecology and Obstetrics, University Hospital Ulm, Ulm, Germany
  88. 88 Department of Epidemiology and Population Health, Stanford University School of Medicine, Stanford, California, USA
  89. 89 Department of Medicine, Division of Oncology, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California, USA
  90. 90 Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands
  91. 91 Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA
  92. 92 Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
  93. 93 Department of Medical Genetics, Oslo University Hospital and University of Oslo, Oslo, Norway
  94. 94 Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
  95. 95 Department of Histopathology and Cytology, Clinical Hospital Acibadem Sistina, Skopje, Macedonia (the former Yugoslav Republic of)
  96. 96 Department of Computational and Quantitative Medicine, City of Hope, Duarte, California, USA
  97. 97 City of Hope Comprehensive Cancer Center, City of Hope, Duarte, California, USA
  98. 98 VIB Center for Cancer Biology, VIB, Gent, Oost-Vlaanderen, Belgium
  99. 99 Laboratory for Translational Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium
  100. 100 Epidemiology Program, University of Hawai'i Cancer Center, Honolulu, Hawaii, USA
  101. 101 Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
  102. 102 Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
  103. 103 German Breast Group, Neu-Isenburg, Germany
  104. 104 Translational Cancer Research Area, University of Eastern Finland, Kuopio, Finland
  105. 105 Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland
  106. 106 Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden
  107. 107 Herbert Wertheim School of Public Health and Human Longevity Science, University of California San Diego, La Jolla, California, USA
  108. 108 Department of Medical Oncology, University Hospital of Heraklion, Heraklion, Greece
  109. 109 MRC Clinical Trials Unit, Institute of Clinical Trials & Methodology, University College London, London, UK
  110. 110 Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
  111. 111 Laboratory Medicine Program, University Health Network, Toronto, Ontario, Canada
  112. 112 Cancer Control Research, BC Cancer, Vancouver, British Columbia, Canada
  113. 113 School of Population and Public Health, The University of British Columbia, Vancouver, British Columbia, Canada
  114. 114 Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
  115. 115 Leuven Multidisciplinary Breast Center, Department of Oncology, Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium
  116. 116 Clinical Genetics Research Lab, Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York City, New York, USA
  117. 117 Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York City, New York, USA
  118. 118 Department of Epidemiology, Gillings School of Global Public Health and UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
  119. 119 Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK
  120. 120 Department of Population Science, American Cancer Society, Atlanta, Georgia, USA
  121. 121 Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK
  122. 122 Research Centre for Genetic Engineering and Biotechnology 'Georgi D. Efremov', MASA, Skopje, Macedonia (the former Yugoslav Republic of)
  123. 123 Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
  124. 124 Clalit National Cancer Control Center, Carmel Medical Center and Technion Faculty of Medicine, Haifa, Israel
  125. 125 Medical Oncology Department, Hospital Universitario Puerta de Hierro, Madrid, Spain
  126. 126 Department of Oncology, University Hospital of Larissa, Larissa, Greece
  127. 127 Epidemiology Branch, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina, USA
  128. 128 Division of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands
  129. 129 Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
  130. 130 Genomics Center, Centre Hospitalier Universitaire de Québec – Université Laval Research Center, Québec City, Québec, Canada
  131. 131 Genetic Epidemiology Group, School of Population and Global Health, The University of Western Australia, Perth, Western Australia, Australia
  132. 132 Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK
  133. 133 Division of Breast Cancer Research, The Institute of Cancer Research, London, UK
  134. 134 Department of Population Health Sciences, Weill Cornell Medicine, New York City, New York, USA
  135. 135 Epigenetic and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina, USA
  136. 136 Department of Epidemiology, Mailman School of Public Health, Columbia University, New York City, New York, USA
  137. 137 Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands
  138. 138 Department of Gynecology and Obstetrics, Helios Clinics Berlin-Buch, Berlin, Germany
  139. 139 Department of Quantitative Health Sciences, Division of Epidemiology, Mayo Clinic, Rochester, Minnesota, USA
  140. 140 Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina, USA
  141. 141 Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
  142. 142 Molecular Diagnostics Laboratory, INRASTES, National Centre for Scientific Research-Demokritos, Athens, Greece
  143. 143 Physical Activity Laboratory, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
  1. Correspondence to Assoc. Prof. Brigid M Lynch, Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia; brigid.lynch{at}cancervic.org.au

Abstract

Objectives Physical inactivity and sedentary behaviour are associated with higher breast cancer risk in observational studies, but ascribing causality is difficult. Mendelian randomisation (MR) assesses causality by simulating randomised trial groups using genotype. We assessed whether lifelong physical activity or sedentary time, assessed using genotype, may be causally associated with breast cancer risk overall, pre/post-menopause, and by case-groups defined by tumour characteristics.

Methods We performed two-sample inverse-variance-weighted MR using individual-level Breast Cancer Association Consortium case-control data from 130 957 European-ancestry women (69 838 invasive cases), and published UK Biobank data (n=91 105–377 234). Genetic instruments were single nucleotide polymorphisms (SNPs) associated in UK Biobank with wrist-worn accelerometer-measured overall physical activity (nsnps=5) or sedentary time (nsnps=6), or accelerometer-measured (nsnps=1) or self-reported (nsnps=5) vigorous physical activity.

Results Greater genetically-predicted overall activity was associated with lower breast cancer overall risk (OR=0.59; 95% confidence interval (CI) 0.42 to 0.83 per-standard deviation (SD;~8 milligravities acceleration)) and for most case-groups. Genetically-predicted vigorous activity was associated with lower risk of pre/perimenopausal breast cancer (OR=0.62; 95% CI 0.45 to 0.87,≥3 vs. 0 self-reported days/week), with consistent estimates for most case-groups. Greater genetically-predicted sedentary time was associated with higher hormone-receptor-negative tumour risk (OR=1.77; 95% CI 1.07 to 2.92 per-SD (~7% time spent sedentary)), with elevated estimates for most case-groups. Results were robust to sensitivity analyses examining pleiotropy (including weighted-median-MR, MR-Egger).

Conclusion Our study provides strong evidence that greater overall physical activity, greater vigorous activity, and lower sedentary time are likely to reduce breast cancer risk. More widespread adoption of active lifestyles may reduce the burden from the most common cancer in women.

  • Breast
  • Physical activity
  • Sedentary Behaviour
  • Genetics

Data availability statement

Data are available upon reasonable request. The data used in this study are de-identified patient data from 76 studies participating in the Breast Cancer Association Consortium (BCAC). Enquiries about accessing BCAC data can be directed to the BCAC coordinators at the University of Cambridge: https://bcac.ccge.medschl.cam.ac.uk/

https://doi.org/10.1136/bjsports-2021-105132

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    Data availability statement

    Data are available upon reasonable request. The data used in this study are de-identified patient data from 76 studies participating in the Breast Cancer Association Consortium (BCAC). Enquiries about accessing BCAC data can be directed to the BCAC coordinators at the University of Cambridge: https://bcac.ccge.medschl.cam.ac.uk/

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    Footnotes

    • RLM and BML are joint senior authors.

    • Twitter @drterryboyle, @drbrigidmlynch

    • RLM and BML contributed equally.

    • Deceased HO deceased.

    • Contributors Project conception – BML, RLM; Project design – SCD, BML, RLM, SJL, RMM, DRE, TB; Acquisition, analysis, or interpretation of data for the work – all authors; initial drafting of manuscript – SCD, BML, RLM, SJL, RMM, DRE, TB; critical input – all authors; final approval of manuscript – all authors. BML is guarantor.

    • Funding This work was supported by the following agencies. Funders had no role in study design, data collection, analysis, interpretation, writing of the report, or the decision to submit the paper for publication. BCAC is funded by the European Union's Horizon 2020 Research and Innovation Programme (grant numbers 634935 and 633784 for BRIDGES and B-CAST respectively), and the PERSPECTIVE I&I project, funded by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the Ministère de l’Économie et de l'Innovation du Québec through Genome Québec, the Quebec Breast Cancer Foundation. The EU Horizon 2020 Research and Innovation Programme funding source had no role in study design, data collection, data analysis, data interpretation or writing of the report. Additional funding for BCAC is provided via the Confluence project which is funded with intramural funds from the National Cancer Institute Intramural Research Program, National Institutes of Health. Genotyping of the OncoArray was funded by the NIH Grant U19 CA148065, and Cancer Research UK Grant C1287/A16563 and the PERSPECTIVE project supported by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research (grant GPH-129344) and, the Ministère de l’Économie, Science et Innovation du Québec through Genome Québec and the PSRSIIRI-701 grant, and the Quebec Breast Cancer Foundation. Funding for iCOGS came from: the European Community's Seventh Framework Programme under grant agreement n° 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565), the National Institutes of Health (CA128978) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112 - the GAME-ON initiative), the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, and Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. The BRIDGES panel sequencing was supported by the European Union Horizon 2020 research and innovation program BRIDGES (grant number, 634935) and the Wellcome Trust (v203477/Z/16/Z). The Australian Breast Cancer Family Study (ABCFS) was supported by grant UM1 CA164920 from the National Cancer Institute (USA). The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the USA Government or the BCFR. The ABCFS was also supported by the National Health and Medical Research Council of Australia, the New South Wales Cancer Council, the Victorian Health Promotion Foundation (Australia) and the Victorian Breast Cancer Research Consortium. J.L.H. is a National Health and Medical Research Council (NHMRC) Senior Principal Research Fellow. M.C.S. is a NHMRC Senior Research Fellow. The ABCS study was supported by the Dutch Cancer Society [grants NKI 2007-3839; 2009 4363]. The Australian Breast Cancer Tissue Bank (ABCTB) was supported by the National Health and Medical Research Council of Australia, The Cancer Institute NSW and the National Breast Cancer Foundation. The AHS study is supported by the intramural research program of the National Institutes of Health, the National Cancer Institute (grant number Z01-CP010119), and the National Institute of Environmental Health Sciences (grant number Z01-ES049030). The work of the BBCC was partly funded by ELANFond of the University Hospital of Erlangen. The BBCS is funded by Cancer Research UK and Breast Cancer Now and acknowledges NHS funding to the NIHR Biomedical Research Centre, and the National Cancer Research Network (NCRN). The BCEES was funded by the National Health and Medical Research Council, Australia and the Cancer Council Western Australia and acknowledges funding from the National Breast Cancer Foundation (JS). For the BCFR-NY, BCFR-PA, BCFR-UT this work was supported by grant UM1 CA164920 from the National Cancer Institute. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organisations imply endorsement by the US Government or the BCFR. The BCINIS study is supported in part by the Breast Cancer Research Foundation (BCRF). The BREast Oncology GAlician Network (BREOGAN) is funded by Acción Estratégica de Salud del Instituto de Salud Carlos III FIS PI12/02125/Cofinanciado and FEDER PI17/00918/Cofinanciado FEDER; Acción Estratégica de Salud del Instituto de Salud Carlos III FIS Intrasalud (PI13/01136); Programa Grupos Emergentes, Cancer Genetics Unit, Instituto de Investigacion Biomedica Galicia Sur. Xerencia de Xestion Integrada de Vigo-SERGAS, Instituto de Salud Carlos III, Spain; Grant 10CSA012E, Consellería de Industria Programa Sectorial de Investigación Aplicada, PEME I + D e I + D Suma del Plan Gallego de Investigación, Desarrollo e Innovación Tecnológica de la Consellería de Industria de la Xunta de Galicia, Spain; Grant EC11-192. Fomento de la Investigación Clínica Independiente, Ministerio de Sanidad, Servicios Sociales e Igualdad, Spain; and Grant FEDERInnterconecta. Ministerio de Economia y Competitividad, Xunta de Galicia, Spain. The BSUCH study was supported by the Dietmar-Hopp Foundation, the Helmholtz Society and the German Cancer Research Center (DKFZ). CBCS is funded by the Canadian Cancer Society (grant # 313404) and the Canadian Institutes of Health Research. CCGP is supported by funding from the University of Crete. The CECILE study was supported by Fondation de France, Institut National du Cancer (INCa), Ligue Nationale contre le Cancer, Agence Nationale de Sécurité Sanitaire, de l'Alimentation, de l'Environnement et du Travail (ANSES), Agence Nationale de la Recherche (ANR). The CGPS was supported by the Chief Physician Johan Boserup and Lise Boserup Fund, the Danish Medical Research Council, and Herlev and Gentofte Hospital. The American Cancer Society funds the creation, maintenance, and updating of the CPS-II cohort. The California Teachers Study (CTS) and the research reported in this publication were supported by the National Cancer Institute of the National Institutes of Health under award number U01-CA199277; P30-CA033572; P30-CA023100; UM1-CA164917; and R01-CA077398. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health. The collection of cancer incidence data used in the California Teachers Study was supported by the California Department of Public Health pursuant to California Health and Safety Code Section 103885; Centers for Disease Control and Prevention’s National Program of Cancer Registries, under cooperative agreement 5NU58DP006344; the National Cancer Institute’s Surveillance, Epidemiology and End Results Program under contract HHSN261201800032I awarded to the University of California, San Francisco, contract HHSN261201800015I awarded to the University of Southern California, and contract HHSN261201800009I awarded to the Public Health Institute. The opinions, findings, and conclusions expressed herein are those of the author(s) and do not necessarily reflect the official views of the State of California, Department of Public Health, the National Cancer Institute, the National Institutes of Health, the Centers for Disease Control and Prevention or their Contractors and Subcontractors, or the Regents of the University of California, or any of its programs. The University of Westminster curates the DietCompLyf database funded by Against Breast Cancer Registered Charity No. 1121258 and the NCRN. 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: 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); German Cancer Aid, German Cancer Research Center (DKFZ), Federal Ministry of Education and Research (BMBF) (Germany); the Hellenic Health Foundation, the Stavros Niarchos 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); Health Research Fund (FIS), PI13/00061 to Granada, PI13/01162 to EPIC-Murcia, Regional Governments of Andalucía, Asturias, Basque Country, Murcia and Navarra, ISCIII RETIC (RD06/0020) (Spain); Cancer Research UK (14136 to EPIC-Norfolk; C570/A16491 and C8221/A19170 to EPIC-Oxford), Medical Research Council (1000143 to EPIC-Norfolk, MR/M012190/1 to EPIC-Oxford) (United Kingdom). The ESTHER study was supported by a grant from the Baden Württemberg Ministry of Science, Research and Arts. Additional cases were recruited in the context of the VERDI study, which was supported by a grant from the German Cancer Aid (Deutsche Krebshilfe). FHRISK and PROCAS are funded from NIHR grant PGfAR 0707-10031. DGE, AH and WGN are supported by the NIHR Manchester Biomedical Research Centre (IS-BRC1215-20007). The GC-HBOC (German Consortium of Hereditary Breast and Ovarian Cancer) is supported by the German Cancer Aid (grant no 110837 and 70114178, coordinator: Rita K. Schmutzler, Cologne) and the Federal Ministry of Education and Research, Germany (grant no 01GY1901). This work was also funded by the European Regional Development Fund and Free State of Saxony, Germany (LIFE - Leipzig Research Centre for Civilization Diseases, project numbers 713- 241202, 713-241202, 14505/2470, 14575/2470). The GENICA was funded by the Federal Ministry of Education and Research (BMBF) Germany grants 01KW9975/5, 01KW9976/8, 01KW9977/0 and 01KW0114, the Robert Bosch Foundation, Stuttgart, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, the Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), Bochum, as well as the Department of Internal Medicine, Johanniter GmbH Bonn, Johanniter Krankenhaus, Bonn, Germany. The GEPARSIXTO study was conducted by the German Breast Group GmbH. The GESBC was supported by the Deutsche Krebshilfe e. V. [70492] and the German Cancer Research Center (DKFZ). The HABCS study was supported by the Claudia von Schilling Foundation for Breast Cancer Research, by the Lower Saxonian Cancer Society, and by the Rudolf Bartling Foundation. The HEBCS was financially supported by the Helsinki University Hospital Research Fund, the Sigrid Juselius Foundation and the Cancer Foundation Finland. The HMBCS was supported by a grant from the Friends of Hannover Medical School and by the Rudolf Bartling Foundation. The HUBCS was supported by a grant from the German Federal Ministry of Research and Education (RUS08/017), B.M. was supported by grant 17-44-020498, 17-29-06014 of the Russian Foundation for Basic Research, and the study was performed as part of the assignment of the Ministry of Science and Higher Education of the Russian Federation (№АААА-А16-116020350032-1). Financial support for KARBAC was provided through the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institutet, the Swedish Cancer Society, The Gustav V Jubilee foundation and Bert von Kantzows foundation. The KARMA study was supported by Märit and Hans Rausings Initiative Against Breast Cancer. The KBCP was financially supported by the special Government Funding (VTR) of Kuopio University Hospital grants, Cancer Fund of North Savo, the Finnish Cancer Organizations, and by the strategic funding of the University of Eastern Finland. LMBC is supported by the 'Stichting tegen Kanker'. DL is supported by the FWO. The MABCS study is funded by the Research Centre for Genetic Engineering and Biotechnology "Georgi D. Efremov", MASA. The MARIE study was supported by the Deutsche Krebshilfe e.V. [70- 2892-BR I, 106332, 108253, 108419, 110826, 110828], the Hamburg Cancer Society, the German Cancer Research Center (DKFZ) and the Federal Ministry of Education and Research (BMBF) Germany [01KH0402]. MBCSG is supported by grants from the Italian Association for Cancer Research (AIRC). The MCBCS was supported by the NIH grants R35CA253187, R01CA192393, R01CA116167, R01CA176785 a NIH Specialized Program of Research Excellence (SPORE) in Breast Cancer [P50CA116201], and the Breast Cancer Research Foundation. The Melbourne Collaborative Cohort Study (MCCS) cohort recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further augmented by Australian National Health and Medical Research Council grants 209057, 396414 and 1074383 and by infrastructure provided by Cancer Council Victoria. Cases and their vital status were ascertained through the Victorian Cancer Registry and the Australian Institute of Health and Welfare, including the National Death Index and the Australian Cancer Database. The MEC was supported by NIH grants CA63464, CA54281, CA098758, CA132839 and CA164973. The MISS study is supported by funding from ERC-2011- 294576 Advanced grant, Swedish Cancer Society, Swedish Research Council, Local hospital funds, Berta Kamprad Foundation, Gunnar Nilsson. The MMHS study was supported by NIH grants CA97396, CA128931, CA116201, CA140286 and CA177150. MSKCC is supported by grants from the Breast Cancer Research Foundation and Robert and Kate Niehaus Clinical Cancer Genetics Initiative. The work of MTLGEBCS was supported by the Quebec Breast Cancer Foundation, the Canadian Institutes of Health Research for the “CIHR Team in Familial Risks of Breast Cancer” program – grant # CRN-87521 and the Ministry of Economic Development, Innovation and Export Trade – grant # PSR-SIIRI-701. The NBCS has received funding from the K.G. Jebsen Centre for Breast Cancer Research; the Research Council of Norway grant 193387/V50 (to A-L Børresen-Dale and V.N. Kristensen) and grant 193387/H10 (to A-L Børresen-Dale and V.N. Kristensen), South Eastern Norway Health Authority (grant 39346 to A-L Børresen-Dale) and the Norwegian Cancer Society (to A-L Børresen-Dale and V.N. Kristensen). The NBHS was supported by NIH grant R01CA100374. Biological sample preparation was conducted the Survey and Biospecimen Shared Resource, which is supported by P30 CA68485. The Northern California Breast Cancer Family Registry (NC-BCFR) and Ontario Familial Breast Cancer Registry (OFBCR) were supported by grant U01CA164920 from the USA National Cancer Institute of the National Institutes of Health. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the USA Government or the BCFR. The Carolina Breast Cancer Study (NCBCS) was funded by Komen Foundation, the National Cancer Institute (P50 CA058223, U54 CA156733, U01 CA179715), and the North Carolina University Cancer Research Fund. The NHS was supported by NIH grants P01 CA87969, UM1 CA186107, and U19 CA148065. The NHS2 was supported by NIH grants UM1 CA176726 and U19 CA148065. The ORIGO study was supported by the Dutch Cancer Society (RUL 1997-1505) and the Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL CP16). The PBCS was funded by Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA. Genotyping for PLCO was supported by the Intramural Research Program of the National Institutes of Health, NCI, Division of Cancer Epidemiology and Genetics. The PLCO is supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics and supported by contracts from the Division of Cancer Prevention, National Cancer Institute, National Institutes of Health. The POSH study is funded by Cancer Research UK (grants C1275/A11699, C1275/C22524, C1275/A19187, C1275/A15956 and Breast Cancer Campaign 2010PR62, 2013PR044. The RBCS was funded by the Dutch Cancer Society (DDHK 2004-3124, DDHK 2009-4318). The SBCS was supported by Sheffield Experimental Cancer Medicine Centre and Breast Cancer Now Tissue Bank. SEARCH is funded by Cancer Research UK [C490/A10124, C490/A16561] and supported by the UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge. The University of Cambridge has received salary support for PDPP from the NHS in the East of England through the Clinical Academic Reserve. The Sister Study (SISTER) is supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01-ES044005 and Z01-ES049033). The Two Sister Study (2SISTER) was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01-ES044005 and Z01- ES102245), and, also by a grant from Susan G. Komen for the Cure, grant FAS0703856. SKKDKFZS is supported by the DKFZ. The SMC is funded by the Swedish Cancer Foundation and the Swedish Research Council (VR 2017-00644) grant for the Swedish Infrastructure for Medical Populationbased Life-course Environmental Research (SIMPLER). The SZBCS was supported by Grant PBZ_KBN_122/P05/2004 and the program of the Minister of Science and Higher Education under the name "Regional Initiative of Excellence" in 2019-2022 project number 002/RID/2018/19 amount of financing 12 000 000 PLN. The TNBCC was supported by: a Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), a grant from the Breast Cancer Research Foundation, a generous gift from the David F. and Margaret T. Grohne Family Foundation. UBCS was supported by funding from National Cancer Institute (NCI) grant R01 CA163353 (to N.J. Camp) and the Women’s Cancer Center at the Huntsman Cancer Institute (HCI). Data collection for UBCS was supported by the Utah Population Database (UPDB) and Utah Cancer Registry (UCR). The UPDB is supported by HCI (including the Huntsman Cancer Foundation), University of Utah program in Personalized Health and Center for Clinical and Translational Science, and NCI grant P30 CA42014. The UCR is funded by the NCI’s SEER Program, Contract No. HHSN261201800016I, the US Center for Disease Control and Prevention's National Program of Cancer Registries, Cooperative Agreement No. NU58DP0063200, the University of Utah and Huntsman Cancer Foundation. The UCIBCS component of this research was supported by the NIH [CA58860, CA92044] and the Lon V Smith Foundation [LVS39420]. The UKBGS is funded by Breast Cancer Now and the Institute of Cancer Research (ICR), London. ICR acknowledges NHS funding to the NIHR Biomedical Research Centre. The UKOPS study was funded by The Eve Appeal (The Oak Foundation) and supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. The USRT Study was funded by Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA. RMM is a National Institute for Health Research Senior Investigator (NIHR202411). RMM is supported by a Cancer Research UK (C18281/A19169) programme grant (the Integrative Cancer Epidemiology Programme). RMM is also supported by the NIHR Bristol Biomedical Research Centre which is funded by the NIHR and is a partnership between University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol. RMM is affiliated with the Medical Research Council Integrative Epidemiology Unit at the University of Bristol which is supported by the Medical Research Council (MC_UU_00011/1, MC_UU_00011/3, MC_UU_00011/6, and MC_UU_00011/4) and the University of Bristol. Department of Health and Social Care disclaimer: The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. DGE, AH and WGN are supported by the NIHR Manchester Biomedical Research Centre (IS-BRC-1215-20007). BML is funded by the Victorian Cancer Agency (MCRF-18005).

    • Competing interests MWB conducts research funded by Amgen, Novartis and Pfizer. PAF conducts research funded by Amgen, Novartis and Pfizer. He received honoraria from Roche, Novartis and Pfizer. AWK declares research funding to her institution from Myriad Genetics for an unrelated project (funding dates 2017-2019). SL declares grants and honoraria paid to her institution from Amgen, Novartis, Pfizer, Roche, and, outside the submitted work, grants and/or honoraria paid to her institution from AbbVie, Celgene, Seattle Genetics, PrIME/Medscape, Daiichi-Sankyo, Lilly, Samsung, BMS, Puma, Immunomedics, AstraZeneca, Pierre Fabre, Merck, GlaxoSmithKlein, EirGenix, and Bayer, and personal fees from Chugai; SL also has a patent EP14153692.0 pending. UM declares stock ownership in Abcodia Ltd. RAM has been a consultant for Pharmavite. No other authors have conflicts to declare.

    • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

    • Provenance and peer review Not commissioned; externally peer reviewed.

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