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1. Risk-reducing salpingo-oophorectomy, natural menopause, and breast cancer risk: an international prospective cohort of BRCA1 and BRCA2 mutation carriers

Author

Mavaddat, N., Antoniou, A.C., Mooij, T.M., Hooning, M.J., Heemskerk-Gerritsen, B.A., Nogues, C., Laborde, L., Breysse, E., Stoppa-Lyonnet, D., Gauthier-Villars, M., Buecher, B., Caron, O., Fourme-Mouret, E., Fricker, J.P., Lasset, C., Bonadona, V., Berthet, P., Faivre, L., Luporsi, E., Mari, V., Gladieff, L., Gesta, P., Sobol, H., Eisinger, F., Longy, M., Dugast, C., Colas, C., Coupier, I., Pujol, P., Corsini, C., Lortholary, A., Vennin, P., Adenis, C., Nguyen, T.D., Delnatte, C., Tinat, J., Tennevet, I., Limacher, J.M., Maugard, C., Bignon, Y.J., Demange, L., Penet, C., Dreyfus, H., Cohen-Haguenauer, O., Venat-Bouvet, L., Leroux, D., Zattara-Cannoni, H., Fert-Ferrer, S., Bera, O., Ellis, S., Barrowdale, D., Frost, D., Evans, D.G., Izatt, L., Adlard, J., Eeles, R., Brewer, C., Tischkowitz, M., Henderson, A., Cook, J., Eccles, D., Hogervorst, F.B.L., Collee, J.M., Asperen, C.J. van, Mensenkamp, A.R., Ausems, M.G.E.M., Meijers-Heijboer, H.E.J., Engelen, K. van, Blok, M.J., Oosterwijk, J.C., Verloop, J., Broek, E. van den, Mourits, M.J.E., Koppert, L.B., Hopper, J.L., John, E.M., Chung, W.K., Andrulis, I.L., Daly, M.B., Buys, S.S., Benitez, J., Caldes, T., Jakubowska, A., Simard, J., Singer, C.F., Tan, Y., Olah, E., Navratilova, M., Foretova, L., Gerdes, A.M., Roos-Blom, M.J., Leeuwen, F.E. van, Arver, B., Olsson, H., Schmutzler, R.K., Engel, C., Kast, K., Phillips, K.A., Terry, M.B., Milne, R.L., Goldgar, D.E., Rookus, M.A., Andrieu, N., Easton, D.F., GENEPSO, EMBRACE, HEBON, kConFab Investigators, IBCCS, kConFab, BCFR, University of Cambridge [UK] (CAM), Netherlands Cancer Institute (NKI), Antoni van Leeuwenhoek Hospital, Erasmus MC Cancer Institute, Rotterdam, Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Institut Curie [Paris], Institut Gustave Roussy (IGR), Département de médecine oncologique [Gustave Roussy], Centre Hospitalier Georges Renon [Niort] (CH Georges Renon Niort), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre Catherine-de-Sienne [Nantes] (CCS), Manchester University NHS Foundation Trust (MFT), Guy's & St Thomas' NHS Foundation Trust, Chapel Allerton Hospital, University of Leeds, Royal Marsden NHS Foundation Trust, Royal Devon & Exeter Hospital, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Sheffield Children's NHS Foundation Trust, Wessex clinical genetics service, Vrije Universiteit Amsterdam [Amsterdam] (VU), University Medical Center Groningen [Groningen] (UMCG), Department of Medical Genetics, University Medical Center [Utrecht], Centre for MEGA Epidemiology, The University of Melbourne, Victoria, Australia, Department of Epidemiology, Cancer Prevention Institute of California, Columbia University [New York], Departments of Molecular Genetics and Laboratory Medicine and Pathobiology, University of Toronto-Cancer Care Ontario, Division of Population Science, Fox Chase Cancer Center, Department of Internal Medicine, Huntsman Cancer Institute, Departemento Genetica Humana, Centro Nacional Investigaciones Oncologicas, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos [Madrid, Spain] (IdISSC), Department of Genetics and Pathology, International Hereditary Cancer Centre-Pomeranian Medical University [Szczecin] (PUM), Cancer Genomics Laboratory, Centre Hospitalier Universitaire de Québec, Division of Special Gynecology, Medizinische Universität Wien = Medical University of Vienna-Department of OB/GYN, Medizinische Universität Wien = Medical University of Vienna, National Institute of Oncology, Masaryk Memorial Cancer Institute (MMCI), Masaryk University [Brno] (MUNI), Department of Clinical Genetics [Copenhagen], Rigshospitalet [Copenhagen], Copenhagen University Hospital-Copenhagen University Hospital, The Netherlands Cancer Institute [Amsterdam, The Netherlands], Radiumhemmet, Karolinska University Hospital [Stockholm], Department of Oncology, Lund University Hospital, Division of Molecular Gyneco-Oncology, Department of Gynaecology and Obstetrics, Clinical Center Un, Institute for Medical Informatics, Statistics and Epidemiology [Leipzig] (IMISE), Universität Leipzig [Leipzig], Department of Gynaecology and Obstetrics, University Hospital Carl Gustav Carus, Dept of Haematology and Medical Oncology, Peter MacCallum Cancer Center, Department of Epidemiology [Columbia University], Columbia University [New York]-Columbia Mailman School of Public Health, Cancer Epidemiology Centre, Cancer Council Victoria, International Agency for Cancer Research (IACR), Netherlands Cancer Institute, Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris sciences et lettres (PSL), Cancer Research U.K. Genetic Epidemiology Unit, Strangeways Research Laboratory, Andrieu, Nadine, Human genetics, Epidemiology and Data Science, Mavaddat, Nasim [0000-0003-0307-055X], Eeles, Ros [0000-0002-3698-6241], Engel, Christoph [0000-0002-7247-282X], Apollo - University of Cambridge Repository, Pomeranian Medical University-International Hereditary Cancer Centre, Masaryk Memorial Cancer Institute (RECAMO), Columbia Mailman School of Public Health-Columbia University [New York], Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Antoniou, Antonis [0000-0001-9223-3116], Tischkowitz, Marc [0000-0002-7880-0628], Easton, Douglas [0000-0003-2444-3247], Medical Oncology, Surgery, Cancer Research UK (Reino Unido), NIH - National Cancer Institute (NCI) (Estados Unidos), United States Department of Health and Human Services, Ministerio de Economía y Competitividad (España), Unión Europea. Comisión Europea. European Research Council (ERC), Norwegian EEA Financial Mechanism, Hungarian Scientific Research Fund (Hungría), Ministry of Education, Youth and Sports (República Checa), MH CZ -DRO (MMCI), National Health and Medical Research Council (Australia), Australian National Breast Cancer Foundation, Cancer Australia, ERA-NET TRANSAN JTC 2012 Cancer, Transcan grant, Biotechnology and Biological Sciences Research Council (Reino Unido), Pink Ribbons Project, Netherlands Organisation of Scientific Research, Dutch Cancer Society (Holanda), Instituto de Salud Carlos III, Deutsche Krebshilfe, National Institute for Health Research (Reino Unido), Unión Europea. Comisión Europea. 7 Programa Marco, Ministry of Economic Development, Innovation and Export Trade-grant, Canadian Institutes of Health Research, Cancer Research UK, NIH National Cancer Institute (NCI), United States Department of Health & Human Services National Institutes of Health (NIH) - USA, Ministerio de Economia y Competividad (MINECO), European Research Council (ERC), Hungarian Research Grants, MEYS -NPS I, National Health and Medical Research Council of Australia, BBMRI grant, Pink Ribbon grants, Netherlands Organisation of Scientific Research grant, KWF Kankerbestrijding, Instituto de Salud Carlos III - ISCIII, National Institute for Health Research (NIHR), European Union Seventh Framework Program (2007-2013), Canadian Institutes of Health Research (CIHR), Damage and Repair in Cancer Development and Cancer Treatment (DARE), Targeted Gynaecologic Oncology (TARGON), United States of Department of Health & Human Services, European Research Council, APH - Quality of Care, APH - Methodology, Graduate School, ARD - Amsterdam Reproduction and Development, RS: GROW - R4 - Reproductive and Perinatal Medicine, and MUMC+: DA KG Lab Centraal Lab (9)

Subjects
endocrine system diseases, SURGERY, [SDV]Life Sciences [q-bio], [SDV.GEN] Life Sciences [q-bio]/Genetics, Cohort Studies, 0302 clinical medicine, BRCA2 Mutation, Breast cancer, Surgical oncology, Prospective Studies, Prospective cohort study, skin and connective tissue diseases, Salpingo-oophorectomy/methods, 0303 health sciences, Natural menopause, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], Obstetrics, BRCA1 Protein, Breast Neoplasms/epidemiology, Incidence (epidemiology), Incidence, WOMEN, ASSOCIATION, Middle Aged, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, OVARIAN, BRCA2 Protein/genetics, 3. Good health, Menopause, Risk-reducing salpingo-oophorectomy, [SDV] Life Sciences [q-bio], 030220 oncology & carcinogenesis, SURVIVAL, Female, Research Article, Cohort study, Adult, medicine.medical_specialty, Salpingo-oophorectomy, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, lcsh:RC254-282, 03 medical and health sciences, breast cancer, SDG 3 - Good Health and Well-being, [SDV.CAN] Life Sciences [q-bio]/Cancer, medicine, Humans, METAANALYSIS, 030304 developmental biology, BRCA2 Protein, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, CONSORTIUM, risk-reducing salpingo-oophorectomy, International Agencies, medicine.disease, BRCA1, BRCA2, KCONFAB, REDUCTION, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, LINK, Mutation, BRCA1 Protein/genetics, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, Risk Reduction Behavior
Abstract

The effect of risk-reducing salpingo-oophorectomy (RRSO) on breast cancer risk for BRCA1 and BRCA2 mutation carriers is uncertain. Retrospective analyses have suggested a protective effect but may be substantially biased. Prospective studies have had limited power, particularly for BRCA2 mutation carriers. Further, previous studies have not considered the effect of RRSO in the context of natural menopause. A multi-centre prospective cohort of 2272 BRCA1 and 1605 BRCA2 mutation carriers was followed for a mean of 5.4 and 4.9 years, respectively; 426 women developed incident breast cancer. RRSO was modelled as a time-dependent covariate in Cox regression, and its effect assessed in premenopausal and postmenopausal women. There was no association between RRSO and breast cancer for BRCA1 (HR = 1.23; 95% CI 0.94-1.61) or BRCA2 (HR = 0.88; 95% CI 0.62-1.24) mutation carriers. For BRCA2 mutation carriers, HRs were 0.68 (95% CI 0.40-1.15) and 1.07 (95% CI 0.69-1.64) for RRSO carried out before or after age 45 years, respectively. The HR for BRCA2 mutation carriers decreased with increasing time since RRSO (HR = 0.51; 95% CI 0.26-0.99 for 5 years or longer after RRSO). Estimates for premenopausal women were similar. We found no evidence that RRSO reduces breast cancer risk for BRCA1 mutation carriers. A potentially beneficial effect for BRCA2 mutation carriers was observed, particularly after 5 years following RRSO. These results may inform counselling and management of carriers with respect to RRSO. The BCFR 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 centres 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. CNIO was partially supported by the Spanish Ministry of Economy and Competitiveness (MINECO) SAF2014-57680-R and the Spanish Research Network on Rare Diseases (CIBERER). CNIO was also partially supported by FISPI16/00440. INHERIT was supported by 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 PERSPECTIVE project was supported by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research (GPH-129344), the Ministere de l'Economie, de la Science et de l' Innovation du Quebec through Genome Quebec, and The Quebec Breast Cancer Foundation. Jacques Simard is a Chairholder of the Canada Research Chair in Oncogenetics. EMBRACE is supported by the Cancer Research UK grants C1287/A23382 and C1287/A16563. D. Gareth Evans is supported by an NIHR grant to the Biomedical Research Centre, Manchester (IS-BRC-1215-20007). The investigators at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust are supported by an NIHR grant to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. Ros Eeles and Elizabeth Bancroft are supported by the Cancer Research UK grant C5047/A8385. Ros Eeles is also supported by NIHR support to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. Antonis C. Antoniou is funded by Cancer Research UK grants C12292/A20861 and C12292/A11174. MT is funded by the European Union Seventh Framework Program (2007-2013)/European Research Council (310018). The German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC) is supported by the German Cancer Aid (grant no 110837, Rita K. Schmutzler). The national French cohort, GENEPSO, had been supported by a grant from the Fondation de France and the Ligue Nationale Contre le Cancer and is being supported by a grant from INCa as part of the European program ERA-NET on Translational Cancer Research (TRANSCAN-JTC2012, no. 2014-008). HCSC was supported by CIBERONC 161200301 from ISCIII (Spain), partially supported by European Regional Development FEDER funds. The HEBON study is supported by the Dutch Cancer Society grants NKI1998-1854, NKI2004-3088, NKI2007-3756, the Netherlands Organisation of Scientific Research grant NWO 91109024, the Pink Ribbon grants 110005 and 2014-187.WO76, the BBMRI grant NWO 184.021.007/CP46, and the Transcan grant JTC 2012 Cancer 12-054. The IHCC was supported by Grant PBZ_ KBN_122/P05/2004 and ERA-NET TRANSAN JTC 2012 Cancer 12-054 (ERA-NET-TRANSCAN/07/2014). This work was supported by grants to kConFab and the kConFab Follow-Up Study from Cancer Australia (809195); the Australian National Breast Cancer Foundation (IF 17); the National Health and Medical Research Council (454508, 288704, 145684); the National Institute of Health U.S.A. (1RO1CA159868); the Queensland Cancer Fund; the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia; and the Cancer Foundation of Western Australia. KAP is an Australian National Breast Cancer Foundation fellow. MODSQUAD-Czech Republic, Brno, was supported by MH CZ -DRO (MMCI, 00209805) and by MEYS -NPS I -LO1413 to LF and MN. The Hungarian Breast and Ovarian Cancer Study was supported by Hungarian Research Grants KTIA-OTKA CK-80745, NKFI OTKA K-112228, and the Norwegian EEA Financial Mechanism HU0115/NA/2008-3/OP-9. Lund-BRCA collaborators are supported by the Swedish Cancer Society, Lund Hospital Funds, and European Research Council Advanced Grant ERC-2011-294576. Stockholm-BRCA collaborators are supported by the Swedish Cancer Society. The funders had no role in the design of the study; the collection, analysis, or interpretation of the data; the writing of the manuscript; or the decision to submit the manuscript for publication. Sí

Published
2020
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2. The Influence of Number and Timing of Pregnancies on Breast Cancer Risk for Women With BRCA1 or BRCA2 Mutations

Author

Terry, MB, Liao, Y, Kast, K, Antoniou, AC, McDonald, JA, Mooij, TM, Engel, C, Nogues, C, Buecher, B, Mari, V, Moretta-Serra, J, Gladieff, L, Luporsi, E, Barrowdale, D, Frost, D, Henderson, A, Brewer, C, Evans, DG, Eccles, D, Cook, J, Ong, K-R, Izatt, L, Ahmed, M, Morrison, PJ, Dommering, CJ, Oosterwijk, JC, Ausems, MGEM, Kriege, M, Buys, SS, Andrulis, IL, John, EM, Daly, M, Friedlander, M, McLachlan, SA, Osorio, A, Caldes, T, Jakubowska, A, Simard, J, Singer, CF, Tan, Y, Olah, E, Navratilova, M, Foretova, L, Gerdes, A-M, Roos-Blom, M-J, Arver, B, Olsson, H, Schmutzler, RK, Hopper, JL, van Leeuwen, FE, Goldgar, D, Milne, RL, Easton, DF, Rookus, MA, Andrieu, N, and EMBRACE, GENEPSO, BCFR, HEBON, kConFab and IBCCS

Subjects
endocrine system diseases, skin and connective tissue diseases
Abstract

Background: Full-term pregnancy (FTP) is associated with a reduced breast cancer (BC) risk over time, but women are at increased BC risk in the immediate years following an FTP. No large prospective studies, however, have examined whether the number and timing of pregnancies are associated with BC risk for BRCA1 and BRCA2 mutation carriers. Methods: Using weighted and time-varying Cox proportional hazards models, we investigated whether reproductive events are associated with BC risk for mutation carriers using a retrospective cohort (5707 BRCA1 and 3525 BRCA2 mutation carriers) and a prospective cohort (2276 BRCA1 and 1610 BRCA2 mutation carriers), separately for each cohort and the combined prospective and retrospective cohort. Results: For BRCA1 mutation carriers, there was no overall association with parity compared with nulliparity (combined hazard ratio [HRc] = 0.99, 95% confidence interval [CI] = 0.83 to 1.18). Relative to being uniparous, an increased number of FTPs was associated with decreased BC risk (HRc = 0.79, 95% CI = 0.69 to 0.91; HRc = 0.70, 95% CI = 0.59 to 0.82; HRc = 0.50, 95% CI = 0.40 to 0.63, for 2, 3, and ≥4 FTPs, respectively, Ptrend < .0001) and increasing duration of breastfeeding was associated with decreased BC risk (combined cohort Ptrend = .0003). Relative to being nulliparous, uniparous BRCA1 mutation carriers were at increased BC risk in the prospective analysis (prospective hazard ration [HRp] = 1.69, 95% CI = 1.09 to 2.62). For BRCA2 mutation carriers, being parous was associated with a 30% increase in BC risk (HRc = 1.33, 95% CI = 1.05 to 1.69), and there was no apparent decrease in risk associated with multiparity except for having at least 4 FTPs vs. 1 FTP (HRc = 0.72, 95% CI = 0.54 to 0.98). Conclusions: These findings suggest differential associations with parity between BRCA1 and BRCA2 mutation carriers with higher risk for uniparous BRCA1 carriers and parous BRCA2 carriers.

Published
2019

3. The Influence of Number and Timing of Pregnancies on Breast Cancer Risk for Women With BRCA1 or BRCA2 Mutations

Author

Douglas F. Easton, T.M. Mooij, Christian F. Singer, Lenka Foretova, Matti A. Rookus, Karin Kast, Kai-ren Ong, Louise Izatt, Jessica Moretta-Serra, Margreet G. E. M. Ausems, Diana Eccles, Patrick J. Morrison, Jan C. Oosterwijk, Mary B. Daly, Alex Henderson, Rita K. Schmutzler, Ana Osorio, Charlotte J. Dommering, Anne-Marie Gerdes, Marie Navratilova, Ibccs, Carole Brewer, Mieke Kriege, Mary Beth Terry, Christoph Engel, D. Gareth Evans, Edith Olah, Jackie Cook, David E. Goldgar, Anna Jakubowska, Antonis C. Antoniou, Jacques Simard, Laurence Gladieff, Catherine Noguès, Esther M. John, Brita Arver, Håkan Olsson, Jasmine A. McDonald, Irene L. Andrulis, Nadine Andrieu, Munaza Ahmed, Yen Y. Tan, Yuyan Liao, Embrace, Genepso, Bcfr, Hebon, kConFab, Trinidad Caldés, Véronique Mari, Roger L. Milne, Michael Friedlander, Elisabeth Luporsi, John L. Hopper, Marie-José Roos-Blom, Flora E. van Leeuwen, Sue-Anne McLachlan, Saundra S. Buys, Debra Frost, Daniel Barrowdale, Bruno Buecher, Department of Epidemiology [Columbia University], Columbia University [New York]-Columbia Mailman School of Public Health, Columbia University [New York], Department of Gynaecology and Obstetrics, University Hospital Carl Gustav Carus, Centre for Cancer Genetic Epidemiology, University of Cambridge [UK] (CAM), Institute for Medical Informatics, Statistics and Epidemiology [Leipzig] (IMISE), Universität Leipzig, Laboratoire d'Oncogénétique, CRLCC René Huguenin, Service de Génétique Oncologique, Institut Curie [Paris], Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Institut Claudius Regaud, Centre Alexis Vautrin (CAV), Newcastle Upon Tyne Hospitals NHS Trust, Department of Clinical Genetics, Royal Devon & Exeter Hospital, St Mary's Hospital, Wessex Clinical Genetics Service, Princess Anne Hospital, Sheffield Clinical Genetics Service, Sheffield Children's NHS Foundation Trust, West Midlands Regional Genetics Service, Birmingham Women's and Children's NHS Foundation Trust, Clinical Genetics, Guy's and St. Thomas' NHS Foundation Trust, Northern Ireland Regional Genetics Centre, Belfast City Hospital, Department of Clinical Genetics and Human Genetics, VU University Medical Center [Amsterdam], Department of Genetics, Department of Medical Genetics, University Medical Center [Utrecht], Erasmus University Medical Center [Rotterdam] (Erasmus MC)-Family Cancer Clinic, Department of Internal Medicine, Huntsman Cancer Institute, Department of Laboratory Medicine and Pathobiology, University of Toronto, Department of Epidemiology, Cancer Prevention Institute of California, Division of Population Science, Fox Chase Cancer Center, Dept of Medical Oncology, Division of Medicine, University of New South Wales [Sydney] (UNSW)-Prince of Wales Hospital Randwick, Human Genetics Group, Spanish National Cancer Research Centre, Molecular Oncology Laboratory, Hospital Clínico San Carlos, Department of Genetics and Pathology, International Hereditary Cancer Centre-Pomeranian Medical University [Szczecin] (PUM), Laboratoire de Génomique des Cancers, Université Laval [Québec] (ULaval), Division of Special Gynecology, Medizinische Universität Wien = Medical University of Vienna-Department of OB/GYN, National Institute of Oncology, Masaryk University [Brno] (MUNI), Odense University Hospital, Radiumhemmet, Karolinska University Hospital [Stockholm], Department of Oncology, Lund University Hospital, Division of Molecular Gyneco-Oncology, Department of Gynaecology and Obstetrics, Clinical Center Un, Centre for MEGA Epidemiology, The University of Melbourne, Victoria, Australia, Departments of Epidemiology and Molecular Pathology, The Netherlands Cancer Institute, Department of Dermatology, University of Utah School of Medicine [Salt Lake City], Cancer Epidemiology Centre, Cancer Council Victoria, Centre for Cancer Genetic Epidemiology [Cambridge], University of Cambridge [UK] (CAM)-Department of Oncology, Netherlands Cancer Institute, Innovation et Développement dans l'Agriculture et l'Alimentation (UMR Innovation), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Institut National de la Recherche Agronomique (INRA)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), This work was supported by grants to kConFab and the kConFab Follow-Up Study from Cancer Australia (809195), the Australian National Breast Cancer Foundation (IF 17), the National Health and Medical Research Council (454508, 288704, 145684), the US National Institute of Health (1RO1CA159868), the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania, and South Australia, and the Cancer Foundation of Western Australia. MODSQUAD Czech Republic, Brno was supported by MH CZ—DRO (MMCI, 00209805) and by MEYS—NPS I - LO1413 to LF, MN. The Hungarian Breast and Ovarian Cancer Study was supported by Hungarian Research grants KTIA-OTKA CK80745 and NKFI OTKA K-112228 and the Norwegian EEA Financial Mechanism HU0115/NA/2008-3/OP-9. € Lund-BRCA collaborators are supported by the Swedish Cancer Society, Lund Hospital Funds, and European Research Council Advanced grant ERC-2011-294576. Stockholm-BRCA collaborators are supported by the Swedish Cancer Society., European Project: 294576,EC:FP7:ERC,ERC-2011-ADG_20110310,RISK FACTORS CANCER(2012), Klinische Genetica, RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA KG Polikliniek (9), MUMC+: DA KG Lab Centraal Lab (9), Universität Leipzig [Leipzig], Institut Curie, Centre Antoine Lacassagne, CRLCC Antoine Lacassagne, CRLCC Institut Claudius Regaud, Sheffield Children's Hospital, Birmingham Women's Hospital Healthcare NHS Trust, Pomeranian Medical University-International Hereditary Cancer Centre, Laval University [Québec], Masaryk Memorial Cancer Institute and Medical Faculty of Masaryk University, Innovation et Développement dans l'Agriculture et l'Agro-alimentaire (Innovation), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Centre national d'études agronomiques des régions chaudes (CNEARC)-Institut National de la Recherche Agronomique (INRA)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Centre International de Hautes Etudes Agronomiques Méditerranéennes - Institut Agronomique Méditerranéen de Montpellier (CIHEAM-IAMM), Centre International de Hautes Études Agronomiques Méditerranéennes (CIHEAM)-Centre International de Hautes Études Agronomiques Méditerranéennes (CIHEAM)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), Andrieu, Nadine, Genetic and environmental risk factors for common malignant tumours especially breast cancer and melanoma. - RISK FACTORS CANCER - - EC:FP7:ERC2012-04-01 - 2017-03-31 - 294576 - VALID, Medical Oncology, Pathology, Radiology & Nuclear Medicine, Columbia Mailman School of Public Health-Columbia University [New York], Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Targeted Gynaecologic Oncology (TARGON), and Damage and Repair in Cancer Development and Cancer Treatment (DARE)

Subjects
0301 basic medicine, Cancer Research, medicine.medical_specialty, INDUCED-ABORTION, endocrine system diseases, BIRTH, [SDV]Life Sciences [q-bio], [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.GEN] Life Sciences [q-bio]/Genetics, SUSCEPTIBILITY, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, SDG 3 - Good Health and Well-being, [SDV.CAN] Life Sciences [q-bio]/Cancer, Medicine, COHORT, Prospective cohort study, skin and connective tissue diseases, REPRODUCTIVE FACTORS, [SDV.GEN]Life Sciences [q-bio]/Genetics, PARITY, business.industry, Proportional hazards model, Obstetrics, Hazard ratio, Retrospective cohort study, medicine.disease, CARRIERS, OVARIAN, Confidence interval, [SDV] Life Sciences [q-bio], KCONFAB, 030104 developmental biology, Oncology, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, 030220 oncology & carcinogenesis, Cohort, COLLABORATIVE REANALYSIS, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, Breast feeding
Abstract

Background Full-term pregnancy (FTP) is associated with a reduced breast cancer (BC) risk over time, but women are at increased BC risk in the immediate years following an FTP. No large prospective studies, however, have examined whether the number and timing of pregnancies are associated with BC risk for BRCA1 and BRCA2 mutation carriers. Methods Using weighted and time-varying Cox proportional hazards models, we investigated whether reproductive events are associated with BC risk for mutation carriers using a retrospective cohort (5707 BRCA1 and 3525 BRCA2 mutation carriers) and a prospective cohort (2276 BRCA1 and 1610 BRCA2 mutation carriers), separately for each cohort and the combined prospective and retrospective cohort. Results For BRCA1 mutation carriers, there was no overall association with parity compared with nulliparity (combined hazard ratio [HRc] = 0.99, 95% confidence interval [CI] = 0.83 to 1.18). Relative to being uniparous, an increased number of FTPs was associated with decreased BC risk (HRc = 0.79, 95% CI = 0.69 to 0.91; HRc = 0.70, 95% CI = 0.59 to 0.82; HRc = 0.50, 95% CI = 0.40 to 0.63, for 2, 3, and ≥4 FTPs, respectively, Ptrend < .0001) and increasing duration of breastfeeding was associated with decreased BC risk (combined cohort Ptrend = .0003). Relative to being nulliparous, uniparous BRCA1 mutation carriers were at increased BC risk in the prospective analysis (prospective hazard ration [HRp] = 1.69, 95% CI = 1.09 to 2.62). For BRCA2 mutation carriers, being parous was associated with a 30% increase in BC risk (HRc = 1.33, 95% CI = 1.05 to 1.69), and there was no apparent decrease in risk associated with multiparity except for having at least 4 FTPs vs. 1 FTP (HRc = 0.72, 95% CI = 0.54 to 0.98). Conclusions These findings suggest differential associations with parity between BRCA1 and BRCA2 mutation carriers with higher risk for uniparous BRCA1 carriers and parous BRCA2 carriers.

Published
2018
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4. Oral Contraceptive Use and Breast Cancer Risk: Retrospective and Prospective Analyses From a BRCA1 and BRCA2 Mutation Carrier Cohort Study

Author

Christian F. Singer, Louise Izatt, Yen Y. Tan, Emmanuelle Mouret-Fourme, Embrace, Genepso, Bcfr, Hebon, kConFab, Marie Navratilova, Lucy Side, Trinidad Caldés, Rosemarie Davidson, Kelly-Anne Phillips, Saundra S. Buys, Dominique Leroux, Mary B. Daly, Melissa C. Southey, Marian J.E. Mourits, Brita Arver, Theo A. M. van Os, Anne-Marie Gerdes, Douglas F. Easton, Marie-José Roos-Blom, Michael Friedlander, Lieske H. Schrijver, David E. Goldgar, Anna Jakubowska, Roger L. Milne, Håkan Olsson, Lisa Walker, Ros Eeles, Flora E. van Leeuwen, Mary Porteous, Sue-Anne McLachlan, Pascaline Berthet, Lenka Foretova, Catherine Noguès, Matti A. Rookus, Debra Frost, Daniel Barrowdale, Esther M. John, Julian Adlard, Encarna B. Gomez Garcia, Nadine Andrieu, Laurence Venat-Bouvet, Anita Bane, John L. Hopper, Mary Beth Terry, Jacques Simard, Ana Osorio, Antonis C. Antoniou, Christoph Engel, Wendy K. Chung, Karin Kast, Ibccs, D. Gareth Evans, Valérie Bonadona, Edith Olah, Steve Ellis, Christi J. van Asperen, T.M. Mooij, Human Genetics, APH - Methodology, APH - Quality of Care, Netherlands Cancer Institute (NKI), Antoni van Leeuwenhoek Hospital, Skane University Hospital [Lund], Lund University [Lund], University of Melbourne, Columbia Mailman School of Public Health, University of Utah School of Medicine [Salt Lake City], Technische Universität Dresden = Dresden University of Technology (TU Dresden), Department of Clinical Sciences [Lund], University of Leipzig [Leipzig, Allemagne], Chapel Allerton Hospital, University of Cambridge [UK] (CAM), Queen Elizabeth University Hospital (Glasgow), Royal Marsden NHS Foundation Trust, University of Manchester [Manchester], Guy's and St Thomas NHS Foundation Trust [London], Western General Hospital [Edinburgh, UK], Great Ormond Street Hospital for Children NHS Foundation Trust [London, UK], Churchill Hospital [Breast Care Unit], Churchill Hospital Oxford Centre for Haematology, Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Centre Hospitalier Universitaire [Grenoble] (CHU), hôpital couple-enfant [CHU Grenoble Alpes], Hôpital René HUGUENIN (Saint-Cloud), Hôpital Dupuytren [CHU Limoges], Huntsman Cancer Institute [Salt Lake City], University of Utah, Monash University [Melbourne], Stanford University School of Medicine [CA, USA], California Sciences Institute, Columbia University [New York], Fox Chase Cancer Center, McMaster University [Hamilton, Ontario], Karolinska Institutet [Stockholm], Leiden University Medical Center (LUMC), School for Oncology and Developmental Biology [Maastricht] (GROW), Maastricht University [Maastricht]-Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht], University Medical Center Groningen [Groningen] (UMCG), Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA), University of New South Wales [Sydney] (UNSW), Prince of Wales Hospital, St. Vincent's Hospital, Sydney, Medizinische Universität Wien = Medical University of Vienna, Masaryk Memorial Cancer Institute (RECAMO), University Hospital of Cologne [Cologne], Copenhagen University Hospital, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos [Madrid, Spain] (IdISSC), Université Laval [Québec] (ULaval), National Institute of Oncology [Budapest, Hungary], Pomeranian Medical University [Szczecin, Poland] (PMU), Spanish National Cancer Centre, Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U1252 INSERM - Aix Marseille Univ - UMR 259 IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Cancer Epidemiology Centre & Cancer Council Victoria [Melbourne, Australia], Melbourne School for Population and Global Health-University of Melbourne, Leipzig University, Great Ormond Street Hospital for Children NHS Foundation Trust [London, UK] (GOSHC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Masaryk Memorial Cancer Institute (MMCI), Pomeranian Medical University [Szczecin] (PUM), Mines Paris - PSL (École nationale supérieure des mines de Paris), University of Melbourne-Melbourne School for Population and Global Health, Malbec, Odile, Universiteit Leiden, RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA KG Polikliniek (9), Klinische Genetica, MUMC+: DA KG Lab Centraal Lab (9), Damage and Repair in Cancer Development and Cancer Treatment (DARE), Targeted Gynaecologic Oncology (TARGON), Life Course Epidemiology (LCE), and ​Basic and Translational Research and Imaging Methodology Development in Groningen (BRIDGE)

Subjects
0301 basic medicine, Cancer Research, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Article, OVARIAN-CANCER, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, medicine, Prospective cohort study, skin and connective tissue diseases, Pregnancy, Proportional hazards model, Obstetrics, business.industry, Hazard ratio, CONSORTIUM, WOMEN, medicine.disease, PREVENTION, Confidence interval, KCONFAB, [SDV] Life Sciences [q-bio], 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Cohort, business, Cohort study
Abstract

Background For BRCA1 and BRCA2 mutation carriers, the association between oral contraceptive preparation (OCP) use and breast cancer (BC) risk is still unclear. Methods Breast camcer risk associations were estimated from OCP data on 6030 BRCA1 and 3809 BRCA2 mutation carriers using age-dependent Cox regression, stratified by study and birth cohort. Prospective, left-truncated retrospective and full-cohort retrospective analyses were performed. Results For BRCA1 mutation carriers, OCP use was not associated with BC risk in prospective analyses (hazard ratio [HR] = 1.08, 95% confidence interval [CI] = 0.75 to 1.56), but in the left-truncated and full-cohort retrospective analyses, risks were increased by 26% (95% CI = 6% to 51%) and 39% (95% CI = 23% to 58%), respectively. For BRCA2 mutation carriers, OCP use was associated with BC risk in prospective analyses (HR = 1.75, 95% CI = 1.03 to 2.97), but retrospective analyses were inconsistent (left-truncated: HR = 1.06, 95% CI = 0.85 to 1.33; full cohort: HR = 1.52, 95% CI = 1.28 to 1.81). There was evidence of increasing risk with duration of use, especially before the first full-term pregnancy (BRCA1: both retrospective analyses, P < .001 and P = .001, respectively; BRCA2: full retrospective analysis, P = .002). Conclusions Prospective analyses did not show that past use of OCP is associated with an increased BC risk for BRCA1 mutation carriers in young middle-aged women (40–50 years). For BRCA2 mutation carriers, a causal association is also not likely at those ages. Findings between retrospective and prospective analyses were inconsistent and could be due to survival bias or a true association for younger women who were underrepresented in the prospective cohort. Given the uncertain safety of long-term OCP use for BRCA1/2 mutation carriers, indications other than contraception should be avoided and nonhormonal contraceptive methods should be discussed.

Published
2018
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5. Risk-reducing salpingo-oophorectomy, natural menopause, and breast cancer risk: an international prospective cohort of BRCA1 and BRCA2 mutation carriers

Author

Mavaddat, Nasim, Antoniou, Antonis C, Mooij, Thea M, Hooning, Maartje J, Heemskerk-Gerritsen, Bernadette A, GENEPSO, Noguès, Catherine, Gauthier-Villars, Marion, Caron, Olivier, Gesta, Paul, Pujol, Pascal, Lortholary, Alain, EMBRACE, Barrowdale, Daniel, Frost, Debra, Evans, D Gareth, Izatt, Louise, Adlard, Julian, Eeles, Ros, Brewer, Carole, Tischkowitz, Marc, Henderson, Alex, Cook, Jackie, Eccles, Diana, HEBON, Van Engelen, Klaartje, Mourits, Marian JE, Ausems, Margreet GEM, Koppert, Linetta B, Hopper, John L, John, Esther M, Chung, Wendy K, Andrulis, Irene L, Daly, Mary B, Buys, Saundra S, KConFab Investigators, Benitez, Javier, Caldes, Trinidad, Jakubowska, Anna, Simard, Jacques, Singer, Christian F, Tan, Yen, Olah, Edith, Navratilova, Marie, Foretova, Lenka, Gerdes, Anne-Marie, Roos-Blom, Marie-José, Van Leeuwen, Flora E, Arver, Brita, Olsson, Håkan, Schmutzler, Rita K, Engel, Christoph, Kast, Karin, Phillips, Kelly-Anne, Terry, Mary Beth, Milne, Roger L, Goldgar, David E, Rookus, Matti A, Andrieu, Nadine, Easton, Douglas F, IBCCS, KConFab, and BCFR

Subjects
Risk-reducing salpingo-oophorectomy, Breast cancer, endocrine system diseases, Mutation, skin and connective tissue diseases, BRCA1, BRCA2, 3. Good health
Abstract

BACKGROUND: The effect of risk-reducing salpingo-oophorectomy (RRSO) on breast cancer risk for BRCA1 and BRCA2 mutation carriers is uncertain. Retrospective analyses have suggested a protective effect but may be substantially biased. Prospective studies have had limited power, particularly for BRCA2 mutation carriers. Further, previous studies have not considered the effect of RRSO in the context of natural menopause. METHODS: A multi-centre prospective cohort of 2272 BRCA1 and 1605 BRCA2 mutation carriers was followed for a mean of 5.4 and 4.9 years, respectively; 426 women developed incident breast cancer. RRSO was modelled as a time-dependent covariate in Cox regression, and its effect assessed in premenopausal and postmenopausal women. RESULTS: There was no association between RRSO and breast cancer for BRCA1 (HR = 1.23; 95% CI 0.94-1.61) or BRCA2 (HR = 0.88; 95% CI 0.62-1.24) mutation carriers. For BRCA2 mutation carriers, HRs were 0.68 (95% CI 0.40-1.15) and 1.07 (95% CI 0.69-1.64) for RRSO carried out before or after age 45 years, respectively. The HR for BRCA2 mutation carriers decreased with increasing time since RRSO (HR = 0.51; 95% CI 0.26-0.99 for 5 years or longer after RRSO). Estimates for premenopausal women were similar. CONCLUSION: We found no evidence that RRSO reduces breast cancer risk for BRCA1 mutation carriers. A potentially beneficial effect for BRCA2 mutation carriers was observed, particularly after 5 years following RRSO. These results may inform counselling and management of carriers with respect to RRSO.

6. Pregnancies, breast-feeding, and breast cancer risk in the International BRCA1/2 Carrier Cohort Study (IBCCS)

Author

Catherine Noguès, Nadine Andrieu, Susan Peock, Flora E. van Leeuwen, Matti A. Rookus, Fiona Douglas, Gareth Evans, Edith Olah, Richard M. Brohet, Brita Arver, David E. Goldgar, Javier Benitez, Irma Kluijt, Diana Eccles, Antonis C. Antoniou, Douglas F. Easton, Agnès Chompret, Jenny Chang-Claude, Marion Gauthier-Villars, Méthodologie statistique et épidémiologie génétique des maladies multifactorielles, Institut National de la Santé et de la Recherche Médicale (INSERM), Service de biostatistique (IC10213), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), International Agency for Cancer Research (IACR), Genetic Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge [UK] (CAM), Departments of Epidemiology and Molecular Pathology, The Netherlands Cancer Institute, Manchester regional genetics service, Manchester regional genetics service, Wessex clinical genetics service, Northern clinical genetics service, Laboratoire d'Oncogénétique, CRLCC René Huguenin, Service d'oncogénétique, Institut Curie [Paris], Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR), Departemento Genetica Humana, Centro Nacional Investigaciones Oncologicas, Radiumhemmet, Karolinska University Hospital [Stockholm], National Institute of Oncology, Division of Clinical Epidemiology, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), EMBRACE, GENEPSO, GEO-HEBON, IBCCS Collaborators' Group, and Andrieu, Nadine

Subjects
Cancer Research, Time Factors, MESH: Pregnan, International Cooperation, Genes, BRCA2, Genes, BRCA1, Cohort Studies, 0302 clinical medicine, Pregnancy, Surveys and Questionnaires, skin and connective tissue diseases, MESH: Cohort Studies, MESH: Heterozygote, 0303 health sciences, education.field_of_study, MESH: Middle Aged, Age Factors, MESH: Genetic Predisposition to Disease, Middle Aged, 3. Good health, Europe, Parity, Breast Feeding, Oncology, 030220 oncology & carcinogenesis, MESH: Breast Feeding, Cohort, Female, MESH: Abortion, Induced, Pregnancy Complications, Neoplastic, Cohort study, Adult, medicine.medical_specialty, Heterozygote, MESH: Mutation, Population, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Article, 03 medical and health sciences, Breast cancer, [SDV.CAN] Life Sciences [q-bio]/Cancer, medicine, Humans, Genetic Predisposition to Disease, Risk factor, education, 030304 developmental biology, Proportional Hazards Models, Retrospective Studies, Gynecology, MESH: Age Factors, MESH: Humans, business.industry, MESH: Parity, Retrospective cohort study, Abortion, Induced, MESH: Adult, medicine.disease, MESH: International Cooperation, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Mutation, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, MESH: Europe, business, Breast feeding, MESH: Female, MESH: Genes, BRCA1, MESH: Breast Neoplasms, MESH: Genes, BRCA2
Abstract

BACKGROUND: Multiparity, young age at first childbirth, and breast-feeding are associated with a reduced risk of breast cancer in the general population. The breast cancer predisposition gene, BRCA1, regulates normal cell differentiation. Because mammary gland cells divide and differentiate during pregnancy, reproductive factors may influence breast cancer risk in BRCA1/2 mutation carriers differently than they do in noncarriers. METHODS: We performed a retrospective cohort study of 1601 women in the International BRCA1/2 Carrier Cohort Study cohort, all of whom carried a mutation in BRCA1 or BRCA2. Information on reproductive factors was obtained from a questionnaire. At the time of interview 853 subjects were classified with breast cancer. Data were analyzed by using a weighted cohort approach. All statistical tests were two-sided. RESULTS: There was no statistically significant difference in the risk of breast cancer between parous and nulliparous women. Among parous women, an increasing number of full-term pregnancies was associated with a statistically significant decrease in the risk of breast cancer (Ptrend = .008); risk was reduced by 14% (95% confidence interval [CI] = 6% to 22%) for each additional birth. This association was the same for carriers of mutations in either BRCA1 or BRCA2 and was restricted to women older than 40 years. In BRCA2 mutation carriers, first childbirth at later ages was associated with an increased risk of breast cancer compared with first childbirth before age 20 years (20-24 years, hazard ratio [HR] = 2.33 [95% CI = 0.93 to 5.83]; 25-29 years, HR = 2.68 [95% CI = 1.02 to 7.07]; > or = 30 years, HR = 1.97 [95% CI = 0.67 to 5.81]), whereas in BRCA1 mutation carriers, first childbirth at age 30 years or later was associated with a reduced risk of breast cancer compared with first childbirth before age 20 years (HR = 0.58 [95% CI = 0.36 to 0.94]). Neither history of interrupted pregnancies (induced abortions or miscarriage) nor history of breast-feeding was statistically significantly associated with the risk of breast cancer. CONCLUSIONS: BRCA1 and BRCA2 mutation carriers older than 40 years show a similar reduction in breast cancer risk with increasing parity as non-carriers.

Published
2006
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