Lieske H Schrijver1, Antonis C Antoniou2, Håkan Olsson3, Thea M Mooij1, Marie-José Roos-Blom1, Leyla Azarang1, Julian Adlard4, Munaza Ahmed5, Daniel Barrowdale2, Rosemarie Davidson6, Alan Donaldson7, Ros Eeles8, D Gareth Evans9, Debra Frost2, Alex Henderson10, Louise Izatt11, Kai-Ren Ong12, Valérie Bonadona13, Isabelle Coupier14, Laurence Faivre15, Jean-Pierre Fricker16, Paul Gesta17, Klaartje van Engelen18, Agnes Jager19, Fred H Menko20, Marian J E Mourits21, Christian F Singer22, Yen Y Tan22, Lenka Foretova23, Marie Navratilova23, Rita K Schmutzler24, Carolina Ellberg25, Anne-Marie Gerdes26, Trinidad Caldes27, Jacques Simard28, Edith Olah29, Anna Jakubowska30, Johanna Rantala31, Ana Osorio32, John L Hopper33, Kelly-Anne Phillips34, Roger L Milne35, Mary Beth Terry36, Catherine Noguès37, Christoph Engel38, Karin Kast39, David E Goldgar40, Flora E van Leeuwen1, Douglas F Easton2, Nadine Andrieu41, Matti A Rookus42. 1. Department of Epidemiology, Netherlands Cancer Institute, Amsterdam, the Netherlands. 2. Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom. 3. Department of Oncology, Lund University Hospital, Lund, Sweden. 4. Yorkshire Regional Genetics Service, Chapel Allerton Hospital, Leeds, United Kingdom. 5. North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom. 6. Department of Clinical Genetics, South Glasgow University Hospitals, Glasgow, United Kingdom. 7. Department of Clinical Genetics, St. Michael's Hospital, Bristol, United Kingdom. 8. Oncogenetics Team, The Institute of Cancer Research, London, United Kingdom. 9. Division of Evolution and Genomic Sciences, Department of Genomic Medicine, Manchester Academic Health Sciences Centre, Manchester University, Manchester University Hospitals NHS Foundation Trust, Manchester, United Kingdom. 10. Centre for Life, Institute of Genetic Medicine, Newcastle upon Tyne Hospitals NHS Trust, Newcastle upon Tyne, United Kingdom. 11. Clinical Genetics, Guy's and St. Thomas' NHS Foundation Trust, London, United Kingdom. 12. West Midlands Regional Genetics Service, Birmingham Women's and Children's NHS Foundation Trust, Edgbaston, Birmingham, United Kingdom. 13. Université Claude Bernard Lyon 1, Villeurbanne, France; Centre National de la Recherche Scientifique, Unités Mixtes de Recherche, Lyon, France; Centre Léon Bérard, Unité de Prévention et Epidémiologie Génétique, Lyon, France. 14. Centre Hospitalier Universitaire de Montpellier, Hôpital Arnaud de Villeneuve, Montpellier, France; Service de Génétique médicale et Oncogénétique, Montpellier, France; Institut National de la Santé et de la Recherche Médicale, Centre de Recherche en Cancérologie de Marseille Val d'Aurel, Montpellier, France. 15. Genomic and Immunotherapy Medical Institute, Hôpital d'Enfants, Centre Hospitalier Universitaire de Dijon, Dijon, France; Unité d'Oncogénétique, Centre de Lutte Contre le Cancer Georges François Leclerc, Dijon, France. 16. Unité d' Oncogénétique, Centre Paul Strauss, Strasbourg, France. 17. Service d'Oncogénétique Régional Poitou-Charentes, Centre Hospitalier Georges Renon, Niort, France. 18. Department of Clinical Genetics, Amsterdam University Medical Center, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands. 19. Department of Medical Oncology, Family Cancer Clinic, Erasmus Medical Center Cancer Institute, Rotterdam, the Netherlands. 20. Family Cancer Clinic, Netherlands Cancer Institute, Amsterdam, the Netherlands. 21. Department of Gynaecology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands. 22. Department of Obstetrics and Gynecology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria. 23. Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic. 24. Medical Faculty, University of Cologne and University Hospital Cologne, Cologne, Germany. 25. Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden. 26. Department of Clinical Genetics, Rigshospitalet, København, Denmark. 27. Molecular Oncology Laboratory, Hospital Clinico San Carlos, Instituto de Investigación Hospital Clínico San Carlos, Centro de Investigación Biomédica en Red de Cáncer, Martin Lagos, Madrid, Spain. 28. Genomics Center, Centre Hospitalier Universitaire de Québec - Université Laval Research Center, Québec City, Québec, Canada. 29. Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary. 30. Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland; Independent Laboratory of Molecular Biology and Genetic Diagnostics, Pomeranian Medical University, Szczecin, Poland. 31. Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden. 32. Human Genetics Group, Centro Nacional De Investigaciones Oncologicas, Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras, Madrid, Spain. 33. Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Victoria, Australia. 34. Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Victoria, Australia; Department of Oncology, Peter MacCallum Cancer Centre, University of Melbourne, Parkville, Australia; Department of Medical Oncology, Peter MacCallum Cancer Centre, Victoria, Australia. 35. Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Victoria, Australia; Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia. 36. Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY. 37. Département d'Anticipation et de Suivi des Cancers, Oncogénétique Clinique, Institut Paoli-Calmettes, Marseille, France; Institut National de la Santé et de la Recherche Médicale, Institut de Recherche pour le Développement, Sciences Economiques and Sociales de la Santé and Traitement de l'Information Médicale, Aix-Marseille University, Marseille, France. 38. Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Germany. 39. Department of Gynecology and Obstetrics, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany. 40. Department of Dermatology, University of Utah School of Medicine, Salt Lake City, UT. 41. Institut National de la Santé et de la Recherche Médicale, Paris, France; Institut Curie, Paris, France; Mines ParisTech, Fontainebleau, Paris, France; Paris Sciences et Lettres University, Paris, France. 42. Department of Epidemiology, Netherlands Cancer Institute, Amsterdam, the Netherlands. Electronic address: m.rookus@nki.nl.
Abstract
BACKGROUND: Ovarian cancer risk in BRCA1 and BRCA2 mutation carriers has been shown to decrease with longer duration of oral contraceptive use. Although the effects of using oral contraceptives in the general population are well established (approximately 50% risk reduction in ovarian cancer), the estimated risk reduction in mutation carriers is much less precise because of potential bias and small sample sizes. In addition, only a few studies on oral contraceptive use have examined the associations of duration of use, time since last use, starting age, and calendar year of start with risk of ovarian cancer. OBJECTIVE: This study aimed to investigate in more detail the associations of various characteristics of oral contraceptive use and risk of ovarian cancer, to provide healthcare providers and carriers with better risk estimates. STUDY DESIGN: In this international retrospective study, ovarian cancer risk associations were assessed using oral contraceptives data on 3989 BRCA1 and 2445 BRCA2 mutation carriers. Age-dependent-weighted Cox regression analyses were stratified by study and birth cohort and included breast cancer diagnosis as a covariate. To minimize survival bias, analyses were left truncated at 5 years before baseline questionnaire. Separate analyses were conducted for each aspect of oral contraceptive use and in a multivariate analysis, including all these aspects. In addition, the analysis of duration of oral contraceptive use was stratified by recency of use. RESULTS: Oral contraceptives were less often used by mutation carriers who were diagnosed with ovarian cancer (ever use: 58.6% for BRCA1 and 53.5% BRCA2) than by unaffected carriers (ever use: 88.9% for BRCA1 and 80.7% for BRCA2). The median duration of use was 7 years for both BRCA1 and BRCA2 carriers who developed ovarian cancer and 9 and 8 years for unaffected BRCA1 and BRCA2 carriers with ovarian cancer, respectively. For BRCA1 mutation carriers, univariate analyses have shown that both a longer duration of oral contraceptive use and more recent oral contraceptive use were associated with a reduction in the risk of ovarian cancer. However, in multivariate analyses, including duration of use, age at first use, and time since last use, duration of oral contraceptive use proved to be the prominent protective factor (compared with <5 years: 5-9 years [hazard ratio, 0.67; 95% confidence interval, 0.40-1.12]; >10 years [hazard ratio, 0.37; 95% confidence interval, 0.19-0.73]; Ptrend=.008). The inverse association between duration of use and ovarian cancer risk persisted for more than 15 years (duration of ≥10 years; BRCA1 <15 years since last use [hazard ratio, 0.24; 95% confidence interval, 0.14-0.43]; BRCA1 >15 years since last use [hazard ratio, 0.56; 95% confidence interval, 0.18-0.59]). Univariate results for BRCA2 mutation carriers were similar but were inconclusive because of limited sample size. CONCLUSION: For BRCA1 mutation carriers, longer duration of oral contraceptive use is associated with a greater reduction in ovarian cancer risk, and the protection is long term.
BACKGROUND:Ovarian cancer risk in BRCA1 and BRCA2 mutation carriers has been shown to decrease with longer duration of oral contraceptive use. Although the effects of using oral contraceptives in the general population are well established (approximately 50% risk reduction in ovarian cancer), the estimated risk reduction in mutation carriers is much less precise because of potential bias and small sample sizes. In addition, only a few studies on oral contraceptive use have examined the associations of duration of use, time since last use, starting age, and calendar year of start with risk of ovarian cancer. OBJECTIVE: This study aimed to investigate in more detail the associations of various characteristics of oral contraceptive use and risk of ovarian cancer, to provide healthcare providers and carriers with better risk estimates. STUDY DESIGN: In this international retrospective study, ovarian cancer risk associations were assessed using oral contraceptives data on 3989 BRCA1 and 2445 BRCA2 mutation carriers. Age-dependent-weighted Cox regression analyses were stratified by study and birth cohort and included breast cancer diagnosis as a covariate. To minimize survival bias, analyses were left truncated at 5 years before baseline questionnaire. Separate analyses were conducted for each aspect of oral contraceptive use and in a multivariate analysis, including all these aspects. In addition, the analysis of duration of oral contraceptive use was stratified by recency of use. RESULTS: Oral contraceptives were less often used by mutation carriers who were diagnosed with ovarian cancer (ever use: 58.6% for BRCA1 and 53.5% BRCA2) than by unaffected carriers (ever use: 88.9% for BRCA1 and 80.7% for BRCA2). The median duration of use was 7 years for both BRCA1 and BRCA2 carriers who developed ovarian cancer and 9 and 8 years for unaffected BRCA1 and BRCA2 carriers with ovarian cancer, respectively. For BRCA1 mutation carriers, univariate analyses have shown that both a longer duration of oral contraceptive use and more recent oral contraceptive use were associated with a reduction in the risk of ovarian cancer. However, in multivariate analyses, including duration of use, age at first use, and time since last use, duration of oral contraceptive use proved to be the prominent protective factor (compared with <5 years: 5-9 years [hazard ratio, 0.67; 95% confidence interval, 0.40-1.12]; >10 years [hazard ratio, 0.37; 95% confidence interval, 0.19-0.73]; Ptrend=.008). The inverse association between duration of use and ovarian cancer risk persisted for more than 15 years (duration of ≥10 years; BRCA1 <15 years since last use [hazard ratio, 0.24; 95% confidence interval, 0.14-0.43]; BRCA1 >15 years since last use [hazard ratio, 0.56; 95% confidence interval, 0.18-0.59]). Univariate results for BRCA2 mutation carriers were similar but were inconclusive because of limited sample size. CONCLUSION: For BRCA1 mutation carriers, longer duration of oral contraceptive use is associated with a greater reduction in ovarian cancer risk, and the protection is long term.
Authors: Lieske H Schrijver; Thea M Mooij; Anouk Pijpe; Gabe S Sonke; Marian J E Mourits; Nadine Andrieu; Antonis C Antoniou; Douglas F Easton; Christoph Engel; David Goldgar; Esther M John; Karin Kast; Roger L Milne; Håkan Olsson; Kelly-Anne Phillips; Mary Beth Terry; John L Hopper; Flora E van Leeuwen; Matti A Rookus Journal: J Natl Cancer Inst Date: 2022-04-11 Impact factor: 13.506