Oral contraceptive use and ovarian cancer risk for BRCA1/2 mutation carriers: an international cohort study

Lieske Schrijver , Antonis Antoniou , Håkan Olsson , Thea Mooij , Marie-José Roos-Blom , Leyla Azarang , Julian Adlard , Munaza Ahmed , Daniel Barrowdale , Rosemarie Davidson , Alan Donaldson , Ros Eeles , D Gareth Evans , Debra Frost , Alex Henderson , Louise Izatt , Kai-Ren Ong , Valérie Bonadona (1, 2) , Isabelle Coupier (3, 4, 5, 6) , Laurence Faivre (7, 8) , Jean-Pierre Fricker (9) , Paul Gesta (10) , Klaartje van Engelen , Agnes Jager , Fred Menko , Marian Mourits , Christian Singer , Yen Tan , Lenka Foretova , Marie Navratilova , Rita Schmutzler , Carolina Ellberg , Anne-Marie Gerdes , Trinidad Caldes , Jacques Simard , Edith Olah , Anna Jakubowska , Johanna Rantala , Ana Osorio , John Hopper , Kelly-Anne Phillips , Roger Milne , Mary Beth Terry , Catherine Noguès (11, 5, 12) , Christoph Engel , Karin Kast , David Goldgar , Flora van Leeuwen , Douglas Easton , Nadine Andrieu (5, 13, 14) , Matti Rookus , D. Gareth Evans , Marian J.E. Mourits , Lilian Laborde , Pauline Pontois , Emanuelle Breysse , Margot Berline , Dominique Stoppa-Lyonnet , Marion Gauthier-Villars , Bruno Buecher , Chrystelle Colas , Olivier Caron , Emmanuelle Mouret-Fourme , Claire Saule , Christine Lasset , Sophie Dussard , Pascaline Berthet , Elisabeth Luporsi , Véronique Mari , Laurence Gladieff , Stéphanie Chieze-Valéro , Jessica Moretta , Hagay Sobol , François Eisinger , Cornel Popovici , Michel Longy , Louise Grivelli , Florent Soubrier , Patrick Benusiglio , Pascal Pujol , Carole Corsini , Marie-Emmanuelle Morin-Meschin , Alain Lortholary , Claude Adenis , Audrey Maillez , Tan Dat Nguyen , Capucine Delnatte , Caroline Abadie , Julie Tinat , Isabelle Tennevet , Christine Maugard , Yves-Jean Bignon , Mathilde Gay Bellile , Clotilde Penet , Hélène Dreyfus , Odile Cohen-Haguenauer , Brigitte Gilbert , Laurence Venat-Bouvet , Dominique Leroux , Clémentine Legrand , Hélène Zattara-Cannoni , Valérie Layet , Elodie Lacaze , Sandra Fert-Ferrer , Odile Bera , Brigitte Gilbert-Dussardier , David Tougeron , Hakima Lallaoui , M.A. Rookus , F.B.L. Hogervorst , F.E. van Leeuwen , M.A. Adank , M.K. Schmidt , D.J. Jenner , J.M. Collée , A.M.W. van den Ouweland , M.J. Hooning , I.A. Boere , C.J. van Asperen , P. Devilee , R.B. van Der Luijt , T.C.T.E.F. van Cronenburg , M.R. Wevers , A.R. Mensenkamp , M.G.E.M. Ausems , M.J. Koudijs , I. van de Beek , J.J.P. Gille , E.B. Gómez García , M.J. Blok , M. de Boer , L.P.V. Berger , A.H. van Der Hout , M.J.E. Mourits , G.H. de Bock , S. Siesling , J. Verloop , E.C. van den Broek

1 UCBL - Université Claude Bernard Lyon 1
2 CNRS - Centre National de la Recherche Scientifique
3 CHRU Montpellier - Centre Hospitalier Régional Universitaire [Montpellier]
4 Hôpital Arnaud de Villeneuve [CHRU Montpellier]
5 INSERM - Institut National de la Santé et de la Recherche Médicale
6 ICM - UNICANCER - Institut régional du Cancer Montpellier Val d'Aurelle
7 CHU Dijon - Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand
8 UNICANCER/CRLCC-CGFL - Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon]
9 Centre Paul Strauss
10 CH Georges Renon Niort - Centre Hospitalier Georges Renon [Niort]
11 Institut Paoli-Calmettes
12 AMU - Aix Marseille Université
13 Institut Curie [Paris]
14 Mines Paris - PSL (École nationale supérieure des mines de Paris)

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.

Keywords: BRCA1; BRCA2; epidemiology; multivariate; observational; oral contraceptives; ovarian cancer; retrospective; risk; survival bias

Domains: Life Sciences [q-bio]

Lieske Schrijver, Antonis Antoniou, Håkan Olsson, Thea Mooij, Marie-José Roos-Blom, et al.. Oral contraceptive use and ovarian cancer risk for BRCA1/2 mutation carriers: an international cohort study. American Journal of Obstetrics and Gynecology, 2021, 225 (1), pp.51.e1-51.e17. ⟨10.1016/j.ajog.2021.01.014⟩. ⟨hal-03664541⟩