Discussion
Reliable estimation of the association between uptake and timing of RRSO and breast cancer risk is critical for informing counselling and clinical management of BRCA1 and BRCA2 mutation carriers. Our study of 3877 mutation carriers with 426 incident breast cancer cases is the largest prospective cohort to date and the first prospective study investigating breast cancer risk after RRSO for BRCA1 and BRCA2 mutation carriers in the context of menopausal status.
We found no significant association between RRSO and breast cancer risk for
BRCA1 or
BRCA2 mutation carriers, although the point estimate for the association for
BRCA2 mutation carriers was less than 1 (HR = 0.88 (95% CI 0.62–1.24)) and lower when RRSO was carried out before the age of 45 (HR = 0.68 (95% CI 0.40–1.15) vs 1.07 (95% CI 0.69–1.64) after age 45). Our overall results are inconsistent with previous reports of ~ 50% reduction in breast cancer risk for
BRCA1 mutation carriers [
3,
6] but more consistent with a study by Kotsopolous et al. reporting risk reduction only for younger
BRCA2 mutation carriers [
16]. The latter study was prospective, but its results were based on only 3 breast cancers in women aged under 50 years; our study included more than twice as many
BRCA2 mutation carriers overall, and the analyses were based on 31 incident breast cancers in premenopausal
BRCA2 mutation carriers. In addition, we investigated associations by time since RRSO. For
BRCA2 mutation carriers, we observed a decreasing trend in HR with increasing time since RRSO; relative to women who did not have an RSSO, the estimated HR > 5 years following RSSO was 0.51. In contrast, for
BRCA1 mutation carriers, the HR was close to 1 at all times since RRSO.
While this is the largest prospective cohort of mutation carriers to date, the number of breast cancer cases was still limited, and hence, the confidence limits for the HR estimates were wide. Additional data would be needed to determine whether or not there is a modest protective effect of RRSO for BRCA1 mutation carriers and whether the suggested protective effect in BRCA2 mutation carriers is real.
There was some suggestion of differences in estimated effect size among studies for
BRCA1 mutation carriers in the < 2-year and ‘2–5-year’ post-RRSO groups (Fig.
1), but the heterogeneity was not statistically significant. For
BRCA2 mutation carriers, there was statistically significant heterogeneity in the RRSO > 5 years group (Fig.
2); this appeared to be driven by a large effect size in GENEPSO, based on only two breast cancers. Studies differed in methodology (including frequency of questionnaires, assessment of breast cancers or RRSO, loss to follow-up, and mean follow-up time). EMBRACE, GENEPSO, and HEBON ascertained participants through cancer genetics clinics, while BCFR used both clinic- and population-based recruitment. There was also some geographical variation in the uptake and age at RRSO (Additional file
1: Table S3). However, the cohorts were recruited and followed up over broadly similar periods (Additional file
1: Table S2).
The strength of this study is its prospective design. Many of the biases identified in previous reports were addressed [
7,
9,
17,
18]. We avoided cancer testing-induced bias by starting follow-up after mutation testing. Women were not selected for inclusion in the study on the basis of RRSO status, and time-dependent covariates were used to examine the effect of RRSO on breast cancer risk. While it is impossible to rule out bias due to unmeasured confounders in an observational study, adjustment for potential confounders (family history of breast and ovarian cancer, parity, age at first birth, and BMI) did not materially influence the results.
In the general population, HRT use is associated with an increased risk of breast cancer. HRT use after RRSO may therefore attenuate the risk reduction due to RRSO. Our preliminary analyses restricted to the subset of women not reporting HRT use gave broadly similar results (Additional file
1: Table S13), but the effects of HRT post-RRSO will need to be further investigated in larger cohorts and studies that consider the type, formulation, and duration of HRT use.
While often considered the ‘gold standard’ for investigating exposure-disease associations, prospective cohort studies are still prone to biases resulting from missing data, loss to follow-up, and informative censoring. In particular, there are gaps in data collection between questionnaires and between the last questionnaire and censoring, during which risk factors can change. We carried out sensitivity analyses in which risk factors were scored according to the most recent questionnaire, thus treating equally women who reached a particular questionnaire follow-up and those who dropped out before reaching this time point. This analysis avoids differential scoring of risk factors between those who developed breast cancer and those who did not develop breast cancer but would be expected to result in loss of power. We also carried out sensitivity analyses excluding two studies, kConFab and BCFR, as these studies were included in a recent analysis of RRSO in women with a family history of breast cancer (Additional file
1: Table S14) [
19]. The results of these analyses were almost identical to those from the primary analyses. Reporting of natural menopause is also subject to recall bias and measurement error, and for about half of women reporting premenopausal status, the questionnaires did not cover the entire follow-up period.
A potential bias in the estimate of the RRSO association could arise if the timing of uptake of RRSO was related to the imminent transition to menopause. If there was a protective effect of early natural menopause on cancer risk for mutation carriers, this could result in an overestimation of the RRSO effect in the overall analysis. However, we found no evidence for a strong association between age at natural menopause and breast cancer risk (Additional file
1: Table S15), so any such bias is likely to be small.
Recent genome-wide association analyses have shown that age at natural menopause is partially determined by variants in DNA repair genes, including common coding variants in
BRCA1 [
20]. Some studies have suggested that natural menopause occurs at a younger age for
BRCA1 and
BRCA2 mutation carriers compared with women from the general population [
21‐
24] and that
BRCA1 mutation carriers have reduced ovarian reserve, and consequently a shortened reproductive lifespan, compared with non-carriers [
25].
BRCA1 mutation carriers have also been found to be more likely to have occult ovarian insufficiency [
21]. The effect of menopause on breast cancer risk might therefore differ in mutation carriers compared with the general population.
It is plausible that oophorectomy may reduce breast cancer risk in
BRCA2 mutation carriers but not in
BRCA1 mutation carriers. Breast cancer incidence peaks or plateaus at a younger age (early 40s) in
BRCA1 than
BRCA2 mutation carriers [
2], perhaps suggesting that much of the carcinogenic process in
BRCA1 mutation carriers takes place before women typically have RRSO and could influence disease incidence. In addition,
BRCA2-related tumours are mainly oestrogen receptor (ER)-positive, and
BRCA1-related tumours are mainly ER-negative. Previous analyses have suggested that in the general population, the association of early menopause with reduced breast cancer risk is larger for ER-positive disease [
26]. Future analyses stratified by molecular subtype of breast cancer should help delineate mechanisms underlying this difference.
Optimum timing of RRSO should take into account reported age-specific incidences of ovarian cancer among
BRCA1 and
BRCA2 mutation carriers [
2]. National Comprehensive Cancer Network (NCCN) guidelines for example recommend RRSO for
BRCA1 mutation carriers, typically between 35 and 40 years of age and upon completion of child-bearing; for
BRCA2 mutation carriers, these guidelines suggest that it is reasonable to delay RRSO until age 40–45 years [
27]. Cancer Australia clinical guidelines recommend RRSO in confirmed mutation carriers around age 40 years, while considering individual risk and circumstances [
28]. Adverse effects of RRSO at a young age, including reduced quality of life, cardiovascular disease, and osteoporosis, should also be taken into consideration. The results of our study indicate that caution should be exercised in conveying information on the risk of breast cancer after RRSO, and emphasise the need for continued surveillance for breast cancer following RRSO for women who do not opt for risk-reducing mastectomy,
The results of our analyses further suggest that continued follow-up of prospective cohorts of mutation carriers, with linkage to end-point and risk factor data, are required. These findings need replication in larger studies of
BRCA1 and
BRCA2 mutation carriers, particularly including more women in whom RRSO was carried out at a young age. More complete data on factors such as a family history of breast or ovarian cancer would be valuable. Prospective studies with long-term follow-up will also be important for analysing the association between HRT use and breast cancer risk following RRSO, as limited data have been available to date. In addition, RRSO has been reported to reduce mortality from breast cancer [
29‐
31], and there is some evidence that breast cancers arising after RRSO are more indolent than those arising without RRSO [
32]. Prospective studies of survival after RRSO would further inform counselling and management of
BRCA1 and
BRCA2 mutation carriers.
Acknowledgements
Study-specific acknowledgments:
We acknowledge the EMBRACE Centres; the Coordinating Centre: University of Cambridge and the Collaborating Centres; Guy’s and St. Thomas’ NHS Foundation Trust, London; Central Manchester University Hospitals NHS Foundation Trust, Manchester: Chapel Allerton Hospital, Leeds; The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, Sutton; Birmingham Women’s Hospital Healthcare NHS Trust, Birmingham; South Glasgow University Hospitals, Glasgow; Addenbrooke’s Hospital, Cambridge; St. Georges, London Royal Devon & Exeter Hospital, Exeter; Southampton University Hospitals NHS Trust, Southampton; Sheffield Children’s Hospital, Sheffield; Newcastle Upon Tyne Hospitals NHS Trust, Newcastle; Great Ormond Street Hospital for Children NHS Trust, London; Churchill Hospital, Oxford; Western General Hospital, Edinburgh; St Michael’s Hospital, Bristol; Belfast City Hospital, Belfast; Nottingham University Hospitals NHS Trust, Nottingham; University Hospital of Wales, Cardiff; Alder Hey Hospital, Liverpool; Kennedy Galton Centre, Harrow; Trinity College Dublin and St James’s Hospital, Dublin; University Hospitals of Leicester NHS Trust, Leicester; NHS Grampian & University of Aberdeen, Aberdeen; Glan Clwyd Hospital, Rhyl; and Singleton Hospital, Swansea. We also wish to thank Steve Ellis (data manager on the EMBRACE study 2010-2014).
BCFR thanks the members and participants in the Breast Cancer Family Registry from the New York, Northern California, Ontario, Philadelphia, Utah, and Australia sites for their contributions to the study.
CNIO thanks the staff for their assistance.
We acknowledge the GENEPSO Centers: the Coordinating Center: Institut Paoli-Calmettes, Marseille, France: Catherine Noguès, Lilian Laborde, Emmanuel Breysse who contributed by centralising, managing the data, and organising BRCA1 and BRCA2 mutation carriers follow-up and the Collaborating Centers which contributed to the mutation carriers recruitment and follow-up: Dominique Stoppa-Lyonnet, PhD, MD, Institut Curie, Paris; Marion Gauthier-Villars, MD, Institut Curie, Paris; Bruno Buecher, MD, Institut Curie, Paris; Olivier Caron, MD, Institut Gustave Roussy, Villejuif; Emmanuelle Fourme-Mouret, MD, Hôpital René Huguenin/Institut Curie, Saint Cloud; Jean-Pierre Fricker, MD, Centre Paul Strauss, Strasbourg; Christine Lasset, MD, Centre Léon Bérard, Lyon; Valérie Bonadona, PhD, MD, Centre Léon Bérard, Lyon; Pascaline Berthet, MD, Centre François Baclesse, Caen; Laurence Faivre, MD, Hôpital d’Enfants CHU and Centre Georges François Leclerc, Dijon; Elisabeth Luporsi, PhD, MD, CHR Metz-Thionville, Hôpital de Mercy, Metz, France; Véronique Mari, MD, Centre Antoine Lacassagne, Nice; Laurence Gladieff, MD, Institut Claudius Regaud, Toulouse; Paul Gesta, MD, Réseau Oncogénétique Poitou Charente, Niort; Hagay Sobol, PhD, MD, Institut Paoli-Calmettes, Marseille; François Eisinger, MD, Institut Paoli-Calmettes, Marseille; Catherine Noguès,MD, Institut Paoli-Calmettes, Marseille; Michel Longy, PhD, MD Institut Bergonié, Bordeaux; Catherine Dugast†, MD, Centre Eugène Marquis, Rennes;Chrystelle Colas, MD, GH Pitié Salpétrière, Paris; Isabelle Coupier, MD, CHU Arnaud de Villeneuve, Montpellier; Pascal Pujol, MD, CHU Arnaud de Villeneuve, Montpellier; Carole Corsini, MD, CHU Arnaud de Villeneuve, Montpellier; Alain Lortholary, MD, Centres Paul Papin, and Catherine de Sienne, Angers, Nantes; Philippe Vennin†,MD, Centre Oscar Lambret, Lille; Claude Adenis, MD, Centre Oscar Lambret, Lille; Tan Dat Nguyen, MD, Institut Jean Godinot, Reims; Capucine Delnatte, MD, Centre René Gauducheau, Nantes; Julie Tinat, MD, Centre Henri Becquerel, Rouen; Isabelle Tennevet, MD, Centre Henri Becquerel, Rouen; Jean-Marc Limacher, MD, Hôpital Civil, Strasbourg; Christine Maugard, PhD, Hôpital Civil, Strasbourg; Yves-Jean Bignon, MD, Centre Jean Perrin, Clermont-Ferrand; Liliane Demange†, MD, Polyclinique Courlancy, Reims; Clotilde Penet, MD, Polyclinique Courlancy, Reims; Hélène Dreyfus, MD, Clinique Sainte Catherine, Avignon; Odile Cohen-Haguenauer, MD, Hôpital Saint-Louis, Paris; Laurence Venat-Bouvet, MD, CHRU Dupuytren, Limoges; Dominique Leroux, MD, Couple-Enfant-CHU de Grenoble; Hélène Dreyfus, MD, Couple-Enfant-CHU de Grenoble; Hélène Zattara-Cannoni, MD, Hôpital de la Timone, Marseille; Sandra Fert-Ferrer, MD, Hôtel Dieu - Centre Hospitalier, Chambery; and Odile Bera, MD, CHU Fort de France, Fort de France. †Deceased.
HCSC acknowledge the staff for their technical assistance.
The Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON) consists of the following Collaborating Centers: Netherlands Cancer Institute (coordinating centre), Amsterdam, NL: F.B.L. Hogervorst; Erasmus Medical Center, Rotterdam, NL: J.M. Collée; Leiden University Medical Center, NL: C.J. van Asperen; Radboud University Nijmegen Medical Center, NL: A.R. Mensenkamp; University Medical Center Utrecht, NL: M.G.E.M. Ausems; Amsterdam Medical Center, NL: H.E.J. Meijers-Heijboer; VU University Medical Center, Amsterdam, NL: K. van Engelen; Maastricht University Medical Center, NL: M.J. Blok; University of Groningen, NL: J.C. Oosterwijk; The Netherlands Comprehensive Cancer Organisation (IKNL): J.Verloop; and the nationwide network and registry of histo- and cytopathology in The Netherlands (PALGA): E. van den Broek. HEBON thanks the study participants and the registration teams of IKNL and PALGA for part of the data collection.
INHERIT would like to thank the staff for the sample management and skilful assistance.
We thank Heather Thorne, Eveline Niedermayr and all the kConFab research nurses and staff, the heads and staff of the Family Cancer Clinics, and the many families who contribute to kConFab for their contributions to this resource.
Czech Republic, MMCI, Brno—for the data collection and management.
We wish to thank the Hungarian Breast and Ovarian Cancer Study Group members; the Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary; and the clinicians and patients for their contributions to this study.
Swedish scientists participating as SWE-BRCA collaborators from the Lund University and University Hospital and from Stockholm and Karolinska University Hospital.