Meta-analysis of risk reduction estimates associated with risk-reducing salpingo-oophorectomy in BRCA1 or BRCA2 mutation carriers
June, 2009
Commentary by Associate Professor Kelly-Anne Phillips
This edition of Clinical Update is a special joint issue between Clinical Update – Breast Cancer and Clinical Update – Ovarian Cancer.
The article
Rebbeck T, Kauff N, Domchek S. Meta-Analysis of Risk Reduction Estimates Associated With Risk-Reducing Salpingo-Oophorectomy in BRCA1 or BRCA2 Mutation Carriers. Journal of National Cancer Institute 2009;101(2):80–7.
The Reviewer
Kelly-Anne Phillips is an Associate Professor of Medicine at the University of Melbourne, the Cancer Council Victoria, Dr John Colebatch Clinical Research Fellow and a Consultant Medical Oncologist at the Peter MacCallum Cancer Centre.
Abbreviations
BRCA1 or BRCA2 (BRCA1/2), Confidence Interval (CI), Hormone Replacement Therapy (HRT), Risk-Reducing Salpingo-Oophorectomy (RRSO).
Summary
Study design
The aim of this fixed-effects meta-analysis was to summarise the magnitude of risk reduction of breast or ovarian cancer in women with BRCA1/2 mutations who have undergone risk-reducing salpingo-oophorectomy (RRSO) compared to those who have not.
A PubMed search for terms “oophorectomy” and “BRCA1” or “BRCA2”, was undertaken to identify reports of RRSO in BRCA1/2 mutations. The search identified 346 studies published between January 1999 and December 2007. Of these, ten studies presenting primary data that provided estimates of risk reduction due to RRSO were included.
Hazard ratios and/or odds ratios (as published in the original studies) were used to estimate the pooled relative risks and 95% CIs. When two or more studies had overlapping study samples, only one published report from each group was included. Separate meta-analyses were carried out in i) BRCA1 mutation carriers, ii) BRCA2 mutation carriers and iii) BRCA1 or BRCA2 mutation carriers (BRCA1/2).
Findings
Breast cancer results
Eight studies estimated the risk of breast cancer in BRCA1/2 mutation carriers who were treated with RRSO relative to BRCA1/2 carriers who did not. RRSO was associated with a statistically significant reduction of breast cancer in BRCA1, BRCA2 and BRCA1/2 mutation carriers:
- BRCA 1 carriers (data from four non-overlapping studies)
HR=0.47, 95% CI= 0.35 to 0.64 - BRCA 2 carriers (data from three non-overlapping studies)
HR=0.47, 95% CI=0.26 to 0.84 - BRCA 1/2 carriers (data from three non-overlapping studies, N=5703)
HR=0.49, 95% CI=0.37 to 0.65
Gynaecologic cancer results
Six studies estimated the risk of gynaecologic cancer in BRCA1/2 mutation carriers treated with RRSO relative to BRCA1/2 carriers who did not. RRSO was associated with statistically significant reduction in the risk of ovarian or fallopian tube cancer for BRCA 1/2 and BRCA 1 mutation carriers:
- BRCA1/2 carriers (data from three non-overlapping studies, N=2840)
HR=0.21, 95% CI=0.12 to 0.39 - BRCA 1 carriers (data from one study)
HR=0.15, 95% CI= 0.04 to 0.56
Data was insufficient to obtain separate estimates for ovarian or fallopian tube cancer risk reduction with RRSO in BRCA2 mutation carriers.
Conclusion
RRSO was strongly associated with reductions in the risk of breast, ovarian and fallopian tube cancers among women BRCA1/2 mutation carriers. The risk reduction estimates should provide guidance to women in planning cancer risk reduction strategies.
Commentary
What does this article add to existing clinical evidence in this area?
Women who carry a mutation in BRCA1 or BRCA2, are at high risk for the development of breast and serous gynaecologic cancer*. These women want to know how they can reduce their cancer risks. The major strategies available are risk-reducing surgery, including bilateral mastectomy and salpingo-oophorectomy (RRSO), and chemoprevention. Once childbearing is complete, these women are usually counselled to consider RRSO and they are strongly encouraged to do so once post-menopausal.
It has been known for some time, from the results of individual studies, that RRSO decreases the risk of breast cancer (in pre-menopausal mutation carriers) and serous gynaecologic cancer. The current meta-analysis adds to that evidence by providing more precise estimates of the risk reduction. It showed that RRSO reduced the risk of breast cancer in BRCA1 mutation carriers by an estimated 53% (hazard ratio = 0.47; 95% confidence intervals 0.35-0.64) and by a similar amount in BRCA2 mutation carriers (hazard ratio = 0.47; 95% confidence intervals 0.26-0.84). The risk of serous gynaecologic cancer was reduced by 79% (hazard ratio = 0.21; 95% confidence intervals 0.12-0.39) in mutation carriers, although there were insufficient data to separately estimate the risk reductions for gynaecologic cancer in BRCA1 versus BRCA2 mutation carriers.
How adequate was the methodology used in addressing the aim of this study?
The methodology used in this study was of high quality. There are no relevant randomised controlled trials, so this well-conducted meta-analysis relied on data from observational case-control and cohort studies. The investigators identified all relevant publications, excluded studies with overlapping study samples (a major problem with research in this area) and attempted to identify relevant unpublished data. They also evaluated, and reassuringly did not find, interstudy heterogeneity and they tested for publication bias.
The study’s limitations reflect the inherent limitations of the observational data used in the meta-analysis. Most of the studies were retrospective so the potential for survival bias is considerable, and in the few prospective studies, the follow-up time was short. There was not adequate data available to evaluate the optimal timing of RRSO, particularly the impact of RRSO on breast cancer risk in premenopausal versus post-menopausal women. There were also inadequate data available to estimate the benefit of RRSO on serous gynaecologic cancer risk for BRCA1 and BRCA2 mutation carriers separately. There were no data from Australian women included, nevertheless the study findings are likely to be generalisable to women who are BRCA1 or BRCA 2 mutation carriers seen in Family Cancer Clinics in this country.
What are the implications of this study for clinical practice in Australia?
These estimates of risk reduction after RRSO are the most precise currently available and should be used by clinicians when counselling BRCA1 and BRCA2 mutation carriers.
Although not specifically addressed in this meta-analysis, clinicians should be cautious in using these breast cancer risk reduction estimates in counselling post-menopausal women. The benefit of RRSO on breast cancer risk likely acts through hormonal mechanisms, and it is difficult to imagine what the biological basis for reduction in risk of breast cancer would be in a post-menopausal woman. Indeed, Eisen and colleagues 1 have shown no reduction in breast cancer risk in mutation carriers who underwent RRSO after age 50 (although RRSO is the most effective way to reduce the risk of serous gynaecological cancer in such women).
RRSO in pre-menopausal women has substantial potential morbidity which must be discussed in detail with women. This meta-analysis does not address the issue of the safety or otherwise of hormone replacement therapy (HRT) after RRSO. A previous study by these authors 2 suggested that short-term HRT may not affect breast cancer risk in carriers after RRSO, however survivor bias may have been a major issue in that study and it should be interpreted with due caution.
Even after RRSO women who carry mutations in BRCA1 or BRCA2 have substantial residual risk for breast cancer and need to undertake additional risk management strategies. Risk-reducing mastectomy remains the most effective way of reducing breast cancer risk and some women choose to have both types of risk-reducing surgery to most effectively minimise their risk of breast and serous gynaecologic cancer. Women who have had RRSO but retain breast tissue should undergo regular breast cancer screening. Data are urgently needed regarding the efficacy of chemoprevention with tamoxifen or (in post-menopausal women) raloxifene in mutation carriers especially after RRSO and currently an analysis of data from three existing cohort studies (from Australia, US and Europe) is being undertaken which will address this question.
The risk management of women with mutations in BRCA1 or BRCA2 is complex, multidisciplinary and needs to be tailored to account for the preferences of each individual woman. It is a dynamic process, changing over time for each woman depending on her circumstances (such as with childbearing, menopause etc) and the need to incorporate new evidence as it emerges. These women require regular follow-up, such as that provided in multidisciplinary risk management clinics associated with some Family Cancer Clinics, 3 or by individual specialists with expertise in the area.
* The term “serous gynaecologic cancer” has been used throughout this commentary rather than “ovarian cancer”. It has recently become clear that the majority of gynaecologic cancers occurring in BRCA1 and BRCA2 mutation carriers may originate in the fimbrial end of the fallopian tube rather than the ovary, although they often resemble, and are thus labelled, “ovarian cancer” at diagnosis.
References
1. Eisen A, Lubinski J, Klijn J, et al. Breast Cancer Risk Following Bilateral Oophorectomy in BRCA1 and BRCA2 Mutation Carriers: An International Case-Control Study. J Clin Oncol 2005;23:7491–6
2. Rebbeck T, Friebel T, Wagner T, et al. Effect of Short-Term Hormone Replacement Therapy on Breast Cancer Risk Reduction After Bilateral Prophylactic Oophorectomy in BRCA1 and BRCA2 Mutation Carriers: The PROSE Study Group. J Clin Oncol 2005;23:7804–10.
3. Antill Y, Shanahan M, Phillips KA. The integrated, multidisciplinary clinic: a new model for the ongoing management of women at high genetic risk for breast and ovarian cancer. Cancer Forum 2005;29(1):107–10.
Editor: Dr Anne Nelson, General Manager, National Breast and Ovarian Cancer Centre
Clinical Update – Breast Cancer Editorial Committee: Mr John Collins - Surgeon, Ms Jo Keyser - Specialist Breast Nurse, Dr Warwick Lee - Radiologist, A/Prof Liz Lobb – Senior Research Fellow, Dr Sue-Anne McLachlan - Medical Oncologist, Dr Sally Meade - Breast Surgeon, Dr Sue Pendlebury - Radiation Oncologist, A/Prof Martin Stockler - Medical Oncologist.
Clinical Update – Ovarian Cancer Editorial Committee: Prof Michael Friedlander – Medical Oncologist, Prof Neville Hacker – Gynaecological Oncologist, Ms Kim Hobbs – Social Worker, Dr Gillian Mitchell – Medical Oncologist, Dr Deborah Neesham – Gynaecological Oncologist, Ms Georgie Richter – Gynaecological Nurse.
Disclaimer
Clinical Update is produced by National Breast and Ovarian Cancer Centre (NBOCC) and is intended to provide health professionals with timely expert commentary on new research in breast and ovarian cancer. Commentaries included in Clinical Update do not replace recommendations included in NBOCC clinical practice guidelines.
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