Hormone replacement therapy after prophylactic risk-reducing salpingo-oophorectomy and breast cancer risk in BRCA1 and BRCA2 mutation carriers: A meta-analysis

https://doi.org/10.1016/j.critrevonc.2018.09.018Get rights and content

Highlights

  • The safety of hormone replacement therapy (HRT) in BRCA mutation carriers is still debated.

  • HRT after risk-reducing salpingo-oophorectomy (RRSO) should be weighed against the possible increased breast cancer risk.

  • This is the first meta-analysis available in literature performed to clarify this clinical issue.

  • This meta-analysis suggests that HRT after RRSO does not affect breast cancer risk in BRCA mutation carriers.

Abstract

Background

Hormone replacement therapy (HRT) has been tested in women with BRCA1 and BRCA2 mutations who underwent risk-reducing salpingo-oophorectomy (RRSO), but its effect on breast cancer (BC) risk has never been appraised using meta-analysis comparison. We performed the first meta-analysis aimed to clarify whether HRT after RRSO could negatively impact on BC risk in women carriers of BRCA1 and BRCA2 mutations.

Methods and material

Pubmed and Scopus databases were searched to retrieve articles written in the English language. Trials comparing RRSO with or without HRT were identified and only those trials with available BC events were included. BC risk was the main endpoint.

Results

Three trials with 1100 patients were included. There was not a significantly higher BC risk in BRCA1 and BRCA2 mutation carriers receiving HRT after RRSO (HR = 0.98; 95% CI 0.63–1.52). There was a slightly but not significantly, benefit in BC risk reduction in favor of estrogen alone HRT versus estrogen plus progesterone HRT formulation (OR = 0.53; 95% CI 0.25–1.15).

Conclusion

HRT use after RRSO in BRCA 1 and BRCA2 mutation carries does not affect BC risk. Comparison of the different HRT types suggests that estrogen alone should be related to lowest BC risk.

Introduction

Mutations in DNA repair pathways, including breast-cancer susceptibility gene 1 (BRCA1) and breast-cancer susceptibility gene 2 (BRCA2) mutation carries, predispose women to an elevated lifetime risk for ovarian cancer (OC) and breast cancer (BC) (National Comprehensive Cancer Network Guidelines, 2018). While the role of bilateral risk-reducing mastectomy is still controversial, risk-reducing salpingo-oophorectomy (RRSO) represents nowadays the main effective prophylactic OC risk measure that should be proposed to BRCA carries, especially once childbearing is complete (National Comprehensive Cancer Network Guidelines, 2018; Paluch-Shimon et al., 2016; De Felice et al., 2015). In fact, in this setting of patients, prophylactic RRSO is associated with an OC risk-reduction of approximately 80% (hazard ratio, HR 0.19, 95% confidence interval, CI = 0.13 – 0.27) and it seems also to reduce BC risk by approximately 50% (HR 0.53, 95% CI = 0.33 – 0.84) (Rebbeck et al., 1999; Marchetti et al., 2014a). Subsequent hormone replacement therapy (HRT), including estrogen and progesterone alone or in combined therapy, remains a major concern, especially concerning its potential influence on BC risk. In clinical practice, HRT choice after RSSO is mainly driven by physician and patient preference to manage acute symptoms of surgically-induced menopause (De Felice et al., 2017).

This meta-analysis aims to stress the real impact of HRT after RSSO on BC risk in order to define the better standard of care for the management of BRCA1 and BRCA2 mutation carriers after prophylactic RSSO.

Section snippets

Search strategy and selection criteria

The preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement was followed to perform this meta-analysis. It includes both prospective cohort trials and retrospective studies, written in English, without any restrictions on publication date. To be eligible, published and unpublished trials had to estimate BC incidence in BRCA1 and BRCA2 mutation carriers who underwent RRSO and received or not received HRT after prophylactic surgery. Systematic literature electronic

Results

A total of 3 studies were identified (Kotsopoulos et al., 2018; Rebbeck et al., 2005; Gabriel et al., 2009). The vast majority of articles were excluded due to different topic and format, such as review and case report/series. Of the 6 potentially eligible studies, 3 were excluded because of the absence of BC incidence data (n = 2) or overlapping data (n = 1). Overall, 3 studies representing 1100 patients were included in the meta-analysis. Details by study are presented in Table 1.

BC risk

Discussion

We demonstrated that HRT seems to be a safe therapeutic option in BRCA 1 and 2 mutation carriers undergoing RRSO, regardless of the study design (HR = 0.98; 95% CI 0.63–1.52). Data were also confirmed in the subgroup analysis including only prospective/observational studies. Further, it seems that those who receive E-alone have a lower, not significant trend for BC risk compared with those who receive estrogen plus progesterone (OR = 0.53; 95% CI 0.25–1.15).

A woman identified as a BRCA mutation

Conclusion

This meta-analysis suggests that there is no clear indication of choice on BC risk in prescribe or not prescribe HRT after prophylactic RRSO. Surely, further clinical investigation is needed.

Conflict of interest statement

The authors declare that they have no competing interests.

Funding sources

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Authors’ contributions

Conception and design: XXX.

Collection and assembly of data: XXX.

Data analysis and interpretation: XXX.

Manuscript writing: XXX.

Final approval of manuscript: All authors.

Acknowledgement

None.

Francesca De Felice was born in Rome in 1983. She graduated from the Faculty of Medicine of the University of Rome “Sapienza” in 2007. She obtained the license to practice medicine in Italy in 2008. She was specialized in Radiation Oncology at the University of Rome “Sapienza” in 2012. In 2013 she was a medical attendant at the Département de Radiothérapie, Institut de Cancérologie Gustave Roussy, Villejuif-Parigi and in 2014 she was a medical attendant at the Division of Clinical Oncology,

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    Francesca De Felice was born in Rome in 1983. She graduated from the Faculty of Medicine of the University of Rome “Sapienza” in 2007. She obtained the license to practice medicine in Italy in 2008. She was specialized in Radiation Oncology at the University of Rome “Sapienza” in 2012. In 2013 she was a medical attendant at the Département de Radiothérapie, Institut de Cancérologie Gustave Roussy, Villejuif-Parigi and in 2014 she was a medical attendant at the Division of Clinical Oncology, Guy’s and st. Thomas’ Hospital, King’s College, London, UK. From 2012 onwards she is a PhD student at the Department of Radiological Sciences, Oncology, and Pathology, University of Rome "Sapienza". She is author of several indexed papers, all in the field of clinical and experimental oncology.

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    Equal contribution.

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