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. 2022 May 31;11(11):3114. doi: 10.3390/jcm11113114

Endometrial Cancer and BRCA Mutations: A Systematic Review

Maria Luisa Gasparri 1,2, Serena Bellaminutti 1,3,4,*, Ammad Ahmad Farooqi 5, Ilaria Cuccu 6, Violante Di Donato 6, Andrea Papadia 1,2
Editor: Michael Eichbaum
PMCID: PMC9181458  PMID: 35683509

Abstract

This systematic review identifies, evaluates, and summarises the findings of all relevant individual studies on the prevalence of BRCA mutation (BRCAm) in endometrial cancer patients and the incidence of endometrial cancer in BRCAm women patients. Consequently, the benefits and limits of a prophylactic hysterectomy at the time of the risk-reducing salpingo-oophorectomy are analysed and discussed. A systematic literature search was performed in the databases of PubMed, Cochrane, and Web of Science until May 2022; 13 studies met the eligibility criteria. Overall, 1613 endometrial cancer patients from 11 cohorts were tested for BRCA1/2 mutation. BRCA1/2m were identified in 4.3% of women with endometrial cancer (70/1613). BRCA1m was the most represented (71.4%) pathogenic variant. Alongside, a total of 209 BRCAm carriers from 14 studies were diagnosed with endometrial cancer. Only 5 out of 14 studies found a correlation between BRCAm and an increased risk of endometrial cancer. Nevertheless, two studies found a statistical difference only for BRCA1m women. The present systematic review does not provide strong evidence in favour of performing routine hysterectomy at the time of risk-reducing salpingo-oophorectomy; however, it provides epidemiological data that can be useful for counselling patients in order to offer a tailored approach.

Keywords: endometrial cancer, BRCA1, BRCA2, risk-reducing salpingo-oophorectomy, hysterectomy

1. Introduction

Breast cancer gene 1, located on the long arm (q) of chromosome 17, and the BRCA 2 gene, located on the long arm of chromosome 13, are both autosomal dominant tumour suppressor genes involved in DNA damage repair before cell replication. The lifetime risk of breast and ovarian cancer increases for those carrying a pathogenic variant of breast cancer gene 1 (BRCA1) or breast cancer gene 2 (BRCA2) by 40–80% and 11–40%, respectively [1]. In order to reduce the lifetime risk of breast, ovarian, and fallopian tube cancer, NCCN guidelines (National Comprehensive Cancer Network) currently consider a risk-reducing mastectomy (RRM) and recommend salpingo-oophorectomy (RRSO) in women with BRCA mutations (pathogenic variants) (BRCAm) [2]. RRSO is associated with a 42% and 94% reduced risk of developing breast and ovarian cancer in BRCAm carriers, respectively [3], and a 60% reduced all-cause mortality [4].

BRCAm carriers are exposed to a higher risk of other less frequent cancers such as fallopian tube cancer and primary peritoneal cancer [5], pancreatic cancer [6], prostate, and gastric cancer [7].

The risk of uterine cancer in BRCAm women and, consequently, its role as part of the BRCA mutated syndrome is still debated. The analogies between uterine, mainly serous carcinoma and serous ovarian carcinoma, have led to the investigation of potential common pathogenetic features, as well as hereditary causes. Positive family history is noted in approximately 10% of cases of endometrial cancer, suggesting an inherited predisposition, even if the precise genes pattern involved are largely unknown [8].

Uterine serous carcinoma, representing less than 10% of all endometrial cancers, is an aggressive histologic subtype with a poor prognosis. It accounts for about 25% of the entire endometrial cancer mortality, with an overall survival rate at 5 years of 18–27% due to frequent advanced disease at diagnosis and a high rate of distant recurrences even in patients with early-stage disease [9,10]

Some authors [11,12,13] confirmed a higher risk of endometrial cancer in BRCAm women, especially for uterine serous cancer in BRCA1m, while others [14,15] did not support this correlation.

Hence, while RRSO is a well-established procedure for women with BRCAm at 35–40 years of age for BRCA1m and at 40–45 years for BRCA2m [2], prophylactic hysterectomy at the time of RRSO is still a matter of debate [16]. If women carrying BRCA1m are confirmed to be at an increased risk for serous or serous-like endometrial cancer, this should be considered when counselling a patient with regards to the risks and benefits of the addition of hysterectomy at the time of RRSO.

This systematic review aims to assess the risk of endometrial cancer and examine the benefits and limits of a prophylactic hysterectomy in BRCAm women, analysing both the prevalence of BRCAm in endometrial cancer patients and the incidence of endometrial cancer found in BRCAm patients undergoing RRSO with hysterectomy.

2. Material and Methods

2.1. Information Sources

A systematic literature search was performed in the databases of PubMed, Cochrane, and Web of Science until May 2022. No beginning date limit or language restrictions were used. The review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [17].

2.2. Search Strategy

The search terms consisted of “BRCA” and “endometrial cancer” or “uterine cancer”. Reference lists of identified systematic reviews and included studies were manually screened for any other eligible studies.

2.3. Study Selection

Titles and abstracts were screened. Articles reporting the incidence of endometrial cancer in BRCAm women or the prevalence of BRCAm in patients affected by endometrial cancer were obtained in full for further evaluation. Studies were excluded if they were case reports, editorials, reviews, or short communications because they did not provide sufficient information to assess the methodological quality.

Title and abstract screening, as well as full-text screening, were performed independently and simultaneously by two authors (SB and MLG) based on pre-defined criteria. All dissents were resolved by consensus.

2.4. Data Extraction

For each eligible article, information was collected concerning the first author, year of publication, country of origin, study period, design of the study, the total number of patients, mean or median age, genotyping testing method (including different BRCA deletions and other genes investigated), number of endometrial cancers and uterine serous carcinoma, FIGO stage, previous Tamoxifen use, history of breast cancer, and type of BRCAm. Median follow-up was expressed in years or women-years. Standard Incidence Ratios (SIR) were reported for assessing endometrial cancer risk in BRCAm women when available.

2.5. Quality Assessment

The evaluation of the risk of bias in estimates of the comparative effectiveness (harm or benefit) of interventions from the included studies was performed with the “Risk Of Bias In Non-randomized Studies-of Interventions” (ROBINS-I) tool [18].

3. Results

3.1. Literature Search

Overall, a total of 291 records were identified. After removing 77 duplicates, 214 manuscripts were screened, and 165 were excluded based on the abstract. A full text was obtained for 48 of 49 records. At the end of the screening process, 24 full-text articles were included in the systematic review. All papers were in English.

Titles/abstracts were screened according to the inclusion and exclusion criteria. Most manuscripts were excluded during the screening process due to differing study objectives (n = 13), publication types such as editorial or review (n = 8), and incomplete data (n = 2).

Details about the literature search results are reported in Figure 1. A total of 11/25 included studies that assessed the prevalence of BRCAm in patients affected by endometrial cancer [8,19,20,21,22,23,24,25,26,27,28], and 14/25 included studies that evaluated the incidence of endometrial cancer in BRCAm [11,12,13,14,15,29,30,31,32,33,34,35,36,37].

Figure 1.

Figure 1

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PRISMA flow chart of study identification.

3.2. Patients Characteristics of the Included Studies

Overall, the total number of patients analysed in this systematic review was 37,286.

The number of patients ranged between 20 and 628 in the included studies concerning the incidence of BRCAm in patients with endometrial cancer and between 315 and 14,621 in the included studies concerning the incidence of endometrial cancer in BRCAm patients.

The mean/median age of patients ranged between 20 and 72 years; most of the included patients had a FIGO stage I, and median follow-up ranged between 1.5–9 years and 1.779–59.199 women-years.

3.3. Methodological Aspects of the Included Studies

A total of 13 observational retrospective cohort studies, 3 retrospective case-control studies, 7 observational prospective cohort studies, 1 prospective case-control study, and 1 longitudinal cohort study were included in this systematic review. Of these, 10 were multicenter-based studies. Additionally, four studies included only Jewish women, and one study included only patients with hereditary endometrial cancer (Lynch syndrome and hereditary breast-ovarian cancer). The main characteristics of eligible studies on the prevalence of BRCAm in patients with endometrial cancer and on the incidence of endometrial cancer in BRCAm patients are shown in Table 1 and Table 2, respectively. The risk of bias assessment is reported in Table 3.

Table 1.

Characteristics of the included studies on the prevalence of BRCAm in patients with endometrial cancer.

Authors Publication Year Country Time Period Study Type Study Group
Niederacher et al. [19] 1998 Germany 1980–1994 Retrospective case-control EC
Goshen et al. [20] 2000 Canada 1996–2006 Retrospective multicenter cohort USC
Levine et al. [21] 2001 Israel 1986–1998 Retrospective cohort Jewish patients, EC
Lavie et al. [22] 2004 Israel 1999–2002 Retrospective multicenter cohort USC
Biron-Shental et al. [23] 2006 Israel 1997–2003 Retrospective cohort Jewish patients, USC
Barak et al. [8] 2010 Israel 1982–2008 Retrospective and prospective cohort Jewish patients, EC
Bruchim et al. [24] 2010 Israel 1997–2007 Retrospective cohort Jewish patients,
USC
Pennington et al. [25] 2013 USA NA Retrospective cohort USC
Mahdi et al. [26] 2015 USA NA Retrospective cohort USC or ovarian serous carcinoma
Kadan et al. [27] 2018 Israel, Arabia 1993–2014 Retrospective multicenter cohort USC
Vietri et al. [28] 2021 Italy NA NA Hereditary EC (LS and HBOC)
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BRCAm: breast cancer gene mutation, EC: endometrial cancer, USC: uterine serous carcinoma, LS: Lynch Syndrome, HBOC: Hereditary Breast and Ovarian Cancer syndrome, NA: not available.

Table 2.

Characteristics of the included studies on the incidence of endometrial cancer in BRCAm patients.

Authors Publication Year Country Time Period Study Type Study Group
Thompson et al. [29] 2002 Western Europe and North America 1960–2002 Retrospective multicenter cohort BRCAm
Beiner et al. [30] 2007 North America, Europe and Israel NA Prospective multicenter cohort BRCAm
Reitsma et al. [14] 2012 The Netherlands 1996–2012 Prospective cohort BRCAm, RRSO
Segev et al. [31] 2013 Canada, Italy, USA, Austria, Poland, Norway NA Prospective multicenter case-control BRCAm
Casey et al. [13] 2015 USA 1959–2013 Retrospective cohort BRCAm with invasive gynecologic and/or peritoneal cancers
Segev et al. [32] 2015 North America, Europe and Israel NA Retrospective multicenter case-control BRCAm
Shu et al. [12] 2016 USA, UK 1995–2011 Prospective multicenter cohort BRCAm, RRSO
Zakhour et al. [33] 2016 USA 2000–2014 Prospective cohort BRCAm, RRSO
Bogani et al. [34] 2017 Italy 2014–2017 Prospective cohort BRCAm or significant family history of breast/ovarian cancer, RRSO ± hysterectomy
Lee et al. [35] 2017 Australia,
New Zealand		 NA Prospective multicenter cohort BRCAm
Minig et al. [36] 2018 Spain 2010–2017 Retrospective
multicenter cohort		 BRCAm, RRSO
Saule et al. [15] 2018 France 1996–2016 Prospective cohort BRCAm, RRSO
Laitman et al. [11] 2019 Israel 1998–2016 Retrospective case-control BRCAm
Kitson et al. [37] 2020 UK 1991–2017 Retrospective cohort BRCAm
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BRCAm: breast cancer gene 1/2 mutation, RRSO: risk-reducing salpingo-oophorectomy, NA: not available.

Table 3.

Quality assessment of individual study.

Author Bias due to Confounding Bias in Selection of Partecipants Bias Due to Missing Data Bias in Classification of
Interventions		 Bias in Measurement of Outcomes Bias in Selection of the Results Overall
Niederacher et al., 1998 [19] Moderate Moderate Moderate Moderate Moderate Moderate Moderate
Goshen et al., 2000 [20] Serious Serious Serious Moderate Moderate Serious Serious
Levine et al., 2001 [21] Moderate Serious Moderate Moderate Moderate Low Serious
Thompson et al., 2002 [29] Moderate Serious Serious Moderate Moderate Moderate Serious
Lavie et al., 2004 [22] Moderate Serious Moderate Moderate Low Low Serious
Biron-Shental et al., 2006 [23] Serious Moderate Moderate Moderate Moderate Low Serious
Beiner et al., 2007 [30] Low Low Low Moderate Moderate Moderate Moderate
Bruchim et al., 2010 [24] Moderate Low Moderate Moderate Moderate Serious Serious
Barak et al., 2010 [8] Moderate Serious Serious Moderate Low Moderate Serious
Reitsma et al., 2012 [14] Low Moderate Low Low Moderate Moderate Moderate
Pennington et al., 2013 [25] Moderate Serious Serious Low Low Low Serious
Segev et al., 2013 [31] Low Low Low Moderate Moderate Moderate Moderate
Casey et al., 2015 [13] Serious Moderate Moderate Moderate Moderate Moderate Serious
Mahdi et al., 2015 [26] Moderate Serious Serious Moderate Low Moderate Serious
Segev et al., 2015 [32] Moderate Serious Moderate Moderate Serious Moderate Serious
Zakhour et al., 2016 [33] Moderate Low Moderate Moderate Moderate Moderate Moderate
Shu et al., 2016 [12] Low Moderate Low Moderate Serious Moderate Serious
Lee et al., 2017 [35] Moderate Low Low Moderate Serious Moderate Serious
Bogani et al., 2017 [34] Low Low Low Moderate Moderate Moderate Moderate
Mining et al., 2018 [36] Moderate Serious Serious Moderate Serious Serious Serious
Saule et al., 2018 [15] Low Moderate Moderate Moderate Moderate Moderate Moderate
Laitman et al., 2018 [11] Moderate Serious Serious Moderate Serious Serious Serious
Kadan et al., 2018 [27] Moderate Moderate Moderate Low Moderate Low Moderate
Kitson et al., 2020 [37] Moderate Moderate Moderate Low Moderate Moderate Moderate
Vietri et al., 2021 [28] Low Low Low Low Low Moderate Moderate
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3.4. Main Findings

A total of 1613 endometrial cancer patients from 11 studies were tested for BRCA1/2 pathological variants [8,19,20,21,22,23,24,25,26,27,28]. Uterine serous carcinoma was diagnosed in 1129 patients. Of note, the diagnosis of uterine serous carcinoma was one of the inclusion criteria for 972 patients out of 1129. The notion of previous breast cancer was reported in 6 out of 10 studies; in particular, 47 out of 344 (13.7%) women with endometrial cancer had a personal history of breast malignancy. Only one paper reported the use of hormone therapy before endometrial cancer diagnosis [23]. BRCA1/2m were identified in 70 women with endometrial cancer out of 1613 (4.3%). Notably, BRCA1m represented 71.4% of BRCA pathological variants found in endometrial cancer patients (50/70).

A significant difference in the increased risk of endometrial cancer among BRCAm patients was found by Beiner [30] [SIR = 5.3 (p = 0.0011)], Saule [15] [SIR = 32.2 (95% CI, 11.5–116.4, p < 0.001)], and Thompson [29] [SIR = 2.65 (1.69–4.16, p < 0.001)]. However, two other studies confirmed this difference only for BRCA1m women [11,31]. Notably, Laitman et al. registered 14 cases of endometrial cancer among 2627 Jewish patients included in their study, assessing an increased overall rate of uterine cancer of almost 4-fold [SIR = 3.98 (95% CI, 2.174–6.673)] [11]. In a sub-analysis, this risk was significantly augmented for BRCA1 patients [SIR = 5.236 (95% CI, 2.659–9.382, p < 0.001)] but not for BRCA2 patients [SIR = 2.339 (95% CI, 0.743–5.642, p = 0.124)] [11]. Segev et al. confirmed the same results [BRCA1 = SIR 1.91 (95% CI, 1.06–3.19, p = 0.03), BRCA2 = SIR 1.75 (95% CI, 0.55–4.23, p = 0.2)] [31]. In contrast, Kitson et al. found no significant increased risk for endometrial cancer in the 2609 included in their study for both BRCA1/2m [SIR = 1.70 (95% CI, 0.74–3.33)] [37] as well as Goshen et al., even if they did not consider 2 of the 3 BRCA1 mutations examined in many other studies [20].

BRCA1/2 testing was generally performed by traditional Sanger sequencing. The next-generation sequencing (NGS) technique was otherwise adopted in 3 studies out of 24 [11,19,25].

The main findings of the included studies on the prevalence of BRCAm in patients with endometrial cancer are reported in Table 4.

Table 4.

Main findings of the included studies on the prevalence of BRCAm in patients with endometrial cancer.

Author Total Patients Age, yr [Mean ± SD/Median (Range)] † Genotyping Total EC EC Histopathology (n. of Patients; %) USC EC with Previous Breast Cancer EC in Patients Using Tamoxifen Positive Family History of Breast Cancer Number of BRCA Mutated Patients EC with BRCAm (%)
Type BRCA Mutation Other Genes Tested FIGO Stage Grade BRCA 1 BRCA 2 Tot
Barak et al. [8] 289 63 ± 12 Traditional Sanger BRCA1 (185delAG, 5383InsC, Tyr978X)
BRCA2 (6174delT,
8765delAG)		 - 289 In situ (2, 0.7%)
I (234, 81%)
II (24, 8%)
III (25, 9%)
IV (4, 1%)		 In situ (2, 0.7%)
I (168, 58%)
II (50, 17%)
III (69, 24%)		 34 NA NA NA 4 1 5 1.7
Biron-Shental et al. [23] 22 72 (56–79) Traditional Sanger BRCA1 (185delAG, 5382insC)
BRCA2 (6174delT)		 - 22 I-II (9, 41%)
III-IV (13; 59%)		 NA 22 7 NA 7 3 3 6 22.7
Bruchim et al. [24] 31 72 (47–87) Traditional Sanger BRCA1
(185delAG, 5382insC)
BRCA2 (617delT)		 - 31 I-II (16, 52%)
III-IV (15; 48%)		 NA 31 7 6 5 4 4 8 25.8
Goshen et al. [20] 56 NA Traditional Sanger BRCA1 (185del AG, 5382insC,
dup(ex13))
BRCA2 (6174delT)		 - 56 I (27; 48%)
II (6, 11%)
III (13, 23%)
IV (6, 11%)
NA (4, 7%)		 NA 56 6 NA 6 0 0 0 0
Kadan et al. [27] 64 66 ± 9.7 ** Traditional Sanger BRCA1 (185delAG, 5382insC)
BRCA2 (6174delT)		 - 64 I (32; 50%)
II (3, 5%)
III (12, 19%)
IV (16, 25%)
NA (1, 1%)		 NA 64 18 NA NA 9 5 14 21.9
Lavie et al. [22] 20 72
(56–91)		 Traditional Sanger BRCA1 (185delAG, 5382insC)
BRCA2 (6174delT)		 - 20 I (NA, 30%)
II (NA, 15%)
III (NA; 40%)
IV (NA, 15%)		 NA 20 7 NA 7 4 0 4 20
Levine et al. [21] 199 66 ± 11 Traditional Sanger BRCA1 (185delAG, 5382insC)
BRCA2 (6174delT)		 - 199 I (144; 72%)
II (17, 9%)
III (22, 11%)
IV (14, 7%)
NA (2, 1%)		 1 (73, 37%)
2 (70, 35%)
3 (53, 27%)
NA (3, 1%)		 17 NA NA NA 1 2 3 1.5
Mahdi et al. [26] 241/628 * 68 (44–94) NGS NA ABL1,
AKT1, ALK, APC, ATM, BRAF, CDH1, CSF1R,
CTNNB1, EGFR, ERBB2, ERBB4, FBXW7, FGFR1, FGFR2, FLT3,
GNA11, GNAS, GNAQ, HNF1A, HRAS, IDH1, JAK2, JAK3, KDR
(VEGFR2), KIT, KRAS, MET, MLH1, MPL, NOTCH1, NPM1, NRAS,
PDGFR, PIK3CA, PTEN, PTPN11, RB1, RET, SMAD4, SMARCB1,SMO, STK11, TP53, VHL		 628 NA NA 628 NA NA NA 3 2 5 0.8
Niederacher et al. [19] 113 NA Traditional Sanger BRCA1-D17S855 TP53- AFM051, TCRD, ESR, D11S35, D16S511 113 I (69; 61%)
II (18, 16%)
III (15, 13%)
IV (11, 10%)		 1 (52, 46%)
2 (30, 27%)
3 (21, 19%)
NA (10, 8%)		 106 NA NA NA 13 0 13 11.5
Pennington et al. [25] 151 68 NGS NA APC
ATM
BAP1
BARD1
BMPR1A
BRIP1
BUB1B
CDH1
CDK4
CDKN2A
CHEK2
KIT
MLH1
MRE11A
MSH2 (.EPCAM)
MSH6
MUTYH
NBN
PALB2
PMS2
TEN (.KILLIN)
RAD50
RAD51C
RET
SMAD4
STK11
TP53 VHL		 151 I (61; 40%)
II (16, 11%)
III (34, 23%)
IV (38, 25%)
NA (2, 1%)		 NA 151 2 NA 22 3 0 3 2
Vietri et al. [28] 40 35 (20–54) *** NGS MLH1, MSH2 40 NA NA NA NA NA 6 3 9 22.5
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USC: uterine serous carcinoma; BRCAm breast cancer gene mutated patient, EC endometrial cancer, NA not available. † Data are expressed in mean or median as reported in each study. * Mahdi et al. included 5936 patients, of whom 5335 were affected by an ovarian serous carcinoma and 628 were affected by endometrial cancer, of which 241 were tested with NGS. ** Mean age of BRCA mutation carrier group. *** Mean age in EC patients.

A total of 209 BRCAm carriers from 14 studies diagnosed with BRCA1/2m were diagnosed with endometrial cancer [11,12,13,14,15,29,30,31,32,33,34,35,36,37]. A total of 9 studies out of 14 calculated the standardised incidence ratio (SIR) for the risk of uterine cancer in BRCAm women, dividing the total number of observed cases by the total number of expected cases [11,12,14,15,29,30,31,35,37]. Five authors found a statistical difference in the risk of endometrial cancer for BRCAm patients [11,15,29,30,31]. Nevertheless, two studies found a statistical difference only for BRCA1m women [11,31]. One study demonstrated an increased risk of developing aggressive and serous-like endometrial cancer, especially in BRCA1 mutation carriers [11]. The main findings of the included studies on the incidence of endometrial cancer in BRCAm patients are reported in Table 5.

Table 5.

Main findings of the included studies on the incidence of endometrial cancer in BRCAm patients.

Author Total Patients Age, yr [Mean ± SD/Median (Range)] † Total EC EC Histopathology (n. of Patients; %) EC with Previous Breast Cancer EC in Patients Using Tamoxifen/Tot Patients Using Tamoxifen History of Breast Cancer Number of BRCA Mutated Patients EC with BRCAm Follow-Up [Mean/Median (Range), yr] or Women-Years (Median) EC Risk in BRCAm (SIR [95% CI, p])
FIGO Stage Grade BRCA 1 (BRCA1mEC/EC) BRCA 2 (BRCA2mEC/EC) Tot
Beiner et al. [30] 857 54 (45–70) 6 I (4, 66%)
II (1, 17%)
NA (1, 17%)		 1 (4, 66%)
2 (1 (17%)
3 (1, 17%)		 5 0 4/226 551 619 (4/6) 236 (2/6) 857 6 3.3 (0.01–9.6) 5.3 (p = 0.0011)
Casey et al. [13] 101 NA 8 NA 1 (2, 25%)
2 (2, 25%)
3 (3, 38%)
NA (1, 12%)		 6 3 2/8 6/8 89 (7/8) 12 (1/8) 101 8 NA NA
Kitson et al. [37] 2609 20 (20–32) 14 I (5, 36%)
II (1, 7%)
III (2, 14%)
NA (6, 43%)		 NA NA NA NA NA 1350 (7/14) 1259 (7/14) 2609 14 59,199 (23.8) women years 1.70 (0.74–3.33)
Laitman et al. [11] 2627 43 ± 7.7 14 NA NA 7 5 2/178 1240 1746 (10/14) 1367 (4/14) 2627 14 32.744 † women years
20.468 †† women years		 USC *** 14.29 (4.64–33.34, p < 0.001)
Sarcoma *** 37.74 (10.28–96.62, p < 0.001)
BRCA1 5.236 (2.659–9.382, p < 0.001)
BRCA2 2.339 (0.743–5.642, p = 0.124)
Lee et al. [35] 828 43 (34–52) 5 I (3, 60%)
II (2, 40%)		 1 (2, 40%)
2 (1, 20%)
3 (2, 40%)		 3 0 3/160 419 438 (3/5) 390 (2/5) 828 5 9.0 2.45 (95% CI: 0.80–5.72, p = 0.11)
BRCA1 2.87 (95% CI 0.59–8.43, p = 0.18)
BRCA2 2.01 (95% CI 0.24–7.30, p = 0.52)
Minig et al. [36] 359 49 ± 9.0 1 I (1, 100%) NA 1 1 NA 225 223 (NA) 141 (NA) 359 1 2.4 (0.3–7.7) NA
Reitsman et al. [14] 315 43 (30–71) 2 I (2, 100%) NA 1 0 0/19 118 201 (1/2) 114 (1/2) 315 2 6 (0– 27) 2.13 (0.24–7.69; p = 0.27)
Saule et al. [15] 369 BRCA1 47 ± 1.3
BRCA 2 53 ± 6.8		 2 IV (2, 100%) NA 0 2 0/5 0 238 (2/2) 131 (0/2) 369 2 1779 woman-years 32.2 (11.5–116.4, p < 0.001)
Segev et al. [31] 4456 43 17 NA (17, 100%) 1 (5, 29%)
2 (1, 6%)
NA (11, 65%)		 10 1 8/697 1837 3536 (13/17) 920 (4/17) 4456 17 5.7 1.87, (1.13–2.94, p = 0.01)
BRCA1 1.91 (1.06–3.19, p = 0.03)
BRCA2 1.75 (0.55–4.23, p = 0.2)
Shu et al. [12] 1083 46 (41–53) 8 I (5, 63%)
II (2, 25%)
III (1, 12%)		 NA 4 5 3/273 727 630 (5/8) 456 (3/8) 1083 8 5.1 (3.0–8.4) 1.9 (0.8–3.7, p = 0.09)
Thompson et al. [29] 7106 ** NA 47 NA NA NA NA NA 1928 2245 (11/11) 0 2245 11 NA 2.65 (1.69–4.16, p < 0.001)
Segev et al. [32] 14,621 52 (23–67) **** 83 NA NA 46 NA 17/76 394/46 951 (62/83) 76 (21/83) 1027 83 NA NA
Zakhour et al. [33] 257 46 (28–79) 1 II (1, 100%) 3 (1, 100%) NA 0 NA 110 153 103 (1/1) 257 1 NA NA
Bogani et al. [34] 85 47 ± 8.2 1 NA NA 1 0 NA 60 32 (1/1) 25 57 1 1.5 ± 0.4 NA
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BRCAm breast cancer gene mutated patient, EC endometrial cancer, USC uterine serous carcinoma, NA not available, BRCA1mEC breast cancer gene. One mutated patient with EC, BRCA2mEC breast cancer gene 2 mutated patient with EC. † women-years of follow up in BRCAm group. †† women-years of follow up in non-BRCA group. ** Thompson et al. included 11,847 patients, of whom 7106 were women. *** Risk in carriers group. **** Median age for cases.

4. Discussion

In this systematic review, we summarised all the studies that tested endometrial cancer patients for BRCAm and the incidence of endometrial cancer in BRCAm women. Controversial data have been found in the literature, and the correlation between BRCA mutations and uterine cancer is still debated. If a clear correlation were to be demonstrated, hysterectomy should systematically be added to bilateral salpingo-oophorectomy as a risk-reducing surgery. Shu et al. investigated the role of concomitant hysterectomy during RRSO in BRCAm patients to reduce the risk of uterine cancer and found that even though the overall risk for uterine cancer after RRSO was not increased, the risk for uterine serous cancer was increased in BRCA1m patients [12].

The Royal Australian and New Zealand College of Obstetricians and Gynaecologists classifies laparoscopic surgeries in 6 levels of complexity: 1. Diagnostic laparoscopy, 2. Salpingo-oophorectomy; 3. Laparoscopic-assisted vaginal hysterectomy; 4. Excision of ASRM stage 3 endometriosis and laparoscopic hysterectomy; 5. Laparoscopic myomectomy, excision of stage IV endometriosis; 6. excision of stage IV endometriosis necessitating bowel or urological resection, retroperitoneal lymphadenectomy, sacrocolpopexis [38]. Hence, adding hysterectomy to the risk-reducing procedures increases the degree of complexity of the procedure. This may reflect on various aspects. Firstly, a procedure that can nowadays be performed by virtually every gynaecologist may require a gynaecologist with more advanced surgical skills. Secondly, the addition of the hysterectomy to the bilateral salpingo-oophorectomy will increase operating room (OR) time and estimated blood loss, leading to an increase in direct costs linked to the length of hospital stay, medications required, OR time, etc. and indirect costs due to a loss of workdays related to the longer recovery period. Also, since the complication rate is usually related to the complexity of the procedure, a larger number of complications has to be expected. This aspect is of particular relevance when evaluating the risk-benefit balance of a prophylactic measure which is offered to women who are affected with a medical condition (BRCAm) but not with an illness. Usually, in experienced hands, the risk of iatrogenic lesions during a laparoscopic hysterectomy without additional complexity (e.g., endometriosis, fibroids, and adhesions) is very small. Furthermore, the long-term consequences of the hysterectomy need to be put into the equation, as well. A history of hysterectomy is associated with a slight increase in the risk of developing pelvic organ prolapse. In nulliparous women, who lack the most important risk factor for pelvic organ prolapse, namely having given vaginal birth, a history of hysterectomy increases the risk of developing pelvic organ prolapse by 60%. However, this increase in risk has a small clinical impact as it increases the risk from 12.7 to 20.5 per 100,000 risk years [39].

Another open question is how to process the endometrial lining of the uterus in case of risk-reducing surgery. Occult high grade serous ovarian cancer is identified in 6–17% of BRCAm carriers undergoing a risk-reducing salpingo-oophorectomy [40,41]. Nowadays, the pathological analysis of the tubes removed for risk-reducing surgery in BRCAm carriers is substantially different and more thorough as compared to when the tubes are removed secondary to another indication. In the first case, multiple sections of the ovaries and tubes should be performed to look for occult carcinoma using a specific protocol for patients at high risk of occult malignancy [40,41,42,43]. This labour-intense analysis increases the detection rate of occult ovarian or fallopian tube cancer in BRCAm women seven-fold [41]. Serous endometrial intraepithelial carcinoma (SEIC), a malignant lesion associated with p53 mutation in a background of atrophic endometrium, has been postulated to be a precursor of uterine serous carcinoma [44,45]. SEIC has been identified in 40–89% of patients diagnosed with serous endometrial cancer [46,47,48,49]. Furthermore, concordant genetic mutations have been demonstrated in both components of SEIC and serous endometrial cancer [50]. SEIC lesions may be focal and small, making the histological diagnosis and an extensive sampling of the uterus necessary to identify an invasive component [51]. This is of utmost importance since an extrauterine spread of disease in the absence of myometrial invasion has been described [51,52,53,54].

The advantages of a concomitant hysterectomy at the time of RRSO should also be taken into account for the management of menopause symptoms after surgery in BRCAm patients. Premature menopause in young women is one of the most important secondary effects of RRSO, leading to an increased risk of cardiovascular disease, bone mineral loss, and cognitive dysfunctions [55]. Many authors in the last decade have investigated the role and risks of hormone replacement therapy (HRT) in BRCAm women, and a distinction should be made between estrogen-only and combined estrogen and progestin HRT [56]. For women under 45 years of age who underwent RRSO, Kostopoulos et al. recorded a statistically significant protective effect on breast cancer of an estrogen-only HRT with an 18% risk reduction per year of treatment (95% CI, 0.69–0.97) [57]. On the contrary, a combined estrogen-progestin HRT confers a non-significative increase in breast cancer risk of 14% (95% CI 0.90–1.46) [57]. A striking pro-oncogenic role on mammary epithelial cells has been demonstrated for progesterone in a murine model [58].

In BRCA2m cancer-free women who do not want to undergo a prophylactic mastectomy, a chemoprevention strategy with Tamoxifen can be offered to reduce the incidence of breast cancer by 62% [59]. However, Tamoxifen is associated with a 2–3 fold increase in uterine malignancies [60,61,62]; therefore, hysterectomy at the time of the RRSO may be an option to avoid this risk. This option can also be considered for women with a BRCA1/2 mutation who underwent a mastectomy for breast cancer and who are taking Tamoxifen as adjuvant therapy.

5. Conclusions

This systemic review aims to provide clinicians with all recent data necessary for clear and exhaustive counselling about the benefits and risks of hysterectomy at the time of RRSO for BRCAm patients. As of now, data supporting the need to perform a hysterectomy at the time of RRSO are inconclusive, so a routine removal of the uterus should not be performed. However, this information should be discussed with the patient in order to offer a tailored approach.

Even if, to date, no guidelines recommend performing a hysterectomy as a risk-reducing procedure for HBOC syndrome, potential complications and costs of the surgical procedure (bleeding, infection, organ lesions, and vaginal cuff dehiscence) should be individually balanced with the potential increased risk of uterine cancer in this population and the reduced risks associated with an estrogen-only HRT.

Author Contributions

Conceived the idea: M.L.G.; Designed the manuscript and the analysis: M.L.G.; Reviewed the literature: S.B. and M.L.G.; Drafted the paper: S.B., I.C. and A.A.F.; Tables: S.B.; Risk of bias assessment: V.D.D. and I.C.; Editing and Revision: M.L.G. and V.D.D.; Final revision: A.P. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

Ethical review and approval were waived for this study due to the nature of the study (systematic review).

Informed Consent Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

Funding Statement

This research received no external funding.

Footnotes

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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