Endometrial Cancer and BRCA Mutations: A Systematic Review

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.


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].

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.

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.

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.

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].

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).
BRCAm. Median follow-up was expressed in years or women-years. Standa Ratios (SIR) were reported for assessing endometrial cancer risk in BRCAm w available.

Quality Assessment
The evaluation of the risk of bias in estimates of the comparative effectiv or benefit) of interventions from the included studies was performed with Bias In Non-randomized Studies-of Interventions" (ROBINS-I) tool [18].

Literature Search
Overall, a total of 291 records were identified. After removing 77 duplica uscripts were screened, and 165 were excluded based on the abstract. A full tained for 48 of 49 records. At the end of the screening process, 24 full-text included in the systematic review. All papers were in English.

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.

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 Tables 1 and 2, respectively. The risk of bias assessment is reported in Table 3.
The main findings of the included studies on the prevalence of BRCAm in patients with endometrial cancer are reported in Table 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 salpingooophorectomy 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.

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 riskreducing 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.