Fertility Preservation in the Era of Immuno-Oncology: Lights and Shadows.

In recent years, immuno-oncology has revolutionized the cancer treatment field by harnessing the immune system's power to counteract cancer cells. While this innovative approach holds great promise for improving cancer outcomes, it also raises important considerations related to fertility and reproductive toxicity. In fact, most young females receiving gonadotoxic anti-cancer treatments undergo iatrogenic ovarian exhaustion, resulting in a permanent illness that precludes the vocation of motherhood as a natural female sexual identity. Although commonly used, oocyte cryopreservation for future in vitro fertilization and even ovarian cortex transplantation are considered unsafe procedures in cancer patients due to their oncogenic risks; whereas, ovarian stem cells might support neo-oogenesis, providing a novel stemness model of regenerative medicine for future fertility preservation programs in oncology. Recent scientific evidence has postulated that immune checkpoint inhibitors (ICIs) might in some way reduce fertility by inducing either primary or secondary hypogonadism, whose incidence and mechanisms are not yet known. Therefore, considering the lack of data, it is currently not possible to define the most suitable FP procedure for young patients who are candidates for ICIs. In this report, we will investigate the few available data concerning the molecular regulation of ICI therapy and their resulting gonadal toxicity, to hypothesize the most suitable fertility preservation strategy for patients receiving these drugs.

BRCA Mutation Patients: Are There Other Predisposing Factors for Ovarian Cancer Occurrence? A Multicenter Retrospective Study.

OBJECTIVES: The objective of this multicenter retrospective study aimed to evaluate the association of clinical variables and the incidence of ovarian cancer in patients with BRCA 1-2 mutation carriers who underwent risk-reducing salpingo-oophorectomy (RRSO). DESIGN: Patients with a pathogenic mutation of BRCA 1-2 genes and with no evidence of disease are considered eligible. The exclusion criterion was the refusal to undergo the surgery. The retrospective study included all RRSO performed from May 2015 to April 2022 in the three gynecological Institutions of Southern Italy for were included in this retrospective study. PARTICIPANTS/MATERIALS, SETTING, METHODS: Age, menarche age, BMI, menopause at time of RRSO, breast cancer first- and second-degree relatives, ovarian cancer first- and second-degree relatives, estroprogestin use, pregnancy normal full-term delivery, history of endometriosis, previous breast cancer and histologic type, previous abdominal/pelvic surgery, BRCA 1 or BRCA 2 status, preoperative serum CA-125 levels (IU/mL), age at time of RRSO and histological analysis were collected. RESULTS: 184 were recruited. One was excluded. To assess cancer risk, the outcome variable was classified into three classes: no event, cancer, and other conditions excluding cancer. 14 women presented ovarian cancer and tubal intraepithelial carcinoma (STIC) on histopathologic final report. Ovarian cancer was found in 8 patients, whereas the presence of STIC was found in 6 of them. LIMITATIONS: The low incidence of patients diagnosed with ovarian cancer or STIC compared with the total number of patients undergoing RRSO is a potential bias. CONCLUSIONS: Our study did not demonstrate a correlation between clinical features and the occurrence of precancerous or cancerous lesions in BRCA mutation carrier patients.

A human-interpretable machine learning pipeline based on ultrasound to support leiomyosarcoma diagnosis.

The preoperative evaluation of myometrial tumors is essential to avoid delayed treatment and to establish the appropriate surgical approach. Specifically, the differential diagnosis of leiomyosarcoma (LMS) is particularly challenging due to the overlapping of clinical, laboratory and ultrasound features between fibroids and LMS. In this work, we present a human-interpretable machine learning (ML) pipeline to support the preoperative differential diagnosis of LMS from leiomyomas, based on both clinical data and gynecological ultrasound assessment of 68 patients (8 with LMS diagnosis). The pipeline provides the following novel contributions: (i) end-users have been involved both in the definition of the ML tasks and in the evaluation of the overall approach; (ii) clinical specialists get a full understanding of both the decision-making mechanisms of the ML algorithms and the impact of the features on each automatic decision. Moreover, the proposed pipeline addresses some of the problems concerning both the imbalance of the two classes by analyzing and selecting the best combination of the synthetic oversampling strategy of the minority class and the classification algorithm among different choices, and the explainability of the features at global and local levels. The results show very high performance of the best strategy (AUC = 0.99, F1 = 0.87) and the strong and stable impact of two ultrasound-based features (i.e., tumor borders and consistency of the lesions). Furthermore, the SHAP algorithm was exploited to quantify the impact of the features at the local level and a specific module was developed to provide a template-based natural language (NL) translation of the explanations for enhancing their interpretability and fostering the use of ML in the clinical setting.

Contraception as chemoprevention of ovarian cancer in BRCA1 and BRCA2 women.

Ovarian cancer is the seventh most common cancer in women in the world, with an estimated worldwide mortality of over 207'000 women every year. This cancer, due to the current lack of adequate screening techniques, is commonly diagnosed late and has a poor prognosis. The oral contraceptive pill is considered the most effective prevention strategy for ovarian cancer in the general population, being associated with a decreased incidence while also having a substantial positive impact on the mortality rate, which is reduced by up to 50%. BRCA1 and BRCA2 germline mutated women have an augmented risk of ovary and breast cancer: despite international guidelines that consider prophylactic surgery as the gold standard for ovarian cancer prevention, there are currently no effective non-invasive preventive methods. In BRCA1\2 mutated patients, clinicians should weigh the benefits of contraceptive pills against the risk of long-term thromboembolic side effects and hormonal malignancies such as breast and cervical cancer. A multidisciplinary team should counsel patients on the most appropriate risk-reduction strategy tailored to their needs and expectations, proposing the oral contraceptive pill to selected patients after balancing the risks of adverse effects and the benefits on both contraception and chemoprevention.

Endometrial Osseous Metaplasia: An Hysteroscopic Incidental Finding - An Overview.

Endometrial osseous metaplasia (EOM) is an uncommon clinical entity with the presence of bone in the endometrium which requires clinical and therapeutic framework. It is also described by various other names such as endometrial ossification, ectopic intrauterine bone, and heterotopic intrauterine bone. Ossification could have various locations as the cervix the ovary, and the vagina. This overview highlights the attention on the actual pivotal points of EOM.

Management of metastatic endometrial cancer: physicians' choices beyond the first line after approval of checkpoint inhibitors.

Introduction: Endometrial cancer (EC) represents 3.4% of all newly diagnosed cancer cases and is responsible for 2.1% of all cancer-related deaths. Approximately 10%-15% of women with EC are diagnosed with advanced-stage disease, resulting in a reported 5-year survival rate of only 17% for those with distant metastases. A better understanding of its molecular features has ushered in a new era of immunotherapy for the treatment of EC, allowing for alternative therapeutic approaches, even in cases of advanced disease. Methods: We administered a multi-choice online survey for Multicenter Italian Trials in Ovarian cancer and gynecologic malignancies (MITO) members. The questionnaire was available for 2 months, starting in October 2022. Our objective was to evaluate the current attitude of incorporating molecular characterization of EC into routine clinical practice, appraise the implementation of newly available therapies, and compare the outcomes with the previous survey conducted in April-May 2021 to ascertain the actual changes that have transpired during this recent time period. Results: The availability of molecular classification in Italian centers has changed in 1 year. Seventy-five percent of centers performed the molecular classification compared with 55.6% of the previous survey. Although this percentage has increased, only 18% performed all the tests. Significant changes have occurred in the administration of new treatments in EC patients in MITO centers. In 2022, 82.1% of the centers administrated dostarlimab in recurrent or advanced MMR-deficient (dMMR) EC experiencing disease progression after platinum-based chemotherapy regimens, compared to only 24.4% in 2021. In 2022, 85.7% of the centers already administrated the pembrolizumab plus lenvatinib combination as a second-line therapy for MMR-proficient (pMMR) patients with advanced or recurrent EC who had progressed from first-line platinum-based therapy. Conclusion: Both the therapeutic and diagnostic scenarios have changed over the last couple of years in MITO centers, with an increased prescription of immune checkpoint inhibitors and use of the molecular classification.

Optimizing the Ovarian Tissue Cryopreservation in the 'Oncofertility' Institutional Program at an Italian National Cancer Institute.

BACKGROUND: The majority of female cancer patients undergoing anticancer treatments are at risk of experiencing 'cancer treatment-related infertility', which can result in permanent damage to their reproductive prospects. Among the fertility preservation methods, ovarian tissue cryopreservation (OTC) has emerged as an alternative for these patients. The Cancer Institute of Bari initiated a research program to assess the feasibility of OTC. This study compares the viability of ovarian cortical fragments cryopreserved using slow freezing (SF) and ultra-rapid freezing (URF) methods. METHODS: Ovarian cortex biopsies were obtained from 11 fertile women enrolled in our oncofertility service between June 2022 and January 2023. After tissue collection, a histological assessment was performed before cryopreservation. OTC was carried out using both SF and URF methods. Six months later, thawed samples were evaluated for follicle counts and histological integrity. RESULTS: No statistically significant difference was observed in the proportion of intact follicles (means of 31.5% and 73.0% in the SF and URF groups, respectively; p = 0.064). However, there was a significant difference in the number of follicles between the SF group (n = 149) and the URF group (n = 37) (p = 0.046). CONCLUSIONS: We assessed the viability of ovarian cortex after freezing and thawing, focusing on the structural integrity of follicles. Our findings suggest that there are no significant differences between the SF and URF methods.

Innovative Strategies for Fertility Preservation in Female Cancer Survivors: New Hope from Artificial Ovary Construction and Stem Cell-Derived Neo-Folliculogenesis.

Recent advances in anticancer treatment have significantly improved the survival rate of young females; unfortunately, in about one third of cancer survivors the risk of ovarian insufficiency and infertility is still quite relevant. As the possibility of becoming a mother after recovery from a juvenile cancer is an important part of the quality of life, several procedures to preserve fertility have been developed: ovarian surgical transposition, induction of ovarian quiescence by gonadotropin-releasing hormone agonists (GnRH-a) treatment, and oocyte and/or ovarian cortical tissue cryopreservation. Ovarian tissue cryostorage and allografting is a valuable technique that applies even to prepubertal girls; however, some patients cannot benefit from it due to the high risk of reintroducing cancer cells during allograft in cases of ovary-metastasizing neoplasias, such as leukemias or NH lymphomas. Innovative techniques are now under investigation, as in the construction of an artificial ovary made of isolated follicles inserted into an artificial matrix scaffold, and the use of stem cells, including ovarian stem cells (OSCs), to obtain neo-folliculogenesis and the development of fertilizable oocytes from the exhausted ovarian tissue. This review synthesizes and discusses these innovative techniques, which potentially represent interesting strategies in oncofertility programs and a new hope for young female cancer survivors.

Cornual Pregnancy.

Cornual pregnancy (CP) is a subtype of ectopic pregnancy that is implanted in the interstitial segment of the fallopian tube which is defined as the tubal section crossing uterine muscular tissue. Widely recognized risk factors for CP are endometriosis, uterine leiomyomata, or pelvic inflammatory disease; all these diseases can cause tubal anatomic changes and consequently alter embryo physiological implant process. Many treatment options are available for this condition each one must be tailored according to patient and operating scenario. The incidence of uterine ruptures in the scarred uterus appears to be low, but the fear of it remains and therefore medical treatment might be favored over cornual wedge resection. The actual risk of uterine rupture after medical treatment is unknown. Multiple testing strategies exist to diagnose CP, but caution needs to be used to avoid a false diagnosis.

Pregnancy by Oocyte Donation: Reviewing Fetal-Maternal Risks and Complications.

Oocyte donation (OD) has greatly improved over the last three decades, becoming a preferred practice of assisted reproductive technology (ART) for infertile women wishing for motherhood. Through OD, indeed, it has become possible to overcome the physiological limitation due to the ovarian reserve (OR) exhaustion as well as the poor gamete reliability which parallels the increasing age of women. However, despite the great scientific contribution related to the success of OD in the field of infertility, this practice seems to be associated with a higher rate of major risky events during pregnancy as recurrent miscarriage, infections and placental diseases including gestational hypertension, pre-eclampsia and post-partum hemorrhage, as well as several maternal-fetal complications due to gametes manipulation and immune system interaction. Here, we will revisit this questioned topic since a number of studies in the medical literature focus on the successful aspects of the OD procedure in terms of pregnancy rate without, however, neglecting the risks and complications potentially linked to external manipulation or heterologous implantation.

Uterine venous malformations in the puerperium: 2 Atypical cases and literature review.

Uterine arteriovenous malformations (AVMs) is a rare but high-risk cause of uterine bleeding. The clinical management of this condition is challenging, as the ultrasound picture can sometimes be unambiguously interpreted. Moreover, in the puerperium in which acquired AVMs are most frequently formed, it is necessary to discuss the correct management in a multidisciplinary and personalized manner. We present two cases of AVMs developing in the puerperium, both with a vaginal delivery and spontaneous and complete secondment. The symptom of onset was an episode of bright red blood loss in the puerperium, on the 14th and 21st postpartum days, respectively. Transvaginal ultrasound showed a hypervascularized lesion in the myometrium with turbulent vascular flow, confirmed by transabdominal ultrasound and angiography. To date, there are no guidelines on the management of MAVs. In our cases we opted for a conservative approach, in order to preserve the fertility of the patient. These experiences reported have the purpose of enriching a literature still sparse on the subject and in the future to be able to represent a fulcrum for official recommendations.

An explainable machine learning ensemble model to predict the risk of ovarian cancer in BRCA-mutated patients undergoing risk-reducing salpingo-oophorectomy.

Introduction: It has been estimated that 19,880 new cases of ovarian cancer had been diagnosed in 2022. Most epithelial ovarian cancer are sporadic, while in 15%-25% of cases, there is evidence of a familial or inherited component. Approximately 20%-25% of high-grade serous carcinoma cases are caused by germline mutations in the BRCA1 and BRCA2 genes. However, owing to a lack of effective early detection methods, women with BRCA mutations are recommended to undergo bilateral risk-reducing salpingo-oophorectomy (RRSO) after childbearing. Determining the right timing for this procedure is a difficult decision. It is crucial to find a clinical signature to identify high-risk BRCA-mutated patients and determine the appropriate timing for performing RRSO. Methods: In this work, clinical data referred to a cohort of 184 patients, of whom 7.6% were affected by adnexal tumors including invasive carcinomas and intraepithelial lesions after RSSO has been analyzed. Thus, we proposed an explainable machine learning (ML) ensemble approach using clinical data commonly collected in clinical practice to early identify BRCA-mutated patients at high risk of ovarian cancer and consequentially establish the correct timing for RRSO. Results: The ensemble model was able to handle imbalanced data achieving an accuracy value of 83.2%, a specificity value of 85.3%, a sensitivity value of 57.1%, a G-mean value of 69.8%, and an AUC value of 71.1%. Discussion: In agreement with the promising results achieved, the application of suitable ML techniques could play a key role in the definition of a BRCA-mutated patient-centric clinical signature for ovarian cancer risk and consequently personalize the management of these patients. As far as we know, this is the first work addressing this task from an ML perspective.

Cervical cancer benefits from trabectedin combination with the ß-blocker propranolol: in vitro and ex vivo evaluations in patient-derived organoids.

Background: Cervical cancer (CC) is characterized by genomic alterations in DNA repair genes, which could favor treatment with agents causing DNA double-strand breaks (DSBs), such as trabectedin. Hence, we evaluated the capability of trabectedin to inhibit CC viability and used ovarian cancer (OC) models as a reference. Since chronic stress may promote gynecological cancer and may hinder the efficacy of therapy, we investigated the potential of targeting ß-adrenergic receptors with propranolol to enhance trabectedin efficacy and change tumor immunogenicity. Methods: OC cell lines, Caov-3 and SK-OV-3, CC cell lines, HeLa and OV2008, and patient-derived organoids were used as study models. MTT and 3D cell viability assays were used for drug(s) IC50 determination. The analysis of apoptosis, JC-1 mitochondrial membrane depolarization, cell cycle, and protein expression was performed by flow cytometry. Cell target modulation analyses were carried out by gene expression, Western blotting, immunofluorescence, and immunocytochemistry. Results: Trabectedin reduced the proliferation of both CC and OC cell lines and notably of CC patient-derived organoids. Mechanistically, trabectedin caused DNA DSBs and S-phase cell cycle arrest. Despite DNA DSBs, cells failed the formation of nuclear RAD51 foci and underwent apoptosis. Under norepinephrine stimulation, propranolol enhanced trabectedin efficacy, further inducing apoptosis through the involvement of mitochondria, Erk1/2 activation, and the increase of inducible COX-2. Notably, trabectedin and propranolol affected the expression of PD1 in both CC and OC cell lines. Conclusion: Overall, our results show that CC is responsive to trabectedin and provide translational evidence that could benefit CC treatment options. Our study pointed out that combined treatment offset trabectedin resistance caused by ß-adrenergic receptor activation in both ovarian and cervical cancer models.

Robotic Sacrocolpopexy with Autologous Fascia Lata: A Case Series.

Objectives: Apical prolapse involves the upper vagina or vaginal vault after hysterectomy. Treatment is indicated for symptomatic women, and surgical approach is considered for women who failed or refused conservative therapy. We performed 10 pickups of autologous fascia, used for robotic sacrocolpopexy (RSCP). Materials and Methods: We included patients between 60 and 80 years old who showed a Pelvic Organ Prolapse Quantification (POP-q) over the second stage and with symptoms related to prolapse. Results: All of them underwent autologous fascia lata (AFL) pickup from the right leg and after to RSCP. One patient underwent also posterior colporrhaphy. The mean intraoperative time was 199.2 min (183-230 min). No intra-operatory complications were reported. POP-q assessment during follow-up showed improvements: C point gained on average 7.6 points (5-8) and mean values went from -0.6 to - 8.2 cm (-7 to -9 cm). The three women who had anterior compartment defects shows good anatomical reconstitution with a mean Aa and Ba value of - 2.83 cm (-2.5 to -3 cm) and gained 4 points (average gain: 3.5-4.5 cm). Total vaginal lenght (TVL). Conclusion: According to these data, in our experience, AFL employment showed a good anatomical result from the first to last follow-up.

Effect of bevacizumab in advanced low grade serous ovarian cancer: Data from the MITO 22 trial.

OBJECTIVE: The aim of the present analysis was to explore the efficacy of Bevacizumab (Bev) on survival outcome in advanced low grade serous ovarian cancer (LGSOC) both in first line and in recurrent setting. METHODS: In retrospective observational multicenter study, we described the outcome of LGSOC patients enrolled in the MITO 22 study and treated with chemotherapy (CT) with or without Bev. Patients receiving Bev in first-line or in recurrence were considered and compared with patients receiving CT alone (stage III and IV in first line; platinum based-CT in second line). Descriptive and survival analyses were performed for each group. RESULTS: Out of 128 patients included in MITO 22, 46 LGSOC patients receiving Bev in first line setting or at the time of first recurrence were identified. In first line, 30 patients received Bev + CT and 65 CT alone and the median PFS were 47.86 months (95% CI: 31.48 - NR) and 22.63 months (95% CI 15-39.24) (p-value 0.0392), respectively. In the recurrent setting, 16 patients who received Bev + CT were compared to 33 women treated with platinum-based CT alone. Median PFS were 37.1 months (95% CI: 13.42-40.56) and 11.22 months (95% CI: 8.26-15.63) (p-value 0.013), respectively. CONCLUSIONS: Our study suggests that Bev might be effective in LGSOC both at diagnosis and at the time of relapse. These data warrants further studies.

T Cell Immunoglobulin and Mucin Domain 3 (TIM-3) in Cutaneous Melanoma: A Narrative Review.

T cell immunoglobulin and mucin domain 3 (TIM-3) is an inhibitory immunocheckpoint that belongs to the TIM gene family. Monney et al. first discovered it about 20 years ago and linked it to some autoimmune diseases; subsequent studies have revealed that some tumours, including melanoma, have the capacity to produce inhibitory ligands that bind to these receptor checkpoints on tumour-specific immune cells. We conducted a literature search using PubMed, Web of Science (WoS), Scopus, Google Scholar, and Cochrane, searching for the following keywords: "T cell immunoglobulin and mucin-domain containing-3", "TIM-3" and/or "Immunocheckpoint inhibitors" in combination with "malignant melanoma" or "human malignant melanoma" or "cutaneous melanoma". The literature search initially turned up 117 documents, 23 of which were duplicates. After verifying eligibility and inclusion criteria, 17 publications were ultimately included. A growing body of scientific evidence considers TIM-3 a valid inhibitory immuno-checkpoint with a very interesting potential in the field of melanoma. However, other recent studies have discovered new roles for TIM-3 that seem almost to contradict previous findings in this regard. All this demonstrates how common and valid the concept of 'pleiotropism' is in the TME field, in that the same molecule can behave completely or partially differently depending on the cell type considered or on temporary conditions. Further studies, large case series, and a special focus on the immunophenotype of TIM-3 are absolutely necessary in order to explore this highly promising topic in the near future.

Overlap of Suspicious and Non-Suspicious Features in the Ultrasound Evaluations of Leiomyosarcoma: A Single-Center Experience.

Leiomyosarcoma (LMS) is a rare type of mesenchymal tumor. Suspecting LMS before surgery is crucial for proper patient management. Ultrasound is the primary method for assessing myometrial lesions. The overlapping of clinical, laboratory, as well as ultrasound features between fibroids and LMS makes differential diagnosis difficult. We report our single-center experience in ultrasound imaging assessment of LMS patients, highlighting that misleading findings such as shadowing and absent or minimal vascularization may also occur in LMS. To avoid mistakes, a comprehensive evaluation of potentially overlapping ultrasound features is necessary in preoperative ultrasound evaluations of all myometrial tumors.

Ultrasound Control of Cervical Regeneration after Large Loop Excision of the Transformation Zone: Results of an Innovative Measurement Technique.

The objective of this research is to evaluate cervical regeneration after large loop excision of the transformation zone (LLETZ) through the identification of a new sonographic reference point at the level of the uterine margins. In the period March 2021-January 2022, a total of 42 patients affected by CIN 2-3 were treated with LLETZ at the University Hospital of Bari (Italy). Before performing LLETZ, cervical length and volume were measured with trans-vaginal 3D ultrasound. From the multiplanar images, the cervical volume was obtained using the Virtual Organ Computer-aided AnaLysis (VOCAL™) program with manual contour mode. The line that connects the points where the common trunk of the uterine arteries reaches the uterus splitting into the ascending major branch and the cervical branch was considered as the upper limit of the cervical canal. From the acquired 3D volume, the length and the volume of the cervix were measured between this line and the external uterine os. Immediately after LLETZ, the removed cone was measured using Vernier's caliper, and before fixation in formalin, the volume of the excised tissue was evaluated by the fluid displacement technique based on the Archimedes principle. The proportion of excised cervical volume was 25.50 ± 17.43%. The volume and the height of the excised cone were 1.61 ± 0.82 mL and 9.65 ± 2.49 mm corresponding to 14.74 ± 11.91% and 36.26 ± 15.49% of baseline values, respectively. The volume and length of the residual cervix were also assessed using 3D ultrasound up to the sixth month after excision. At 6 weeks, about 50% of cases reported an unchanged or lower cervical volume compared to the baseline pre-LLETZ values. The average percentage of volume regeneration in examined patients was equal to 9.77 ± 55.33%. In the same period, the cervical length regeneration rate was 69.41 ± 14.8%. Three months after LLETZ, a volume regeneration rate of 41.36 ± 28.31% was found. For the length, an average regeneration rate of 82.48 ± 15.25% was calculated. Finally, at 6 months, the percentage of regeneration of the excised volume was 90.99 ± 34.91%. The regrowth percentage of the cervical length was 91.07 ± 8.03%. The cervix measurement technique that we have proposed has the advantage of identifying an unequivocal reference point in 3D cervical measurement. Ultrasound 3D evaluation could be useful in the clinical practice to evaluate the cervical tissue deficit and express the "potential of cervical regeneration" as well as provide the surgeon useful information about the cervical length.

Hormone replacement therapy in BRCA mutation carriers: how shall we do no harm?

Women with a BRCA mutation have an increased risk of developing breast and ovarian cancer. Bilateral salpingo-oophorectomy is the only effective strategy to reduce this risk. Risk-reducing bilateral salpingo-oophorectomy (RRSO) is recommended between the ages of 35 and 40 for women carriers of BRCA1 and between the ages of 40 and 45 for women carriers of BRCA1 and BRCA2 mutations. Most women undergo this procedure prior to their natural menopause subsequently developing an anticipated lack of hormones. This condition affects the quality of life and longevity, while it is more pronounced in women carrying a BRCA1 mutation compared to BRCA2 because they are likely to have surgery earlier. Hormone replacement therapy (HRT) is the only strategy able to significantly compensate for the loss of ovarian hormone production and counteract menopausal symptoms. There is strong evidence that short-term HRT use does not increase the risk of breast cancer among women with a BRCA1 mutation. Few data are available on BRCA2 mutation carriers. Therefore, BRCA mutation carriers require careful counseling about the outcomes of their RRSO, including menopausal symptoms and/or the fear associated with HRT use.