Long-term follow-up of efficacy and safety of selinexor maintenance treatment in patients with TP53wt advanced or recurrent endometrial cancer: A subgroup analysis of the ENGOT-EN5/GOG-3055/SIENDO study.

OBJECTIVE: To report long-term efficacy and safety of selinexor maintenance therapy in adults with TP53 wild-type (TP53wt) stage IV or recurrent endometrial cancer (EC) who achieved partial remission (PR) or complete remission (CR) following chemotherapy. METHODS: Analysis of the prespecified, exploratory subgroup of patients with TP53wt EC from the phase 3 SIENDO study was performed. Progression-free survival (PFS) benefit in patients with TP53wt EC and across other patient subgroups were exploratory endpoints. Safety and tolerability were also assessed. RESULTS: Of the 263 patients enrolled in the SIENDO trial, 113 patients had TP53wt EC; 70/113 (61.9%) had TP53wt/proficient mismatch repair (pMMR) EC, and 29/113 (25.7%) had TP53wt/deficient mismatch repair (dMMR) EC. As of April 1, 2024, the median PFS (mPFS) for TP53wt patients who received selinexor compared with placebo was 28.4 versus 5.2 months (36.8-month follow-up, HR 0.44; 95% CI 0.27-0.73). A benefit in mPFS was seen with selinexor versus placebo regardless of MMR status (patients with TP53wt/pMMR EC: 39.5 vs 4.9 months, HR 0.36; 95% CI 0.19-0.71; patients with TP53wt/dMMR EC: 13.1 vs 3.7 months, HR 0.49; 95% CI 0.18-1.34). Selinexor treatment was generally manageable, with no new safety signals identified. CONCLUSION: In the phase 3 SIENDO study, selinexor maintenance therapy showed a promising efficacy signal and a manageable safety profile in the prespecified subgroup of patients with TP53wt EC who achieved a PR or CR following chemotherapy. These results are being further evaluated in an ongoing randomized phase 3 trial (NCT05611931).

Prophylactic salpingectomy with delayed oophorectomy as a two-staged alternative for primary prevention of ovarian cancer in BRCA1/2 mutation carriers: women's point of view.

OBJECTIVE: This study aimed to determine BRCA -mutation carrier women's interest and acceptability of participating in a study examining prophylactic salpingectomy with delayed oophorectomy (PSDO) as an alternative to the current recommendation for bilateral salpingo-oophorectomy for risk reduction. METHODS: This is a cross-sectional questionnaire-based study. All women visiting the high-risk clinics for hereditary breast and ovarian cancer in a single tertiary medical center were asked to complete a questionnaire concerning the two-stage approach from October 2018 to December 2019. Before completing the questionnaire, detailed explanation was given by a senior physician regarding the procedure, related background, possible risks, and benefits. RESULTS: The study population included 293 women, of whom 183 (62.4%) were BRCA1 mutation carriers, 97 (33.1%) were BRCA2 mutation carriers, and 13 (4.4%) had unknown familial mutation. Risk-reducing surgery was completed in 160 (55.17%) of the women. First-degree and second-degree family history was reported in 166 (57.24%) and 52 (17.9%) of the women, respectively. Among women surveyed, more than half of the women (n = 66 [51%]) who had yet to undergo risk-reducing surgery reported interest in having PSDO. Similarly, among those who had already received prophylactic surgery, 64 (40%) also considered PSDO to be an acceptable alternative. Multivariate logistic regression analysis found family history of related malignancies to be the only independent factor associated with reduced interest in a study of PSDO (odds ratio, 0.15 [95% confidence interval, 0.29-0.77]; P = 0.02). CONCLUSIONS: Overall, BRCA -mutation carrier women indicated interest in PSDO risk-reducing surgery, taking into consideration the potential additional risk. These findings suggest that a clinical study exploring the equivalence of PSDO as alternative treatment is feasible.

Early prediction of urinary retention following radical hysterectomy by 18F-FDG PET/CT imaging.

BACKGROUND: Radical hysterectomy for early cervical cancer is associated with postoperative bladder dysfunction. Postoperative imaging by 18F-FDG PET/CT scanning is often performed to rule out recurrence. Since women are instructed to empty the bladder before imaging, we aim to study if scanned abnormal residual bladder volume is associated with future urinary symptoms. METHODS: Women who underwent radical hysterectomy for cervical cancer between July 2010 and January 2019 were included in the study. Multi-Modality Tumor Tracking® (MMTT) was used to measure residual urinary volume on 18F-FDG PET/CT scans before and after hysterectomy. Demographic, clinical parameters, and urinary tract signs and symptoms, were evaluated among the cohort. RESULTS: Overall, 64 patients were included. Among those, in 24 (38%) the bladder volume reached ≥150 cm3 on postoperative 18F-FDG PET/CT scans. Of these, 9 (37.5%) had voiding difficulties of some degree. In 3 (12.5%) women, the 18F-FDG PET/CT scan has preceded their complaints of voiding difficulties by 2-4 months. Of the 40 women (62%) whose postoperative bladder volumes were <150 cm3, only 1 (2.5%) had urinary retention. Rate of symptomatic voiding difficulties was higher in the post-void volume ≥150 cm3 group; 13 (54.1%) vs. 6 (15.0%), P<0.002, Odds Ratio 95% Confidence Interval 6.6 (2.0-21.8), P=0.001. CONCLUSIONS: Measuring bladder volume on postoperative 18F-FDG PET/CT may facilitate early identification of urinary retention, possibly enabling early treatment and possibly preventing complications.

Sentinel lymph node mapping in endometrial cancer: A comparison of main national and international guidelines.

OBJECTIVES: To compare national and international guidelines regarding sentinel lymph node (SLN) mapping in endometrial cancer. METHODS: A descriptive comparative study of the National Comprehensive Cancer Network (NCCN), the Society of Gynecologic Oncology (SGO), the European Society of Gynecological Oncology (ESGO), the British Gynecological Cancer Society (BGCS), and the Japan Society of Gynecologic Oncology (JSGO) guidelines. RESULTS: There is a broad consensus that SLN mapping is an appropriate alternative to pelvic lymphadenectomy for uterine-confined endometrioid endometrial cancer (five of five guidelines). It is broadly accepted that a full lymphadenectomy should be performed in case of failed SLN mapping (four of five guidelines), and that mapping with the fluorescent dye indocyanine green is superior to other methods (four of five guidelines). It is agreed that the cervix is the preferable site for dye injection (four of five guidelines), and pathology ultrastaging is advocated by most guidelines (three of five guidelines). Regarding high-risk patients (i.e., high-grade histology and non-endometroid carcinomas), some guidelines accept (three of five), but others currently do not advocate (one of five guidelines), SLN mapping as a sole method for lymph node evaluation. There is no consensus regarding para-aortic lymph node evaluation in pelvic SLN-positive patients. CONCLUSION: Guidelines for SLN mapping are comparable with regards to surgical technique, ultrastaging, and management in case of failed mapping. Nevertheless, some variations exist regarding the management of high-grade histology and positive pelvic lymph nodes.

Ethnic disparity in cervical cancer stage at diagnosis: A retrospective study in an Israeli referral-center.

OBJECTIVE: To compare stage and survival of cervical cancer between Jewish and Arab women in a tertiary medical center in Israel. METHODS: Retrospective study of consecutive women diagnosed with cervical cancer in a single institution between 2010 and 2021. We compared Jewish and Arab patients using univariate, multivariable, and survival curves analysis. RESULTS: Overall, 207 Jewish women and 45 Arab women were included with a median follow up of 20 months (interquartile range 7-46 months). The groups did not differ in median body mass index, mean age at diagnosis, or menopausal status. Arab women had higher parity. Arab women were at a higher risk to be diagnosed with advanced stage disease (≥2b) (84.4% vs. 57% Arab and Jewish women, respectively, P < 0.001). In a multivariable regression analysis, Arab descent was found to be the only independent factor associated with advanced stage disease (odds ratio 3.95, 95% confidence interval 1.54-10.10). Overall survival and stage-specific survival were not different between the ethnic groups. CONCLUSIONS: Advanced stage at diagnosis was more prevalent in Arab women compared with Jewish women with cervical cancer, whereas stage-specific survival was similar. Further studies addressing possible contributing factors to inequality should be undertaken to find corrective measures.

Proteomic signature for detection of high-grade ovarian cancer in germline BRCA mutation carriers.

No current screening methods for high-grade ovarian cancer (HGOC) guarantee effective early detection for high-risk women such as germline BRCA mutation carriers. Therefore, the standard-of-care remains risk-reducing salpingo-oophorectomy (RRSO) around age 40. Proximal liquid biopsy is a promising source of biomarkers, but sensitivity has not yet qualified for clinical implementation. We aimed to develop a proteomic assay based on proximal liquid biopsy, as a decision support tool for monitoring high-risk population. Ninety Israeli BRCA1 or BRCA2 mutation carriers were included in the training set (17 HGOC patients and 73 asymptomatic women), (BEDOCA trial; ClinicalTrials.gov Identifier: NCT03150121). The proteome of the microvesicle fraction of the samples was profiled by mass spectrometry and a classifier was developed using logistic regression. An independent cohort of 98 BRCA mutation carriers was used for validation. Safety information was collected for all women who opted for uterine lavage in a clinic setting. We present a 7-protein diagnostic signature, with AUC >0.97 and a negative predictive value (NPV) of 100% for detecting HGOC. The AUC of the biomarker in the independent validation set was >0.94 and the NPV >99%. The sampling procedure was clinically acceptable, with favorable pain scores and safety. We conclude that the acquisition of Müllerian tract proximal liquid biopsies in women at high-risk for HGOC and the application of the BRCA-specific diagnostic assay demonstrates high sensitivity, specificity, technical feasibility and safety. Similar classifier for an average-risk population is warranted.

Ovarian cancer risk management in BRCA-mutation carriers: A comparison of six international and national guidelines.

OBJECTIVE: Germline mutations in the BRCA gene account for most hereditary ovarian and breast cancer. Management of healthy carriers aims to prevent and allow early detection of breast and ovarian cancer. This study compares six different hereditary ovarian cancer management guidelines, highlighting areas of controversy between different societies. We aim to compare international and national guidelines regarding BRCA carriers' management. STUDY DESIGN: A comparative study. We retrieved, reviewed, and compared the most recent guidelines of BRCA mutation carriers from the specializing societies NCCN (National Comprehensive National network) and ESMO (European society of medical oncology), and national societies of the United States (American College of Obstetricians and Gynecologists), England (the Royal College of Obstetricians and Gynecologists), Canada (the Society of Obstetricians and Gynaecologists of Canada) and Spain (Sociedad Española de Oncología Médica). RESULTS: There is a broad consensus regarding the limited role of screening for early ovarian cancer detection (4 out of 6) (4/6) and regarding the recommendation for implementation of Risk-reducing salpingo-oophorectomy (RRSO) (6/6), some variations exist for age at RRSO. It is widely accepted that risk reducing salpingectomy should be performed only as part of research (5/6), and that the addition of risk-reducing hysterectomy should be individualized (3/6). Not all guidelines address fertility issues, and controversy exists regarding hormone replacement therapy (HRT) recommendations in unaffected young BRCA-mutation carriers following RRSO. CONCLUSION: BRCA carrier's management guidelines consist of well-agreed topics such as the ineffective screening for early detection of ovarian cancer and the recommendation of RRSO. HRT remains controversial. Conforming unified recommendations is needed for providing evidence-based recommendations.

Palliative urinary diversion in patients with malignant ureteric obstruction due to gynaecological cancer.

OBJECTIVES: To identify factors aiding the selection of patients with gynaecological cancer with malignant urinary obstruction who are least likely to benefit from palliative urinary diversion (UD), and to create a risk-stratification model for decision-making. METHODS: This historic cohort study comprised 74 consecutive patients with urinary obstruction resulting from gynaecological malignancies. All underwent palliative UD by percutaneous nephrostomy (PCN). Using the Cox proportional hazards regression model and Kaplan-Meier curves with the log-rank test, we developed a prognostic score identifying candidates least likely to benefit from the intervention. RESULTS: The median follow-up was 4.72 (range 0-5.71) years. Hydronephrosis was diagnosed in most patients on recurrent or persistent disease (81%). It was bilateral in 37.8%. Intervention-related complications included urinary sepsis (8%), catheter dislodgment requiring replacement (17%) and gross haematuria necessitating blood transfusions (13%). After PCN, conversion to an internal ureteral stent was feasible in 46%. The median survival was 11.13 (range 0-67) months. Two patients died within a month of UD. Multivariate analysis identified diabetes mellitus (DM), poor Eastern Cooperative Oncology Group (ECOG) performance status >1 and ascites as significant negative survival factors. A prognostic index based on those factors identified the short-term and long-term survivors. Risk factor-based mortality HRs were 11.37 (95% CI 4.12 to 31.37) with one factor, 26.57 (95% CI 9.14 to 77.26) with two factors and 67.25 (95% CI 15.6 to 289.63) with three factors (all with p<0.0001). CONCLUSIONS: Our proposed prognostic index, based on ascites, ECOG performance status and DM, might help select patients with gynaecological cancer least likely to benefit from palliative UD.

Risk-reducing salpingo-oophorectomy and breast cancer incidence among Jewish BRCA1/BRCA2-mutation carriers-an Israeli matched-pair study.

OBJECTIVE: To study the association of risk-reducing bilateral salpingo-oophorectomy (RRBSO) and breast cancer risk among BRCA pathogenic sequence variants (PSV). METHODS: Jewish Israeli BRCA carriers who underwent RRBSO were matched with those who did not-by the mutated gene and year of birth (±1 year). Breast cancer rates were compared. RESULTS: Overall, 127 pairs met the inclusion criteria, 79 (60.6%) pairs harbored BRCA1 PSV and 50 (39.4%) pairs harbored BRCA2 PSV. Median follow up was 8.7 years (interquartile range 4.6-16.1 years). Breast cancer rate for all BRCA carriers combined was not affected by RRBSO (RRBSO 21 [16.5%] versus no RRBSO 31 [24.4%], hazard ratio [HR] for breast cancer 0.61, 95% confidence interval [CI] 0.33-1.14, P = 0.127). No association between RRBSO and breast cancer incidence was noted among BRCA1 PSV carriers. In BRCA2 PSV carriers, RRBSO was associated with a decreased overall breast cancer incidence (HR 0.20, 95% CI 0.44-0.91, P = 0.038), as well as after 5, 10, 15, and 20 years. Hormone replacement therapy was used by 62 PSV carriers, 52 in the RRBSO group and 10 in the no-RRBSO group and did not affect breast cancer risk (P = 0.463). CONCLUSION: RRBSO is associated with breast cancer risk reduction in Jewish Israeli BRCA2 PSV carriers. Risk-reducing bilateral salpingo-oophorectomy was associated with breast cancer risk reduction in Jewish Israeli BRCA2 pathogenic sequence variant carriers.

Spontaneous versus morcellator-related benign metastasizing leiomyoma-A retrospective study.

OBJECTIVE: To compare characteristics, disease course, and prognosis of spontaneous versus iatrogenic benign metastasizing leiomyoma (BML). METHODS: A retrospective cohort study comparing iatrogenic and spontaneous BML. RESULTS: Twenty cases were included, 12 (60%) spontaneous and 8 (40.0%) iatrogenic with a median follow up of 3.4 years. The rate of asymptomatic presentation did not differ between study groups (P = 0.157). When symptoms occurred, dyspnea was more common in the spontaneous group (66.6% vs 0%, P = 0.023) and self-palpation was more common in the iatrogenic group (57.1% vs 0%, P = 0.023). Intravascular masses were more common in the spontaneous group (66.6% vs 0%, P = 0.029). Rate of BML located in abdominal/pelvic cavity was higher in the iatrogenic group (100.0% vs 41.6%, P = 0.014). Of the 12 women in the spontaneous group, 50% had recurrent disease following surgical resection or unresectable lesions surgical resection was successfully attempted in seven of the eight (87.5%) women in the iatrogenic group, with no residual/recurrent disease. None of the patients died of her disease. CONCLUSION: Spontaneous and iatrogenic BML can probably be regarded as two separate etiologies of the same pathologic phenomenon, usually with favorable prognosis. However, spontaneous BML may have a less favorable course.

Minimally invasive approach in endometrial cancer with lower uterine segment involvement in stage ≥ II: A retrospective study.

OBJECTIVE: To compare oncological outcomes in women with lower uterine segment involvement (LUSI) in endometrial carcinoma (EC) stage ≥ II - staged by a minimally invasive surgery (MIS) versus laparotomy. STUDY DESIGN: A retrospective multi-center cohort study. Univariate analysis, Kaplan-Meier survival and Cox proportional hazard analysis were performed to compare between women staged by MIS and those staged by laparotomy. RESULTS: Over a median follow-up period of 3 years (interquartile range, 1.5-6 years) 212 women were included, 68 (32.1%) were surgically staged by MIS. Stages of disease did not vary between MIS and laparotomy and were 32.1%, 51.9%, and 16.0%, in stages II, III and IV - respectively. Adjuvant radiation and chemotherapy rate did not differ between groups. Overall recurrence rate was comparable (p = 0.084). Locoregional recurrence rate was higher in the MIS group odds ratio 2.17, 95% confidence interval 1.19-4.20). Overall and progression free survival were similar in both groups (log rank test p = 0.08 and p = 0.912 respectively). In Cox regression model adjusting for age, comorbidities, tumor grade, stage and adjuvant therapy, route of surgery (MIS vs. laparotomy) was not associated with overall survival (p = 0.169). CONCLUSIONS: In women with advanced EC and LUSI, although MIS is associated with locoregional recurrences, survival is comparable to laparotomy.

Fertility treatments and breast cancer risk in Jewish Israeli BRCA mutation carriers.

OBJECTIVE: To determine whether fertility treatments impact the risk of breast cancer in Jewish Israeli BRCA1/2 mutation carriers. DESIGN: Historical cohort study. SETTING: University-affiliated tertiary medical center. PATIENT(S): A total of 1,824 Jewish Israeli BRCA1/2 mutation carriers from a single center were stratified into 1,492 (81.8%) carriers who were not treated for infertility and 332 (18.2%) carriers who underwent fertility treatment with clomiphene citrate (n = 134), gonadotropin (n = 119), in vitro fertilization (n = 183), or a combination of treatments (n = 89). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Hazard ratios (HR) and 95% confidence intervals (CI) for the association of breast cancer with fertility treatment and other hormonal and reproductive variables. RESULT(S): Breast cancer was diagnosed in 687 BRCA1/2 mutation carriers. Multivariate analysis, either of the whole group or stratified by each gene, showed no association between fertility treatment and breast cancer risk, regardless of the type of treatment (clomiphene citrate: HR 0.77, 95% CI 0.49-1.19; gonadotropin: HR 0.54, 95% CI 0.28-1.01; in vitro fertilization: HR 0.65, 95% CI 0.39-1.08; and combined treatments: HR 1.23, 95% CI 0.49-3.06). An increased breast cancer risk was associated with paternal origin of the mutation (HR 1.43, 95% CI 1.17-1.75) and use of oral contraceptives for >5 years (HR 1.62, 95% CI 1.27-2.06) in both BRCA1 and BRCA2 mutation carriers. Ovarian cancer risk was decreased with the use of any oral contraceptive (HR 0.61; 95% CI 0.46-0.82). CONCLUSION(S): Fertility treatment for BRCA1/2 mutation carriers is not associated with a discernible increase in breast cancer risk.

Frequency and prediction of deep uterine involvement in advanced high-grade epithelial ovarian cancer: is uterine preservation an option?

INTRODUCTION: Hysterectomy is traditionally part of the surgical treatment for advanced high-grade epithelial ovarian carcinomas, although the incidence of uterine involvement has not been fully investigated. Some young patients with advanced high-grade epithelial ovarian carcinomas want uterine preservation. We aimed to determine the frequency of non-serosal (deep) uterine involvement in patients with high-grade epithelial ovarian carcinomas and to establish predictive factors for such involvement. METHODS: A retrospective cohort study was performed of 366 consecutive patients with advanced high-grade epithelial ovarian carcinomas who had surgery between January 2012 and December 2019. Data collected included demographic and clinical details, and surgical and pathological reports to determine macroscopic and microscopic deep uterine involvement. The characteristics of the patients with and without deep uterine involvement were compared and univariate and multivariate Cox proportional hazard models were used to assess correlations and determine risk factors. RESULTS: A total of 311 patients were included in the final analysis. The mean age was 62±11.6 years, with 32 (10.3%) being younger than 45. Most (92.3%) had serous carcinoma. Uterine involvement, excluding superficial (serosa-only), was present microscopically in 194 patients (62.4%) but was detected macroscopically at surgery in only 166 patients. Deep involvement was missed at surgery in 28 patients (14.4%), including parametrial involvement (n=18), parametria plus cervix (n=2), cervical involvement (n=3), endometrium (n=3), and myometrium (n=2). Multivariate analysis identified factors associated with deep uterine involvement including residual disease at surgery (HR 2.43, 95% CI 1.13 to 4.48; p=0.004) and CA125 >1000 U (HR 1.8, 95% CI 1.09 to 2.94; p=0.02). CONCLUSIONS: The incidence of deep uterine involvement in high-grade epithelial ovarian carcinomas is high. It can be diagnosed in most but not all cases on gross examination at surgery and is associated with residual disease and CA125 >1000 U. Patients who desire uterine preservation should be advised on an individual basis, given these factors and the operative findings.

Time interval from biopsy to surgery and risk for adjuvant therapy in patients with low-risk endometrial cancer.

OBJECTIVE: Among patients with endometrial cancer, longer wait times to surgery were associated with decreased survival. Although endometrial cancer survival rate is high, about 45% of patients receive adjuvant therapy. The aim of this study was to examine whether a longer interval from diagnosis to surgery is associated with increased need for adjuvant treatment among patients with low-risk endometrial cancer. METHODS: A retrospective cohort study of endometrioid endometrial cancer patients treated with surgery between the years 1999 and 2013 was conducted. Patients with pre-operative histology of hyperplasia, grade 1/2 cancers were included. Patients with stage IV disease were excluded. Demographic, clinicopathologic and surgical parameters were collected and correlation with wait time was evaluated. The risk for adjuvant therapy was in two-week intervals from biopsy to hysterectomy. RESULTS: 468 patients were included in the final cohort. 84.3% had stage I disease and 43.8% patients received adjuvant treatment. Mean time from diagnosis to surgery was 63.88 days (SD 10.3, 31-94). The risk for adjuvant therapy was not increased at any of the time intervals that were examined. CONCLUSION: In low risk endometrial cancer, longer time interval between diagnosis and surgery did not increase the need for adjuvant therapy.

Menopausal hormone therapy for BRCA-mutation carriers: attitudes of Israeli healthcare providers before and after a brief educational intervention.

OBJECTIVE: BRCA-mutation carriers are offered risk-reducing bilateral salpingo-oophorectomy (RRBSO) at age 35 to 40 years, leading to major life-quality and health-related issues associated with early menopause. Hormone therapy (HT) may significantly alleviate menopausal symptoms without increasing breast or ovarian cancer risk in BRCA carriers. We investigated attitudes of Israeli healthcare providers to HT post-RRBSO in BRCA carriers, before and after a brief educational intervention. METHODS: In this pre-post survey of gynecologic departments in Israel, healthcare providers were given questionnaires (based on scores of 1-4) assessing attitudes to prescribing HT in different clinical scenarios, before and after an educational intervention on current knowledge about HT in BRCA-mutation carriers. Higher scores indicated higher tendency to prescribe HT. Mean and median scores were calculated for each scenario, and the association between scores and various healthcare providers' characteristics were assessed. The change in attitude pre versus postintervention was evaluated, and the Cohen's d effect size was calculated. RESULTS: Of the 200 healthcare providers who were offered participation, 162 responded. Of them, 25.3% were obstetricians, 13.6% gynecologists, 5.55% gynecologic-oncologists, 8% medical oncologists, 38.9% obstetrics-gynecology residents, and 8.6% were nurses. Median age was 44 (interquartile range 36-58); 42.6% were males. Higher score correlated weakly with older age, but did not correlate with gender or personal HT/menopause experience. Significantly higher mean and median preintervention scores were obtained by gynecologists (3.2±0.96; 4 [2.25-4]) and gynecologic-oncologists (3.6 ±â€Š0.78; 4 [3.6-4.0]) than by medical oncologists (2.6 ±â€Š1.06; 2.13 [1.88-3.81]), obstetricians (2.7 ±â€Š1.09; 2.25 [1.88-4.0]), residents (2.48 ±â€Š0.99; 2 [1.69-3.56]) or nurses (2.2 ±â€Š0.92; 2 [1.5-2.69]). Overall scores were higher postintervention (P < 0.001, effect size d = 0.901). The change in scores postintervention was most prominent among younger participants and nurses. CONCLUSIONS: In Israel, it is acceptable to offer HT post-RRBSO to healthy BRCA-mutation carriers. Younger healthcare workers and nurses tend to be more hesitant, yet they are more likely to adopt a pro-HT attitude after an educational intervention. Such intervention is likely to improve overall care for BRCA-mutation carriers.

Brain Metastases from Ovarian Carcinoma: An Evaluation of Prognostic Factors and Treatment.

AIMS AND OBJECTIVES: To review a series of patients with brain metastases from ovarian cancer at a single institution. To describe treatment modalities, their outcomes and to determine prognostic factors. PATIENTS AND METHODS: Between January 1995 and December 2014, 25 patients with ovarian cancer brain metastases were treated at The Sheba Medical Center. The medical records were retrospectively reviewed to collect demographic, clinical, and imaging data as well as the information on the treatment modalities used and their outcomes. RESULTS: Mean patient age at the time of brain metastasis diagnosis was 62.7 years. The median interval between the diagnosis of primary cancer and brain metastasis was 42.3 months. Neurologic deficits, headache, and seizure were the most common symptoms. The brain was the only site of metastasis in 20% of the patients. Active ovarian cancer at the time of diagnosis of brain metastasis was observed in half of the patients with systemic disease. Multiple brain metastases were observed in 25% of the patients. We treated 11 patients with surgery plus radiation therapy protocols in various orders: surgery followed by complementary whole-brain radiation therapy (WBRT), surgery followed by stereotactic radiosurgery (SRS), and surgery followed by WBRT and then by adjuvant SRS. Five patients underwent surgery alone and nine patients were treated with radiation alone (WBRT, SRS, or both). Univariate analysis for predictors of survival demonstrated that age above 62.7 years at the time of central nervous system involvement was a significant risk factor and leptomeningeal disease was a poor prognostic factor in reference to supra-tentorial lesions. Multivariate analysis for predictors of survival, however, showed that multiple brain lesions (>4) were a poor prognostic factor, and multivariate analysis of the time to progression revealed that combined treatments of surgery and radiation resulted in longer median periods of progression-free survival than each modality alone. CONCLUSION: We conclude that the only significant predictors of survival or progression-free survival in our cohort were the number of brain metastases and the treatment modality.

Microvesicle Proteomic Profiling of Uterine Liquid Biopsy for Ovarian Cancer Early Detection.

High-grade ovarian cancer (HGOC) is the leading cause of mortality from gynecological malignancies, because of diagnosis at a metastatic stage. Current screening options fail to improve mortality because of the absence of early-stage-specific biomarkers. We postulated that a liquid biopsy, such as utero-tubal lavage (UtL), may identify localized lesions better than systemic approaches of serum/plasma analysis. Further, while mutation-based assays are challenged by the rarity of tumor DNA within nonmutated DNA, analyzing the proteomic profile, is expected to enable earlier detection, as it reveals perturbations in both the tumor as well as in its microenvironment. To attain deep proteomic coverage and overcome the high dynamic range of this body fluid, we applied our method for microvesicle proteomics to the UtL samples. Liquid biopsies from HGOC patients (n = 49) and controls (n = 127) were divided into a discovery and validation sets. Data-dependent analysis of the samples on the Q-Exactive mass spectrometer provided depth of 8578 UtL proteins in total, and on average ∼3000 proteins per sample. We used support vector machine algorithms for sample classification, and crossed three feature-selection algorithms, to construct and validate a 9-protein classifier with 70% sensitivity and 76.2% specificity. The signature correctly identified all Stage I lesions. These results demonstrate the potential power of microvesicle-based proteomic biomarkers for early cancer diagnosis.

Impact of adjuvant treatment on outcome in high-risk early-stage endometrial cancer: a retrospective three-center study.

OBJECTIVE: High grade and non-endometrioid endometrial cancers carry a poor prognosis, and the lack of randomized prospective data has led to a wide range of practice regarding adjuvant therapy. The objective of this study was to evaluate the outcomes of different treatment strategies in patients with high-risk, early-stage endometrial cancer. METHODS: Patients with high-grade endometrioid, serous endometrial cancer and carcinosarcoma diagnosed between 2000 and 2012 were identified from databases in three gynecologic oncology divisions, in Toronto and in Israel. Adjuvant treatment practices differed across the centers, creating a heterogeneous cohort. A comparison of stage I patients stratified by adjuvant treatment was undertaken. Log-rank tests and Cox proportional hazards models were employed to compare recurrence and survival across treatment groups. RESULTS: 490patients with high risk endometrial cancer were identified, among them 213 patients with stage I disease. Israeli patients received more chemotherapy (41% vs 10% in stage I disease; P<0.001) than patients in Toronto. Chemotherapy was not associated with improved disease-free, disease-specific or overall survival, nor was it associated with fewer distant recurrences (50% vs 54%). Radiation was also not associated with improved recurrence or survival, nor did it affect the pattern of recurrence. On Cox multivariable analysis, neither radiation treatment nor chemotherapy were significantly associated with outcome (HR for recurrence, 0.72 for pelvic radiation (P=0.46) and 1.99 for chemotherapy (P=0.09); HR for death, 0.67 for pelvic radiation (P=0.29) and 1.03 for chemotherapy (P=0.94)). CONCLUSIONS: In this retrospective analysis, neither adjuvant radiation nor chemotherapy were associated with improved outcome in stage I, high risk endometrial cancer.

Uterine cancer in Jewish Israeli BRCA1/2 mutation carriers.

BACKGROUND: BRCA1/2 mutation carriers have an increased risk of developing ovarian cancer, leading to the recommendation of risk-reducing salpingo-oophorectomy (RRSO) at 35-40 years of age. The role, if any, that BRCA mutations play in conferring uterine cancer risk, is unresolved. METHOD: Jewish Israeli women, carriers of one of the predominant Jewish mutations in BRCA1/2 from 1998 to 2016, were recruited. Cancer diagnoses were determined through the Israeli National Cancer Registry. Uterine cancer risk was assessed by computing the standardized incidence ratio of observed-to-expected number of cases, using the exact 2-sided P value of Poisson count. RESULTS: Overall, 2627 eligible mutation carriers were recruited from 1998 to 2016, 2312 (88%) of whom were Ashkenazi Jews (1463 BRCA1, 1154 BRCA2 mutation carriers, 10 double mutation carriers). Among these participants, 1310 underwent RRSO without hysterectomy at a mean (± standard deviation) age of 43.6 years (± 4.4 years). During 32,774 women-years of follow up, 14 women developed uterine cancer, and the observed-to-expected rate of all histological subtypes was 3.98 (95% confidence interval [CI], 2.17-6.67; P < .001). For serous papillary (n = 5), the observed-to-expected ratio was 14.29 (95% CI, 4.64-33.34; P < .001), and for sarcoma (n = 4) it was 37.74 (95% CI, 10.28-96.62). These rates were also higher than those detected in a group of 1844 age- and ethnicity-matched women (53% with breast cancer). CONCLUSION: Israeli BRCA1 or BRCA2 mutation carriers are at an increased risk for developing uterine cancer, especially serous papillary and sarcoma. These elevated risks of uterine cancer should be discussed with BRCA carriers.