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Objectives: Current risk-reducing salpingo-oophorectomy (RRSO) guidelines for individuals with BRCA1/2 mutations do not account for risk variability due to BRCA1/2 cluster region mutations that are associated with varying risks for the development of breast and ovarian cancer. We assessed whether current recommendations are appropriate for individual patients considering mutation-specific risks., Methods: Using a hypothetical cohort of patients with BRCA1/2 mutations, we constructed Markov models allowing for the estimation of mean life expectancy based upon BRCA1/2 mutation, the presence of a cluster region mutation (Ovarian Cancer Cluster Region (OCCR), Breast Cancer Cluster Region (BCCR), or non-BCCR/OCCR), age at time of BRCA1/2 diagnosis (20-65), and age at time of RRSO (21-80)., Results: For all BRCA1/2 mutation types, the optimal strategy was to undergo RRSO as early as possible. For BRCA1/2 carriers who delayed RRSO or who were identified with a mutation later in life, the OCCR mutation tended to be associated with lower life expectancy estimates than the BCCR and non-BCCR/OCCR mutations. Minimal delays in RRSO (i.e., neighboring 5-year intervals) were associated with minor losses in life expectancy. Variables associated with greatest impact on life expectancy included ovarian cancer risk after RRSO, breast cancer mortality rate, non-cancer mortality associated with RRSO, and breast cancer stage distribution., Conclusions: BRCA1/2 cluster regions may provide more precise estimates of life expectancy in counselling and shared decision-making. The most appropriate timing for RRSO is a complex decision and must be individualized for each patient., Competing Interests: Declaration of competing interest The authors report no proprietary or commercial interest in any product mentioned or concept discussed in this article., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Ovarian cancer is the leading cause of gynecologic cancer death in the world, and its prevention and early diagnosis remain the key to its treatment, especially for high-grade serous carcinoma (HGSC). Accumulating epidemiological and molecular evidence has shown that HGSC originates from fallopian tube secretory cells through serous tubal intraepithelial carcinoma. Comprehensive molecular analyses and mouse studies have uncovered the key driver events for serous carcinogenesis, providing novel molecular targets. Risk-reducing bilateral salpingo-oophorectomy (RRSO) has been proposed to reduce the subsequent occurrence of serous carcinoma in high-risk patients with BRCA mutations. However, there is no management strategy for isolated precursors detected at RRSO, and the role of subsequent surgery or chemotherapy in preventing serous carcinoma remains unclear. Surgical menopause due to RRSO provides a variety of problems related to patients' quality of life, and the risks and benefits of hormone replacement are under investigation, especially for women without a previous history of breast cancer. An additional surgical option, salpingectomy with delayed oophorectomy, has been proposed to prevent surgical menopause. The number of opportunistic salpingectomies at the time of surgery for benign disease to prevent the future occurrence of HGSC has increased worldwide. Thus, the changing concept of the origin of serous carcinoma has provided us a great opportunity to develop novel diagnostic and therapeutic approaches., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Objective: Germline BRCA mutation rates in the Latina population are yet to be well described. We aimed to quantitate the rates of referral for genetic testing in qualifying women and testing completion rates in a population of women presenting for gynecologic oncology care. Results were then stratified by ethnic/racial background., Methods: Charts of new patients evaluated at a comprehensive cancer center in Southern California were reviewed. Patients qualifying for genetic testing in accordance with NCCN Guidelines version 1.2017 for breast and/or ovarian cancer genetic assessment were identified. The actual rates of prescriptions for genetic testing placed, testing completion rates, test results, as well as patients' family history were abstracted. Data were analyzed with chi-square tests., Results: Five hundred and seventy-two of 2,053 patients met testing criteria, and 256/572 (45%) were prescribed testing in accordance with the guidelines. By ethnicity, testing was prescribed in 44% of Non-Hispanic White (NHW), 44% of Latina, 46% of African-American, and 60% of Asian (p = 0.6) patients. Testing was completed in 65% of NHW, 66% of Latina, 65% of African-American, and 67% of Asian patients (p = 0.97). Completion rates were low overall: 28% of those who met testing criteria were tested (p = 0.85). Pathogenic BRCA mutations were found in 29% of NHW and 21% of Latina, 45% of African-American, and 20% of Asian patients (p = 0.4)., Conclusions: There was no difference by ethnicity in rates of testing prescription, completion, or presence of BRCA mutations. Overall, testing rates were suboptimal. BRCA mutations were found in large percentage of Latinas (21%). Further studies are underway to identify barriers to testing prescriptions and completion for Latina women., (© 2020 S. Karger AG, Basel.)

Objective: BRCA mutations are the most frequent mutations causing homologous recombination defects in epithelial ovarian cancers (EOC). Germline mutation carriers are heterozygous for the mutation and harbor one defective allele in all cells. This has been hypothesized to cause increased susceptibility to DNA damage in healthy cells as well as neoplastic ones. Our objective was to assess chemotherapy-associated toxicities in patients with epithelial ovarian cancer with and without a germline BRCA mutation., Mateials and Methods: A retrospective cohort study of patients with EOC receiving first-line platinum-based chemotherapy at a single center between 2006 and 2016. Indices of chemotoxicity, including blood counts, transfusion requirements, granulocyte colony-stimulating factor (gCSF) prescriptions, episodes of febrile neutropenia, and treatment delays were compared for BRCA mutation carriers and noncarriers., Results: A total of 90 women met the inclusion criteria, including 31 BRCA mutation carriers (34%) and 59 noncarriers (66%). Mean hemoglobin, neutrophil count, and platelet counts during treatment were comparable for the two patient groups. There was a trend toward a higher frequency of hematological events in BRCA mutation carriers (neutropenia <1500 per mL: 6% vs. 0%, p = .12; thrombocytopenia <100,000 per mL: 23% vs. 9%, p = .07), but these differences were not statistically significant. Similarly, no significant differences were found in surrogates of bone marrow toxicity such as blood transfusions, use of gCSF, episodes of febrile neutropenia, or treatment delays., Conclusion: BRCA mutation carriers and noncarriers receiving first-line platinum-based chemotherapy for EOC have similar hematologic toxicity profiles. Clinicians treating these patients can be reassured that chemotherapy dosing or schedule do not require adjustment in patients carrying BRCA mutations., Implications for Practice: Patients with ovarian cancer carrying BRCA mutations are more likely to have serous tumors and present with higher CA125 levels. Germline BRCA mutation status is not associated with increased frequency of adverse hematologic events among patients with ovarian cancer being treated with first-line platinum-based chemotherapy. Germline BRCA mutations are also not associated with more treatment delays or a lower number of courses completed in this patient population. These findings should reassure practitioners engaged in care for patients with ovarian cancer that BRCA mutation status most likely will not affect chemotherapy dosing or schedule., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2019.)

Background Clinical practices and testing strategies in patients with ovarian cancer differ worldwide. We therefor wanted to give an overview over the current data to advise best clinical practice. Materials and methods A systematic review of the literature was performed with the aim to define which ovarian cancer patients to refer for genetic counseling and how to perform genetic testing. We also discuss the timing of genetic testing and clinical relevance of the BRCA mutation status. Results The germline mutation rate in patients with ovarian cancer is high, independent of family history, age at diagnosis and histology. BRCA mutation carriers with ovarian cancer have improved survival rates. In recurrent ovarian cancer treatment by poly ADP ribose polymerase (PARP) inhibitors improves the disease-free survival in patients with BRCA mutations or homologous recombination deficiency with hazard ratios up to 0.23. But also patients with BRCA wild type show a benefit. The recently published SOLO-1 trial demonstrated a significant benefit for patients with germline BRCA mutations in the first line setting. By tumor testing about 7% additional BRCA mutations can be found but the somatic testing and interpretation of the results remains a challenge. Despite the clinical impact, analysis of our own data and also international publications show insufficient referral rates for genetic counseling. Conclusions Genetic testing in ovarian cancer has a prognostic and predictive value. Referral rates must be improved.

Ovarian cancer is the second most common and the most lethal gynecological malignancy in the western world. Unfortunately, there are lack of methods for early screening and diagnosis of the disease. Because of this, most of the cases are diagnosed at an advanced stage and have poor prognosis. The standard treatment of ovarian cancer is maximal cytoreductive surgical debulking followed by platinum-based chemotherapy. There are new molecular agents available for maintenance therapy of ovarian cancer including anti-angiogenic therapies, poly adenosine diphosphate ribose polymerase inhibitors, inhibitors of growth factor signaling, or folate receptor inhibitors, as well as several immunotherapeutic approaches. Niraparib is a poly adenosine diphosphate ribose polymerase inhibitor that has shown to be clinically effective as maintenance therapy in patients with platinum sensitive, recurrent ovarian cancer. Studies have shown the median duration of progression-free survival was significantly longer among those receiving niraparib than among those receiving placebo, regardless of presence or absence of BRCA gene mutations or homologous recombination deficiency status. Studies have shown that treatment-emergent Grade 3 or Grade 4 hematological events were observed in patients receiving niraparib including thrombocytopenia (33.8%), anemia (25.3%) and neutropenia (19.6%). Most of the hematological laboratory abnormalities occurred within the first three treatment cycles. After dose adjustment, the incidence of hematological abnormalities was infrequent beyond cycle 3. We are reporting two cases of Grade III/IV neutropenia and thrombocytopenia in patients treated with niraparib in our institution. Unfortunately, one of the patients succumbed to septic shock secondary to right lower lobe pneumonia while severely neutropenic. The second patient's blood counts improved after discontinuing the medication and with supportive transfusions during the hospitalization.

PARP inhibitors (PARPis) have remarkable antitumor activity in BRCA mutant ovarian carcinoma. Emerging evidence has shown that responses to PARPis are not limited to BRCA mutant tumors, but could expand to other homologous recombination deficiency (HRD) carcinomas. However, relatively little is known about the efficacy of PARPis in patients with HRD when compared to non-HRD carriers. In this systematic review, 13 clinical trials were included and analyzed for the treatment effect of PARPis on progression free survival (PFS) and overall survival (OS) for HRD (BRCA mutant HRD, n = 697; BRCA wild-type HRD, n = 478) vs. non-HRD (n = 1,417) patients. Pooled analyses of the effect of PARPis in both ovarian and nonovarian carcinoma groups showed significantly higher PFS rates at 6 months and 12 months (PFS6 and PFS12) in the HRD subgroup, as compared to the non-HRD subgroup. Within the HRD subgroup, the BRCA-mutant population achieved significantly higher PFS6 (OR: 2.29, 95% CI: 1.03-5.08) and PFS12 (OR: 1.95, 95% CI: 1.26-3.01) when compared to BRCA wild-type patients. Furthermore, within BRCA wild-type carcinomas, mutations in other HRD-related genes also led to increased PFS6 (OR: 1.72, 95% CI: 1.27-2.43) and PFS12 (OR: 1.85, 95% CI: 1.31-2.62), as compared to non-HRD counterparts. Therefore, patients with HRD carcinomas exhibited pronounced PFS advantages upon treatment with PARPis, as compared to non-HRD carcinomas. In addition to BRCA mutations, other non-BRCA HRD-related aberrations may serve as novel biomarkers for the prediction of PARPi efficacy., (© 2019 UICC.)

Introduction : The implementation of poly-ADP-ribose polymerase (PARP) inhibitors for therapy has created potential treatments for a wide spectrum of malignancies involving DNA damage repair gene abnormalities. PARPs are a group of enzymes that are responsible for detecting and repairing DNA damage and therefore play a key role in maintaining cell function and integrity. PARP inhibitors are drugs that target DNA repair deficiencies. Inhibiting PARP activity in cancer cells causes cell death. Areas covered : This review summarizes the role of PARP inhibitors in the treatment of cancer. We performed a systematic literature search in February 2019 in the electronic databases PubMed and EMBASE. Our search terms were the following: PARP, PARP inhibitors, PARPi, Poly ADP ribose polymerase, cancer treatment. We discuss PARP inhibitors currently being investigated in cancer clinical trials, their safety profiles, clinical resistance, combined therapeutic approaches and future challenges. Expert Opinion : The future could bring novel PARP inhibitors with greater DNA trapping potential, better safety profiles and improved combined therapies involving hormonal, chemo-, radio- or immunotherapies. Progress may afford wider indications for PARP inhibitors in the treatment of cancer and the utilization for cancer prevention in high-risk mutation carriers. Research efforts should focus on identifying novel drugs that target DNA repair deficiencies.

Background: Limited evidence exists on the impact of adding a taxane, using endocrine therapy and carrying a deleterious germline BRCA mutation on ovarian reserve measured by anti-müllerian hormone (AMH) levels of young breast cancer patients receiving (neo)adjuvant cyclophosphamide- and anthracycline-based chemotherapy. Methods: This is a biomarker analysis including young (≤ 40 years) early breast cancer patients with known germline BRCA mutational status and available prospectively collected frozen plasma samples before and after chemotherapy. Chemotherapy consisted of either six cycles of FEC (5 fluorouracil 500 mg/m 2 , epirubicin 100 mg/m 2 , cyclophosphamide 500 mg/m 2 ) or three cycles of FEC followed by three cycles of docetaxel (D, 100 mg/m 2 ). Endocrine therapy consisted of tamoxifen (±GnRH agonists). AMH levels at baseline, 1 and 3 years after diagnosis were compared according to type of chemotherapy (FEC only vs. FEC-D), use of endocrine therapy (yes vs. no) and deleterious germline BRCA mutations (mutated vs. negative). Results: Out of 148 included patients, 127 (86%) received D following FEC chemotherapy, 90 (61%) underwent endocrine therapy, and 35 (24%) had deleterious germline BRCA mutations. In the whole cohort, AMH levels drastically dropped 1 year after diagnosis ( p < 0.0001) with a slight but significant recovery at 3 years ( p < 0.0001). One year after diagnosis, patients treated with FEC only had higher median AMH levels than those who received FEC-D (0.22 vs. 0.04 μg/L, p = 0.0006); no difference was observed at 3 years (0.06 and 0.18 μg/L, p = 0.47). Patients under endocrine therapy had significantly higher AMH levels than those who did not receive this treatment 1 year after diagnosis (0.12 vs. 0.02 μg/L; p = 0.008), with no difference at 3 years (0.11 and 0.20 μg/L, p = 0.22). AMH levels were similar between BRCA -mutated and BRCA -negative patients at baseline (1.94 vs. 1.66 μg/L, p = 0.53), 1 year (0.09 vs. 0.06 μg/L, p = 0.39) and 3 years (0.25 vs. 0.16 μg/L; p = 0.43) after diagnosis. Conclusions: In breast cancer patients receiving FEC chemotherapy, adding D appeared to negatively impact on their ovarian reserve in the short-term; no further detrimental effect was observed for endocrine therapy use and presence of a deleterious germline BRCA mutation.

The role of poly ADP ribose polymerase inhibitors in ovarian cancer is rapidly evolving. Three different poly ADP ribose polymerase inhibitors (olaparib, niraparib and rucaparib) have been already approved as maintenance after response to platinum-based chemotherapy; two of them (olaparib and rucaparib) also as single agents. Veliparib, a novel PARPI, showed promising results in preclinical and early clinical settings. The aim of this review is to discuss veliparib's mechanisms of action, to provide a clinical update on its safety and activity in ovarian cancer, and to highlight future perspectives for its optimal use. Veliparib favorable toxicity profile encourages its use either as monotherapy or in combination. Its peculiar neuroprotective and radio-sensitizing effect warrant further investigation.

Triple negative breast cancer (TNBC) represents a heterogeneous subtype of breast cancer characterized by an unfavorable prognosis due to its aggressive biology. The median overall survival (OS) for patients with metastatic TNBC is around 9-12 months with conventional cytotoxic agents. Considering this suboptimal outcome, which is induced despite of medical treatment, new therapeutic strategies would be urgently needed. The ultimate goal of precision medicine is to identify specific molecular alterations that permit considering effective targeted drug(s). Germline BRCA mutations occur in 10-20% of TNBC patients while somatic mutations occur in 3-5% of them. Alterations in the homologous recombination (HR) system are typical of BRCA mutant tumors, but can also be identified in tumors that do not carry this mutation, defining a subgroup of patients referred to as BRCAness. In this review, we focus on the role of homologous recombination deficiency (HRD) as both predictive and prognostic factor in different settings of TNBC patients treated with DNA damaging drugs and poly ADP ribose polymerase (PARP) inhibitors., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Research Question: This study explored the knowledge, attitudes and practice of physicians towards fertility and pregnancy-related issues in young BRCA-mutated breast cancer patients., Design: Physicians attending two international breast cancer conferences completed a 26-item questionnaire exploring fertility preservation, pregnancy during (BCP) or after breast cancer. A statistical comparison was carried out of the responses exploring the same issues in young breast cancer patients overall or specifically in those with BRCA mutations., Results: The survey was completed by 273 physicians. Ovarian tissue cryopreservation (33% versus 40%; P = 0.009) and gonadotrophin-releasing hormone analogues during chemotherapy (74% versus 81%; P = 0.001) were less commonly suggested in BRCA-mutated patients than in the overall breast cancer population. 42% of respondents agreed or were neutral on the statement that ovarian stimulation should not be considered safe in BRCA-mutated breast cancer patients. 45% and 30% agreed or were neutral on the statement that pregnancy in breast cancer survivors may increase the risk of recurrence in BRCA-mutated patients or in the overall breast cancer population, respectively (P < 0.001). 15% and 3% disagreed that transplanting the cryopreserved ovarian tissue can be considered safe in BRCA-mutated patients or in the overall breast cancer population, respectively (P < 0.001). 33.3% were against the addition of platinum agents as neoadjuvant chemotherapy in BRCA-mutated patients with BCP., Conclusions: Several misconceptions on fertility preservation and pregnancy-related issues in breast cancer patients persist even among physicians directly involved in breast cancer care. Focused research efforts to address these issues in BRCA-mutated breast cancer patients and education to improve physicians' knowledge and adherence to available guidelines are urgently needed., (Copyright © 2019 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

BRCA gene mutations are found in up to 10% of pancreatic adenocarcinoma cases. We present a description of 4 cases along with a review of the current literature regarding pathogenesis, target treatment, response and survival rates in these types of malignancies. We describe four cases of pancreatic adenocarcinoma, in three of which the BRCA2 mutation was identified, in one - BRCA1 gene alteration. Two patients underwent surgery following the neoadjuvant treatment with Folfirinox and radiotherapy; in the first case, a distal pancreatectomy with splenectomy was performed and in the second one - the Whipple's procedure. In both cases, a complete pathological response was reported. Other 2 patients were treated with Folfirinox after BRCA mutation identification and acceptable life expectancy was obtained. The association of pathologic complete response (PCR) with lower rates of local recurrence and better survival in patients with various types of adenocarcinomas is well known. Identification of such patients carrying BRCA mutations could provide an application of better personalized treatment. In some patients with pancreatic cancer, especially when there is clinical or demographic reason to suspect a genetic predisposition, a confirmation of the presence of BRCA mutations could provide an opportunity to use target treatment with beneficial outcomes regarding survival.

Background: To systematically assess the prevalence of BRCA1 and BRCA2 gene mutations in women with Hereditary Breast and/or Ovarian Cancer (HBOC) in Arab countries and to describe the variability in the BRCA gene mutations in different regions of the Arab world., Methods: Observational studies reporting prevalence of BRCA mutations from 22 Arab countries were systematically searched in databases including PUBMED, EMBASE, Web of Science, and Google Scholar. Two reviewers independently screened the studies and extracted data and assessed the risk of bias. Hoy's risk of Bias tool was used to assess the biases in individual studies. Due to substantial heterogeneity, pooled weighted estimates were calculated using Quality Effect Models (QEM) that adjust for bias, while the Random Effect Models (REM) estimates served as the sensitivity estimates., Results: Fourteen studies reporting prevalence of BRCA were included. The pooled estimate of BRCA among HBOC was 20% (95% CI: 7-36%). Subgroup analysis including only those with low risk of bias provided an estimate of 11% (95% CI: 1-27%). Levant region had higher prevalence 28% (95% CI: 11-49%) compared to Arabian Gulf region and North Africa but differences are not statistically significant, when tested using Z-test for proportions., Conclusion: Given the pooled estimates vary widely with substantial heterogeneity, larger, well-designed studies are warranted to better understand the frequency and the impact of BRCA gene mutations among Arab women., Trial Registration: International Prospective Register of Systematic Reviews (PROSPERO) registration number: CRD42018095905 .

Objective: High glucocorticoid receptor (GR) protein expression is associated with decreased progression-free survival in ovarian cancer patients and decreased sensitivity to chemotherapy in preclinical models. Prior studies suggest wild type BRCA1 promotes GR activation. The objective of this study was to characterize the relationship of tumor GR gene expression to outcome in ovarian cancer, and to evaluate the relationship of GR expression with BRCA status., Methods: Whole exome and whole genome sequencing, gene expression, and clinical data were obtained for high-grade serous ovarian cancers in The Cancer Genome Atlas. Cases with pathogenic somatic or germline BRCA1 or BRCA2 mutations were identified and classified as BRCA mutated. High or low glucocorticoid receptor expression was defined as expression above or below median of the GR / nuclear receptor subfamily 3  C1 ( NR3C1 ) gene level. Overall survival was estimated by the Kaplan-Meier method and compared by Cox regression analysis., Results: Combined germline DNA sequencing and tumor microarray expression data were available for 222 high-grade serous ovarian cancer cases. Among these, 47 had a deleterious germline and/or somatic mutation in BRCA1 or BRCA2 . In multivariate analysis, high glucocorticoid receptor gene expression was associated with decreased overall survival among ovarian cancer patients, independently of BRCA mutation status. No correlation of GR/NR3C1 gene expression with BRCA mutation status or BRCA1 or BRCA2 mRNA level was observed., Conclusions: Increased GR gene expression is associated with decreased overall survival in ovarian cancer patients, independently of BRCA mutation status. High-grade serous ovarian cancers with high GR expression and wild type BRCA have a particularly poor outcome., Competing Interests: Competing interests: SDC and The University of Chicago have been issued patents on methods of measuring GR expression in triple-negative breast cancer (TNBC) and using GR antagonists in TNBC, which while not directly related to this work on ovarian cancer, could be considered broadly relevant. The spouse of JTV has been employed at Abbott Laboratories and Takeda. JEC reports contributions from UpToDate, Inc, outside the submitted work., (© IGCS and ESGO 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Women with a germline pathogenic variant in the BReast CAncer susceptibility genes (BRCA1 or BRCA2) have an increased risk of early-onset breast and ovarian cancer. In addition to weighing cancer screening and risk-reduction options, healthy BRCA mutation carriers of childbearing age may choose to preclude passing the mutation to the next generation. In the current study, we report on preimplantation genetic diagnosis (PGD) practices in BRCA-positive Israeli women who were offered PGD at no cost. Methods: we measured PGD uptake, decision satisfaction or regret, and predictors of uptake. Of the 70 participant female carriers, only 25.7% chose to use PGD to prevent transmission of the mutation, and were not predicted by age or religious affiliation. For those who chose IVF/PGD, satisfaction with the decision regarding IVF and PGD was significantly higher than those who did not have IVF and PGD (p < 0.04). Experiencing previous infertility was the only significant predictor of uptake of IVF/PGD (p < 0.001), which may suggest that BRCA status is secondary to infertility in the decision-making process for PGD in women with a BRCA mutation.

Objective: Estimate the prevalence of cardiovascular disease risk factors and endpoints in women with BRCA mutations., Methods: Women, age 40 and older, with BRCA mutations identified in Kaiser Permanente Northern California completed a questionnaire and underwent a lipid and fasting glucose panel. Bivariable analysis of clinical and demographic factors was performed. The Atherosclerotic Cardiovascular Disease (ASCVD) calculator was used to predict 10-year risk of a cardiovascular event., Results: Of the 233 women, 19 women had intact ovaries (median age 56.0) and 214 had undergone risk-reducing salpingo-oophorectomy (RRSO). Among the 108 women with RRSO under age 50 (median age 51.0), compared to the 106 women who had RRSO at or over age 50 (median age 63.5) 6.5% vs 10.4% reported diabetes (p = 0.30), 23.2% versus 28.3% had elevated fasting blood glucose (p = 0.39), 21.3% versus 34.0% reported hypertension (p = 0.04) with median systolic blood pressure of 118 mmHg versus 125.5 mmHg (p < 0.009), 25% versus 32% reported hyperlipidemia (p = 0.40), and 42% versus 49% had any abnormal lipid test (p = 0.28). An elevated 10-year ASCVD risk of over 10% was seen in 6.1% versus 24.8% respectively (p = 0.0001)., Conclusion: Women who underwent RRSO at age of 50 and over, had higher ASCVD 10-year risk than women who underwent RRSO at younger ages most likely owing to older age at study entry. The ASCVD risks for women with BRCA mutation who had RRSO did not suggest increased risk associated with being a BRCA mutation carrier., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Epithelial ovarian cancer (EOC) remains a leading cause of cancer death in women. Approximately 10-15% of patients with EOC harbor a genetic predisposition due to mutations in BRCA1/2 genes. In the recurrent setting, prolonging time to platinum-resistance may improve progression-free survival. In BRCA1/2 mutated ovarian cancer, the use of a polyadenosine diphosphate-ribose polymerase inhibitors has been studied in the maintenance and recurrent setting. In the pivotal Phase III NOVA trial, maintenance therapy post platinum response with niraparib significantly improved outcomes in all subgroups, leading to the first polyadenosine diphosphate-ribose polymerase inhibitors approval by the US FDA in this setting. In this review, we will focus on the role of niraparib in the treatment of EOC.

Rucaparib is a potent small-molecule inhibitor of poly (ADP-ribose) polymerase (PARP) proteins (PARP-1, PARP-2 and PARP-3) that play an important role in repairing DNA damage and maintaining genomic stability. Tumors with mutations in BRCA1/2 or other homologous recombination deficiency (HRD) genes are particularly sensitive to PARP inhibitors because of "synthetic lethality", whereby a therapeutic agent can take advantage of an intrinsic weakness in DNA repair. Rucaparib has been investigated in several preclinical and clinical studies showing promising activity in BRCA -mutant and BRCA -wild-type epithelial ovarian cancers (EOCs). Dose-escalation Phase I studies have established the recommended Phase II dose to be 600 mg twice a day for oral rucaparib. Phase II and III studies have defined its role as treatment for BRCA -mutant recurrent high-grade EOC and as maintenance treatment for platinum-sensitive relapsed EOC following response to platinum-based chemotherapy. Genomic loss of heterozygosity has also been investigated as a potential signature of HRD and as a potential predictive biomarker of response. Treatment-induced adverse events (AEs) have been observed in almost all patients treated with rucaparib, but mainly lower grade; with the most common being nausea, vomiting, asthenia/fatigue, anemia and transient transaminitis. The majority of AEs occurred early in treatment, were transient and have been easily managed with supportive treatment, dose interruption or discontinuation. This review will analyze the results of clinical trials investigating efficacy and safety of rucaparib in patients with ovarian cancer., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Background: Male BRCA mutation carriers are at risk for an early onset aggressive prostate cancer. No data exist on the association of testosterone levels among these patients. We aimed to analyze testosterone and associated hormonal levels among male BRCA carriers and non-carriers., Patients and Methods: Overall 87 male carriers and 43 non-carriers aged 40-70 were prospectively enrolled. Clinical data were collected and all patients were tested for total testosterone (TT), prostate specific antigen (PSA), follicle stimulating hormone (FSH), luteinizing hormone (LH), free androgen index (FAI), sex hormone binding globulin (SHBG) and prolactin. Multivariate linear regression analysis was performed to predict TT levels., Results: The median age, mean BMI, comorbidities, PSA, FSH, LH and SHBG levels in both groups were similar. However, mean TT and FAI were higher in the carriers (16.7 nmol/l vs 13.5 nmol/l, p=0.03 and 39.5 vs 34.8, p=0.05, respectively), while prolactin was significantly lower. Multivariate analysis demonstrated that while BMI was inversely correlated to TT levels in both groups, LH was a predictor only in non-carriers., Conclusions: Carriers have higher TT and FAI levels and lower prolactin levels; but LH does not predict their TT levels. Further research in a larger cohort of BRCA carriers with and without prostate cancer should be performed., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest.

Ovarian cancer is the first cause of death from gynaecological malignancy. Germline mutation in BRCA1 and 2 , two genes involved in the mechanisms of reparation of DNA damage, are showed to be related with the incidence of breast and ovarian cancer, both sporadic and familiar. PARP is a family of enzymes involved in the base excision repair (BER) system. The introduction of inhibitors of PARP in patients with BRCA -mutated ovarian cancer is correlated with the concept of synthetic lethality. Among the PARP inhibitors introduced in clinical practice, niraparib showed interesting results in a phase III trial in the setting of maintenance treatment in ovarian cancer, after platinum-based chemotherapy. Interestingly, was niraparib showed to be efficacious not only in BRCA -mutated patients, but also in patients with other alterations of the homologous recombination (HR) system and in patients with unknown alterations. These results position niraparib as the first PARP-inhibitor with clinically and statistically significant results also in patients with no alterations in BRCA 1/2 and other genes involved in the DNA repair system. Even if the results are potentially practice-changing, the action of niraparib must be further studied and deepened., Competing Interests: Conflict of interest statement: The authors declare that there is no conflict of interest.

Inhibitors of poly(ADP-ribose) polymerase (PARP) are considered one of the most active and exciting new therapies for the treatment of ovarian cancer. The anticancer activity of PARP inhibitors is based on the DNA repair vulnerability of many ovarian cancer cells, and multiple mechanisms of action of PARP inhibitors have been identified. As single agents, PARP inhibitors have demonstrated their greatest activity in ovarian cancer cells that harbor mutations in BRCA genes. Additionally, recent phase III studies have shown that single-agent PARP inhibitor activity extends beyond BRCA-related cancers and can benefit patients with ovarian cancers that do not have known BRCA mutations, especially when clinical characteristics such as platinum sensitivity and high-grade serous histology are present. PARP inhibitors have also been combined with chemotherapy, however, overlapping myelosuppression observed with PARP inhibitor and chemotherapy combinations has hampered development of these combinations. Contrariwise, PARP inhibitor and biologic agent combinations, specifically antiangiogenic agents, appear well tolerated and show promising activity in both BRCA mutated ( BRCA m) and BRCA wild-type ( BRCA wt) cancers. Currently, multiple clinical trials are underway examining the antitumor activity of PARP inhibitor combination therapy., Competing Interests: Conflict of interest statement: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr. Matulonis reports the following conflicts of interest: Clovis: advisory board Astrazeneca: advisory board and consulting Genentech Roche: advisory board Immunogen: consulting Eli Lilly: advisory board.

The development and current widespread acceptance of clinical trials is one of the major conceptual advances in research medicine introduced during the second half of the 20th century. Despite general agreement on the scientific merits of randomization, many patients and physicians are however reluctant to participate in randomized, controlled trials. If we focus on chemoprevention in healthy subjects, it is even more essential to evaluate the ethics, logistics, patient's and doctor's acceptability, acute and late toxic effect, patient accrual and compliance of treatment. Furthermore, the decision-making process about participating in a cancer chemoprevention trial is often poorly understood. Adherence to a cancer prevention trial requires in fact a strong sense of awareness and an ability to carefully assess risks and benefits. We review the main aspects in the chemo-preventive approach to patients at high risk for breast and ovarian cancer, focusing on different pharmacological risk reduction strategies, ongoing phase III chemoprevention studies in carriers of BRCA1/2 germline mutation, the psychological and clinical factors implicated in decision making about a trial, and the possible impact of the trial design on the overall acceptability and adherence. [ABSTRACT FROM AUTHOR]

Objective: Despite substantial survival benefits of risk-reducing mastectomy (RRM) and risk-reducing bilateral salpingo-oophorectomy (RRBSO) among BRCA mutation carriers, only a minority elect to undergo these procedures. This study investigates factors that might influence decision making regarding prophylactic surgeries among women with BRCA mutations. Study Design: Unaffected BRCA mutation carriers who were counseled at our center and either underwent prophylactic surgery or participated in a high-risk surveillance program at our institution from 1998 through 2010 were included in the study. Medical records were reviewed and data collected included age, family history, parity, mutation type, history of breast biopsy or cosmetic surgery, and uptake of prophylactic surgeries. Results: Among 136 unaffected women with BRCA mutations, uptake of RRM was 42% and uptake of RRBSO was 52%. Family history of first- and second-degree relatives being deceased from breast cancer was predictive of uptake of RRM and of RRBSO (odds ratio [OR], 11.0; P = .005; and OR, 15.8; P = .023, respectively), and history of a mother lost to pelvic cancer was predictive of uptake of RRBSO (OR, 7.9; P = .001). Parity also predicted both RRM and RRBSO uptake (OR, 4.2; P = .001; and OR, 5.4; P = .003, respectively). Age at the time of genetic testing and history of breast biopsy or cosmetic surgery were not predictive of RRM uptake. Conclusion: Perceptions of cancer risk are heavily influenced by particular features of an individual''s family history and may be motivators in preventive surgery more than actual cancer risk estimations themselves. Awareness of subtle factors beyond the statistical risk for cancers is relevant when counseling at-risk women. [Copyright &y& Elsevier]

Few cell line models of epithelial ovarian cancer (EOC) have been developed for the high-grade serous (HGS) subtype, which is the most common and lethal form of gynaecological cancer. Here we describe the establishment of six new EOC cell lines spontaneously derived from HGS tumors (TOV2978G, TOV3041G and TOV3291G) or ascites (OV866(2), OV4453 and OV4485). Exome sequencing revealed somatic TP53 mutations in five of the cell lines. One cell line has a novel BRCA1 splice-site mutation, and another, a recurrent BRCA2 nonsense mutation, both of germline origin. The novel BRCA1 mutation induced abnormal splicing, mRNA instability, resulting in the absence of BRCA1 protein. None of the cell lines harbor mutations in KRAS or BRAF, which are characteristic of other EOC subtypes. SNP arrays showed that all of the cell lines exhibited structural chromosomal abnormalities, copy number alterations and regions of loss of heterozygosity, consistent with those described for HGS. Four cell lines were able to produce 3D-spheroids, two exhibited anchorage-independent growth, and three (including the BRCA1 and BRCA2 mutated cell lines) formed tumors in SCID mice. These novel HGS EOC cell lines and their detailed characterization provide new research tools for investigating the most common and lethal form of EOC.

Objective: To determine whether BRCA carriers have a decreased ovarian reserve compared with women without BRCA mutations, because BRCA mutations may lead to accelerated oocyte apoptosis due to accumulation of damaged DNA., Design: Cross-sectional study., Setting: Academic tertiary care center., Patient(s): A total of 143 women, aged 18-45 years, who underwent clinical genetic testing for BRCA deleterious mutations because of a family history of cancer, were included. The cohort was classified into three groups: BRCA1 carriers, BRCA2 carriers, and women without BRCA mutations (controls). None had a personal history of breast or ovarian cancer., Intervention(s): None., Main Outcome Measure(s): The main outcome was serum antimüllerian hormone (AMH) level. Linear and logistic regression models adjusting for age and body mass index (BMI) were performed to determine the association between BRCA mutations and AMH., Result(s): BRCA1 mutation carriers had a significant decrease in AMH levels compared with controls after adjusting for age and BMI (0.53 ng/mL [95% confidence interval (CI) 0.33-0.77 ng/mL] vs. 1.05 ng/mL [95% CI 0.76-1.40 ng/mL]). Logistic regression confirmed that BRCA1 carriers had a fourfold greater odds of having AMH <1 ng/mL compared with controls (odds ratio 4.22, 95% CI 1.48-12.0). There was no difference in AMH levels between BRCA2 carriers and controls., Conclusion(s): BRCA1 carriers have lower age- and BMI-adjusted serum AMH levels compared with women without BRCA mutations. Our results contribute to the current body of literature regarding BRCA carriers and their reproductive outcomes. Larger prospective studies with clinical outcomes such as infertility and age at menopause in this population are needed to further substantiate our findings., (Copyright © 2014 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)