BRCA1 Mutation Carriers Research Articles

Trends in frontline PARP inhibitor maintenance in advanced epithelial ovarian cancer across the United States.

5581 Background: Advanced epithelial ovarian cancer (AEOC) is the fifth commonest cancer mortality among women in the United States. Despite 80% initial treatment response, most recur within two years and succumb from disease. Prolonging disease free interval with maintenance therapy is of interest. Options include Poly-(ADP) ribose polymerase inhibitors (PARPi’s) and Bevacizumab, an anti-angiogenesis agent; eligibility criteria are based on clinical trials. Here we examine national approach to front line maintenance therapy following treatment in AEOC with focus on PARPi use. Methods: Protocol for data collection was IRB approved and institutional IRB approved. A retrospective, observational cohort study using Flatiron Health electronic health record (EHR)-derived, de-identified database patients diagnosed with AEOC between March 2017-June 2020, following FDA approval of PARPi use in AEOC. Demographics were summarized using descriptive statistics by use of maintenance treatment, and associations were tested using ANOVA and Chi-squared tests. Trends in use and type of maintenance therapy were summarized by year. Time trends assessed by Cochran–Armitage tests. Results: 1196 patients met inclusion criteria: Age>18, Stage III-IV, 90-day gap rule, systemic therapy after diagnosis. Majority were >65, White, Stage III with ECOG 0 at diagnosis. Only 31.6% of patients received maintenance after frontline therapy. Single agent PARPi was most used (12.9%), and Olaparib was most used PARPi (57%). Use of maintenance therapy significantly differed by ECOG value at diagnosis (p=.005), region of practice (p=.003), use of surgery (p=<.001) and extent of debulking (p=.002). Maintenance therapy was used more often when ECOG low at diagnosis, optimal debulking achieved and with treatment in the Southern US. Maintenance therapy significantly increased by year (p=<0.001); highest in 2020 (46.9%). Type of maintenance therapy had a significantly different trend by year with PARPi becoming more common (p=<.001). Conclusions: Despite known high rates of response to maintenance PARPi and increased use over time, less than 50% of patients with AEOC receive this regimen. Reasons for low adoption of maintenance PARPi in this population with poor prognosis deserves further investigation. Olaparib, approved for single use in BRCA mutation carriers in the front-line maintenance setting was used more often than Niraparib, approved for all comers. [Table: see text]

Associations of Plasma Bioactive Adrenomedullin Levels with Cardiovascular Risk Factors in BRCA1/2 Mutation Carriers

Background Cardiovascular disease (CVD) is an important cause of morbidity and mortality in breast cancer survivors. Effective screening modalities to identify CVD risk are lacking in this population. Adrenomedullin (ADM) has been suggested as a biomarker for subclinical cardiac dysfunction in the general population. Levels of ADM have been proven to be responsive to lifestyle changes that lead to improved cardiovascular health. As BRCA1/2 mutation carriers are deemed to be at an increased risk for CVD, the aim of this study was to examine plasma ADM levels in a cohort of BRCA mutation carriers and to assess their association with cardiovascular risk factors. Methods Plasma ADM concentrations were measured in 292 female BRCA1/2 mutation carriers with and without a history of breast cancer. Subjects were classified into high versus low ADM levels based on the median ADM level in the entire cohort (13.8 pg/mL). Logistic regression models were used to estimate the odds ratios (OR) of having elevated ADM levels by several cardiovascular risk factors. Results Of all women (median age: 43 years), 57.5% had a previous diagnosis of breast cancer. The median time between diagnosis and study entry was three years (range: 0 – 32 years). Women presenting with metabolic syndrome had 22-fold increased odds of having elevated ADM levels (p < 0.001). Elevated ADM levels were associated with lower cardiorespiratory fitness (OR = 0.88, p < 0.001) and several parameters of obesity (p < 0.001). ADM levels were higher in women who have ever smoked (OR = 1.72, p = 0.02). ADM levels were not associated with a previous diagnosis of breast cancer (p = 0.28). Conclusions This is the first study in BRCA mutation carriers that has linked circulating ADM levels to traditional cardiovascular risk factors. The long-term clinical implications of these findings are yet to be determined.

Methylated DNA markers discriminate ovarian cancer from benign tissue in BRCA carriers.

e17610 Background: Methylated DNA markers (MDMs) associated with sporadic ovarian cancer (OC) are detected in plasma from patients with treatment naïve tumors, but not cancer-free controls. To assess potential benefits to patients at risk for hereditary OC, the aim of this study was to measure the performance of validated sporadic OC MDMs in OC and benign ovarian tissue (BOT), surgically obtained from germline BRCA1 or BRCA2 ( BRCA1/2) mutation carriers. Methods: BRCA1/2 carriers with OC and BRCA1/2 carriers who had undergone risk-reducing salpingo-oophorectomy (SO) were identified at a comprehensive cancer center. BRCA1/2 carriers in both OC and BOT groups were balanced on age and year of surgery with non- BRCA carriers with sporadic OC or benign indications for SO. OC and BOT formalin fixed paraffin embedded (FFPE) tissues were macrodissected following pathologist selection of representative sites; DNA was extracted, and bisulfite converted. 15 OC MDMs ( GDF6, IFFO1, MAX.chr1.147790358, MAX.chr6.10382190, MAX.chr11.14926602, C2CD4D, PDRM14, NCOR2, SKI, DSCR6, SIM2, PALLD, CDO1, GPRIN1, BCAT1) previously identified in sporadic OC were assayed by quantitative methylation specific PCR, normalized by β-actin, by blinded personnel. Areas under the receiver operating characteristic curve (AUC) were generated for each MDM to assess discrimination of OC from benign tissue and compared between BRCA1/2 and sporadic (non- BRCA) patients, using a z-test. Results: Among BRCA1/2 carriers, there were 48 OC ( BRCA-OC) and 48 BOT ( BRCA-BOT); among non- BRCA, we matched 48 OC (Sporadic-OC) and 48 BOT (non- BRCA-BOT). The median AUC for OC MDM discriminated between OC and BOT with AUCs in BRCA1/2 carriers was 0.87, (IQR, 0.83-0.93). Sporadic-OC vs non- BRCA-BOT median AUC was 0.88 (IQR, 0.83-0.92). AUCs were not significantly different for each MDM when stratified by BRCA or sporadic status. MDMs with an AUC of ≥0.9 in either group are shown (Table). Conclusions: OC MDMs identified and validated in sporadic OC are highly discriminant for OC from BOT in DNA extracted from tissues of people who carry a BRCA1/2 mutation. Testing the performance of these OC MDMs in plasma from BRCA1/2 carriers with and without OC may be of clinical value for high-risk patients and inform multi-cancer early detection testing strategies.[Table: see text]

BRCA1/2 genes mutations frequency in patients with various histological types of ovarian cancer (data for South of Russia).

e17548 Background: About 10-15% of malignant ovarian tumors (OC) are associated with hereditary diseases, and about 65-85% of hereditary OC have a mutation in BRCA1/2 genes. The aim of the study was to analyze BRCA1/2 genes hereditary mutation spectrum in patients in the South of Russia diagnosed with OC. Methods: We used EDTA venous blood and FFPE-blocks of 324 patients with histologically verified epithelial OC (T1-3cNx-1Mx-1, stage I-IV). BRCA1 gene mutations (185delAG, 300T &gt; C, 2080delA, 4153delA, 5382insC, 3819delGTAAA, 3875delGTCT) and BRCA2 gene mutations (6174delT) were determined by real-time PCR. Results: The most common types of OC were poorly differentiated serous carcinoma (high degree of malignancy) - 75.6%, well-differentiated serous carcinoma (low degree of malignancy) - 13%, mucinous tumors - 2.8%, endometrioid tumors - 4.3%, clear cell adenocarcinomas - 4.3%. BRCA1/2 genes mutations were found in 52 (16%) patients with OC. The frequency of detected BRCA1/2 genes mutations was: 5382insC - 53.8%, 4153 delA - 9.6%, 300T &gt; G - 21.2%, 2080delA - 7.7%, 185delAG - 3.8%, 6174delT - 3.8%. 3819delGTAAA and 3875delGTCT mutations were not found in the BRCA1 gene. All carriers were confirmed to have the same mutations in the tumor. There were no cases of sporadic changes in BRCA1/2. BRCA1 mutation carriers prevailed in the group of high-grade serous carcinoma patients (11.1%), where all cases of BRCA2 gene mutations were identified. In the group of low-grade serous carcinoma patients, the mutation rate was 1.5%, in the endometrioid adenocarcinomas group - 0.6%, in the mixed epithelial tumors group - 2.8%. In the group of patients with mucinous tumors, mutations were not detected. Conclusions: Thus, frequency of BRCA1/2 gene mutations in OC patients living in the South of Russia was 16.0%. Distribution of mutation types in the BRCA1 gene, with a predominance of 5382insC (53.8%) and 300T &gt; G (21.2%), corresponded to their occurrence ratio in the European populations. BRCA1/2 gene mutations were registered more often in the group of high-grade serous carcinoma patients.

P23 Single-cell analysis of the tubal transcriptome in germline BRCA1 mutation carriers: exploring early events in carcinogenesis

P23 Single-cell analysis of the tubal transcriptome in germline BRCA1 mutation carriers: exploring early events in carcinogenesis

NRG-CC008: A nonrandomized prospective clinical trial comparing the non-inferiority of salpingectomy to salpingo-oophorectomy to reduce the risk of ovarian cancer among BRCA1 carriers [SOROCk

TPS10615 Background: Studies of ovarian cancer screening in the general population have not demonstrated a reduction in ovarian cancer mortality. High-grade pelvic serous carcinomas (HGSCs) have traditionally been thought to originate from the ovarian surface epithelium. However, more recent data strongly suggests that most HGSCs originate from precursor lesions found in the distal fallopian tube. Serous tubal intra-epithelial carcinoma (STIC) lesions are found in association with HGSCs in 50-60% of cases and other early serous precursor lesions can be identified in an additional 25% of cases. The Society of Gynecologic Oncology has recently issued recommendations that salpingectomy can be considered at the completion of childbearing in indiviuals at increased genetic risk of ovarian cancer who do not agree to salpingo-oophorectomy. They also indicated that approximately 30% of BRCA1 mutation carriers choose not to remove their ovaries, and the mean age at RRSO for those who do is in the late 40s, much later than recommended age per guidelines. The purpose of this study is to compare risk-reducing approaches in high-risk women with deleterious germline BRCA1mutations; specifically, to demonstrate the non-inferiority of bilateral salpingectomy compared to bilateral salpingo-oophorectomy to reduce the incidence of ovarian cancer among deleterious germline BRCA1mutation carriers. Methods: This is a non-randomized prospective trial to determine if bilateral salpingectomy is non-inferior to bilateral salpingo-oophorectomy in terms ovarian, primary peritoneal, and fallopian tube cancer risk among gBRCA1m carriers between 35 and 50 years old. Individuals choose the treatment they want to receive in collaboration with their physician(s). The primary endpoint is the time to development of incident HGSC, specifically ovarian, primary peritoneal, or fallopian tube cancers. Secondary endpoints include measurement of health-related quality of life, estrogen deprivation symptoms, sexual function, menopausal symptoms, cancer distress, Medical Decision Making, and adverse events. Results: As of 1/31/2022, 116 individuals have been enrolled into this trial. A recent amendment was put forward to allow the following individuals to also participate in this trial: 1) Individuals who are receiving hormonal therapy for maintenance therapy (eg, tamoxifen, AIs, etc), 2) Individuals with a history of any prior cancer and have completed chemotherapy, at least 30 days ago, and 3) Individuals who are considering Assisted Reproductive Technologies (eg, IVF). Furthermore, there is ongoing consideration of allowing general Ob/Gyn providers to recruit patients to this trial and perform procedures, with proper pathology training and sign off at their hospitals. NCI grant UG1CA189867. Clinical trial information: NCT04251052.

PACSIN3 is a novel biomarker for platinum resistance BRCA mutated platinum resistance epithelial ovarian cancer.

e17540 Background: Mutations in breast cancer susceptibility gene type 1 and type 2 (BRCA1 and BRCA2) put women at a higher risk of developing epithelial ovarian cancer (EOC). In individual carrying BRCA1 mutation has about 39-49% of the probability developing EOC in a lifetime. With BRCA2 mutations, the probability of developing EOC is about 11- 18 %. EOC patients with BRCA mutations shows an advanced histological grade compared to patients with BRCA wile type and respond better to platinum therapy, showing better survival. Patients with BRCA mutation shows better response to the platinum therapy, because in the absence of functional BRCA protein, cells fail to repair intra-strand crosslinks formed by DNA cross linking agents such as platinum drugs, leading to apoptotic cell death. However, despite the good response to platinum-based chemotherapy, EOC patients inevitably develop resistance to platinum drugs resulting in disease recurrent and is a major roadblock in a clinical management of cancer that carry BRCA mutation. Therefore, here we investigated the potential novel biomarkers with bioinformatics tools by analyzing an our own RNA sequencing. Methods: RNA sequencing data from 4 platinum sensitive BRCA mutated EOC patients and 4 Platinum resistance BRCA mutated EOC patients were analysed with various bioinformatic tools including Spatial Analysis of Functional Enrichment (SAFE) analysis, and the bioinformatic analysis result was verified with variuos ovarian cancer cell lines and public data. Results: Therefore, here we investigated the potential novel biomarkers with bioinformatics tools by analyzing an our own RNA sequencing data from 4 platinum sensitive BRCA mutated EOC patients and 4 Platinum resistance BRCA mutated EOC patients. The results of our study showed 308 total differentially expressed genes (DEGs) with 138 upregulated genes and 170 downregulated genes. By applying Spatial Analysis of Functional Enrichment (SAFE) analysis, we investigated that G2/M transition of mitotic cell cycle, MAPK cascade, double strand break repair via homologous recombination were the enriched pathways with upregulation of PABPC1, DCAF13, RAD21, PACSIN3 and downregulation of GCG11, HECW2, PSMA1. Their altered expression was verified in ovarian cancer cell lines and public database which showed the significant altered expression of PACSIN3 was observed in ovarian cancer cell lines suggesting as a potential biomarker for EOC treatment. Conclusions: Platinum resistance BRCA mutation EOC is an important issue to overcome the low survival rate for EOC patients. However, until now, there was relatively not much studies in discovring the biomarker or candidate gene of target therapy. Therefore, here we suggest the PACSIN3 as a new candidate gene for target therapy in platinum resistance BRCA mutation EOC.

PARP inhibitors – a new direction in the treatment of breast and ovarian cancer

Ovarian cancer, like breast cancer, may either develop spontaneously or as a result of a family history. BRCA1 and BRCA2 mutations significantly increase the risk of both cancers at all ages. It is estimated that 3–5% of women are BRCA mutation carriers. BRCA1 mutation carriers have a 65% risk of breast cancer and 39% risk of ovarian cancer. These risks are lower among BRCA2 mutation carriers, i.e. 45% and 11% for breast and ovarian cancer, respectively. In breast and ovarian cancer with BRCA mutations, blocking the function of poly(ADP-ribose) polymerase (PARP) enzymes, including PARP1 and PARP2, causes an accumulation of DNA damage that ultimately leads to cancer cell death. Based on this mechanism, PARP inhibitors have been used in the treatment of hereditary neoplasms, in which the proper functioning of DNA damage repair systems is disturbed. In clinical trials to date, PARP inhibitors significantly extended the progression-free survival in patients with confirmed BRCA mutations. Similar results have been obtained for patients without confirmed genetic background. Currently, PARP inhibitors are increasingly approved for use in the treatment of ovarian and breast cancer. From May 2021, the Ministry of Health has reimbursed maintenance therapy with PARP inhibitors in patients with known BRCA mutation status.

Endometrial Cancer and BRCA Mutations: A Systematic Review.

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

BRCA1 haploinsufficiency promotes chromosomal amplification under Fenton reaction-based carcinogenesis through ferroptosis-resistance

Germline-mutation in BRCA1 tumor suppressor gene is an established risk for carcinogenesis not only in females but also in males. Deficiency in the repair of DNA double-strand breaks is hypothesized as a responsible mechanism for carcinogenesis. However, supporting data is insufficient both in the mutation spectra of cancers in the patients with BRCA1 germline-mutation and in murine knockout/knock-in models of Brca1 haploinsufficiency. Furthermore, information on the driving force toward carcinogenesis in BRCA1 mutation carriers is lacking. Here we applied Fenton reaction-based renal carcinogenesis to a rat heterozygously knockout model of BRCA1 haploinsufficiency (mutant [MUT] model; L63X/+). Rat MUT model revealed significant promotion of renal cell carcinoma (RCC) induced by ferric nitrilotriacetate (Fe-NTA). Array-based comparative genome hybridization of the RCCs identified significant increase in chromosomal amplification, syntenic to those in breast cancers of BRCA1 mutation carriers, including c-Myc, in comparison to those in the wild-type. Subacute-phase analysis of the kidney after repeated Fe-NTA treatment in the MUT model revealed dysregulated iron metabolism with mitochondrial malfunction assessed by expression microarray and electron microscopy, leading to renal tubular proliferation with iron overload. In conclusion, we for the first time demonstrate that biallelic wild-type BRCA1 provides more robust protection for mitochondrial metabolism under iron-catalyzed oxidative stress, preventing the emergence of neoplastic cells with chromosomal amplification. Our results suggest that oxidative stress via excess iron is a major driving force for carcinogenesis in BRCA1 haploinsufficiency, which can be a target for cancer prevention and therapeutics.

BRCA1 and BRCA2 screening of nine Chilean founder mutations through allelic-discrimination and real-time PCR in breast/ovarian cancer patients.

BackgroundIn a previous work, we identified nine founder mutations present in close to 80% of BRCA1 and BRCA2 mutation carriers, and distributed across the country. The presence of founder mutations constitutes a valuable opportunity to develop new strategies for genetic screening. Genetic tests are primarily performed by NGS sequencing, which requires sophisticated and expensive equipment, and it takes 2–3 weeks for the results to be informed to the patient. In addition, genetic tests are not covered by insurance companies in Latin American countries. In this work, we present the standardization and technical validation of a real-time PCR based methodology for allelic discrimination in order to identify the nine Chilean founder mutations in BRCA1 and BRCA2 genes.Methods and resultsWe designed nine pairs of probes and nine pairs of primers to amplify synchronically nine regions of the BRCA1/BRCA2 genes by real-time PCR, in order to identify the nine founder mutations through allelic discrimination analyses. Technical validation was performed using 90 positive and 90 negative samples for each mutation. The methodology was tested in a second group of 60 patients. Our method correctly classified carriers and non-carriers of one of the nine Chilean founder mutations with a 100% specificity and 100% sensitivity, compared with Sanger sequencing performance.ConclusionsWe develop an inexpensive, simple, and fast mutation detection method that could be implemented locally in Hospitals from the Private to Public health system. This methodology may be useful for the screening of BRCA1 and BRCA2 mutations in other populations.Supplementary InformationThe online version contains supplementary material available at 10.1007/s11033-022-07561-4.

Comparison of Outcomes Between BRCA Pathogenic Variant Carriers Undergoing Breast-Conserving Surgery Versus Mastectomy.

Although outcomes are similar following breast-conserving surgery (BCS) or mastectomy among sporadic breast cancer patients, data are mixed for women with a germline BRCA mutation. We sought to compare outcomes among a modern cohort of BRCA mutation carriers undergoing BCS versus mastectomy. Women with a BRCA mutation and an index breast cancer from 2006-2015 were retrospectively identified from institutional databases. Factors, including date of genetic testing, clinicopathologic details, and treatment characteristics, were identified. Subsequent locoregional recurrence (LRR), distant recurrence, contralateral breast cancer (CBC), breast cancer-specific survival (BCSS), and overall survival (OS) events were compared between groups. A total of 395 BRCA mutation carriers with 424 cancers were identified. Surgical treatment included BCS for 99 cancers and mastectomy for 325 cancers. Patients choosing mastectomy were more likely to have bilateral breast cancer, be younger/premenopausal, and be aware of their genetic status before surgery, and were less likely to receive radiation therapy (p < 0.001). At 7.9 years median follow-up, LRR, distant recurrence, BCSS, and OS rates did not differ between groups. CBC occurred in 5 versus 0 women treated with unilateral versus bilateral surgery, respectively, resulting is a 10-year estimated CBC risk of 14% among unilateral breast surgery patients (p < 0.001). With nearly 8 years follow-up, we report no difference in LRR, BCSS, and OS among BRCA mutation carriers who underwent BCS or mastectomy; however, we report a higher incidence of CBC among those undergoing unilateral breast surgery. These data support BCS as an option for BRCA mutation carriers willing to continue high-risk screening.

Survival of BRCA1/BRCA2-associated pT1 breast cancer patients, a cohort study

PurposeIntensive screening in BRCA1/2 mutation carriers aims to improve breast cancer (BC) prognosis. Our aim is to clarify the prognostic impact of tumor size in BRCA mutation carriers with a pT1 BC, which is currently unclear. We are especially interested in differences between pT1a, pT1b, and pT1c regarding the prognosis of node-negative breast cancer, the effect of chemotherapy, and the prevalence of lymph node involvement.MethodsFor this study, BRCA1/2-associated BC patients were selected from a nationwide cohort. Primary outcomes were 10-year overall survival (OS) per pT1a-b-c group and the effect of chemotherapy on prognosis of node-negative BC, using Kaplan–Meier and Cox models. Finally, we evaluated lymph node involvement per pT1a-b-c group.Results963 women with pT1 BRCA1/2-associated BC diagnosed between 1990 and 2017 were included, of which 679 had pN0 BC. After a median follow-up of 10.5 years, 10-year OS in patients without chemotherapy was 77.1% in pT1cN0 and lower than for pT1aN0 (91.4%, p = 0.119) and pT1bN0 (90.8%, p = 0.024). OS was better with than without chemotherapy for pT1cN0 (91.6% vs. 77.1%, p = 0.001; hazard ratio (HR) 0.56, 95% confidence interval (CI): 0.21–1.48). Lymph node involvement was 24.9% in pT1c, 18.8% in pT1b, and 8.6% in pT1a.ConclusionSmaller tumor size is associated with better OS and less lymph node involvement in pT1 BRCA1/2-associated BC patients. The results suggest that early detection in BRCA1/2 mutation carriers of pT1a/b BC may reduce mortality and the need for systemic therapy.

Common Variant in ALDH2 Modifies the Risk of Breast Cancer Among Carriers of the p.K3326* Variant in BRCA2.

The BRCA2 p.K3326* variant is considered a low-penetrance variant for breast cancer. Aldehydes that accumulate in cells under insufficient aldehyde oxidation were most recently shown to trigger carcinogenesis by promoting depletion of BRCA2 protein. Allele T of the common variant rs10744777 in the ALDH2 gene was associated with reduced expression of aldehyde dehydrogenase, the main enzyme in aldehyde oxidation. We hypothesized that this allele could modify breast cancer risk in women with the BRCA2 p.K3326* low-penetrance variant through reduced function of ALDH2, increased accumulation of cellular aldehydes, and depletion of BRCA2 protein. We genotyped 11,873 Polish women diagnosed with breast cancer and 7,615 ethnically matched controls for these two variants. Next, we extended our analysis of rs10744777 to 231 carriers of pathogenic BRCA2 mutations. BRCA2 p.K3326* variant was associated with significant increase in breast cancer risk only in those who were homozygous for the T allele of the ALDH2 rs10744777 variant (odds ratio = 1.72; 95% CI, 1.19 to 2.48; P = .003). The BRCA2 p.K3326* variant did not increase the risk of breast cancer among those who were heterozygous or homozygous for the C allele of the ALDH2 rs10744777 variant (odds ratio = 1.05; 95% CI, 0.73 to 1.51; P = .81). In the carriers of high-risk BRCA2 mutations, the TT genotype of rs10744777 conferred a modest (18%) and not significant increase in breast cancer risk. Our results suggest that BRCA2 p.K3326* variant, which is low-penetrance by itself, confers increased breast cancer risk on the background of the TT genotype of the ALDH2 rs10744777 variant in the Polish population.

Content specification for a patient decision aid for BRCA mutation carriers

Women with a pathogenic mutation in the BRCA1 or BRCA2 genes have an elevated lifetime risk of developing breast and ovarian cancer. To address this risk, women are managed with a combination of surveillance and/or risk-reduction strategies. Decisions about risk-management strategies can be complex, personal and multifactorial. The overall aim of this project is the development of a web-based patient decision-aid toolkit for BRCA mutation carriers that will improve the decision-making process by providing the user with information about their cancer risk, options for risk-management and potential benefits and side-effects.

Surgical management of BRCA-mutation carriers: A single institution experience

IntroductionThe optimal surgical management of BRCA-mutation carriers remains a subject of debate. To evaluate the appropriateness of breast cancer (BC) treatment, the oncological outcomes of BRCA-mutation carriers treated either with breast-conserving therapy (BCT) or mastectomy were compared. Additionally, the role of bilateral salpingo-oophorectomy (BSO) and potential independent predictive factors for BC treatment were analyzed. Materials and methodsWe retrospectively reviewed all the consecutive patients with a pathogenic germline mutation in the BRCA1/2 genes tested at our Institution between July 2008 and October 2018. Primary end-points were disease-free survival (DFS), distant disease-free survival (DDFS), and overall survival (OS). ResultsThe characteristics and outcomes of 124 BRCA-associated BC patients were analyzed. Overall, 69 (55.7%) and 55 (44.3%) patients underwent BCT and mastectomy, respectively; 72 (58.1%) patients underwent BSO. After a median interval of 13.3 months, 24 patients underwent mastectomy after primary BCT. There was no significant difference in terms of DFS, DDFS, and OS between patients treated with BCT or mastectomy (p = 0.39,p = 0.27,p = 0.265, respectively). Patients treated with BSO had significantly better DDFS and OS compared to ovarian conservation (p = 0.033,p = 0.040, respectively). Three independent predictive factors for BCT were identified: age ≤41 years, genetic testing performed post-operatively, and breast tumors ≤21 mm. ConclusionsOur data suggest that BRCA-mutation carriers treated with BCT present similar oncological outcomes compared to mastectomy. Ovarian preservation decreases survival. Young BRCA-mutated patients with small BCs may not need up-front mastectomy, and BSO might be performed when ovarian cancer risk epidemiologically rises and potential reproductive desire is fulfilled.

Dermatological and Dermoscopic Baselines in BRCA Mutation Carriers.

Breast cancer-associated genes 1 and 2 (BRCA1 and BRCA2) are tumor suppressor genes encoding a large protein that is involved in many essential biological processes. BRCA mutated patients show an increased risk to develop several malignancies, including cutaneous malignancies, although inconsistently across multiple studies. We carried out an observational study on the main dermatological and dermoscopic aspects in a population of patients with BRCA 1/2 mutations, to identify the main clinical and dermoscopical features in this class of patients. A total of 52 patients with BRCA mutations were included in the current analysis. Clinical, dermoscopical, and pathological data were obtained during the dermatologic visits. Out of the entire cohort, 67.3% of patients showed brown hairs and 63.5% of patients showed brown eyes, with phototype III as the most frequent phototype (69.2%). A total of 2.017 melanocytic lesions in all patients were analyzed; specifically, 40 patients (76.9%) showed a total number of nevi > 10, while regarding the main observed dermoscopic features, a prevalence of reticular pattern in 63% of cases was observed, followed by a mixed pattern in 19.2% of cases. Regarding the cutaneous examination, eruptive angiomas (eCAs) were the main dermatologic manifestations in 46.2% of patients. Out of 52 patients and during a follow-up of 24 months one patient developed an in situ melanoma. Interestingly, none of the patients with eCAs showed a TN > 10, highlighting an inverse correlation. To date, there is insufficient evidence to warrant increased surveillance in patients with BRCA mutations or with a positive family history for BRCA mutations, in the absence of standard cutaneous risk factors. Further studies with larger samples of patients are needed to better investigate dermatological and dermatoscopic features in BRCA mutation carriers.

Brain metastases in patients with ovarian cancer

Background Brain metastasis (BM) are uncommon among women with epithelial ovarian cancer (EOC). The frequency, risk factors and clinical repercussions of BM in these patients are not well described. Methods We retrospectively evaluated EOC patients treated at our center from 2002 to 2020 and assessed their clinical parameters, risk for BM development and association with overall survival (OS). This cohort has a known high frequency of BRCA mutation carriers (BRCAm) due to women of Ashkenazi Jewish descent. Results Among 1035 EOC patients, 29 (2.8%) were diagnosed with BM. The prevalence of BRCA mutations was more common among women with BM (56.5% vs. 34.3%, p = 0.033). The BM rate in patients with BRCAm was higher than the BM rate in those with wildtype BRCA (BRCAw; 5.1% vs. 2.1%, OR = 2.6; 95% CI: 1.2–5.4, p = 0.013). Median time from diagnosis to BM and from disease recurrence to BM was longer among patients with BRCAm. Median OS was not significantly different among patients with BM versus those without BM (59.4 vs. 73.4 months, p = 0.243). After BM diagnosis, median OS was not statistically significantly different between patients with BRCAm and those with BRCAw (20.6 vs. 12.3 months, p = 0.441). Treatment with poly (ADP-ribose) polymerase inhibitors and bevacizumab had no impact on subsequent development of BM. Conclusions BM are rare among EOC patients. However, the risk is three-fold higher among patients with BRCAm. BM do not significantly alter OS among EOC patients. The higher rate of BM in patients with BRCAm may be related to longer OS in this subpopulation.

Bilateral Oophorectomy and the Risk of Breast Cancer in BRCA1 Mutation Carriers: A Reappraisal.

The lack of consensus on whether bilateral oophorectomy impacts risk of developing breast cancer among BRCA1 mutation carriers might be attributed to various biases, specifically, cancer-induced testing bias due to inclusion of prevalent cases. We conducted two complementary matched case-control analyses to evaluate the association of oophorectomy and BRCA1 breast cancer. A research questionnaire was administered every two years to collect information on exposures and disease. In the first analysis, we limited the study to prevalent breast cancer cases (diagnosed prior to study entry; n = 2,962) who were matched to controls on year of birth and country of residence (n = 4,358). In the second approach, we limited to 330 incident cases (diagnosed in the follow-up period) and 1,548 matched controls. Conditional logistic regression was used to estimate the adjusted odds ratios (OR) and 95% confidence intervals (CI) of invasive breast cancer. In the first approach, there was a significant inverse association between oophorectomy and the risk of developing breast cancer [OR = 0.43; 95% confidence interval (CI), 0.34-0.55; P < 00001]. In the second approach, there was no association between oophorectomy and risk (OR = 1.21; 95% CI, 0.87-1.70; P = 0.26). The inclusion of women with a personal history of breast cancer prior to ascertainment likely impacts upon the association of oophorectomy and BRCA1 breast cancer risk. Oophorectomy is unlikely a determinant of breast cancer risk in BRCA1 mutation carriers but should be offered at age 35 to reduce the risk of ovarian and fallopian tube cancer.

Pathogenic BRCA1 variants disrupt PLK1-regulation of mitotic spindle orientation

Preneoplastic mammary tissues from human female BRCA1 mutation carriers, or Brca1-mutant mice, display unexplained abnormalities in luminal differentiation. We now study the division characteristics of human mammary cells purified from female BRCA1 mutation carriers or non-carrier donors. We show primary BRCA1 mutant/+ cells exhibit defective BRCA1 localization, high radiosensitivity and an accelerated entry into cell division, but fail to orient their cell division axis. We also analyse 15 genetically-edited BRCA1 mutant/+ human mammary cell-lines and find that cells carrying pathogenic BRCA1 mutations acquire an analogous defect in their division axis accompanied by deficient expression of features of mature luminal cells. Importantly, these alterations are independent of accumulated DNA damage, and specifically dependent on elevated PLK1 activity induced by reduced BRCA1 function. This essential PLK1-mediated role of BRCA1 in controlling the cell division axis provides insight into the phenotypes expressed during BRCA1 tumorigenesis.