BRCA1 Germline Mutation Carriers Research Articles

Factors influencing gynecologic risk reduction surgeries for BRCA1 or BRCA2 germline mutation carriers

Factors influencing gynecologic risk reduction surgeries for BRCA1 or BRCA2 germline mutation carriers

Differential methylation of circulating free DNA assessed through cfMeDiP as a new tool for breast cancer diagnosis and detection of BRCA1/2 mutation

BackgroundRecent studies have highlighted the importance of the cell-free DNA (cfDNA) methylation profile in detecting breast cancer (BC) and its different subtypes. We investigated whether plasma cfDNA methylation, using cell-free Methylated DNA Immunoprecipitation and High-Throughput Sequencing (cfMeDIP-seq), may be informative in characterizing breast cancer in patients with BRCA1/2 germline mutations for early cancer detection and response to therapy.MethodsWe enrolled 23 BC patients with germline mutation of BRCA1 and BRCA2 genes, 19 healthy controls without BRCA1/2 mutation, and two healthy individuals who carried BRCA1/2 mutations. Blood samples were collected for all study subjects at the diagnosis, and plasma was isolated by centrifugation. Cell-free DNA was extracted from 1 mL of plasma, and cfMeDIP-seq was performed for each sample. Shallow whole genome sequencing was performed on the immuno-precipitated samples. Then, the differentially methylated 300-bp regions (DMRs) between 25 BRCA germline mutation carriers and 19 non-carriers were identified. DMRs were compared with tumor-specific regions from public datasets to perform an unbiased analysis. Finally, two statistical classifiers were trained based on the GLMnet and random forest model to evaluate if the identified DMRs could discriminate BRCA-positive from healthy samples.ResultsWe identified 7,095 hypermethylated and 212 hypomethylated regions in 25 BRCA germline mutation carriers compared to 19 controls. These regions discriminate tumors from healthy samples with high accuracy and sensitivity. We show that the circulating tumor DNA of BRCA1/2 mutant breast cancers is characterized by the hypomethylation of genes involved in DNA repair and cell cycle. We uncovered the TFs associated with these DRMs and identified that proteins of the Erythroblast Transformation Specific (ETS) family are particularly active in the hypermethylated regions. Finally, we assessed that these regions could discriminate between BRCA positives from healthy samples with an AUC of 0.95, a sensitivity of 88%, and a specificity of 94.74%.ConclusionsOur study emphasizes the importance of tumor cell-derived DNA methylation in BC, reporting a different methylation profile between patients carrying mutations in BRCA1, BRCA2, and wild-type controls. Our minimally invasive approach could allow early cancer diagnosis, assessment of minimal residual disease, and monitoring of response to therapy.

The prognostic and predictive value of homologous recombination deficiency status in patients with advanced stage epithelial ovarian carcinoma after first-line platinum-based chemotherapy.

Homologous recombination (HR) comprises series of interrelated pathways that repair double-stranded DNA breaks and inter-strand crosslinks. It provides support for DNA replication to recover stalled or broken replication forks. Compared with homologous recombination proficiency (HRP), cancers with homologous recombination deficiency (HRD) are more likely to undergo cell death when treated with DNA-damaging agents, such as platinum agents, and have better disease control. Patients diagnosed with stage III/IV ovarian cancer, early stages with recurrence, who received adjuvant chemotherapy after debulking surgery, and who also had known HR status were eligible. Forty-four patients were included, with 21 in the HRD group (including 8 with germline mutations) and 23 in the HRP group. The HRD group was composed predominantly of serous carcinoma (95.2%), while mucinous (n=3) and clear cell (n=1) cases were all found in the HRP group. Stage III/IV disease was 66.7% and 91.3% in HRD and HRP groups, respectively (p=0.064). Patients who were optimally debulked to no residual disease was 90.0% and 72.7% (p=0.243), respectively. Late line use of PARP inhibitors was 33.3% and 17.4% (p=0.303). Median PFS was 22.5 months (95% CI, 18.5 - 66.6) and 21.5 months (95% CI, 18.3-39.5) (p=0.49) in HRD and HRP respectively. Median platinum free interval (PFI) was 15.8 months (95% CI 12.4-60.4) and 15.9 months (95% CI 8.3-34.1) (p=0.24), respectively. Median OS was 88.2 months (95% CI 71.2-NA) and 49.7 months (95% CI 35.1-NA) (p=0.21). The PFS of the patients with germline BRCA mutations (n=5) was 54.3 months (95% CI 23.1-NA) and 21.5 months (95% CI 18.3-39.5) in the HRP group (p=0.095); the PFI difference was 47.7 months (95% CI 17.6-NA) in the BRCA mutation group, and 15.9 months (95% CI 12.4-60.4) in HRP, showing statistical significance (p=0.039); while the median OS was NA and 49.7 months (95% CI 35.1-NA) respectively (p=0.051). When adding two additional patients with somatic BRCA mutations to the germline BRCA mutation carriers, the median OS is NA (95% CI 73, NA) versus 49.7 months (95% CI 35.1, NA) for HRP (p=0.045). HRD status was not associated with longer PFS or PFI in advanced ovarian cancer who received first line adjuvant platinum-based chemotherapy. Its role as a prognostic marker for overall survival is suggested, particularly in the subgroup with germline and somatic BRCA mutations.

Abstract A048: Utero-tubal lavage proteomic analysis: detection of ovarian cancer in BRCA mutation carriers

Abstract A048: Utero-tubal lavage proteomic analysis: detection of ovarian cancer in BRCA mutation carriers

Abstract A035: An analysis of the contribution of the glutathione and thioredoxin antioxidant pathways to triple negative breast cancer development

Abstract The accumulation of reactive oxygen species (ROS), also known as oxidative stress, occurs during tumorigenesis, for example because of changes in cell metabolism or in a cell’s microenvironment. Since elevated ROS can cause senescence or cell death, cells with increased ROS-buffering capacity are selected for during tumor initiation and progression. It is unknown, however, at which stage during carcinogenesis oxidative stress develops, which oxidative response programs are engaged, and whether there is a spatial distribution of oxidative stress within the tissue. Our lab developed a murineTrp53loxp/loxp Brca1loxp/loxp model of triple negative breast cancer (TNBC) that histologically recapitulates the disease progression of human, progressing from normal epithelium, to abnormal proliferation, before advancing to adenocarcinoma. We are applying cyclic immunofluorescence and spatial transcriptomics to study relevant antioxidant pathways in situ. These studies are complemented by analyses of previously published scRNAseq datasets from similar models. Our initial observations have shown that antioxidant expression peaks at a stage of tumorigenesis prior to frank tumor formation, suggesting that nascent tumor cells must overcome oxidative stress to progress. Inhibition of a key antioxidant pathway, the glutathione pathway, did not significantly decrease the Trp53-/- Brca1-/- cell population, and preliminary spatial transcriptomics data do not support an induction of the major players of this pathway during tumorigenesis. A closer examination of the expression patterns of these genes within the mammary gland demonstrates that they are not expressed in the cell of origin of TNBC. In contrast, members of the thioredoxin (TXN) pathway are expressed in the precursor cells of TNBC. One member of the TXN pathway, Txnrd1, is upregulated in Trp53-/- Brca1-/- glands, but not contralateral control glands. This upregulation occurs around the time of epithelial cell expansion post tumor suppressor loss. Furthermore, glutathione pathway inhibition drives Txnrd1 protein expression up in the mutant, but not wildtype glands. Together, our data support an important role for the thioredoxin pathway in reducing oxidative stress during tumorigenesis. Ongoing work aims to assess whether the thioredoxin pathway may represent a viable treatment option to prevent or slow the development of breast cancer in the Trp53/Brca1-deficient background. Insights into vulnerabilities of Brca1-deficient cells may provide BRCA1 germline mutation carriers new approaches for cancer prevention that have otherwise been limited to mastectomy and oophorectomy. Citation Format: Nomeda Girnius, Aylin Z Henstridge, Francesca Silvestri, Carman Man Chung Li, Joan S Brugge. An analysis of the contribution of the glutathione and thioredoxin antioxidant pathways to triple negative breast cancer development [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr A035.

Breast cancers in monoallelic MUTYH germline mutation carriers have clinicopathological features overlapping with those in BRCA1 germline mutation carriers.

Breast cancer patients referred to genetic counseling often undergo genetic testing with broad panels that include both breast cancer susceptibility genes as well as genes more specific for extramammary sites. As a result, patients are often incidentally found to have germline mutations in genes that are not necessarily related to breast cancer risk. One such gene is MUTYH. To understand the role MUTYH may play in breast cancer, the clinicopathological features of patients with monoallelic MUTYH germline mutation and breast cancer were examined. The clinicopathological characteristics of the breast cancers from patients with monoallelic MUTYH mutation were compared to breast cancer patients with other germline mutations in known breast cancer susceptibility genes, including ATM, BRCA1/2, CHEK2, and PALB2. The breast cancer patients who received genetic counseling but tested negative for the aforementioned gene mutations were used as a control group. Histologic characteristics of the breast cancers arising in monoallelic MUTYH mutation carriers had significantly larger tumor size, higher tumor grade, and more high-risk biomarker profiles (i.e., Her2-positive and triple-negative) than breast cancer patients with susceptibility genes, except for BRCA1. MUTYH mutation carriers also showed a trend of more frequent intratumoral divergency in terms of tumor grade and biomarker profiles. Although germline monoallelic MUTYH mutation is not thought to confer a meaningfully increased risk of breast cancer development, it may contribute to pathological aggressiveness and diversity of breast cancers when they sporadically arise in MUTYH carriers.

Aneuploidy Landscape in Precursors of Ovarian Cancer.

Serous tubal intraepithelial carcinoma (STIC) is now recognized as the main precursor of ovarian high-grade serous carcinoma (HGSC). Other potential tubal lesions include p53 signatures and tubal intraepithelial lesions. We aimed to investigate the extent and pattern of aneuploidy in these epithelial lesions and HGSC to define the features that characterize stages of tumor initiation and progression. We applied RealSeqS to compare genome-wide aneuploidy patterns among the precursors, HGSC (cases, n = 85), and histologically unremarkable fallopian tube epithelium (HU-FTE; control, n = 65). On the basis of a discovery set (n = 67), we developed an aneuploidy-based algorithm, REAL-FAST (Repetitive Element AneupLoidy Sequencing Fallopian Tube Aneuploidy in STIC), to correlate the molecular data with pathology diagnoses. We validated the result in an independent validation set (n = 83) to determine its performance. We correlated the molecularly defined precursor subgroups with proliferative activity and histology. We found that nearly all p53 signatures lost the entire Chr17, offering a "two-hit" mechanism involving both TP53 and BRCA1 in BRCA1 germline mutation carriers. Proliferatively active STICs harbor gains of 19q12 (CCNE1), 19q13.2, 8q24 (MYC), or 8q arm, whereas proliferatively dormant STICs show 22q loss. REAL-FAST classified HU-FTE and STICs into 5 clusters and identified a STIC subgroup harboring unique aneuploidy that is associated with increased proliferation and discohesive growth. On the basis of a validation set, REAL-FAST showed 95.8% sensitivity and 97.1% specificity in detecting STIC/HGSC. Morphologically similar STICs are molecularly distinct. The REAL-FAST assay identifies a potentially "aggressive" STIC subgroup harboring unique DNA aneuploidy that is associated with increased cellular proliferation and discohesive growth. REAL-FAST offers a highly reproducible adjunct technique to assist the diagnosis of STIC lesions.

Characteristics and clinical outcome of BRCA germline mutation carriers with advanced breast cancer treated with PARP (poly ADP-ribose polymerase) inhibitors: A single institution experience.

10587 Background: About 5-10% of breast cancers (BC) are related to germline BRCA 1/2 pathogenic variants (PV). Several studies have demonstrated the effectiveness of PARP inhibitors (PARPi) in this population. However, BC patients with BRCA PVs remain a challenge to treat. In this report, we aim to characterize the clinical characteristics and outcome of a single institution cohort of advanced BC patients with a BRCA PV and who received PARPi therapy. Methods: Patients with BRCA 1/2 germline PVs who presented to the University of Texas MD Anderson Cancer Center Breast Medical Oncology clinics and were treated with PARPi between 2008-2022 as part of their treatment for metastatic or recurrent disease were included in the analysis. Variables included in this analysis included age at diagnosis, family history of BC and ovarian cancer, treatment details, tumor characteristics including histological type, receptor status and clinical outcome. Descriptive statistics, the Kaplan-Meier method, and The Cox proportional hazards regression model were used to report patient characteristics and outcomes. Progression free survival (PFS) was defined as the time from treatment initiation of PARPi to disease progression or death. Overall survival (OS) was defined as the time from treatment initiation of PARPi to death of any cause. Results: One hundred and seven patients were treated with PARPi. Median age at diagnosis was 38 years (23-73). Forty-eight (44.9%) and 59 (55.1%) patients had BRCA1 and BRCA2 mutations, respectively. Ninety-seven (90.7%) had invasive ductal carcinoma and 42 (39.3%) had triple negative BC. Nineteen (17.8%) patients were de novo metastatic BC (Stage IV). Sixty-two (57.9%) patients received one or more prior lines of chemotherapy before being treated with PARPi; 24 (22.4%) patients received prior platinum. In 91 patients evaluable for clinical response, the overall response rate (ORR) was 59.4% and the duration of response (DoR) was 7 months (2.1-96.2). In platinum-naïve patients ORR was 70.4% and DoR 7.4 months (2.1-96.2). Median PFS was 8.9 months (95% CI 6.3-10.3) and median OS 25.8 mo (95% CI 18.3-30.9). In univariate analysis, first-line PARPi use (p = 0.0274) and no previous use of platinum (p = 0.0121) were statistically significant for better PFS. Hormone receptor positive BC (p = 0.0105) was statistically significant for better OS. Conclusions: In this real-world single institution cohort of advanced BC patients with BRCA germline PVs who were treated with PARPi, the ORR and outcome of patients is similar to those reported in the previous clinical trials. Platinum naïve and patients who received PARPi as 1st line therapy had a better ORR. Further studies of predictive markers of response and resistance as well as sequencing with platinums are needed to optimize the use of PARPi in this patient population.

Available Systemic Treatments and Emerging Therapies for Breast Cancer Brain Metastases

In 2023, breast cancer brain metastases (BCBrM) remain a major clinical challenge gaining well-deserved attention. Historically managed with local therapies alone, systemic therapies including small molecule inhibitors and antibody-drug conjugates (ADCs) have shown unprecedented activity in recent trials including patients with brain metastases. These advancements stem from efforts to include patients with stable and active BCBrM in early- and late-phase trial design. Tucatinib added to trastuzumab and capecitabine improves intracranial and extracranial progression-free survival and overall survival in stable and active human epidermal growth factor receptor 2 (HER2+)-positive brain metastases. Trastuzumab deruxtecan (T-DXd) has both shown impressive intracranial activity in stable and active HER2+ BCBrMs challenging historical thinking of ADCs' inability to penetrate the central nervous system (CNS). T-DXd has shown potent activity in HER2-low (immunohistochemistry scores of 1+ or 2+, non-amplified by fluorescence in situ hybridization) metastatic breast cancer and will be studied in HER2-low BCBrM as well. Novel endocrine therapies including oral selective estrogen downregulators (SERDs) and complete estrogen receptor antagonists (CERANs) are being studied in hormone receptor-positive BCBrM clinical trials due to robust intracranial activity in preclinical models. Triple-negative breast cancer (TNBC) brain metastases continue to portend the worst prognosis of all subtypes. Clinical trials leading to the approval of immune checkpoint inhibitors have enrolled few BCBrM patients leading to a lack of understanding of immunotherapies contribution in this subgroup. Data surrounding the use of poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors in patients with germline BRCA mutation carriers with CNS disease is hopeful. ADCs including those targeting low-level HER2 expression and TROP2 are under active investigation in triple-negative BCBrMs.

Multimodal treatment with curative intent in a germline BRCA2 mutant metastatic ampullary adenocarcinoma: a case report

BackgroundCancers of the Vater ampulla (ampullary cancers, ACs) account for less than 1% of all gastrointestinal tumors. ACs are usually diagnosed at advanced stage, with poor prognosis and limited therapeutic options. BRCA2 mutations are identified in up to 14% of ACs and, differently from other tumor types, therapeutic implications remain to be defined. Here, we report a clinical case of a metastatic AC patient in which the identification of a BRCA2 germline mutation drove a personalized multimodal approach with curative-intent.Case presentationA 42-year-old woman diagnosed with stage IV BRCA2 germline mutant AC underwent platinum-based first line treatment achieving major tumor response but also life-threatening toxicity. Based on this, as well as on molecular findings and expected low impact of available systemic treatment options, the patient underwent radical complete surgical resection of both primary tumor and metastatic lesions. Following an isolated retroperitoneal nodal recurrence, given the expected enhanced sensitivity to radiotherapy in BRCA2 mutant cancers, the patient underwent imaging-guided radiotherapy leading to long-lasting complete tumor remission. After more than 2 years, the disease remains radiologically and biochemically undetectable. The patient accessed a dedicated screening program for BRCA2 germline mutation carriers and underwent prophylactic bilateral oophorectomy.ConclusionsEven considering the intrinsic limitations of a single clinical report, we suggest that the finding of BRCA germline mutations in ACs should be taken into consideration, together with other clinical variables, given their potential association with remarkable response to cytotoxic chemotherapy that might be burdened with enhanced toxicity. Accordingly, BRCA1/2 mutations might offer the opportunity of personalizing treatment beyond PARP inhibitors up to the choice of a multimodal approach with curative-intent.

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.

Germline BRCA mutation carriers are more likely to undergo cytoreductive surgery for relapsed, platinum sensitive, ovarian cancer

ObjectiveBRCA mutations have been associated with improved outcomes in ovarian cancer patients. This study's objective was to compare the secondary cytoreduction surgery (SCS) rates among ovarian cancer patients by BRCA mutation status. MethodsThe study was retrospective and included platinum sensitive recurrent high grade serous ovarian cancer patients from one Canadian center and two Israeli centers from January 1999 to December 2018. Demographic and genetic data, tumor characteristics, patterns of recurrence and surgical and medical treatments were obtained from electronic charts. Patients were grouped according to BRCA mutation status. Logistic regression analyses were used to explore potential prognostic factors of secondary cytoreduction. Results147 patients were enrolled, including 97 from Canada and 50 from Israel. Forty-seven patients (32%) had a BRCA mutation, including 39 (26.5%) germline mutations and 8 (5.5%) somatic mutations. Thirty-one patients (21.1%) underwent SCS. The rate of SCS was 33.3% among the germline BRCA mutation carriers and 15.7% among patients without germline BRCA mutation (p = 0.026). Predictors of secondary cytoreduction included germline BRCA mutation (OR = 2.5, p = 0.03), time to recurrence (OR = 1.004 per month, p < 0.001), absence of lymphatic recurrence (OR = 3.08, p = 0.013), three or fewer lesions at recurrence (OR = 36.74, p < 0.001) and absence of ascites (OR = 9.1, p = 0.034). After adjusting for the number of lesions at recurrence, no other variable remained a significant predictor. ConclusionGermline BRCA mutation carriers are more likely to undergo secondary cytoreduction. This may be mediated in part by lower volume disease at recurrence. This observation should be considered when planning surveillance for these patients after first-line treatment.

Dissection of transcriptome dysregulation and immune characterization in women with germline BRCA1 mutation at single-cell resolution

BackgroundHigh-grade serous carcinoma (HGSC) is the most frequent and lethal type of ovarian cancer. It has been proposed that tubal secretory cells are the origin of ovarian HGSC in women with familial BRCA1/2 mutations. However, the molecular changes underlying malignant transformation remain unknown.MethodWe performed single-cell RNA and T cell receptor sequencing of tubal fimbriated ends from 3 BRCA1 germline mutation carriers (BRCA1 carriers) and 3 normal controls with no high-risk history (non-BRCA1 carriers).ResultsExploring the transcriptomes of 19,008 cells, predominantly from BRCA1+ samples, we identified 5 major cell populations in the fallopian tubal mucosae. The secretory cells of BRCA1+ samples had differentially expressed genes involved in tumor growth and regulation, chemokine signaling, and antigen presentation compared to the wild-type BRCA1 controls. There are several novel findings in this study. First, a subset of the fallopian tubal secretory cells from one BRCA1 carrier exhibited an epithelial-to-mesenchymal transition (EMT) phenotype, which was also present in the mucosal fibroblasts. Second, we identified a previously unreported phenotypic split of the EMT secretory cells with distinct evolutionary endpoints. Third, we observed increased clonal expansion among the CD8+ T cell population from BRCA1+ carriers. Among those clonally expanded CD8+ T cells, PD-1 was significantly increased in tubal mucosae of BRCA1+ patients compared with that of normal controls, indicating that T cell exhaustion may occur before the development of any premalignant or malignant lesions.ConclusionThese results indicate that EMT and immune evasion in normal-looking tubal mucosae may represent early events leading to the development of HGSC in women with BRCA1 germline mutation. Our findings provide a probable molecular mechanism explaining why some, but not all, women with BRCA1 germline mutation present with early development and rapid dissemination of HGSC.

Single-cell analysis of the tubal transcriptome in germline BRCA1 mutation carriers: Exploring early events in carcinogenesis (123)

<b>Objectives:</b> Loss of ciliated cells in the fallopian tube has been proposed to be a primary step in tumor initiation in high-grade serous ovarian cancer (HGSOC). Our objective was to identify single-cell transcriptional networks related to ciliated cell function in the fallopian tubes of women with germline <i>BRCA1</i> mutations who are at high risk of developing HGSOC. <b>Methods:</b> Four women aged 38-44 years with pathogenic germline <i>BRCA1</i> mutations underwent risk-reducing surgery at an urban, academic tertiary care center. Under the supervision of a pathologist, fallopian tube ampullae were collected, digested and primary cells were reconstituted in a single-cell suspension. Single-cell RNA-sequencing libraries were prepared using the Chromium Next GEM Single Cell 3' kit with a cell recovery target of 2000-8000 cells. Libraries were sequenced on an Illumina NovaSeq 6000. Seurat v3 and Harmony were used for data dimensionality reduction, cell cluster identification, and classification. Ancestry-based cluster analysis and pseudo-time trajectory analysis were performed using Harmony and Monocle 3. <b>Results:</b> Integrated analysis of 6015 cells from four <i>BRCA1</i> tubal epithelia samples identified ten cell clusters with unique transcriptional profiles. Of these, clusters 4 and 10 had features of ciliated cells. Cluster 4 cells expressed <i>PAX8, RFX2, RFX3,</i> and <i>FOXJ1</i> associated with an intermediate phase ciliated and secretory cell phenotype. Gene ontology analysis showed upregulation of cilia-related genes and stemness pathways, including an upregulation of the gene, <i>SNAI2,</i> belonging to stem-cell development pathway (Enrichment score [ES]: 6.30, p=1.83 x 10^-3). Cluster 10 cells expressed <i>RFX2</i> and <i>RFX3</i> associated with early progenitor ciliated cells, and gene ontology analysis showed upregulation of stemness pathways, with <i>SOX17, SOX18,</i> and <i>NOTCH1</i> regulating stem-cell proliferation (ES: 7.45, p=5.79 x10^-4). Trajectory analysis identified an early progenitor ciliated cell population and a late-stage ciliated cell population with stem-cell populations intermediate to the two populations. Cells belonging to Cluster 4 showed transitionary features and are identified at all branch points along the trajectory. <b>Conclusions:</b> Single-cell RNA sequencing analysis of the tubal epithelia from <i>BRCA1</i> mutation carriers identified select clusters having progenitor and stem-like transcriptional profiles of secretory and ciliated cells, with the <i>SOX18, PAX8, RFX2,</i> and <i>RFX3</i> genes defining these cell populations. Trajectory analysis indicated the differential potential of the ciliated cells to be involved in malignant transformation. The implications of these findings will be further explored by comparison to wild-type and HGSOC transcriptomes.

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

Matched cohort study of germline BRCA mutation carriers with triple negative breast cancer in brightness

In the BrighTNess trial, carboplatin added to neoadjuvant chemotherapy (NAC) was associated with increased pathologic complete response (pCR) rates in patients with stage II/III triple-negative breast cancer (TNBC). In this matched cohort study, cases with a germline BRCA1/2 mutation (gBRCA; n = 75) were matched 1:2 with non-gBRCA controls (n = 150) by treatment arm, lymph node status, and age to evaluate pCR rates and association of benefit from platinum/PARP inhibitors with validated RNA expression-based immune, proliferation, and genomic instability scores among gBRCA with the addition of carboplatin ± veliparib to NAC. Among the well-matched cohorts, odds of pCR were not higher in gBRCA cancers who received standard NAC with carboplatin (OR 0.24, 95% CI [0.04-1.24], p = 0.09) or with carboplatin/veliparib (OR 0.44, 95% CI [0.10-1.84], p = 0.26) compared to non-gBRCA cancers. Higher PAM50 proliferation, GeparSixto immune, and CIN70 genomic instability scores were each associated with higher pCR rate in the overall cohort, but not specifically in gBRCA cases. In this study, gBRCA carriers did not have higher odds of pCR than non-gBRCA controls when carboplatin ± veliparib was added to NAC, and showed no significant differences in molecular, immune, chromosomal instability, or proliferation gene expression metrics.

Endometrial cancer in germline BRCA mutation carriers: a systematic review and meta-analysis

<h3>Results:</h3> The search produced a total of 924 results. After duplicate removal and primary review, 41 articles were selected for full review, and 11 studies that reported the outcome of interest were included in the final meta-analysis. In total, 13871 carriers of <i>BRCA1</i> and <i>BRCA2</i> mutations were identified. The pooled prevalence rates of EC and UPSC in <i>BRCA1/2</i> mutations carriers were 82/13827 (0.59%) and 19/11582 (0.16%), respectively. EC prevalence was 46/7429 (0.62%) in <i>BRCA1</i>, and 17/3546 (0.47%) in <i>BRCA2</i> mutation carriers, with RR of 1.18 (95% CI 0.7-2.0). For UPSC, the prevalence was 15/7429 (0.2%) and 3/3546 (0.08%) among <i>BRCA1</i> and <i>BRCA2</i> mutation carriers, respectively, (RR=1.39, 95% CI 0.5-3.7). <h3>Conclusions:</h3> This meta-analysis suggests a slightly increased risk of EC in <i>BRCA</i> mutation carriers, mainly for <i>BRCA1</i>. The absolute risk is low and needs to be balanced with the potential mild increase in surgical morbidity associated with the addition of a hysterectomy.

Determinants of serum adiponectin levels: a cross-sectional study.

To review non-surgical prevention strategies in women with hereditary breast and ovarian cancer syndromes. Women with a gBRCA1 or 2 mutations face a high cumulative breast and ovarian cancer risk. While bilateral mastectomy (PBM) and bilateral salpingo-oophrectomy (PBSO) profoundly reduce the respective cancer risks, they are also associated with considerable side effects. There is therefore an urgent need for alternative and non-surgical risk reduction options. Tamoxifen and aromatase inhibitors have both been evaluated in secondary prevention, but their benefit in primary prevention is currently unknown in BRCA mutation carriers. In addition, their use is compromised by their side effect profile which makes them less appealing for a use in chemoprevention. Denosumab is a well-tolerated osteoprotective drug, which has been demonstrated to have a potential preventive effect particularly in BRCA1-deficient models in vitro. The prospectively randomized double-blind BRCA-P trial is currently investigating the preventative effect of denosumab in healthy BRCA1 germ line mutation carriers.

Management of a Prostate Cancer Patient With Inherited Germline BRCA1 and BRCA2 Mutations: A Case Report

The Breast Cancer Gene (BRCA) confers an 8.6-fold higher risk of developing prostate cancer in men ≤ 65 years of age and portends a worse prognosis as compared to noncarriers even in patients with low volume, localized disease. The BRCA2 gene, in particular, imparts a more biologically aggressive form of prostate cancer and a higher prostate cancer specific mortality. From a treatment standpoint, this translates to worse overall clinical outcomes for such patients. The most appropriate screening and management strategy for germline BRCA mutation carriers with prostate cancer is not known. Herein, we present an incidentally discovered prostate cancer in a 61-year-old BRCA1 and BRCA2 germline mutation carrier who was screened and managed using an individualized treatment approach.

Gastric Cancer in BRCA1 Germline Mutation Carriers: Results of Endoscopic Screening and Molecular Analysis of Tumor Tissues

Introduction: There is some evidence suggesting a link between BRCA1/2 germline mutations and increased risk of gastric cancer. Methods: Endoscopic screening for stomach malignancies was performed in 120 BRCA1 mutation carriers in order to evaluate the probability of detecting the tumor disease. Results: No instances of gastric cancer were revealed at the first visit. The analysis of atrophic changes performed by OLGA (Operative Link for Gastritis Assessment) criteria revealed that OLGA stages I–IV alterations were observed in 26 of 41 (63%) subjects aged >50 years as compared to 29 of 79 (37%) in younger subjects (p = 0.007, χ² test). One BRCA1 mutation carrier developed gastric cancer 4 years after the first visit for endoscopic examination. We performed next-generation sequencing analysis for this tumor and additional 4 archival gastric cancers obtained from BRCA1/2 mutation carriers. Somatic loss of the remaining BRCA1/2 allele was observed in 3 out of 5 tumors analyzed; all of these carcinomas, but none of the malignancies with the retained BRCA1/2 copy, showed chromosomal instability. Conclusion: Taken together, these data justify further studies on the relationships between the BRCA1/2 and gastric cancer.