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Hereditary or familial cancer syndromes are caused by inherited pathogenic variants in cancer susceptibility genes and are associated with an increased risk of developing malignancies occurring at an earlier age. BRCA-associated Hereditary Breast and Ovarian Cancer and Lynch Syndromes are the most common conditions encountered in gynaecology. Identification presents opportunities to prevent or reduce the risk of cancer, or to detect cancers at earlier stages with improved outcomes. When cancer does occur, there may be options for personalized therapeutic approaches. Cancer prevention invariably requires risk-reducing surgical treatment, which may result in irreversible loss of fertility and premature menopause; issues which must be addressed through a personalized management approach. Regular review with adjustments to plans are required as individuals pass through different reproductive life-stages. Comprehensive management requires a multi-professional approach including specialist genetics input, prevention of cancer by education, modification of risk factors and specific interventions, in addition to psychosocial support. [ABSTRACT FROM AUTHOR]

The precise classification of DNA sequences is pivotal in genomics, holding significant implications for personalized medicine. The stakes are particularly high when classifying key genetic markers such as BRAC, related to breast cancer susceptibility; BRAF, associated with various malignancies; and KRAS, a recognized oncogene. Conventional machine learning techniques often necessitate intricate feature engineering and may not capture the full spectrum of sequence dependencies. To ameliorate these limitations, this study employs an adapted U-Net architecture, originally designed for biomedical image segmentation, to classify DNA sequences.The attention mechanism was also tested LONG WITH u-Net architecture to precisely classify DNA sequences into BRAC, BRAF, and KRAS categories. Our comprehensive methodology includes rigorous data preprocessing, model training, and a multi-faceted evaluation approach. The adapted U-Net model exhibited exceptional performance, achieving an overall accuracy of 0.96. The model also achieved high precision and recall rates across the classes, with precision ranging from 0.93 to 1.00 and recall between 0.95 and 0.97 for the key markers BRAC, BRAF, and KRAS. The F1-score for these critical markers ranged from 0.95 to 0.98. These empirical results substantiate the architecture's capability to capture local and global features in DNA sequences, affirming its applicability for critical, sequence-based bioinformatics challenges. [ABSTRACT FROM AUTHOR]

Malignant pleural mesothelioma (MPM) is a rare cancer with high malignancy and aggressiveness on the pleural, caused by the following risk factors including asbestos inhalation, genetic factors, and genetic mutation. The present chemotherapy, antiangiogenic therapy, and immunotherapy methods are ineffective and the survival time of patients is very short. There is an urgent need to find potential therapeutic targets for MPM. At present, it has been found the following types of targets: gene mutation targets such as BRCA associated protein 1 (BAP1) and cyclin-dependent kinase 2A (CDKN2A); epigenetic targets such as lysine (K)-specific demethylase 4A (KDM4A) and lysine-specific demethylase 1 (LSD1), and signal protein targets such as glucose-regulated protein 78 (GRP78) and signal transducer and activator of transcription 3 (STAT3). So far, available clinical trials include phase II clinical trials of histone methyltransferase inhibitor Tazemetostat, poly (ADPribose) polymerase (PARP) inhibitor Rucaparib and cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor Abemaciclib, as well as phase I clinical trials of mesothelin-targeting chimeric antigen receptor T-cell immunotherapy (CAR-T) cell injection in the thoracic cavity and TEA domain family member (TEAD) inhibitor VT3989 and IK-930, and the results of these trials have showed certain clinical efficacy. [ABSTRACT FROM AUTHOR]

Radiotherapy is widely used in the management of advanced colorectal cancer (CRC). However, the clinical efficacy is limited by the safe irradiated dose. Sensitizing tumor cells to radiotherapy via interrupting DNA repair is a promising approach to conquering the limitation. The BRCA1–BARD1 complex has been demonstrated to play a critical role in homologous recombination (HR) DSB repair, and its functions may be affected by HERC2 or BAP1. Accumulated evidence illustrates that the ubiquitination–deubiquitination balance is involved in these processes; however, the precise mechanism for the cross-talk among these proteins in HR repair following radiation hasn't been defined. Through activity-based profiling, we identified PT33 as an active entity for HR repair suppression. Subsequently, we revealed that BAP1 serves as a novel molecular target of PT33 via a CRISPR-based deubiquitinase screen. Mechanistically, pharmacological covalent inhibition of BAP1 with PT33 recruits HERC2 to compete with BARD1 for BRCA1 interaction, interrupting HR repair. Consequently, PT33 treatment can substantially enhance the sensitivity of CRC cells to radiotherapy in vitro and in vivo. Overall, these findings provide a mechanistic basis for PT33-induced HR suppression and may guide an effective strategy to improve therapeutic gain. Pharmacological covalent inhibition of BAP1 with PT33 recruits HERC2 to compete with BARD1 for BRCA1 interaction, resulting in the interruption of BRCA1-mediated HR repair. [Display omitted] [ABSTRACT FROM AUTHOR]

Copyright of Cukurova Medical Journal / Çukurova Üniversitesi Tip Fakültesi Dergisi is the property of Cukurova University, Faculty of Medicine and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Quantifying the effect of mutations in the BRCA1 gene is useful for understanding their clinical consequences on breast cancer. Machine learning models can be applied to predict the landscape of protein variant effects that might not be always accessible by experiments. In this work, we propose a simple semi-supervised learning method using a Gaussian mixture model to predict ∼90% of the unlabeled missense variants of the BRCA1 gene collected from the ClinVar database. High-quality embeddings are used as a feature of the protein sequences, extracted using the latest pre-trained transformer-based language protein model. A statistical test show that the protein embeddings are effective and robust for predicting pathogenicity. Further, the lower representations of the features are then fed into the semi-supervised model. The prediction performance of the model only for the labeled testing data achieves an AUC score and an accuracy of 79.27% and 71.58%, respectively. Using our defined pathogenic probability score, we find that ∼94% of variants in our unlabeled dataset are well-separated into either benign or pathogenic classes according to that scoring. Our scores obtain a moderate Spearman rank correlation with the results of established unsupervised variant effect models. Finally, our approach can potentially be developed for more accurate and biologically reliable predictions of the variant effects. [ABSTRACT FROM AUTHOR]

Background: Increasing evidence has suggested a strong association of Q223R (rs1137101) and K109R (rs1137100) polymorphisms in leptin receptor (LEPR) gene with susceptibility of breast cancer (BC), but inconsistent results were obtained. To provide a quantitative assessment of this association, a systematic review and meta-analysis was performed. Methods: A literature search of PubMed, EMBASE, Google Scholar, and the Chinese National Knowledge Infrastructure was collected. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. Results: A total of 20 case-control studies for Q223R polymorphism and 8 case-control studies for K109R polymorphism were included. Significant association between Q223R polymorphism and BC risk was not found in total, Asian or Caucasian population, but in African population: allelic model, OR = 0.72, 95% CI = 0.60-0.86, p < 0.001; recessive model, OR = 0.67, 95%CI = 0.52-0.87, P = 0.003; dominant model, OR = 1.58, 95% CI = 1.15-2.17, p = 0.004; homozygous model, OR = 0.51, 95% CI = 0.36-0.78, p < 0.001. Significant association between K109R polymorphism and BC risk was not found in total or Caucasian population, but in Asian population: dominant model, OR = 0.24, 95% CI = 0.07-0.84, p = 0.03; heterozygous model, OR = 1.87, 95% CI = 1.07-3.26, p = 0.03. Conclusion: The available evidence suggests that Q223R polymorphism may be significantly associated with BC risk in African population. K109R polymorphism may be significantly associated with BC risk in Asian population. [ABSTRACT FROM AUTHOR]

Germline pathogenic variants mutations) in the BRCA1 and BRCA2 genes cause an increased risk of breast cancer and ovarian cancer. Mainstream cancer genetic testing (MCG) was introduced for breast cancer patients in our unit in 2013. Non-geneticist clinicians have been trained to offer genetic testing during initial treatment planning. We assessed the impact of timely test results on surgical decision-making. Women who had undergone mainstream genetic testing for breast cancer between September 2013 and September 2018 were identified from a prospective database. Surgical data were collected retrospectively. 580 eligible women had mainstream genetic testing. For 474 this was their first breast cancer diagnosis. The median age was 46 years (interquartile range (IQR) 38–57). The indications were: age ≤45 years for 233 (49%); triple negative disease for 192 women (40.5%); bilateral breast cancer age <60 for 39 (8%) and other for 72 (14%) women. The median time for test initiation to result was 18 days (IQR 15-21). 302 (64% received results before surgery. 88% of those found to have a BRCA mutation before surgery opted for bilateral mastectomy (compared to 5% with BRCA wild type). An additional 106 patients had a new diagnosis on a background of previous treatment. Of these all with a pathogenic variant chose bilateral mastectomy. Timely BRCA gene testing influences surgeons' and patients' choice of surgery. It reassures women with a negative result and allows those with a positive result to take an active decision about the management of their future risk. • Early access to rapid genetic testing for high risk women allows results to contribute to surgical decision-making. • Median time to receiving results was 29 calendar days9% had a pathogenic mutation. • Women with mutations were more likely to have bilateral mastectomy as their primary surgery if results were available before surgery. Those for whom results were available after surgery often chose additional risk-reducing surgery. • Only 4% of women without a mutation had bilateral mastectomy. [ABSTRACT FROM AUTHOR]

Background: Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is an immune checkpoint and regulates the immune function of T cells. However, previous findings regarding the association of CTLA-4 polymorphisms and breast cancer remain inconclusive. Therefore, we performed a meta-analysis to investigate the potential effects of Ave polymorphisms (-1722 T/C, -1661 A/G -318 C/T, +49 A/G, and CT60 A/G) in the CTLA-4 gene on breast cancer susceptibility. Methods: Relevant literatures were systematically searched through electronic databases including PubMed, EMBASE, and Web of Science up to October 10, 2021. Available data were extracted and odds ratios (ORs) with 95% confidence intervals were used to estimate the pooling effect size. The Newcastle-Ottawa Scale was applied for assessing the quality of included studies. We conducted subgroup analyses based on ethnicity and control sources to explore levels of heterogeneity. Moreover, sensitivity analysis and publication bias were assessed. Results: Finally, a total of 12 eligible studies regarding CTLA-4 polymorphisms and breast cancer were included. For overall analyses, only the +49 A/G polymorphism was significantly associated with breast cancer under allelic (OR = 1.19), dominant (OR = 1.27), and recessive (OR = 1.27) models. Ethnicity-based subgroup analysis found that the +49 A/G polymorphism has a significant risk (OR = 2.03) of breast cancer under the recessive model in the non-Asian population. Studies with hospital-based controls showed that the +49 A/G polymorphism has significant breast cancer risks under allelic (OR = 1.44), dominant (OR = 1.86), and recessive (OR = 1.60) models. In addition, those with population-based controls found that -1722 T/C polymorphism has a significant breast cancer risk under allelic (OR = 1.19) and dominant (OR = 1.26) models. Conclusion: This meta-analysis suggested that CTLA-4 + 49 A/G polymorphism may significantly associate with breast cancer susceptibility. Future studies containing various populations are helpful for evaluating the impacts of CTLA-4 polymorphisms on breast cancer susceptibility. [ABSTRACT FROM AUTHOR]

Approximately 5–10% of unselected breast cancer (BC) patients retain a hereditary predisposition related to a germline mutation in BRCA1/2 genes. The poly-ADP ribose polymerase (PARP)-inhibitors olaparib and talazoparib have been granted marketing authorization by both FDA and EMA for adults with BRCA1/2 germline mutations and HER2-negative (HER2-) advanced BC based on the results from the phase III OlympiAd and EMBRACA trials. The panel of the Italian Association of Medical Oncology (AIOM) Clinical Practice Guidelines on Breast Cancer addressed two critical clinical questions, adopting the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) approach and the Evidence to Decision framework (EtD), to develop recommendations on the use of PARP-inhibitors, with respect to single-agent chemotherapy, in patients with BRCA-related triple-negative (clinical question 1) and hormone receptor-positive (HR+)/HER2- (clinical question 2) advanced BC. Two studies were eligible (OlympiAd and EMBRACA). For both clinical questions, the Panel judged the benefit/harm balance probably in favor of the intervention, given the favorable impact in terms of PFS, ORR, and QoL at an acceptable cost in terms of toxicity; the overall certainty of the evidence was low. The panel's final recommendations were conditional in favor of PARP-inhibitors over single-agent chemotherapy in both HR+/HER2-and triple-negative BC. Finally, the Panel identified and discussed areas of uncertainty calling for further exploration. The Panel of AIOM BC Clinical Practice Guideline provided clinical recommendations on the use of PARP-inhibitors, with respect to single-agent chemotherapy, in patients with BRCA-related HER2-advanced BC by adopting the GRADE methodology. • Use of PARP-inhibitors in BRCA-related HER2-advanced BC has been addressed by the Italian Association of Medical Oncology. • The Grades of Recommendation, Assessment, Development and Evaluation (GRADE) approach has been adopted. • HR+/HER2-and triple-negative BC subtypes have been addressed in two separate clinical questions. • Germline BRCA testing in HER2-advanced BC has a predictive value, being indicated independently from familial criteria. [ABSTRACT FROM AUTHOR]

Current guidelines for the treatment of human epidermal growth factor receptor 2‒negative (HER2−) advanced breast cancer (ABC) are informed by tumor characteristics and include platinum- and non–platinum-based chemotherapy, chemotherapy plus immunotherapy, endocrine monotherapy, or endocrine therapy plus a targeted therapy. In addition, poly(adenosine diphosphate-ribose) polymerase inhibitors (PARPi) have recently demonstrated improved clinical and patient-reported outcomes and manageable toxicity profiles compared with chemotherapy in patients with germline breast cancer susceptibility gene 1 or 2 (g BRCA1/ 2)‒mutated HER2− ABC in clinical trials and are now approved to treat this patient population. This study provides complementary real-world data regarding treatment patterns, adverse events, and physician-reported treatment satisfaction in this population. This retrospective analysis using the Adelphi Real World ABC Disease Specific Programme in the United States, European Union, and Israel included patients aged ≥18 years receiving therapy for stage IIIb or IV g BRCA1/ 2-mutated HER2− ABC. Oncologists completed a patient record form detailing patient demographics, clinical assessments, and treatment history and a survey regarding their use of and satisfaction with treatments. Among the 543 patients, mean age was 55 years, 25% were premenopausal, 70% had hormone receptor‒positive (HR+) ABC, and 30% had triple-negative breast cancer (TNBC). PARPi were used in 5%, 11%, and 12% of first-line, second-line, and third-line therapies, respectively, for patients with HR+ ABC; for TNBC, percentages were 18%, 44%, and 36%. Across treatment lines, neutropenia, anemia, and nausea occurred in 16%, 24%, and 32% of patients receiving PARPi, respectively; 22%, 38%, and 33% of patients receiving platinum chemotherapy; and 20%, 20%, and 33% of patients receiving non–platinum-based chemotherapy. Physician satisfaction was highest with PARPi and with chemotherapy plus immunotherapy. Findings in this real-world population complement clinical trial observations and provide further support for treatment of patients with PARPi in g BRCA1/2 -mutated HER2− ABC. • Treatments were evaluated in germline BRCA1/2 -mutated HER2− breast cancer patients. • Physician-reported treatment patterns demonstrated PARPi use in this population. • Nausea and anemia were the most common adverse events in those receiving PARPi. • Physician satisfaction was highest with PARPi and chemotherapy plus immunotherapy. • These real-world findings lend further support for PARPi use in this population. [ABSTRACT FROM AUTHOR]

Platinum-based chemotherapy (PBC) remains the mainstay of treatments for triple-negative breast cancer (TNBC). TNBC is a heterogeneous group, the issue of whether BRCA1/2 mutation carriers have a particular sensitivity to platinum agents is inconclusive. We conducted a meta-analysis to explore the relationship between BRCA1/2 mutation and PBC susceptibility in individuals with TNBC, aiming to gain more information on the size of the benefit of PBC in BRCA1/2 mutation carriers. All studies applying PBC with a subgroup of BRCA1/2 status were included. All endpoints, including pCR and RCB in the neoadjuvant phase, DFS in the adjuvant phase, ORR, PFS, and OS in the advanced phase, were assessed using HRs and 95% Cl. From the 22 studies included, there were 2158 patients with TNBC, with 392 (18%) bearing the BRCA1/2 gene mutation. Based on 13 studies applying neoadjuvant PBC, we discovered that BRCA1/2 mutation was substantially associated with a 17.6% increased pCR rate (HR 1.32, 95% CI 1.17–1.49, p < 0.00001; I2 = 51%). Same result was observed in RCB0/I index (HR 1.38, 95% CI 1.08–1.76, P = 0.009; I2 = 0%). The meta-analysis of 6 trials addressing advanced therapy revealed that ORR rates were significantly higher in patients with BRCA1/2 mutation (HR 1.91, 95% CI 1.48–2.47, p < 0.00001; I2 = 32%), as well as PFS(HR 1.13, 95% CI 0.81–1.57, P = 0.47; I2 = 0%) and OS (HR 1.89, 95% CI 1.22–2.92, P = 0.004; I2 = 0%). According to our meta-analysis of 22 trials in TNBC, BRCA1/2 mutation carriers were significantly more sensitive to PBC regimens, especially in neoadjuvant and advanced therapy. • The platinum-based chemotherapy is recommended to apply in TNBC patients with a BRCA1/2 mutation. • BRCA1/2 mutation increases pCR rate and the incidence of RCB0/1 in TNBC patients with platinum-based neoadjuvant treatment. • BRCA1/2 mutation increases ORR rate and survival benefits in advanced TNBC patients with platinum-based treatment. [ABSTRACT FROM AUTHOR]

The objective of this study was to elucidate the molecular mechanisms underlying the potential contribution of commonly utilized plasticizers, including Diethyl phthalate (DEP), Dimethyl phthalate (DMP), and Dioctyl phthalate (DOP), to the pathogenesis of breast cancer. This study aimed to highlight the complex interactions between these environmental chemicals and key molecular pathways implicated in tumorigenesis. We employed network toxicology and molecular docking techniques to analyze the interactions between plasticizers and key proteins implicated in breast cancer. Utilizing databases such as the TCGA, we performed an expression analysis of selected key genes in breast cancer tissue compared to normal controls. Enrichment analysis was conducted to identify the biological pathways associated with these genes. Enrichment analysis highlighted the association of these plasticizer-targeted genes with pathways integral to adenocarcinoma development, suggesting a broad impact of plasticizers on hormone-dependent and other forms of cancers. Subsequent expression analysis using data from the TCGA breast cancer database indicated significant upregulation or downregulation of these genes in breast cancer tissues compared to normal controls, confirming their pivotal roles in tumor biology. Furthermore, the molecular docking analysis revealed that plasticizers, including DEP, DMP, and DOP, exhibit specific binding interactions with key proteins such as MAPK1, AKT1, SRC, ESR1, and ALB, which are crucial in the regulation of breast cancer pathogenesis. The study provides evidence that exposure to plasticizers may influence breast cancer pathogenesis through interactions with critical proteins and signaling pathways. By employing network pharmacology, protein interactions, and molecular docking, our findings highlight the potential risks posed by plasticizers. These results underscore the need for further epidemiological and clinical research to fully understand the implications of plasticizer exposure on breast cancer risk, thus informing future preventive and therapeutic strategies. [Display omitted] • This study applies network toxicology and molecular docking to elucidate the complex mechanisms through which plasticizers, including DEP, DMP, and DOP, contribute to breast cancer pathogenesis, providing a comprehensive molecular understanding of their carcinogenic potential. • By revealing the core targets and key pathways affected by plasticizers, this research highlights the intricate interactions between these chemicals and biological processes involved in the development and progression of breast cancer, shedding light on potential targets for therapeutic intervention. • The use of network toxicology and molecular docking techniques in this study promotes a more effective assessment of the toxicity of plasticizers, unveiling their molecular mechanisms of action. This approach not only advances our understanding of chemical safety but also sets a new standard for evaluating environmental factors contributing to cancer. [ABSTRACT FROM AUTHOR]

In the Emilia-Romagna region of Italy, a unique Hub and Spoke model was adopted to recognize BRCA -related breast cancer (BC) patients. Characteristics and outcomes of tumors identified by this model will be presented. This multicenter retrospective cohort study involved patients diagnosed with BRCA -related BC identified in the Emilia-Romagna region between January 2000 and December 2013. Seven provinces collected data on patient and tumor characteristics; clinical and gene testing information were also registered. Comparisons between BRCA1 and BRCA2 BC were performed. To balance different variants to identify significant predictors of survival, an inverse probability of treatment weighting (IPTW) analysis on Cox regression was conducted. From 2000 to 2013, 284 BRCA -related BC were registered (171 BRCA1 , 110 BRCA2 , and 3 BRCA1 and BRCA2). BRCA1 were diagnosed at an earlier stage compared to BRCA2 (50.1 % vs 30 %, respectively, in stage I, P = 0.0015). BRCA2 patients underwent more up-front surgery (85 % vs. 74.9 %, P = 0.049) and less chemotherapy (69.1 % vs 88.9 %, P = 0.004) than BRCA1 patients. At 11.8 years median follow-up, BRCA1 patients developed more second contralateral BC (P = 0.09), while BRCA2 had more visceral relapses (P = 0.013). No differences in overall survival (OS) between BRCA1 and BRCA2 patients (P = 0.07) were found. An advantage in OS was independently seen for patients who underwent contralateral prophylactic mastectomy (P = 0.0001) and oophorectomy (P < 0.0001). In conclusion, adopting a homogeneous regional framework provides important information about prevention and treatment strategies of BRCA -related BC and suggests using maximal surgery to improve OS. [ABSTRACT FROM AUTHOR]

To evaluate the efficacy and safety of the combination of olaparib plus trastuzumab in patients with HER2-positive advanced breast cancer (ABC) and germinal BRCA mutations (gBRCAm). OPHELIA (NCT03931551) was a single-arm, open-label, phase 2 clinical trial. Patients aged ≥18 years diagnosed with HER2-positive ABC with germinal deleterious mutations in BRCA1 or BRCA2 who had received at least one prior systemic regimen for advanced disease were enrolled. Patients received olaparib plus trastuzumab until disease progression, unacceptable toxicity, or consent withdrawal. The primary endpoint was investigator-assessed clinical benefit rate for at least 24 weeks as per RECIST v.1.1. Key secondary endpoints included overall response rate (ORR) and safety profile. A total of 68 pre-treated HER2-positive ABC patients were screened. Due to slow accrual the trial was stopped after enrolling 5 patients instead of the planned sample size of 20. Four patients achieved clinical benefit (80.0 %, 95 % CI; 28.4–99.5, p < 0.001) and the primary endpoint was met. The ORR was 60.0 % (95 % CI; 14.7–94.7), including one complete response. Four (80.0 %) patients experienced at least one treatment-related treatment-emergent adverse event (TEAE). Most TEAEs were grade 1 or 2. There were no treatment-related deaths and no new safety signals were identified. This study suggests that the combination of olaparib plus trastuzumab may be effective and safe in pre-treated patients with HER2-positive g BRCA m ABC. This ABC patient population should be further studied and not be pre-emptively excluded from clinical trials of targeted therapy for BRCA1/2 -driven cancers. • HER2 overexpression in g BRCA m is infrequent. • Olaparib plus trastuzumab showed promising efficacy in patients with HER2-positive ABC and g BRCA m. • This patient population should not be excluded from clinical trials of targeted therapy for BRCA1/2 -driven cancers. [ABSTRACT FROM AUTHOR]

• Hereditary breast cancer is not limited to pathogenic variants in BRCA1/2 but also to the presence of pathogenic variants in other BC-related high, moderate and low penetrance genes. • The clinical management of patients with hereditary BC, particularly those with gPVs in genes other than BRCA1/2, is a complex task. This complexity underscores the urgent need for guidelines based on recent evidence to ensure effective and personalised patient care. • The presence of gPVs in high, moderate, and low penetrance genes can profoundly impact BC prevention, diagnosis, and treatment strategies for patients and their families. • gPVs in BC-related genes could interfere with the response to treatment, determining resistance to some drugs or conversely being targets and predictive biomarkers for agnostic or emerging new BC therapeutic strategies. The detection of germline pathogenic variants (gPVs) in BRCA1/2 and other breast cancer (BC) genes is rising exponentially thanks to the advent of multi-gene panel testing. This promising technology, coupled with the availability of specific therapies for BC BRCA-related, has increased the number of patients eligible for genetic testing. Implementing multi-gene panel testing for hereditary BC screening holds promise to maximise benefits for patients at hereditary risk of BC. These benefits range from prevention programs to antineoplastic-targeted therapies. However, the clinical management of these patients is complex and requires guidelines based on recent evidence. Furthermore, applying multi-gene panel testing into clinical practice increases the detection of variants of uncertain significance (VUSs). This augments the complexity of patients' clinical management, becoming an unmet need for medical oncologists. This review aims to collect updated evidence on the most common BC-related genes besides BRCA1/2 , from their biological role in BC development to their potential impact in tailoring prevention and treatment strategies. [ABSTRACT FROM AUTHOR]

HER2-positive breast cancers are rare amongst BRCA mutation carriers. No data exist regarding clinicopathological characteristics and prognosis of this subgroup of patients. Using a retrospective matched cohort design, we collected data from 700 women who were diagnosed with operable invasive breast cancer from January 2006 to December 2016 and were screened for germline BRCA mutations. Clinicopathological features and survival rates were analyzed by BRCA and HER2 status. One hundred and fifteen HER2-positive/BRCA mutated cases were evaluated in comparison to the three control groups: HER2-positive/BRCA wild type (n = 129), HER2-negative/BRCA mutated (n = 222), HER2-negative/BRCA wild type (n = 234). HER2-positive breast cancers were more likely to have high histologic grade and high proliferation rate than HER2-negative neoplasms, regardless of BRCA mutation status. An interaction between BRCA mutations and HER2-positive status was found to correlate with worse survival after adjusting for prognostic variables (HR = 3.4; 95% CI: 1.3–16.7). Co-occurrence of BRCA mutations and HER2-positive status is a poor prognostic factor in patients with early or locally advanced breast cancer. This finding may be a proof of concept that a combined pharmacological intervention directed to these targets could be synergistic. • Co-occurrence of BRCA mutations and HER2-positive status is a poor prognostic factor in patients with breast cancer. • Consider an actionable role for BRCA mutations in HER2-positive disease. • Combinations of PARPi plus anti-HER2 therapies are warranted in this setting. [ABSTRACT FROM AUTHOR]

BRCA1/2 mutations play a significant role in cancer pathogenesis and predisposition particularly in breast, ovarian and prostate cancers. Thus, germline analysis of BRCA1 and BRCA2 is essential for clinical management strategies aiming at the identification of recurrent and novel mutations that could be used as a first screening approach. We analyzed germline variants of BRCA1/2 genes for 2168 individuals who had cancer diagnosis or high risk assessment due to BRCAs related cancers, referred to 10 health care centers distributed across 7 regions covering the Turkish landscape. Overall, 68 and 157 distinct mutations were identified in BRCA1 and BRCA2 , respectively. Twenty-two novel variants were reported from both genes while BRCA2 showed higher mutational heterogeneity. We herein report the collective data as BRCA Turkish consortium that confirm the molecular heterogeneity in BRCAs among Turkish population, and also as the first study presenting the both geographical, demographical and gene based landscape of all recurrent and novel mutations which some might be a founder effect in comparison to global databases. This wider perspective leads to the most accurate variant interpretations which pave the way for the more precise and efficient management affecting the clinical and molecular aspects. • A similar percentage of clinically unaffected individuals were also identified with potentially pathogenic variants. • Based on the geographic examinations, Eastern Anatolian and the Mediterranean region had the lowest positivity rates. • The Southeastern Anatolian region showed the lowest density of both patients and clinically relevant genetic changes. [ABSTRACT FROM AUTHOR]

The 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. We 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). The 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. Our 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. [ABSTRACT FROM AUTHOR]

BRCA mutation carriers have a high lifetime risk of developing breast cancer (BC) and ovarian cancer (OC). Risk-reducing salpingo-oophorectomy (RRSO) has been shown to reduce OC risk. This meta-analysis was aim to analyze the effect of RRSO on the BC risk among BRCA1/2 mutation carriers. Embase, PubMed, Web of Science, and Cochrane databases were searched for all studies investigating the effect of RRSO on BC risk. The pooled results were used to evaluate the association between RRSO and BC risk. This meta-analysis included 13,965 BRCA1 and 7,057 BRCA2 mutation carriers from 14 observational studies. The pooled results showed that RRSO lowered BC risk among BRCA1 mutation carriers [hazard ratio (HR) = 0.63, 95% confidence interval (CI): 0.49–0.81, P < 0.01] and BRCA2 mutation carriers (HR = 0.51, 95% CI: 0.34–0.75, P < 0.01). RRSO reduced BC risk in younger women with BRCA1 mutation (HR = 0.48, 95% CI: 0.30–0.77, P < 0.01) and BRCA2 mutation (HR = 0.22, 95% CI: 0.08–0.65, P < 0.01). Analysis of the efficacy of RRSO at different time intervals after surgery showed a reduction of BC risk at <5 years after surgery in BRCA1 mutation carriers (HR = 0.60, 95% CI: 0.40–0.89, P = 0.01) and BRCA2 mutation carriers (HR = 0.42, 95% CI: 0.20–0.86, P = 0.02). RRSO is an effective way to reduce BC risk among women with BRCA1/2 mutation, especially in younger women. BRCA1/2 mutation carriers could benefit from RRSO in the immediate 5 years after surgery. [ABSTRACT FROM AUTHOR]

Breast cancer remains an important public health issue, emphasizing the need for accurate and timely diagnostic methods. It is mainly characterised by BRCA gene mutations due to genetic alterations specifically BRCA1 and BRCA2 genes which maintains healthy state responsible for DNA repair in the cells. When these genes undergo mutation, they lose the ability in cellular repair mechanisms thus leading to cancer development in the target cells which is observed biologically by differential gene expression analysis or by studying the cellular morphology differences between normal and cancerous cells. In this research project, we propose a machine learning classification (ML) method to detect breast cancer based on nuclear measurements from biopsy samples due to its predictive capability to detect patterns from a given dataset and categorise types of data based on their distribution. Based on a comprehensive set of ten nuclear features, we aim to distinguish malignant mass from benign mass, providing a reliable tool for early detection and improving patient outcomes between malignant and benign tumor stages. Early detection of malignancies leads to timely intervention, potentially reducing disease progression and improving patient survival rates. In addition, the non-invasive nature of biopsy sampling coupled with the efficiency of our ML model allows for simple and accessible breast cancer screening in a variety of clinical settings. In summary, our study demonstrates the capability of ML techniques to revolutionize breast cancer detection. The potency of nuclear measurements into our classification model provides a powerful and reliable tool for early diagnosis, improving patient outcomes and enhancing breast cancer screening methods. Ultimately, we envision this technology contributing to a proactive, data-driven approach to the diagnose against breast cancer, providing contribution to be proactive for a future with detection, treatment and care. [ABSTRACT FROM AUTHOR]

Copyright of Archives Medical Review Journal / Arsiv Kaynak Tarama Dergisi is the property of Cukurova University, Faculty of Medicine and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

BRCA1/2 mutation carriers with primary breast cancer (PBC) are at high risk of contralateral breast cancer (CBC). In a nationwide cohort, we investigated the effects of chemotherapeutic agents given for PBC on CBC risk separately in BRCA1 and BRCA2 mutation carriers. BRCA1 or BRCA2 mutation carriers with an invasive PBC diagnosis from 1990 to 2017 were selected from a Dutch cohort. We estimated cumulative CBC incidence using competing risks analysis. Hazard ratios (HR) for the effect of neo-adjuvant or adjuvant chemotherapy and different chemotherapeutic agents on CBC risk were estimated using Cox regression. We included 1090 BRCA1 and 568 BRCA2 mutation carriers; median follow-up was 8.9 and 8.4 years, respectively. Ten-year cumulative CBC incidence for treatment with and without chemotherapy was 6.7% [95%CI: 5.1–8.6] and 16.7% [95%CI: 10.8–23.7] in BRCA1 and 4.8% [95%CI: 2.7–7.8] and 16.0% [95%CI: 9.3–24.4] in BRCA2 mutation carriers, respectively. Chemotherapy was associated with reduced CBC risk in BRCA1 (multivariable HR: 0.46, 95%CI: 0.29–0.74); a similar trend was observed in BRCA2 mutation carriers (HR: 0.63, 95%CI: 0.29–1.39). In BRCA1 , risk reduction was most pronounced in the first 5 years (HR: 0.32, 95%CI: 0.17–0.61). Anthracyclines and the combination of anthracyclines with taxanes were associated with substantial CBC risk reduction in BRCA1 carriers (HR: 0.34, 95%CI: 0.17–0.68 and HR: 0.22, 95%CI: 0.08–0.62, respectively). Risk-reducing effects of chemotherapy are substantial for at least 5 years and may be used in personalised CBC risk prediction in any case for BRCA1 mutation carriers. • Contralateral breast cancer (CBC) risk is high in BRCA1/2 mutation carriers. • Chemotherapy for primary breast cancer results in decreased CBC risk in BRCA1. • Anthracyclines with/without taxanes show the largest CBC risk reduction in BRCA1. • For BRCA2 similar trends are observed as in BRCA1 mutation carriers. • Chemotherapy must be considered in personalised CBC risk models. [ABSTRACT FROM AUTHOR]

Mutations in the genes called BRCA1 and BRCA2 are associated with significantly elevated lifetime risk of developing breast and ovarian cancer. This year marks 25 years since genetic tests for BRCA 1/2 mutations became available to the public. Currently, comprehensive guidelines exist regarding BRCA 1/2 testing and preventive measures in mutation carriers. As such, BRCA1/2 testing represents a precedent not only in genetic testing and management of genetic cancer risk, but also in bioethics. The goal of the current research was to offer a review and an ethical primer of the main ethical challenges related to BRCA testing. A systematic scoping review was undertaken following the PRISMA Extension for Scoping Reviews (PRISMA-ScR). Four databases were searched and 18 articles that met the inclusion criteria were synthetized narratively into a conceptual map. Ethical discussions revolved around the BRCA 1/2 gene discovery, how tests are distributed for clinical use, the choice to undergo testing, unresolved issues in receiving and disclosing test results, reproductive decision-making, and culture-specific ethics. Several unique properties of the latest developments in testing circumstances (e.g., incorporation of BRCA 1/2 testing in multi-gene or whole genome sequence panels and tests sold directly to consumers) significantly raised the complexity of ethical debates. Multidisciplinary ethical discussion is necessary to guide not only individual decision making but also societal practices and medical guidelines in light of the new technologies available and the latest results regarding psychological, social, and health outcomes in cancer previvors and survivors affected by BRCA mutations. • BRCA genetic testing is starting to expand to a broader range of individuals. • This review aims to introduce readers into the major ethical complexities of BRCA testing. • Multi-gene panels and tests sold directly to consumers significantly raise the complexity of ethical debates. • Multidisciplinary ethical discussion is necessary to guide individual decision making, medical guidelines, and societal practices. [ABSTRACT FROM AUTHOR]

To assess whether contralateral parenchymal enhancement (CPE) on MRI is associated with gene expression pathways in ER+/HER2-breast cancer, and if so, whether such pathways are related to survival. Preoperative breast MRIs were analyzed of early ER+/HER2-breast cancer patients eligible for breast-conserving surgery included in a prospective observational cohort study (MARGINS). The contralateral parenchyma was segmented and CPE was calculated as the average of the top-10% delayed enhancement. Total tumor RNA sequencing was performed and gene set enrichment analysis was used to reveal gene expression pathways associated with CPE (N = 226) and related to overall survival (OS) and invasive disease-free survival (IDFS) in multivariable survival analysis. The latter was also done for the METABRIC cohort (N = 1355). CPE was most strongly correlated with proteasome pathways (normalized enrichment statistic = 2.04, false discovery rate =.11). Patients with high CPE showed lower tumor proteasome gene expression. Proteasome gene expression had a hazard ratio (HR) of 1.40 (95% CI = 0.89, 2.16; P =.143) for OS in the MARGINS cohort and 1.53 (95% CI = 1.08, 2.14; P =.017) for IDFS, in METABRIC proteasome gene expression had an HR of 1.09 (95% CI = 1.01, 1.18; P =.020) for OS and 1.10 (95% CI = 1.02, 1.18; P =.012) for IDFS. CPE was negatively correlated with tumor proteasome gene expression in early ER+/HER2-breast cancer patients. Low tumor proteasome gene expression was associated with improved survival in the METABRIC data. • Contralateral parenchymal enhancement on MRI was associated with tumor proteasome gene expression in ER+/HER2-breast cancer. • A high contralateral parenchymal enhancement was associated with a low proteasome gene expression in the breast cancer. • Low proteasome tumor gene expression was associated with improved survival in an independent patient cohort. [ABSTRACT FROM AUTHOR]

Preliminary clinical evidence suggests a detrimental effect of pathogenic variants of BRCA1 and 2 genes on fertility outcome. This meta-analysis evaluates whether women carrying BRCA mutations (BRCAm) have decreased ovarian reserve, in terms of Anti-Muellerian Hormone (AMH), compared to women without BRCAm (wild-type). Systematic searches of PubMed, Medline, Scopus, Embase, Science Direct and the Cochrane Library from inception until July 2020 were conducted. All studies comparing AMH level in fertile age women, with and without BRCA pathogenic variants were considered. Sub-analyses were performed according to age, presence of breast cancer, and type of mutation. Among 64 studies, 10 series were included. For the entire cohort, a trend of reduced AMH level were found between BRCAm carriers and women without pathogenic variants. BRCAm carriers aged 41-years or younger had lower AMH levels compared to 41-years or younger wild type women (OR: 0.73 [95%CI-1.12;-0.35]; p = 0.0002). This finding was confirmed for BRCA1m carriers (OR: 1 [95%CI-1.96;-0.05]; p = 0.004) whereas no difference was observed between BRCA2m carriers and wild type women. The same analysis on breast cancer patients with and without BRCAm achieved the same results. Young BRCA1m carriers seem to have lower AMH level compared with wild type women and therefore a potential decreased ovarian reserve. [Display omitted] • BRCAm carriers have similar AMH levels to wild-type women. • In women under 42 years old, AMH level is statistically lower in BRCA1m. • Fertility preservation counselling should be offered once BRCA pathogenic variant is diagnosed. [ABSTRACT FROM AUTHOR]

Copyright of Biomédica: Revista del Instituto Nacional de Salud is the property of Instituto Nacional de Salud of Colombia and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Abstract: In May 2020, the poly(ADP-ribose) polymerase (PARP) inhibitors rucaparib and olaparib were Food and Drug Administration approved for the management of metastatic castration-resistant prostate cancers. Rucaparib was approved for tumors that harbor alterations in BRCA1 and BRCA2 following progression on chemotherapy and androgen receptor-directed therapy, whereas olaparib was approved for tumors that harbor alterations in a broader range of DNA damage repair genes following progression on androgen receptor-directed therapy. Loss-of-function mutations in genes such as BRCA1 and BRCA2 increase reliance on PARP-mediated mechanisms of DNA repair, and inhibition of this pathway results in the accumulation of lethal levels of DNA damage. This dependence is advantageous in the management of prostate cancer, as mutations in DNA damage repair genes are frequent. This review summarizes the role of PARP in cell homeostasis, methods of targeting PARP in cancer cells, and current clinical trials in the management of advanced prostate cancer with PARP inhibitors. [ABSTRACT FROM AUTHOR]

Some studies suggested a decreased ovarian reserve among BRCA1/2 pathogenic variant carriers, with conflicting results. We conducted a retrospective single-center observational study of ovarian reserve and spontaneous fertility comparing BRCA1/2 pathogenic variant carriers to controls (women who attended consultations to discuss fertility preservation before gonadotoxic treatment). Measures of associations between plasma AMH concentration, AFC and BRCA1/2 status were modelled by nonlinear generalized additive regression models and logistic regressions adjusted for age at plasma storage, oral contraceptive use, body mass index, cigarette smoking, and the AMH assay technique. The whole population comprised 119 BRCA 1/2 pathogenic variant carriers and 92 controls. A total of 110 women (42 carriers, among whom 30 were cancer-free, and 68 controls) underwent an ovarian reserve evaluation. Spontaneous fertility analysis included all women who previously attempted to become pregnant (134 women). We observed a tendency towards a premature decrease in ovarian reserve in BRCA1/2 pathogenic variant carriers, but no difference in mean AMH or AFC levels was found between BRCA1/2 pathogenic variant carriers and controls. An analysis of the extreme levels of AMH (≤5 pmol/l) and AFC (≤7 follicles) by logistic regression suggested a higher risk of low ovarian reserve among BRCA1/2 pathogenic variant carriers (adjusted odds ratio (OR) = 3.57, 95% CI = 1.00–12.8, p = 0.05; and adjusted OR = 4.99, 95% CI = 1.10–22.62, p = 0.04, respectively). Attention should be paid to BRCA1/2 pathogenic variant carriers' ovarian reserve, considering this potential risk of premature alteration. • A tendency towards a premature decrease in the ovarian reserve in BRCA 1/2 pathogenic variant carriers was found. • BRCA 1/2 pathogenic variant carriers presented a higher risk of a low ovarian reserve. • Information and education regarding reproduction is mandatory among BRCA 1/2 pathogenic variant carriers. [ABSTRACT FROM AUTHOR]

Risk-reducing mastectomy (RRM) is one of key prevention strategies in female carriers of germline BRCA pathogenic/likely pathogenic variants (PV/LPV). We retrospectively investigated the rate, timing and longitudinal trends of bilateral RRM uptake and the incidence and types of cancers among unaffected BRCA carriers who underwent genetic counseling at the Institute of Oncology Ljubljana in Slovenia. Female BRCA carriers without personal history of cancer were included in the study. Clinical data on PV/LPV type, date of RRM, type of reconstructive procedure, occult carcinoma and histopathology results was collected and analyzed. Of the 346 unaffected BRCA carriers (median age 43 years, 70% BRCA1 , 30% BRCA2 , median follow-up 46 months) who underwent genetic testing between October 1999 and December 2019, 25.1% had a RRM (range 35–50 years, median age at surgery 38 years). A significant difference in time to prophylactic surgery between women undergoing RRM only vs. women undergoing RRM combined with risk-reducing salpingo-oophorectomy was observed (22.6 vs 8.7 months, p = 0.0009). We observed an upward trend in the annual uptake in line with the previously observed Angelina Jolie effect. In 5.7% of cases, occult breast cancer was detected. No women developed breast cancer after RRM. Women who did not opt for surgical prevention developed BRCA1/2 -related cancers (9.3%). The uptake of RRM among unaffected BRCA carriers is 25.1% and is similar to our neighboring countries. No women developed breast cancer after RRM while women who did not opt for surgical prevention developed BRCA1/2 related cancers in 9.3% of cases. The reported data may provide meaningful aid for carriers when deciding on an optimal prevention strategy. [ABSTRACT FROM AUTHOR]

Background: Bladder cancer is considered heterogeneous diseases with two major subgroups: non-muscle- invasive bladder cancer (NMIBC) and muscle invasive bladder cancer (MIBC). It is a major healthcare problem, and it is one of the leading causes of mortality worldwide. Genetic mutations are not only a cause for carcinogenesis but are also a way for treatment strategy. The present study aimed to investigate breast cancer (BRCA genes) tumor suppressor gene mutations in bladder cancer tissue and combined blood samples for patients who developed secondary tumor after or during trimodal therapy. Fresh tissue samples and their matched blood samples were collected from four patients with bladder cancer. The objective regions for the examined genes (BRCA1 and BRCA2) were sequenced using next-generation sequencing (NGS); generated BAM files were uploaded to the cloud-based Ionreporter server, and the Oncomine BRCA-specific plugin was used to analyze the paired normal and tumor sample for each patient using the default plugin parameters. Results: Intronic BRCA1 mutation c.5050-104 C >T was reported among the four investigated bladder cancer patients, and three somatic mutations were reported as follows: two of them were found to be benign rs1064793056 and rs28897679 on the Clinivar database and one nonsense pathogenic variant rs80357006. BRCA 2 gene mutation reported an exonic synonymous mutation rs397507876 in the tissue and germline DNA. Patients were treated with trimodal; however, three bladder cancer patients who reported BRCA mutations developed secondary tumors. Conclusion: Identification of mutational BRCA changes in bladder cancer is a promising marker for better treatment strategy. Further studies are encouraged on a large cohort of bladder cancer patients to confirm our findings. [ABSTRACT FROM AUTHOR]

Mammary tumors are the most common tumors in women and non-spayed female dogs. One of the reasons for mammary tumors is mutations of the tumor suppressor gene, BRCA2. BRCA2 participates in homologous recombination repair by interacting with the RAD51 recombinase. BRCA2 has two RAD51-binding domains, consisting of BRC repeats and the C-terminal RAD51-binding domain, respectively. Although several studies have addressed the function of the C-terminal RAD51-binding domain of human BRCA2, the amino acid sequences required for the RAD51-interaction activity remain unclear. In this study, the C-terminal RAD51- binding domains of canine and human BRCA2 were compared; the canine domain displayed a weaker interaction with RAD51. This difference was attributed to the C-terminal portion of the domain via a comparison between canine and human domains. Furthermore, peptides shorter than those previously reported displayed RAD51-interacting activity, and a core motif of this domain consisting of 25 amino acids was identified. Since a mutation (S3323N) was reported in the core motif of this domain, the effect of this mutation was evaluated. The mutant exhibited similar RAD51-binding activity as that of the wild-type protein, suggesting that the mutation was functionally neutral. These data suggested that the C-terminal portion of the BRCA2 C-terminal RAD51-binding domain influenced its RAD51-interaction activity, and a minimum core motif of 25 amino acids was identified in this domain. These data may help clarify BRCA2 function, as well as the tumorigenic effects of BRCA2 mutation. [ABSTRACT FROM AUTHOR]

Autophagy is a critical cellular homeostatic mechanism, and its dysfunction is linked to invasive breast carcinoma (BRCA). Recently, several omics methods have been applied to explore autophagic regulators in BRCA; however, more reliable and robust approaches for identifying crucial regulators and druggable targets remain to be discovered. Thus, we report here the results of multi-omics approaches to identify potential autophagic regulators in BRCA, including gene expression (EXP), DNA methylation (MET) and copy number alterations (CNAs) from The Cancer Genome Atlas (TCGA). Newly identified candidate genes, such as SF3B3 , TRAPPC10 , SIRT3 , MTERFD1 , and FBXO5 , were confirmed to be involved in the positive or negative regulation of autophagy in BRCA. SF3B3 was identified firstly as a negative autophagic regulator, and siRNA/shRNA- SF3B3 were shown to induce autophagy-associated cell death in in vitro and in vivo breast cancer models. Moreover, a novel small-molecule activator of SIRT3 , 1-methylbenzylamino amiodarone, was discovered to induce autophagy in vitro and in vivo. Together, these results provide multi-omics approaches to identify some key candidate autophagic regulators, such as the negative regulator SF3B3 and positive regulator SIRT3 in BRCA, and highlight SF3B3 and SIRT3 as new druggable targets that could be used to fill the gap between autophagy and cancer drug development. This study provides multi-omics approaches to identify some key candidate autophagic regulators, such as the negative regulator SF3B3 and positive regulator SIRT3 in invasive breast carcinoma, and highlight them as new druggable targets. [Display omitted] [ABSTRACT FROM AUTHOR]

The knowledge of BRCA status offers a chance to evaluate the role of the intraperitoneal route in patients selected by biomolecular profiles after primary cytoreduction surgery in advanced ovarian cancer. We performed a retrospective, multicenter study to assess oncological outcomes depending on adjuvant treatment (intraperitoneal [IP] vs intravenous [IV]) and BRCA status (BRCA1/2 mutated vs. BRCA wild type [WT]). The primary endpoint was to determine progression-free survival. The secondary objectives were overall survival and toxicity. A total of 288 women from eight centers were included: 177 in the IP arm and 111 in the IV arm, grouped into four arms according to BRCA1/2 status. Significantly better PFS was observed in BRCA1/2-mutated patients with IP chemotherapy (HR: 0.35; 95% CI, 0.16–0.75, p = 0.007), which was not present in BRCA1/2-mutated patients with IV chemotherapy (HR: 0.65; 95% CI, 0.37–1.12, p = 0.14). Significantly better OS was also observed in IP chemotherapy (HR: 0.17; 95% CI, 0.06–043, p < 0.0001), but was not present in IV chemotherapy in relation with BRCA mutation (HR: 0.52; 95% CI, 0.22–1.27, p = 0.15). For BRCA WT patients, worse survival was observed regardless of the adjuvant route used. The IP route was more toxic compared to the IV route, but toxicity was equivalent at the long-term follow-up. This retrospective study suggests that BRCA status can help to offer an individualized, systematic treatment after optimal primary surgery for advanced ovarian cancer, but is limited by the small sample size. Prospective trials are essential to confirm these results. [ABSTRACT FROM AUTHOR]

Breast cancers (BC) are rare in men and are often caused by constitutional predisposing factors. In women, mosaic BRCA1 promoter methylations (MBPM) are frequent events, detected in 4–8% of healthy subjects. This constitutional epimutation increases risk of early-onset and triple-negative BC. However, the role of MBPM in male BC predisposition has never been assessed. We screened 40 blood samples from men affected by BC, and performed extensive tumour analysis on MBPM-positive patients. We detected two patients carrying MBPM. Surprisingly, tumour analysis revealed that neither of these two male BCs were caused by the constitutional BRCA1 epimutations carried by the patients. • Mosaic BRCA1 promoter methylations (MBPM) are frequent epimutations in women. • We report the first two male breast cancer patients carrying MBPM. • They presented invasive breast cancers expressing estrogen receptors. • Their breast cancers were not due to BRCA1 : no homologous recombination deficiency. • Additional studies are necessary to use MBPM status to guide clinical decisions. [ABSTRACT FROM AUTHOR]

To evaluate the effect of secondary cytoreductive surgery (SeCRS) followed by platinum-based chemotherapy (PBC) and olaparib tablets as maintenance therapy in patients with BRCA mutated recurrent epithelial ovarian cancer. This was a retrospective study of a prospective database. We collected information on 623 patients diagnosed with BRCA mutated recurrent epithelial ovarian cancer, all of whom underwent SeCRS followed by PBC in combination with or without olaparib. Overall survival and progression-free survival were measured to evaluate treatment effectiveness. Of the 623 patients recruited, 240 underwent SeCRS plus hyperthermic intraperitoneal chemotherapy followed by PBC and olaparib maintenance therapy (Group A), 248 underwent SeCRS followed by PBC and olaparib maintenance therapy (Group B), and 135 underwent SeCRS followed by PBC only upon recurrence (Group C). The median progression-free survival for Group A was significantly longer than that for Group B (32.5 vs. 24.2 months, P<0.001), and Group B was significantly longer than Group C (24.2 vs. 15.1 months, P<0.001). The median overall survival for Groups A was significantly longer than that for Group B (71.4 vs. 63.5 months, P<0.001), and Group B was significantly longer than Group C (63.5 vs. 47.5 months, P<0.001). This study suggested that SeCRS followed by PBC and olaparib maintenance therapy resulted in longer overall survival and progression-free survival than SeCRS followed by PBC only in patients with BRCA mutated recurrent ovarian cancer, especially in patients treated with SeCRS plus hyperthermic intraperitoneal chemotherapy. [ABSTRACT FROM AUTHOR]

The non-inferiority of combined breast conservation surgery (BCS) and radiotherapy (breast conservation therapy or BCT) compared to mastectomy in sporadic breast cancer cases is well recognised. Uncertainty remains regarding optimal surgical practice in BRCA mutation carriers. To evaluate the oncological safety of combined BCT versus mastectomy in BRCA mutation carriers following breast cancer diagnosis. A systematic review was performed as per PRISMA and MOOSE guidelines. Observational studies comparing BCS and mastectomy in BRCA carriers were identified. Dichotomous variables were pooled as odds ratios (OR) using the Mantel–Haenszel method. Log hazard ratios (lnHR) for locoregional recurrence (LRR), contralateral breast cancer, disease-free and overall survival and their standard errors were calculated from Kaplan-Meier or cox-regression analyses and pooled using the inverse variance method. Twenty three studies of 3807 patients met inclusion criteria; 2200 (57.7%) were BRCA1 and 1212 (31.8%) were BRCA2 carriers. Median age at diagnosis was 41 years with 96 months follow up. BCS was performed on 2157 (56.7%) while 1408 (41.5%) underwent mastectomy. An increased risk of LRR was observed in patients treated with BCS (HR:4.54, 95% Confidence Interval: 2.77–7.42, P < 0.001, heterogeneity (I 2 ) = 0%). However, the risks of contralateral breast cancer (HR:1.51, 95%CI: 0.44–5.11, P = 0.510, I 2 = 80%), disease recurrence (HR:1.16, 95%CI: 0.78–1.72, P = 0.470, I 2 = 44%), disease-specific recurrence (HR:1.58, 95%CI: 0.79–3.15, P = 0.200, I 2 = 38%) and death (HR:1.10, 95%CI: 0.72–1.69, P = 0.660, I 2 = 38%) were equivalent for combined BCT and mastectomy. Survival outcomes following combined BCT is comparable to mastectomy in BRCA carriers. However, the risk of LRR is increased. Patient counselling should be tailored to incorporate these findings. • BRCA carriers see similar survival after breast conservation therapy and mastectomy. • Locoregional recurrence rates are increased following breast conservation. • Surgical counselling may reflect these findings for BRCA mutation carriers. [ABSTRACT FROM AUTHOR]

Chondroitin polymerizing factor (CHPF) plays an important role in the development of certain malignant tumors. However, the role of CHPF in breast carcinoma (BRCA) and its underlying mechanism are still not fully elucidated. Expression profiles for CHPF in BRCA tissues were retrieved from The Cancer Genome Atlas database and used for prognostic analysis. Cell viability, invasion and migration were measured in vitro using MCF7 and MDA‐MB‐231 cell lines upon knockdown or over‐expression of CHPF. Bioinformatic analysis showed that CHPF was substantially upregulated in BRCA tissues, and a quantitative reverse transcriptase‐PCR was performed to confirm its upregulation in BRCA cells. High expression of CHPF was observed to be significantly associated with pathologic stage, metastasis and worse prognosis. We also observed that depletion of CHPF significantly inhibited cell proliferative, invasive and migratory abilities, whereas overexpression of CHPF exerted the opposite effects. Furthermore, analysis of the GEPIA database revealed that CHPF expression is positively correlated with the epithelial–mesenchymal transition‐related markers vimentin, Snail, Slug and motion‐related protein matrix metallopeptidase 2; these findings were confirmed via western blotting. Our data suggest that CHPF may contribute to BRCA progression by modulating epithelial–mesenchymal transition‐related markers and matrix metallopeptidase 2 expression. [ABSTRACT FROM AUTHOR]

Abstract: Poly(ADP-ribose) polymerase (PARP) is involved in single-strand DNA break base excision repair. PARP inhibition causes synthetic lethality in breast cancers associated with germline BRCA1 and BRCA2 mutations and is routinely used in clinical practice for metastatic breast cancer. Breast cancers with homologous recombination deficiency or BRCAness, most commonly triple-negative breast cancers, may also benefit. Currently, PARP inhibitor use for triple-negative breast cancer with wild-type BRCA does not have definitive efficacy; however, this is an area of active research. Further clinical and translational data may identify additional patient populations that will benefit from PARP inhibitor therapy. [ABSTRACT FROM AUTHOR]

This study was aimed to design the first dual-target small-molecule inhibitor co-targeting poly (ADP-ribose) polymerase-1 (PARP1) and bromodomain containing protein 4 (BRD4), which had important cross relation in the global network of breast cancer, reflecting the synthetic lethal effect. A series of new BRD4 and PARP1 dual-target inhibitors were discovered and synthesized by fragment-based combinatorial screening and activity assays that together led to the chemical optimization. Among these compounds, 19d was selected and exhibited micromole enzymatic potencies against BRD4 and PARP1, respectively. Compound 19d was further shown to efficiently modulate the expression of BRD4 and PARP1. Subsequently, compound 19d was found to induce breast cancer cell apoptosis and stimulate cell cycle arrest at G1 phase. Following pharmacokinetic studies, compound 19d showed its antitumor activity in breast cancer susceptibility gene 1/2 (BRCA1/2) wild-type MDA-MB-468 and MCF-7 xenograft models without apparent toxicity and loss of body weight. These results together demonstrated that a highly potent dual-targeted inhibitor was successfully synthesized and indicated that co-targeting of BRD4 and PARP1 based on the concept of synthetic lethality would be a promising therapeutic strategy for breast cancer. The first potential BRD4 and PARP1 inhibitors 19d named ADTL-BPI1901 was discovered and synthesized by fragment-based combinatorial screening and activity assays led to the three rounds of structural optimization. Preliminary structure−activity relationships, molecular modeling, pharmacokinetics and favorable in vivo antitumor efficacy of 19d were investigated. Image 1 [ABSTRACT FROM AUTHOR]

Aftiphilin (AFTPH) plays an important role in regulating intracellular trafficking, exocytosis, and the pro‐inflammatory response. However, the potential prognostic role of AFTPH in cancers remains unclear. Here, we examined the expression profiles and prognostic significance of AFTPH in breast invasive carcinoma (BRCA), diffuse large B‐cell lymphoma (DLBC), lung squamous cell carcinoma (LUSC), and pancreatic adenocarcinoma (PADD) using the GEPIA and UALCAN databases. AFTPH expression was observed to be higher in cancer tissues than in normal tissues, but expression did not differ significantly between tumor stages for the four cancer types. AFTPH expression in cancer cell lines was investigated using the CCLE database; AFTPH was found to be highly expressed in four cancer cell lines. The relationship between AFTPH expression and patient prognosis was analyzed using GEPIA, LinkedOmics, and Kaplan–Meier plotter databases. Low expression of AFTPH was associated with improved prognosis for BRCA, DLBC, LUSC, and PAAD. Genetic alterations of AFTPH in cancers were explored using the cBioPortal website, revealing that gene copy number gains and amplification are common in BRCA, DLBC, LUSC, and PAAD. Related genes and markers associated with AFTPH were discovered using the LinkedOmics database. Furthermore, transfection of cells with AFTPH siRNA demonstrated that AFTPH exerts positive effects on cell proliferation in BRCA, LUSC, and PAAD cells. In conclusion, AFTPH may be a potential therapeutic target and prognostic biomarker for BRCA, DLBC, LUSC, and/or PAAD. [ABSTRACT FROM AUTHOR]

Breast cancer is the most prevalent cancer in the United Arab Emirates (UAE). This is the first study to provide data on predisposition of breast cancer susceptibility genes with associated clinical and pathological aspects in the UAE. A retrospective chart review for breast cancer patients undergoing genetic testing from 2016 to 2018. According to National Comprehensive Cancer Network (NCCN) guidelines genetic testing was offered. The analyzed data included; age, ethnicity, family cancer history, pathogenic variant, histopathology, stage, molecular subtype and proliferation. 309 patients underwent genetic testing with a positive result in 130 patients (11.9%) over a period of 36 months. In 34.6% pathogenic and likely pathogenic variants were identified. BRCA2 was the most common gene identified. The mean age was 42.9 years (±9.01). Positive family history was identified in 66 patients (50.7%). Majority had stage 1 or 2 disease (66.2%), invasive ductal carcinoma (81.5%) and hormone receptor positive cancer (45.3%). This is the first study in the UAE to describe the clinical and pathological characteristics of hereditary breast cancer in a mixed ethnic group with dominant Arabic population. Further genetic studies will be required in the UAE population, as the prevalence of breast cancer continues to rise. • First study about breast cancer genetics in the United Arab Emirates with a mixed ethnic population. • BRCA2 is the most common mutation detected. • Most hereditary breast cancers with a dominant Arabic ethnic group is diagnosed at a lower stage. • Most hereditary breast cancers diagnosed a decade earlier compared to western population. [ABSTRACT FROM AUTHOR]

The molecular mechanism of autophagy in Lactoferrin (LF) induced osteoblast differentiation is not fully demonstrated. In this study, alkaline phosphatase (ALP) activity, alizarin red S staining and ELISA were used to study N-terminal propeptide of type I procollagen (PINP) expression. mRFP-GFP-LC3 adenoviruses, mono-dansylcadaverine (MDC) staining, scanning electron microscopy, and western blot analysis was employed to probe the LF induced autophagy. The interaction between autophagy receptor Neighbor of Brca1 gene (Nbr1) and pp38 was studied. 3-methyladenine (3-MA) and chloroquine (CQ) could inhibit the activity of ALP, PINP and the autophagy in LF group. LF treatment could up-regulate and down-regulate the expressions of pp38 and Nbr1with a dose-dependent manner, respectively. LF could inhibit the recognition of pp38 and Nbr1. In addition, LF can prompt Nbr1-medicated autophagy and prevent pp38 degradation by autophagy. LF can induce Nbr1-mediated autophagy and inhibit pp38 entering into autophagy flux in the physiological process of osteoblast differentiation. Abbreviations: CQ:chloroquine；LF: Lactoferrin; 3-MA: 3-methyladenine; ALP: Alkaline phosphatase; ANOVA: Analysis of variance; CCK-8: Cell Counting Kit-8; LC3: Microtubule-associated protein light chain3; MDC: Monodansylcadaverine; Nbr1: neighbor of Brca1 gene; PINP: N-terminal propeptide of type I procollagen; PVDF: Polychlorotrifluoroethylene; pp38: phosphorylation p38; RAPA: Rapamycin; SDS: sodium dodecyl sulfate. LF can induce Nbr1-mediated autophagy and inhibit pp38 entering into autophagy flux in the physiological process of osteoblast differentiation. [ABSTRACT FROM AUTHOR]

Breast cancer susceptibility gene 1 (BRCA1) is a tumor suppressor gene, which is frequently mutated in breast and ovarian cancers. BRCA1 plays a key role in the homologous recombination directed DNA repair, allowing its deficiency to act as a therapeutic target of DNA damaging agents. In this study, we found that inhibition of the class I histone deacetylases (HDAC) exhibited synthetic lethality with BRCA1 deficiency in breast cancer cells. Transcriptome profiling and validation study showed that HDAC inhibition enhanced the expression of thioredoxin interaction protein (TXNIP), causing reactive oxygen species (ROS)-mediated DNA damage. This effect induced preferential apoptosis in BRCA1 −/− breast cancer cells where DNA repair system is compromised. Two animal experiments and gene expression-associated patients' survival analysis further confirmed in vivo synthetic lethality between BRCA1 and HDAC. Finally, the combination of inhibitors of HDAC and bromodomain and extra-terminal motif (BET), another BRCA1 synthetic lethality target that also works through oxidative stress-mediated DNA damage, showed a strong anticancer effect in BRCA1 −/− breast cancer cells. Together, this study provides a new therapeutic strategy for BRCA1-deficient breast cancer by targeting two epigenetic machineries, HDAC and BET. Histone deacetylase (HDAC) inhibition upregulates the expression of pro-oxidant protein, thioredoxin interaction protein (TXNIP), leading to reactive oxygen species (ROS) accumulation and high DNA double-strand breaks in cells. Breast cancer susceptibility gene 1 (BRCA1)-deficient breast cancer cells were highly sensitive to HDAC inhibition due to the lack of homologous recombination DNA repair system and hence underwent synthetic lethality. Image 1 [ABSTRACT FROM AUTHOR]

Small interfering RNA (siRNA) therapy is a promising approach for treatment of a wide range of cancers, including breast cancers that display variable phenotypic features. To explore the general utility of siRNA therapy to control aberrant expression of genes in breast cancer, we conducted a detailed analysis of siRNA delivery and silencing response in vitro in 6 separate breast cancer cell models (MDA-MB-231, MDA-MB-231-KRas-CRM, MCF-7, AU565, MDA-MB-435 and MDA-MB-468 cells). Using lipopolymers for siRNA complexation and delivery, we found a large variation in siRNA delivery efficiency depending on the specific lipopolymer used for siRNA complexation and delivery. Some lipopolymers were effective in all cell types used in this study, indicating the possibility of universal carriers for siRNA therapy. The delivery efficiency for effective lipopolymers was not correlated with dextran uptake in the cells tested, which indicated a receptor-mediated internalization for siRNA complexes with lipopolymers, unlike fluid-phase transfer associated with dextran uptake. Consistent with this, specific inhibitors involved in clathrin- and caveolin-mediated endocytosis significantly (>50%) reduced the internalization of siRNA complexes in all cell types. Using JAK2 and STAT3 silencing in MDA-MB-231 and MDA-MB-468 cells, a general correlation between the uptake and silencing efficiency at the mRNA level was evident, but it appeared that the choice of the target rather than the cell type was more critical for consistent silencing. We conclude that siRNA therapy with lipopolymers can be undertaken in multiple breast cancer cell phenotypes with similar efficiency, indicating the general applicability of non-viral RNAi in clinical management of molecularly heterogeneous breast cancers. The manuscript investigated the efficacy of siRNA carriers across multiple breast cancer cell lines. The lipopolymeric carriers were capable of delivering effective dose of siRNA to a range of breast cancer cells. Despite some differences in uptake efficiency among cell types, the mechanism of delivery was similar, with CME and CvME significantly involved in the internalization of polyplexes, while fluid-phase endocytosis was not significant. Specific target silencing was correlated to delivery efficiency, but we did notice the presence of lipopolymers that achieved high silencing with minimal siRNA delivery. Silencing specific targets in different cell types were more uniformly achieved as compared to targeting different targets in the same cells. Our studies enhance the feasibility of delivering siRNA to different types of breast cancer cells. Image, graphical abstract [ABSTRACT FROM AUTHOR]