Christine Brezden-Masley

BRCA1 is an essential regulator of heart function and survival following myocardial infarction

The tumour suppressor BRCA1 is mutated in familial breast and ovarian cancer but its role in protecting other tissues from DNA damage has not been explored. Here we show a new role for BRCA1 as a gatekeeper of cardiac function and survival. In mice, loss of BRCA1 in cardiomyocytes results in adverse cardiac remodelling, poor ventricular function and higher mortality in response to ischaemic or genotoxic stress. Mechanistically, loss of cardiomyocyte BRCA1 results in impaired DNA double-strand break repair and activated p53-mediated pro-apoptotic signalling culminating in increased cardiomyocyte apoptosis, whereas deletion of the p53 gene rescues BRCA1-deficient mice from cardiac failure. In human adult and fetal cardiac tissues, ischaemia induces double-strand breaks and upregulates BRCA1 expression. These data reveal BRCA1 as a novel and essential adaptive response molecule shielding cardiomyocytes from DNA damage, apoptosis and heart dysfunction. BRCA1 mutation carriers, in addition to risk of breast and ovarian cancer, may be at a previously unrecognized risk of cardiac failure.

Quality of Abstracts Describing Randomized Trials in the Proceedings of American Society of Clinical Oncology Meetings: Guidelines for Improved Reporting

PURPOSE To evaluate the quality of reporting in abstracts describing randomized controlled trials (RCTs) included in the Proceedings of American Society of Clinical Oncology (ASCO) meetings and to propose reporting guidelines for abstracts that are submitted to future meetings. METHODS Guidelines for reporting of RCTs in abstracts were developed by extracting key elements from published guidelines for full reports of RCTs, and modified based on an expert survey. Abstracts presenting results of RCTs with sample size > or = 200 were identified from the ASCO Proceedings for the years 1989 to 1998. Information regarding the quality of each abstract was extracted, and a quality score (possible range, 0 to 10) was assigned based on adherence to the guidelines. RESULTS Brief description of the intervention, explicit identification of the primary end point, and presentation of results accompanied by statistical tests were regarded by experts as the most important items to include in an abstract, whereas presentation of secondary and subgroup analyses was the least important. Deficiencies in reporting were present in almost all of the 510 abstracts; for example, only 22% of the abstracts provided explicit identification of the primary end point. The median quality score was 5.5 (range, 2.0 to 8.5); the quality score improved with time (P <.0001) and was better for oral or plenary presentations (P =.0003). CONCLUSION The quality of reporting of RCTs in abstracts submitted to Annual Meetings of ASCO is suboptimal. Although space precludes the inclusion of details required in the final report, abstracts could be improved through the use of explicit minimal guidelines, which are suggested in this article.

Mammographic microcalcifications and breast cancer tumorigenesis: a radiologic-pathologic analysis

BackgroundMicrocalcifications (MCs) are tiny deposits of calcium in breast soft tissue. Approximately 30% of early invasive breast cancers have fine, granular MCs detectable on mammography; however, their significance in breast tumorigenesis is controversial. This study had two objectives: (1) to find associations between mammographic MCs and tumor pathology, and (2) to compare the diagnostic value of mammograms and breast biopsies in identifying malignant MCs.MethodsA retrospective chart review was performed for 937 women treated for breast cancer during 2000–2012 at St. Michael’s Hospital. Demographic information (age and menopausal status), tumor pathology (size, histology, grade, nodal status and lymphovascular invasion), hormonal status (ER and PR), HER-2 over-expression and presence of MCs were collected. Chi-square tests were performed for categorical variables and t-tests were performed for continuous variables. All p-values less than 0.05 were considered statistically significant.ResultsA total of 937 patient charts were included. About 38.3% of the patients presented with mammographic MCs on routine mammographic screening. Patients were more likely to have MCs if they were HER-2 positive (52.9%; p < 0.001). There was a significant association between MCs and peri-menopausal status with a mean age of 50 (64%; p = 0.012). Patients with invasive ductal carcinomas (40.9%; p = 0.001) were more likely to present with MCs than were patients with other tumor histologies. Patients with a heterogeneous breast density (p = 0.031) and multifocal breast disease (p = 0.044) were more likely to have MCs on mammograms. There was a positive correlation between MCs and tumor grade (p = 0.057), with grade III tumors presenting with the most MCs (41.3%). A total of 52.2% of MCs were missed on mammograms which were visible on pathology (p < 0.001).ConclusionThis is the largest study suggesting the appearance of MCs on mammograms is strongly associated with HER-2 over-expression, invasive ductal carcinomas, peri-menopausal status, heterogeneous breast density and multifocal disease.

BRCA1 shields vascular smooth muscle cells from oxidative stress

BACKGROUND Excessive production of reactive oxygen species (ROS), in part via upregulation of DNA damage pathways, is a central mechanism governing pathologic activation of vascular smooth muscle cells (VSMCs). We hypothesized that the breast cancer 1, early onset (BRCA1) gene that is involved in cellular resistance to DNA damage limits ROS production and oxidative stress in VSMCs. METHODS We evaluated basal and H2O2-stimulated expression of BRCA1 in human aortic smooth muscle cells (HASMCs). In vitro gain-of-function experiments were performed in BRCA1 adenovirus (Ad-BRCA1)-transfected HASMCs. ROS production and expression of Nox1 and its key regulatory subunit p47phox, key components of the ROS-generating nicotinamide adenine dinucleotide phosphate (NADPH) oxidase system, were evaluated. In vivo gain-of-function experiments were performed in spontaneously hypertensive (SHR) rats treated with Ad-BRCA1 (5 × 10(10) IU/rat). Blood pressure, vascular ROS generation, Nox1, and p47phox expression were measured. RESULTS BRCA1 was constitutively expressed in murine, rat, and human smooth muscle cells (SMCs). H2O2 significantly reduced BRCA1 expression with a resultant increase in ROS generation. BRCA1-overexpressing HASMCs were protected against H2O2-induced ROS generation, in part, via downregulation of the ROS-producing NADPH oxidase subunits Nox1 and p47phox. Ad-BRCA1 treatment in SHR rats was associated with a sustained increase in aortic BRCA1 expression, lower aortic ROS production, reduced γH2A.X levels, greater RAD51 foci, and decreases in blood pressure. CONCLUSIONS BRCA1 is a novel and previously unrecognized target that may shield VSMCs from oxidative stress by inhibiting NADPH Nox1-dependent ROS production. Gene- and/or cell-based approaches that improve BRCA1 bioavailability may represent a new approach in the treatment of diverse vascular diseases associated with an aberrant VSMC phenotype.

Outlooks on Epstein-Barr virus associated gastric cancer

Epstein-Barr virus associated gastric cancer (EBVaGC) comprises approximately 10% of gastric carcinomas. Multiple factors contribute to tumorigenesis, including EBV driven hypermethylation of tumor suppressor genes, inflammatory changes in gastric mucosa, host immune evasion by EBV and changes in cell cycle pathways. The unique molecular characteristics of EBVaGC, such as programmed death ligand 1 (PD-L1) overexpression, highlight the potential for using EBV as a biomarker for response to immunotherapy. Few studies have reported benefit from immunotherapy in EBV positive cancers, and clinical trials investigating the impact of checkpoint inhibitors in EBVaGC are currently underway. This review provides the most recent updates on molecular pathophysiology, epidemiology, clinical features and treatment advances pertaining to EBVaGC.

Association of hospital and physician case volumes with cardiac monitoring and cardiotoxicity during adjuvant trastuzumab treatment for breast cancer: a retrospective cohort study

BACKGROUND Adjuvant trastuzumab is the standard of care for patients with HER2 overexpressing breast cancer, but use of trastuzumab may lead to cardiotoxicity. Our goal was to evaluate the relationship between hospital and physician case volume and cardiac outcomes in this population. METHODS In this retrospective cohort study, we identified all female patients in Ontario with a breast cancer diagnosis in 2003-2009 who underwent treatment with trastuzumab through a provincial drug-funding program and linked these patients to administrative databases to ascertain patient demographics, treating hospital and physician characteristics, admissions to hospital, cardiac risk factors, cardiac imaging and comorbidities. Insufficient cardiac monitoring was defined as per the Canadian Trastuzumab Working Group guideline. Cardiotoxicity was defined as receiving fewer than 16 of 18 doses of trastuzumab because of heart failure admission, heart failure diagnosis or discontinuation of the drug after cardiac imaging. We constructed hierarchical multivariable logistic regression models to evaluate the effect of annual hospital volume, cumulative physician volume and treatment period on cardiac monitoring and cardiotoxicity. RESULTS Of 3777 women treated by 214 oncologists at 68 hospitals, 918 (24.3%) had insufficient cardiac monitoring and cardiotoxicity developed in 640 (16.9%). Cardiotoxicity occurred in 389 (42.4%) and 251 (8.8%) patients in the insufficient- and sufficient-monitoring groups, respectively. Higher annual hospital and cumulative physician volumes, and more recent calendar period, were all independent predictors for decreased cardiotoxicity. Adjustment for rates of cardiac monitoring annulled the relationships between case volume and cardiotoxicity. INTERPRETATION Greater hospital and physician case volumes are associated with reduced rates of trastuzumab-related cardiotoxicity, most likely because of better cardiac monitoring at higher volume centres.

Association of Metabolic, Inflammatory, and Tumor Markers With Circulating Tumor Cells in Metastatic Breast Cancer

Abstract Background Circulating tumor cells (CTCs) are associated with worse prognosis in metastatic breast cancer (BC). We evaluated the association of metabolic, inflammatory, and tumor markers with CTCs in women with metastatic BC before commencing a new systemic therapy. Methods Ninety-six patients with newly diagnosed or progressing metastatic BC without current diabetes or use of anti-inflammatory agents were recruited from four Ontario hospitals. Women provided fasting blood for measurement of metabolic, inflammatory, and tumor markers and CTCs. CTCs were assayed within 72 hours of collection using CellSearch. Other blood was frozen at –80°C, and assays were performed in a single batch. Associations between CTC counts with study factors were evaluated using Spearman correlation, and the chi-square or Fisher exact test. All statistical tests were two-sided and P value ≤ .05 was considered statistically significant. Results The median age was 60.5 years; 90.6% were postmenopausal. The cohort included hormone receptor–positive (87.5%), HER2–positive (15.6%), and triple-negative (10.4%) BCs. Patients were starting firstline (35.5%), second-line (26.0%), or third-or-later-line therapy (38.5%). CTC counts (per 7.5 mL of blood) ranged from 0 to 1238 (median 2); an elevated CTC count, defined as five or more CTCs, was detected in 42 (43.8%) patients. Those with liver metastases (vs not) more frequently had an elevated CTC count (59.0% vs 33.3%, P = .02). CTCs were significantly associated with C-reactive protein (R = .22, P = .02), interleukin (IL)-6 (R = .25, P = .01), IL-8 (R = .38, P = .0001), plasminogen activator inhibitor 1 (R = .31, P = .001), carcinoembryonic antigen (R = .31, P = .002), and cancer antigen 15-3 (R = .40, P = .0001) and inversely associated with body mass index (R = –.23, P = .02) and leptin (R = –.26, P = .01). Conclusions CTC counts were positively associated with tumor and inflammatory markers and inversely associated with some metabolic markers, potentially reflecting tumor burden and cachexia.