Universal genetic testing for women with newly diagnosed breast cancer in the context of multidisciplinary team care.

OBJECTIVE: To determine the feasibility of universal genetic testing of women with newly diagnosed breast cancer, to estimate the incidence of pathogenic gene variants and their impact on patient management, and to evaluate patient and clinician acceptance of universal testing. DESIGN, SETTING, PARTICIPANTS: Prospective study of women with invasive or high grade in situ breast cancer and unknown germline status discussed at the Parkville Breast Service (Melbourne) multidisciplinary team meeting. Women were recruited to the pilot (12 June 2020 - 22 March 2021) and expansion phases (17 October 2021 - 8 November 2022) of the Mutational Assessment of newly diagnosed breast cancer using Germline and tumour genomICs (MAGIC) study. MAIN OUTCOME MEASURES: Germline testing by DNA sequencing, filtered for nineteen hereditary breast and ovarian cancer genes that could be classified as actionable; only pathogenic variants were reported. Surveys before and after genetic testing assessed pilot phase participants' perceptions of genetic testing, and psychological distress and cancer-specific worry. A separate survey assessed clinicians' views on universal testing. RESULTS: Pathogenic germline variants were identified in 31 of 474 expanded study phase participants (6.5%), including 28 of 429 women with invasive breast cancer (6.5%). Eighteen of the 31 did not meet current genetic testing eligibility guidelines (probability of a germline pathogenic variant ≥ 10%, based on CanRisk, or Manchester score ≥ 15). Clinical management was changed for 24 of 31 women after identification of a pathogenic variant. Including 68 further women who underwent genetic testing outside the study, 44 of 542 women carried pathogenic variants (8.1%). Acceptance of universal testing was high among both patients (90 of 103, 87%) and clinicians; no decision regret or adverse impact on psychological distress or cancer-specific worry were reported. CONCLUSION: Universal genetic testing following the diagnosis of breast cancer detects clinically significant germline pathogenic variants that might otherwise be missed because of testing guidelines. Routine testing and reporting of pathogenic variants is feasible and acceptable for both patients and clinicians.

Molecular characterization of low-grade serous ovarian carcinoma identifies genomic aberrations according to hormone receptor expression.

Hormone receptor expression is a characteristic of low-grade serous ovarian carcinoma (LGSOC). Studies investigating estrogen receptor (ER) and progesterone receptor (PR) expression levels suggest its prognostic and predictive significance, although their associations with key molecular aberrations are not well understood. As such, we sought to describe the specific genomic profiles associated with different ER/PR expression patterns and survival outcomes in a cohort of patients with advanced disease. The study comprised fifty-five advanced-staged (III/IV) LGSOCs from the Canadian Ovarian Experimental Unified Resource (COEUR) for which targeted mutation sequencing, copy-number aberration, clinical and follow-up data were available. ER, PR, and p16 expression were assessed by immunohistochemistry. Tumors were divided into low and high ER/PR expression groups based on Allred scoring. Copy number analysis revealed that PR-low tumors (Allred score <2) had a higher fraction of the genome altered by copy number changes compared to PR-high tumors (p = 0.001), with cancer genes affected within specific loci linked to altered peptidyl-tyrosine kinase, MAP-kinase, and PI3-kinase signaling. Cox regression analysis showed that ER-high (p = 0.02), PR-high (p = 0.03), stage III disease (p = 0.02), low residual disease burden (p = 0.01) and normal p16 expression (p<0.001) were all significantly associated with improved overall survival. This study provides evidence that genomic aberrations are linked to ER/PR expression in primary LGSOC.

Loss of SMAD4 Is Sufficient to Promote Tumorigenesis in a Model of Dysplastic Barrett's Esophagus.

BACKGROUND & AIMS: Esophageal adenocarcinoma (EAC) develops from its precursor Barrett's esophagus through intermediate stages of low- and high-grade dysplasia. However, knowledge of genetic drivers and molecular mechanisms implicated in disease progression is limited. Herein, we investigated the effect of Mothers against decapentaplegic homolog 4 (SMAD4) loss on transforming growth factor ß (TGF-ß) signaling functionality and in vivo tumorigenicity in high-grade dysplastic Barrett's cells. METHODS: An in vivo xenograft model was used to test tumorigenicity of SMAD4 knockdown or knockout in CP-B high-grade dysplastic Barrett's cells. RT2 polymerase chain reaction arrays were used to analyze TGF-ß signaling functionality, and low-coverage whole-genome sequencing was performed to detect copy number alterations upon SMAD4 loss. RESULTS: We found that SMAD4 knockout significantly alters the TGF-ß pathway target gene expression profile. SMAD4 knockout positively regulates potential oncogenes such as CRYAB, ACTA2, and CDC6, whereas the CDKN2A/B tumor-suppressor locus was regulated negatively. We verified that SMAD4 in combination with CDC6-CDKN2A/B or CRYAB genetic alterations in patient tumors have significant predictive value for poor prognosis. Importantly, we investigated the effect of SMAD4 inactivation in Barrett's tumorigenesis. We found that genetic knockdown or knockout of SMAD4 was sufficient to promote tumorigenesis in dysplastic Barrett's esophagus cells in vivo. Progression to invasive EAC was accompanied by distinctive and consistent copy number alterations in SMAD4 knockdown or knockout xenografts. CONCLUSIONS: Altogether, up-regulation of oncogenes, down-regulation of tumor-suppressor genes, and chromosomal instability within the tumors after SMAD4 loss implicates SMAD4 as a protector of genome integrity in EAC development and progression. Foremost, SMAD4 loss promotes tumorigenesis from dysplastic Barrett's toward EAC.

Treatment and outcomes of metastatic colorectal cancer patients in public and private hospitals: results from the South Australian Metastatic Colorectal Cancer Registry.

BACKGROUND: Studies have reported significant differences in baseline characteristics and outcomes of metastatic colorectal cancer (mCRC) patients when managed in private versus public hospitals. AIMS: To compare disease, treatment and survival outcomes of patients with mCRC in public versus private hospitals in South Australia (SA). METHODS: Analysis of prospectively collected data from the SA mCRC Registry. Patterns of care and outcome data according to location of care and socioeconomic status based on Index of Relative Socio-Economic Advantage and Disadvantage were analysed. RESULTS: A total of 3470 patients' data was analysed during February 2006-January 2015. The majority (70%) of patients received treatment in public hospitals. Patients in the upper 50% for Index of Relative Socio-Economic Advantage and Disadvantage score were more likely to receive treatment at a private hospital (41.2% vs 21.56%) compared to <50%. Public patients had higher burden of disease (10.49% vs 7.41%, P = 0.005). Public patients received less treatment compared to the private patients (odds ratio = 0.48 (0.38-0.61), P = 0.01) and rates of surgical resections were lower in public patients. After adjusting for the covariates, public patients survive 1.33 months (P = 0.025) shorter than private patients with follow-up time of 5 years. Patients receiving metastasectomy and more than three lines of treatment were shown to have the greatest survival benefit. CONCLUSION: Public patients have a higher burden of disease and in comparison are less likely to receive systemic therapy and have lower survival than patients treated in private hospitals.

Insulin resistance in prostate cancer patients and predisposing them to acute ischemic heart disease.

Lack of insulin or insulin resistance (IR) plays a central role in diabetes mellitus and makes diabetics prone to acute ischemic heart disease (AIHD). It has likewise been found that many cancer patients, including prostate cancer patients die of AIHD. Previously it has been delineated from our laboratory that dermcidin could induce anomalous platelet aggregation in AIHD and also impaired nitric oxide and insulin activity and furthermore dermcidin was also found in a few types of cancer patients. To determine the role of this protein in prostatic malignancy, a retrospective case-control study was conducted and blood was collected from prostate cancer patients and healthy normal volunteers. So, we measured the level of dermcidin protein and analyzed the IR by Homeostasis Model Assessment (HOMA) score calculation. Nitric oxide was measured by methemoglobin method. HDL, glycated hemoglobin (HbA1c), BMI, hs-cTroponin-T were measured for the validation of the patients' status in the presence of Dermcidin isoform-2 (DCN-2). Multiple logistic regression model adjusted for age and BMI identified that the HOMA score was significantly elevated in prostate cancer patients (OR = 7.19, P<0.001). Prostate cancer patients are associated with lower level of NO and higher level of both proteins dermcidin (OR = 1.12, P<0.001) and hs-TroponinT (OR = 1.76, P<0.001). From the results, it can be interpreted that IR plays a key role in the pathophysiology of prostate cancer where dermcidin was the cause of IR through NO inhibition leading to AIHD was also explained by high-sensitive fifth generation cTroponin-T (hs-cTroponinT) and HbA1c level which are associated with endothelial dysfunction.

Predictors of Success of Workplace Physical Activity Interventions: A Systematic Review.

BACKGROUND: Despite holding great potential for addressing concerns regarding public health, recent systematic reviews have found effect sizes for interventions targeting physical activity to be small. Before interventions can be improved, the factors influencing outcomes must be identified. This systematic review aimed to identify predictors of success, measured in terms of engagement (eg, involvement duration) and health behavior change (eg, increased step counts), of workplace interventions targeting physical activity. METHODS: A structured search of 3 databases (PubMed, PsycINFO, and Web of Science) was conducted to identify articles published between January 2000 and April 2017. For inclusion, articles needed to test a workplace intervention targeting physical activity and perform a quantitative analysis, identifying predictors of engagement or health behavior change. RESULTS: Twenty-two studies were identified for review (median quality score = 70%). Demographic variables (eg, gender, age) were inconsistent predictors of success. However, employees in better health and physically active at baseline were found to have a greater likelihood of success. CONCLUSIONS: It appears that achieving successful results among employees at high risk of poor health outcomes remains a significant challenge for interventions. It is hoped that program developers can use this information to create effective interventions particularly for more sedentary employees.

Statistical methods to model and evaluate physical activity programs, using step counts: A systematic review.

BACKGROUND: Physical activity reduces the risk of noncommunicable diseases and is therefore an essential component of a healthy lifestyle. Regular engagement in physical activity can produce immediate and long term health benefits. However, physical activity levels are not as high as might be expected. For example, according to the global World Health Organization (WHO) 2017 statistics, more than 80% of the world's adolescents are insufficiently physically active. In response to this problem, physical activity programs have become popular, with step counts commonly used to measure program performance. Analysing step count data and the statistical modeling of this data is therefore important for evaluating individual and program performance. This study reviews the statistical methods that are used to model and evaluate physical activity programs, using step counts. METHODS: Adhering to PRISMA guidelines, this review systematically searched for relevant journal articles which were published between January 2000 and August 2017 in any of three databases (PubMed, PsycINFO and Web of Science). Only the journal articles which used a statistical model in analysing step counts for a healthy sample of participants, enrolled in an intervention involving physical exercise or a physical activity program, were included in this study. In these programs the activities considered were natural elements of everyday life rather than special activity interventions. RESULTS: This systematic review was able to identify 78 unique articles describing statistical models for analysing step counts obtained through physical activity programs. General linear models and generalized linear models were the most popular methods used followed by multilevel models, while structural equation modeling was only used for measuring the personal and psychological factors related to step counts. Surprisingly no use was made of time series analysis for analysing step count data. The review also suggested several strategies for the personalisation of physical activity programs. CONCLUSIONS: Overall, it appears that the physical activity levels of people involved in such programs vary across individuals depending on psychosocial, demographic, weather and climatic factors. Statistical models can provide a better understanding of the impact of these factors, allowing for the provision of more personalised physical activity programs, which are expected to produce better immediate and long-term outcomes for participants. It is hoped that this review will identify the statistical methods which are most suitable for this purpose.

Promoting Psychological Well-Being at Work by Reducing Stress and Improving Sleep: Mixed-Methods Analysis.

BACKGROUND: Workplace programs designed to improve the health and psychological well-being of employees are becoming increasingly popular. However, there are mixed reports regarding the effectiveness of such programs and little analysis of what helps people to engage with such programs. OBJECTIVE: This evaluation of a particularly broad, team-based, digital health and well-being program uses mixed methods to identify the elements of the program that reduce work stress and promote psychological well-being, sleep quality, and productivity of employees. METHODS: Participation in the Virgin Pulse Global Challenge program during May to September 2016 was studied. Self-reported stress, sleep quality, productivity, and psychological well-being data were collected both pre- and postprogram. Participant experience data were collected through a third final survey. However, the response rates for the last 2 surveys were only 48% and 10%, respectively. A random forest was used to estimate the probability of the completion of the last 2 surveys based on the preprogram assessment data and the demographic data for the entire sample (N=178,350). The inverse of these estimated probabilities were used as weights in hierarchical linear models in an attempt to address any estimation bias caused by the low response rates. These linear models described changes in psychological well-being, stress, sleep, and productivity over the duration of the program in relation to gender and age, engagement with each of the modules, each of the program features, and participant descriptions of the Virgin Pulse Global Challenge. A 0.1% significance level was used due to the large sample size for the final survey (N=18,653). RESULTS: The final analysis suggested that the program is more beneficial for older people, with 2.9% greater psychological well-being improvements observed on average in the case of women than men (P<.001). With one exception, all the program modules contributed significantly to the outcome measures with the following average improvements observed: psychological well-being, 4.1%-6.0%; quality of sleep, 3.2%-6.9%; work-related stress, 1.7%-6.8%; and productivity, 1.9%-4.2%. However, only 4 of the program features were found to have significant associations with the outcome measures with the following average improvements observed: psychological well-being, 3.7%-5.6%; quality of sleep, 3.4%-6.5%; work-related stress, 4.1%-6.4%; and productivity, 1.6%-3.2%. Finally, descriptions of the Virgin Pulse Global Challenge produced 5 text topics that were related to the outcome measures. Healthy lifestyle descriptions showed a positive association with outcomes, whereas physical activity and step count tracking descriptions showed a negative association with outcomes. CONCLUSIONS: The complementary use of qualitative and quantitative survey data in a mixed-methods analysis provided rich information that will inform the development of this and other programs designed to improve employee health. However, the low response rates and the lack of a control group are limitations, despite the attempts to address these problems in the analysis.