A bioinformatics approach to discovery of estrogen-responsive genetic pathways in breast cancer

Breast cancers fall into two major classes depending on their estrogen receptor (ER) status. ER+ and ER- tumors have very different molecular phenotypes, and may have distinct cells of origin. ER- tumors generally fail to respond to endocrine therapy and have a poorer prognosis. To develop a comprehensive understanding of the gene networks active in ER+ compared to ER- breast cancers, we performed a meta-analysis of Grade 3 breast cancers from five published datasets. A measure of association with ER status taking into account intra- and inter-study variability was calculated for every probe set.The meta-analysis revealed that ER-/Grade 3 tumors show increased expression of proliferation-associated functional categories when compared to ER+/Grade 3 tumors. Using Gene Set Enrichment Analysis we show that transcript levels of direct transcriptional targets of ER are lower in ER- tumors, but that expression of other estrogen-induced genes is higher in ER- tumors. Transcript levels of both direct and other targets of the estrogen-regulated MYC gene and the E2F family of genes are significantly higher in ER- tumors. The increased expression of targets of MYC and E2F is particularly pronounced in the "basal" subgroup of ER- tumors. This suggests that a study assessing the association of these genes with clinical outcome in ER- patients is warranted, but is not currently feasible due to lack of suitable publicly available data. The contribution of genes regulated or bound by estrogen, MYC or E2F to increased risk of relapse in ER+ tamoxifen-treated patients was assessed in a pilot study using Cox proportional hazards models and Gene Set Enrichment Analysis. The high expression of several gene sets containing genes induced by estrogen and/or MYC and direct targets of MYC and E2F was correlated with poor outcome in these patients.We conclude that over-expression or constitutive activation of MYC, possibly in conjunction with elevated E2F activity, may lead to the induction of a set of genes characteristic of the estrogen response thereby contributing to increased proliferation in ER- breast tumors, particularly in the basal subgroup. A pilot survival study indicated that MYC- and E2F-activity may play a role in tamoxifen-resistance

Using the community pharmacy to identify patients at risk of poor asthma control and factors which contribute to this poor control

Background. Although asthma can be well controlled by appropriate medication delivered in an appropriate way at an appropriate time, there is evidence that management is often suboptimal. This results in poor asthma control, poor quality of life, and significant morbidity. Methods. The objective of this study was to describe a population recruited in community pharmacy identified by trained community pharmacists as being at risk for poor asthma outcomes and to identify factors associated with poor asthma control. It used a cross-sectional design in 96 pharmacies in metropolitan and regional New South Wales, Victoria, Queensland, and Australian Capital Territory in Australia. Community pharmacists with specialized asthma training enrolled 570 patients aged ≥18 years with doctor-diagnosed asthma who were considered at risk of poor asthma outcomes and then conducted a comprehensive asthma assessment. In this assessment, asthma control was classified using a symptom and activity tool based on self-reported frequency of symptoms during the previous month and categorized as poor, fair, or good. Asthma history was discussed, and lung function and inhaler technique were also assessed by the pharmacist. Medication use/adherence was recorded from both pharmacy records and the Brief Medication Questionnaire (BMQ). Results. The symptom and activity tool identified that 437 (77%%) recruited patients had poor asthma control. Of the 570 patients, 117 (21%%) smoked, 108 (19%%) had an action plan, 372 (69%%) used combination of inhaled corticosteroid (ICS)/long-acting β2-agonist (LABA) medications, and only 17-28%% (depending on device) used their inhaler device correctly. In terms of adherence, 90% had their ICS or ICS/LABA dispensed <6 times in the previous 6 months, which is inconsistent with regular use; this low adherence was confirmed from the BMQ scores. A logistic regression model showed that patients who smoked had incorrect inhaler technique or low adherence (assessed by either dispensing history or BMQ) and were more likely to have poor control. Conclusion. Community pharmacists were able to identify patients with asthma at risk of suboptimal control, and factors that contributed to this were elicited. This poorly controlled group that was identified may not be visible or accessible to other health-care professionals. There is an opportunity within pharmacies to target poorly controlled asthma and provide timely and tailored interventions