Adjuvant tamoxifen and exemestane in postmenopausal early breast cancer:ten-year analysis of the randomised phase III TEAM trial

Surgical oncolog

Minimizing early relapse and maximizing treatment outcomes in hormone-sensitive postmenopausal breast cancer: efficacy review of AI trials

Breast cancer is one of the leading causes of cancer-related deaths in women. Regardless of prognosis, all women with breast cancer are at risk for early recurrence. Nearly 50% of early recurrences occur within 5 years of surgery, and they peak at 2 years after surgery in women treated with adjuvant tamoxifen. Most early recurrences are distant metastases, which strongly correlate with increased mortality. Treatments that mitigate the risk of early distant metastases (DM) are, therefore, likely to improve overall survival in women with early breast cancer (EBC). Aromatase inhibitors (AIs)—anastrozole, letrozole, and exemestane—have been investigated as alternatives to tamoxifen for adjuvant treatment of hormone receptor-positive (HR+) EBC in postmenopausal women (PMW). AIs are better at minimizing risk of early relapse compared with tamoxifen. However, it is not clear if preferential use of AIs over tamoxifen will benefit all PMW with HR+ EBC. The ability to subtype HR+ breast cancer on the basis of biomarkers predictive of response to AIs and tamoxifen would likely be key to determining the most beneficial hormonal treatment within patient subpopulations, but this process requires thorough investigation. Until then, adjuvant therapies that provide the greatest reduction in risk of DM should be considered for all PMW with HR+ EBC. This article reviews the clinical trials of AI adjuvant therapies for hormone-sensitive breast cancer, particularly in the context of how they compare with tamoxifen in minimizing the risk of relapse, occurrence of DM, and breast cancer-related deaths

Predictive Biomarkers for Endocrine Therapy:Retrospective Study in Tamoxifen and Exemestane Adjuvant Multinational (TEAM) Trial

Background: Aromatase inhibitors improve disease-free survival compared with tamoxifen in postmenopausal women with hormone receptor–positive breast cancer. The Tamoxifen and Exemestane Adjuvant Multinational (TEAM) trial compared exemestane monotherapy with sequential therapy of tamoxifen followed by exemestane. The trial failed to show a statistically significant difference between treatment arms. A robust translational program was established to investigate predictive biomarkers. Methods: A tissue microarray was retrospectively constructed using a subset of patient tissues (n = 4631) from the TEAM trial (n = 9766). Immunohistochemistry was performed for biomarkers, classed into three groups: MAPK pathway, NF-kappa B pathway, and estrogen receptor (ER) phosphorylation. Expression was analyzed for association with relapse-free survival (RFS) at 2.5 and 10 years and treatment regimen using Kaplan-Meier curves and log-rank analysis. All statistical tests were two-sided. Results: In univariate analysis, ER167 (hazard ratio [HR] = 0.71, 95% confidence interval [CI] = 0.59 to 0.85, P < .001), IKKα (HR = 0.74, 95% CI = 0.60 to 0.92, P = .005), Raf-1338 (HR = 0.64, 95% CI = 0.52 to 0.80, P < .001), and p44/42 MAPK202/204 (HR = 0.77, 95% CI = 0.64 to 0.92, P = .004) were statistically significantly associated with improved RFS at 10 years in patients receiving sequential therapy. Associations were strengthened when IKKα, Raf-1338, and ER167 were combined into a cumulative prognostic score (HR = 0.64, 95% CI = 0.52 to 0.77, P <.001). Patients with an all negative IKKα, Raf-1338, and ER167 score favored exemestane monotherapy (odds ratio = 0.56, 95% CI = 0.35 to 0.90). In multivariable analysis, the IKKα, Raf-1338, and ER167 score (P = .001) was an independent prognostic factor for RFS at 10 years in patients receiving sequential therapy. Conclusions: The IKKα, Raf-1338, and ER167 score is an independent predictive biomarker for lower recurrence on sequential therapy. Negative expression may further offer predictive value for exemestane monotherapy

Pathway-based subnetworks enable cross-disease biomarker discovery.

Biomarkers lie at the heart of precision medicine. Surprisingly, while rapid genomic profiling is becoming ubiquitous, the development of biomarkers usually involves the application of bespoke techniques that cannot be directly applied to other datasets. There is an urgent need for a systematic methodology to create biologically-interpretable molecular models that robustly predict key phenotypes. Here we present SIMMS (Subnetwork Integration for Multi-Modal Signatures): an algorithm that fragments pathways into functional modules and uses these to predict phenotypes. We apply SIMMS to multiple data types across five diseases, and in each it reproducibly identifies known and novel subtypes, and makes superior predictions to the best bespoke approaches. To demonstrate its ability on a new dataset, we profile 33 genes/nodes of the PI3K pathway in 1734 FFPE breast tumors and create a four-subnetwork prediction model. This model out-performs a clinically-validated molecular test in an independent cohort of 1742 patients. SIMMS is generic and enables systematic data integration for robust biomarker discovery

Effect of aromatase inhibitors on the lipid profile of postmenopausal breast cancer patients

The two most commonly used alternative strategies of endocrine treatment in postmenopausal women with hormone-receptor-positive breast cancers are either the interference with estrogen signaling by a selective estrogen-receptor modulator, such as tamoxifen, or the inhibition of endogenous estrogen production via an aromatase inhibitor (Al). Tamoxifen has been used effectively for over 30 years and it is generally accepted that it exerts a beneficial effect on lipid profiles. Still, its use has been questioned especially in recent years, following indication of an increased risk of endometrial cancer, thromboembolic events and tolerability concerns, along with, most importantly, the development of resistance during long-term adjuvant treatment. On the other hand, inhibition of aromatase, the enzyme that converts androgens to estrogens, with an Al has been shown to be an effective alternative to tamoxifen in multiple clinical trials with anastrozole, letrozole and exemestane. At the same time, due to the high levels of estrogen deprivation caused by Als, there is uncertainty over the long-term safety of these agents, in particular with respect to the effects on bone metabolism of postmenopausal women and the lipid profile, and thus, cardiovascular disease. Current data on Als showing favorable, neutral or unfavorable effect on different lipid parameters in various studies, do not allow the drawing of any final conclusions about their effect on lipid metabolism. However, considering disease outcome, particularly in high-risk patients, the benefits of receiving an Al are likely to outweigh the disadvantages of any changes to lipid profiles. Therefore, each patient should be carefully evaluated before the appropriate therapy is decided and blood lipid levels should be monitored during adjuvant hormonal treatment; the instigation of lipid-lowering treatment should be undertaken if required

The development of primary school students’ 3D geometrical thinking within a dynamic transformation context

This study examines children’s thinking about geometrical solids through an investigation of dynamic transformations employed by young children making mental transformations of an orthogonal parallelepiped. The focus of the study is on the investigation of the role that a dynamic environment could play in the development of children’s geometrical thinking concerning geometrical solids and their properties. Twenty 6th grade children, who had previously worked with dynamic transformations of physical models of geometrical solids in their classroom, were interviewed. Analysis of the data resulted in a categorization of children’s thinking, and indicated a development from a perceptual to a geometrical consideration of the solid. Although not all the children reached an advanced level of thinking, the context of dynamic transformations promoted the development of most children’s geometrical thinking. There is also an indication that children’s experience with dynamic transformations of physical models in a mathematics classroom environment can act to allow children to transfer experience to the context of mental transformations

Combination of Calcium Hydroxyapatite Antibiotic Carrier with Cement Spacers in Peri- Prosthetic Knee Infections

Background: Forty-six patients (38 females and 8 males) with infected knee arthroplasties were included in this study. In 31 patients (group A) an antibiotic-impregnated articulating spacer was used, whereas in 15 patients (group B) a combination of spacer and antibiotic carrier was used. Methods: All patients were reviewed weekly with laboratory examinations (white blood cell count [WBC], erythrocyte sedimentation rate [ESR], C-reactive protein [CRP]) prior to re-implantation. At a mean follow-up of 36mo (range, 8-60mo) no patient was lost to follow-up or had died. Results: White blood cell count and ESR showed no differences at any time interval. C-reactive protein values had a statistically significant difference between the two groups after the second week (third week p=0.042) and group B had significantly lower CRP values at every checkpoint thereafter. The re-infection rate was 16.12% in group A and 6.6% in group B (p=0.192)

Collaborative inquiry driving leadership growth and school improvement

Australia’s largest schooling system, the NSW Department of Education, is in a period of unprecedented change as the Department of Education initiates a range of reforms. One critical reform occurred in 2014 when the Department of Education and the New South Wales Teachers’ Federation agreed to link teachers’ salaries with accreditation. For the first time, all Department of Education principals, executives and teachers must complete an annual Performance and Development Plan. This article describes the work of a team of academics from the School of Education, Southern Cross University, and the Department of Education school leaders in northern NSW, exploring opportunities to accomplish school improvement through the “North Coast Initiative for School Improvement” (NCISI). The impetus for this initiative is based on the work of Alberta academics and researchers, Dr. David Townsend and Dr. Pamela Adams. The approach is based upon small teams, comprising a member of a school district’s central office, a district principal and university academics, who once a month visit the leadership team of a school in order to build instructional leadership. This process involves the use of a guiding question, generative dialogue and a collaborative inquiry methodology. Early findings indicate the NCISI’s approach is having positive impact leadership growth, through collaboration. Key elements of trust and professional identity have developed within teams. The very positive reaction of school communities to the project in its early stages is heartening and shows that there is a strong desire by school leaders to draw upon collaborative support in order to grow professionally. The project also demonstrates a strong level of commitment from a regional university to build productive relationships with schools