Actionable pharmacogenetic markers for prediction and prognosis in breast cancer

We would like to thank Professor Christian Scerri for advice and constructive discussions.Breast cancer is a heterogeneous disease that necessitates proper patient classification to direct surgery, pharmacotherapy, and radiotherapy. Despite patients within the same subgroup receiving similar pharmacotherapy, substantial variation in clinical outcomes is observed. Pharmacogenetic variations with direct effect on pharmacokinetics and pharmacodynamics play a central role in clinical outcomes. Pharmacogenetic markers associated with clinical outcome are known as biomarkers. They are termed prognostic biomarkers when their presence is associated with a specific clinical outcome. If the presence of such biomarkers guides treatment, they are termed predictive biomarkers. A number of pharmacogenetic markers have been described in relation to breast cancer pharmacotherapy both in the adjuvant and neoadjuvant setting. CYP2D6 allelic variants produce variable rates of tamoxifen metabolism and are associated with survival outcomes. Other biomarkers have been described in relation to other forms of endocrine therapy and trastuzumab. In neoadjuvant and adjuvant breast cancer chemotherapy, specific biomarkers were correlated with clinical outcomes and risk of drug toxicity. This review highlights key biomarkers in breast cancer pharmacotherapy with the potential of translating such study outcomes into clinical practice.peer-reviewe

Leptin signalling, obesity and prostate cancer: molecular and clinical perspective on the old dilemma

The prevalence of global obesity is increasing. Obesity is associated with general cancer-related morbidity and mortality and is a known risk factor for development of specific cancers. A recent large systematic review of 24 studies based on meta-analysis of 11,149 patients with prostate cancer showed a significant correlation between obesity and the risk of advanced prostate cancer. Further, a sustained reduction in BMI correlates with a decreased risk of developing aggressive disease. On the other hand, the correlation between consuming different products and prostate cancer occurrence/risk is limited. Here, we review the role of adipose tissue from an endocrine perspective and outline the effect of adipokines on cancer metabolism, with particular focus on leptin. Leptin exerts its physiological and pathological effects through modification of intracellular signalling, most notably activating the Janus kinase (JAK) 2/signal transducer and activator of transcription (STAT) 3 pathway and recently shown sphingolipid pathway. Both high levels of leptin in circulation and leptin receptor mutation are associated with prostate cancer risk in human patients; however, the in vivo mechanistic evidence is less conclusive. Given the complexity of metabolic cancer pathways, it is possible that leptin may have varying effects on prostate cancer at different stages of its development, a point that may be addressed by further epidemiological studies

The influence of innate and adaptive immunity on Crohn’s disease severity

This article was originally published in a special issue, entitled: "Inflammatory Bowel Disease", Edited by Nancy Louis, Emory University, USA and Ostanin Dmitry Vladimirovich, Louisiana State University Health Sciences Center, USAStricturing and penetrating disease are classified as severe Crohn’s disease types and are frequently associated with an increased risk for bowel surgery. Research has shown that early treatment with aggressive immunosuppression (including biological and thiopurine therapies – the so-called “top-down approach”) results in a diminished risk of developing these complicated disease types. However, these therapies carry significant risks and cost. Being able to predict which patients are at an increased risk of developing severe Crohn’s disease may enable us to treat patients individually, with the aggressive “top-down approach” started at diagnosis in patients with a significantly increased risk of developing complicated disease types. Defects of innate and adaptive immunity both play a role in Crohn’s disease pathophysiology. Identifying whether defects of innate immunity (through gene mutations) or adaptive immunity (through antibodies to microbial antigens) are associated with stricturing/penetrating disease types may enable us to predict the course of the disease and therefore decide on who would benefit most from the “top-down approach”. This review discusses the role of NOD2 and other gene polymorphisms in predicting Crohn’s disease severity. It also highlights the evidence linking the role of the various antibodies involved in adaptive immunity (ASCA, OmpC, GM-CSF) and complicated Crohn’s disease types.peer-reviewe

Molecular classification of breast cancer patients using formalin-fixed paraffin-embedded derived RNA samples

The use of archival formalin-fixed paraffin-embedded (FFPE) material to analyse gene expression is limited by the low quality of extracted RNA. In this paper, we utilised an RNA based assay to quantify expression of luminal and basal markers, together with ERBB2 probes, in FFPE archival tissue from 2009 to 2010, all of which had clinical and therapeutic information of more than 5 years. Receptor status of the patients was characterised using the QuantiGene® Plex assay with 100% concordance to immunohistochemical (IHC) and fluorescence in situ hybridisation (FISH) results. A panel of molecular markers known to classify luminal and basal tumours were used and correlated with receptor status of the tumours. As expected, the triple negative breast cancer (TNBC) samples were classified as basal and oestrogen receptor (ER) positive cases as luminal. In summary, the QuantiGene® Plex technology provides a platform to quantitate novel panels of biomarkers on archival material. Moreover, multiplex analysis allows the use of minimal amounts of material providing an opportunity to utilise laser micro-dissected material. FFPE tissue samples are an invaluable resource for retrospective studies to interrogate current novel biomarkers, particularly to generate disease free survival and overall survival graphs to measure predictive value using well annotated retrospective samples with full clinical and pharmacological outcomes.This study was funded by the Faculty of Medicine and Surgery, University of Malta and the Italia Malta Genome Breast Cancer Cross Border Risk Surveillance (ImaGenX) project financed under Operational Program Italia Malta 2007-2013 and co-financed by the University of Malta.peer-reviewe

Propulsion simulator for magnetically-suspended wind tunnel models

In order to demonstrate the measurement of aerodynamic forces/moments, including the effects of exhaust jets in Magnetic Suspension and Balance System (MSBS) wind tunnels, two propulsion simulator models were developed at Physical Sciences Inc. (PSI). Both the small-scale model (1 in. diameter X 8 in. long) and the large-scale model (2.5 in. diameter X 15 in. long) employed compressed, liquefied carbon dioxide as a propellant. The small-scale simulator, made from a highly magnetizable iron alloy, was demonstrated in the 7 in. MSBS wind tunnel at the University of Southampton. It developed a maximum thrust of approximate 1.3 lbf with a 0.098 in. diameter nozzle and 0.7 lbf with a 0.295 in. diameter nozzle. The Southampton MSBS was able to control the simulator at angles-of attack up to 20 deg. The large-scale simulator was demonstrated to operate in both a steady-state and a pulse mode via a miniaturized solinoid valve. It developed a stable and repeatable thrust of 2.75 lbf over a period of 4s and a nozzle pressure ratio (NPR) of 5

Physical inactivity is a strong risk factor for stroke in the oldest old: Findings from a multi-ethnic population (the Northern Manhattan Study)

Background The fastest growing segment of the population is those age ≥80 who have the highest stroke incidence. Risk factor management is complicated by polypharmacy-related adverse events. Aims To characterize the impact of physical inactivity for stroke by age in a multi-ethnic prospective cohort study (NOMAS, n = 3298). Methods Leisure time physical activity was assessed by a validated questionnaire and our primary exposure was physical inactivity (PI). Participants were followed annually for incident stroke. We fit Cox-proportional hazard models to calculate hazard ratios and 95% confidence intervals (HR 95% CI) for the association of PI and other risk factors with risk of stroke including two-way interaction terms between the primary exposures and age (<80 vs. ≥80). Results The mean age was 69 ± 10.3 years and 562 (17%) were ≥80 at enrolment. PI was common in the cohort (40.8%). Over a median of 14 years, we found 391 strokes. We found a significant interaction of age ≥80 on the risk of stroke with PI (p = 0.03). In stratified models, PI versus any activity (adjusted HR 1.60, 95%CI 1.05–2.42) was associated with an increased risk of stroke among those ≥80. Conclusion Physical inactivity is a treatable risk factor for stroke among those older than age 80. Improving activity may reduce the risk of stroke in this segment of the population

Disease-free survival in molecular subtypes of breast cancer in Malta

Introduction: Breast cancer is the commonest incident tumour in the Maltese islands. The disease is heterogeneous and exhibits diverse clinical prognosis and survival rates. Proper patient classification helps stratify breast cancer groups to ascertain likely prognostic ontcome and select treatment. Breast cancer survival has commonly been described in terms of disease- free survival and five-year overall survival. The aim of this study is to determine disease-free survival together with site of metastasis while stratifying clinical outcomes with known prognostic markers and novel genetic markers.peer-reviewe

Leptomeningeal carcinomatosis as the primary presentation of relapse in breast cancer

Leptomeningeal metastasis (LM) is an uncommon presentation of relapse in breast cancer, which is associated with poor clinical outcomes and poor prognosis. Notably, LM most commonly occurs in breast cancer. The aim of the present review was to investigate the occurrence of LM as the primary presentation of relapse following remission in breast cancer patients and to determine whether specific histological subtypes are predisposed to meningeal metastases. In addition, the present review evaluated whether patients presenting with LM as the primary site of relapse exhibit differences in survival when compared with patients exhibiting metastasis to other sites. Cross-sectional studies have demonstrated that LM is commonly associated with other sites of distant metastasis including lung, liver and bone metastases. The histological breast cancer subtype most commonly associated with LM was invasive lobular carcinoma, while triple-negative breast cancer patients appear to be predisposed to the development of LM when considering the overall prevalence of histological breast cancer subtypes. At present, data regarding LM as the primary site of relapse are limited due to its rarity as the first site of metastasis in breast cancer. Case-controlled studies are required to investigate the incidence of LM as the primary site of recurrence in breast cancer patients as this would enable treatment standardization and identification of prognostic factors for improved survival

Histone deacetylases as new therapy targets for platinum-resistant epithelial ovarian cancer

Introduction: In developed countries, ovarian cancer is the fourth most common cancer in women. Due to the nonspecific symptomatology associated with the disease many patients with ovarian cancer are diagnosed late, which leads to significantly poorer prognosis. Apart from surgery and radiotherapy, a substantial number of ovarian cancer patients will undergo chemotherapy and platinum based agents are the mainstream first-line therapy for this disease. Despite the initial efficacy of these therapies, many women relapse; therefore, strategies for second-line therapies are required. Regulation of DNA transcription is crucial for tumour progression, metastasis and chemoresistance which offers potential for novel drug targets. Methods: We have reviewed the existing literature on the role of histone deacetylases, nuclear enzymes regulating gene transcription. Results and conclusion: Analysis of available data suggests that a signifant proportion of drug resistance stems from abberant gene expression, therefore HDAC inhibitors are amongst the most promising therapeutic targets for cancer treatment. Together with genetic testing, they may have a potential to serve as base for patient-adapted therapies