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Polley M.-Y.C.,U.S. National Cancer Institute | Leung S.C.Y.,University of British Columbia | McShane L.M.,U.S. National Cancer Institute | Gao D.,University of British Columbia | And 14 more authors.
Journal of the National Cancer Institute | Year: 2013

BackgroundIn breast cancer, immunohistochemical assessment of proliferation using the marker Ki67 has potential use in both research and clinical management. However, lack of consistency across laboratories has limited Ki67's value. A working group was assembled to devise a strategy to harmonize Ki67 analysis and increase scoring concordance. Toward that goal, we conducted a Ki67 reproducibility study.MethodsEight laboratories received 100 breast cancer cases arranged into 1-mm core tissue microarrays-one set stained by the participating laboratory and one set stained by the central laboratory, both using antibody MIB-1. Each laboratory scored Ki67 as percentage of positively stained invasive tumor cells using its own method. Six laboratories repeated scoring of 50 locally stained cases on 3 different days. Sources of variation were analyzed using random effects models with log2-transformed measurements. Reproducibility was quantified by intraclass correlation coefficient (ICC), and the approximate two-sided 95% confidence intervals (CIs) for the true intraclass correlation coefficients in these experiments were provided. ResultsIntralaboratory reproducibility was high (ICC = 0.94; 95% CI = 0.93 to 0.97). Interlaboratory reproducibility was only moderate (central staining: ICC = 0.71, 95% CI = 0.47 to 0.78; local staining: ICC = 0.59, 95% CI = 0.37 to 0.68). Geometric mean of Ki67 values for each laboratory across the 100 cases ranged 7.1% to 23.9% with central staining and 6.1% to 30.1% with local staining. Factors contributing to interlaboratory discordance included tumor region selection, counting method, and subjective assessment of staining positivity. Formal counting methods gave more consistent results than visual estimation.ConclusionsSubstantial variability in Ki67 scoring was observed among some of the world's most experienced laboratories. Ki67 values and cutoffs for clinical decision-making cannot be transferred between laboratories without standardizing scoring methodology because analytical validity is limited. © 2013 The Author .

Hall P.S.,University of Leeds | McCabe C.,University of Leeds | Brown J.M.,University of Leeds | Cameron D.A.,Edinburgh Cancer Research Center
European Journal of Cancer | Year: 2010

In order to decide whether a new treatment should be used in patients, a robust estimate of efficacy and toxicity is no longer sufficient. As a result of increasing healthcare costs across the globe healthcare payers and providers now seek estimates of cost-effectiveness as well. Most trials currently being designed still only consider the need for prospective efficacy and toxicity data during the development life-cycle of a new intervention. Hence the cost-effectiveness estimates are inevitably less precise than the clinical data on which they are based. Methods based on decision theory are being developed by health economists that can contribute to the design of clinical trials in such a way that they can more effectively lead to better informed drug funding decisions on the basis of cost-effectiveness in addition to clinical outcomes. There is an opportunity to apply these techniques prospectively in the design of future clinical trials. This article describes the problems encountered by those responsible for drug reimbursement decisions as a consequence of the current drug development pathway. The potential for decision theoretic methods to help overcome these problems is introduced and potential obstacles in implementation are highlighted. © 2010 Elsevier Ltd. All rights reserved.

Hall P.S.,University of Leeds | Hulme C.,University of Leeds | McCabe C.,University of Leeds | Oluboyede Y.,University of Leeds | And 3 more authors.
PharmacoEconomics | Year: 2011

Background: Trastuzumab has significantly improved survival outcomes for women with Human Epidermal growth factor Receptor 2 (HER2)-positive early breast cancer. Trastuzumab was established as a cost-effective adjuvant treatment in 2006. We present an updated cost-effectiveness analysis from the UK perspective, which explores assumptions about the duration of benefit from treatment, pattern of metastatic recurrence and long-term cardiac toxicity. Objective: The objective of this study was to calculate, from the UK NHS perspective, expected costs (year 2008 values) and benefits over the lifetime of an average cohort of women with HER2-positive early breast cancer treated with or without 1 year of adjuvant trastuzumab sequentially after chemotherapy. Methods: A cost-utility analysis was performed using a discrete-state timedependent semi-Markov model. Probabilistic sensitivity analysis was used to characterize uncertainty around expected outcomes. Value-of-information (VOI) analysis was used to identify areas of priority for further research. Results: The cost-effectiveness estimates were highly sensitive to the estimated duration of treatment benefit. Trastuzumab remained a cost-effective treatment strategy at a willingness-to-pay threshold of d30 000 per QALY provided the duration of benefit was more than 3.6 years from treatment initiation, assuming the hazard ratio for disease-free survival was 0.63. An increasing proportion of brain metastases with trastuzumab produced a small change towards worse cost effectiveness. Long-term cardiac toxicity needed to rise to high levels to affect overall life expectancy and cost effectiveness. VOI analysis placed highest value on research into the duration of treatment benefit. The relationships between progression-free survival and overall survival and the costs of cancer recurrence were also important. Conclusion: The cost effectiveness of adjuvant trastuzumab remains uncertain and dependent on assumptions regarding its clinical effect. Uncertainty around cost effectiveness could be reduced by further research into the duration of treatment effect, particularly in subgroups where this may be shorter. Longterm follow-up is warranted and methods to accurately measure duration of treatment effect and late toxicities should be developed for future adjuvant drug studies. © 2011 Adis Data Information BV. All rights reserved.

Sheridan D.,University of Edinburgh | Foo I.,Critical Care and Pain Medicine | O'Shea H.,Critical Care and Pain Medicine | Gillanders D.,University of Edinburgh | And 3 more authors.
Journal of Pain and Symptom Management | Year: 2012

Context. Persistent pain after treatment for breast cancer (PPBCT) is a common side effect of breast cancer treatment, with prevalence as high as 50%. It is predominantly a neuropathic condition. Objectives. The aim of this cross-sectional, questionnaire-based study was to examine the emotional characteristics of patients with PPBCT in long-term breast cancer patients. A secondary objective was to characterize the risk factors and severity of that pain. Methods. From March 1, 2010 to April 9, 2010, long-term follow-up patients were invited to complete a questionnaire. This recorded their surgical and demographic data and ascertained whether they had PPBCT. If the patient had pain, she completed a range of validated self-report questionnaires and questions about the nature of the pain, including a visual analogue scale. Results. One hundred eleven patients completed the questionnaire; 33 (29.7%) patients reported chronic pain at a median time of 64 months postoperatively (interquartile range 54.25). Patients with persistent pain were not significantly more anxious (t105 =-0.369, P = 0.713) or depressed (t105 = 0.713, P = 0.507) than patients without pain. Patients with constant pain compared with intermittent pain were significantly more anxious (t25=-3.460, P = 0.002). Preoperative pain conferred a fivefold increased risk of PPBCT (odds ratio [OR] = 5.17, 95% confidence interval [CI] = 1.79e14.97, P = 0.002); chemotherapy conferred a threefold increased risk (OR = 3.004, 95% CI = 1.22-7.40, P = 0.017). Conclusion. We have shown significant numbers of patients suffer from PPBCT. At a median time of 64.5 months, women with pain are not significantly more anxious or depressed than women without pain. Preoperative pain and chemotherapy have been highlighted as risk factors. © 2012 U.S. Cancer Pain Relief Committee.

Meek D.W.,University of Dundee | Hupp T.R.,Edinburgh Cancer Research Center
Seminars in Cancer Biology | Year: 2010

The p53 tumour suppressor is a tightly controlled transcription factor that coordinates a broad programme of gene expression in response to various cellular stresses leading to the outcomes of growth arrest, senescence, or apoptosis. MDM2 is an E3 ubiquitin ligase that plays a key role in maintaining p53 at critical physiological levels by targeting it for proteasome-mediated degradation. Expression of the MDM2 gene is p53-dependent and thus p53 and MDM2 operate within a negative feedback loop in which p53 controls the levels of its own regulator. Induction and activation of p53 involves mainly the uncoupling of p53 from its negative regulators, principally MDM2 and MDMX, an MDM2-related and -interacting protein that inhibits p53 transactivation function. MDM2 is tightly regulated through various mechanisms including gene expression, protein turnover (mediated by auto-ubiquitylation), protein-protein interaction with key regulators, and post-translational modification, mainly, but not exclusively, by multisite phosphorylation. The purpose of the present article is to review our current knowledge of the signalling mechanisms that focus on MDM2, and indeed MDMX, through both phosphorylation mechanisms and peptide-docking events and to consider the wider implications of these regulatory events in the context of coordinated regulation of the p53 response. This analysis also provides an opportunity to consider the signalling pathways regulating MDM2 as potential targets for non-genotoxic therapies aimed at restoring p53 function in tumour cells. © 2009 Elsevier Ltd.

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