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Marmot M.G.,University College London | Altman D.G.,University of Oxford | Cameron D.A.,University of Edinburgh | Dewar J.A.,Medical School | And 2 more authors.
British Journal of Cancer

1.1 Introduction: The breast cancer screening programmes in the United Kingdom currently invite women aged 50-70 years for screening mammography every 3 years. Since the time the screening programmes were established, there has been debate, at times sharply polarised, over the magnitude of their benefit and harm, and the balance between them. The expected major benefit is reduction in mortality from breast cancer. The major harm is overdiagnosis and its consequences; overdiagnosis refers to the detection of cancers on screening, which would not have become clinically apparent in the woman's lifetime in the absence of screening. Professor Sir Mike Richards, National Cancer Director, England, and Dr Harpal Kumar, Chief Executive Officer of Cancer Research UK, asked Professor Sir Michael Marmot to convene and chair an independent panel to review the evidence on benefits and harms of breast screening in the context of the UK breast screening programmes. The panel, authors of this report, reviewed the extensive literature and heard testimony from experts in the field who were the main contributors to the debate. The nature of information communicated to the public, which too has sparked debate, was not part of the terms of reference of the panel, which are listed in Appendix 1. 1.2 Relative mortality benefit: The purpose of screening is to advance the time of diagnosis so that prognosis can be improved by earlier intervention. A consequence of earlier diagnosis is that it increases the apparent incidence of breast cancer in a screened population and extends the average time from diagnosis to death, even if screening were to confer no benefit. The appropriate measure of benefit, therefore, is reduction in mortality from breast cancer in women offered screening compared with women not offered screening. In the panel's judgement, the best evidence for the relative benefit of screening on mortality reduction comes from 11 randomised controlled trials (RCTs) of breast screening. Meta-analysis of these trials with 13 years of follow-up estimated a 20% reduction in breast cancer mortality in women invited for screening. The relative reduction in mortality will be higher for women actually attending screening, but by how much is difficult to say because women who do not attend are likely to have a different background risk. Three types of uncertainties surround this estimate of 20% reduction in breast cancer mortality. The first is statistical: the 95% confidence interval (CI) around the relative risk (RR) reduction of 20% was 11-27%. The second is bias: there are a number of potential sources of distortion in the trials that have been widely discussed in the literature ranging from suboptimal randomisation to problems in adjudicating cause of death. The third is the relevance of these old trials to the current screening programmes. The panel acknowledged these uncertainties, but concluded that a 20% reduction is still the most reasonable estimate of the effect of the current UK screening programmes on breast cancer mortality. Most other reviews of the RCTs have yielded similar estimates of relative benefit. The RCTs were all conducted at least 20-30 years ago. More contemporary estimates of the benefit of breast cancer screening come from observational studies. The panel reviewed three types of observational studies. The first were ecological studies comparing areas, or time periods, when screening programmes were and were not in place. These have generated diverse findings, partly because of the major advances in treatment of breast cancer, which have a demonstrably larger influence on mortality trends than does screening, and partly because of the difficulty of excluding imbalances in other factors that could affect breast cancer mortality. The panel did not consider these studies helpful in estimating the effect of screening on mortality. The other two types of studies, case-control studies and incidence-based mortality studies, showed breast screening to confer a greater benefit than did the trials. Although these studies, in general, attempted to control for non-comparability of screened and unscreened women, the panel was concerned that residual bias could inflate the estimate of benefit. However, the panel notes that these studies' findings are in the same direction as the trials. 1.3 Absolute mortality benefit: Estimates of absolute benefit of screening have varied from one breast cancer death avoided for 2000 women invited to screening to 1 avoided for about 100 women screened, about a 20-fold difference. Major determinants of that large variation are the age of women screened, and the durations of screening and follow-up. The age of the women invited is important, as mortality from breast cancer increases markedly with age. The panel therefore applied the relative mortality reduction of 20% to achieve the observed cumulative absolute risk of breast cancer mortality over the ages 55-79 years for women in the United Kingdom, assuming that women who began screening at 50 years would gain no benefit in the first 5 years, but that the mortality reduction would continue for 10 years after screening ended. This yielded the estimate that for every 235 women invited to screening, one breast cancer death would be prevented; correspondingly 180 women would need to be screened to prevent one breast cancer death. Uncertainties in the figure of a 20% RR reduction would carry through to these estimates of absolute mortality benefit. Nonetheless, the panel's estimate of benefit is in the range of one breast cancer death prevented for B250 women invited, rather than the range of 1 in 2000. 1.4 Overdiagnosis: The major harm of screening considered by the panel was that of overdiagnosis. Given the definition of an overdiagnosed cancer, either invasive or non-invasive, as one diagnosed by screening, which would not otherwise have come to attention in the woman's lifetime, there is need for a long follow-up to assess the frequency of overdiagnosis. In the view of the panel, some cancers detected by screening will be overdiagnosed, but the uncertainty surrounding the extent of overdiagnosis is greater than that for the estimate of mortality benefit because there are few sources of reliable data. The issue for the UK screening programmes is the magnitude of overdiagnosis in women who have been in a screening programme from age 50 to 70, then followed for the rest of their lives. There are no data to answer this question directly. Any estimate will therefore be, at best, provisional. Although the definition of an overdiagnosed case, and thus the numerator in a ratio, is clear, the choice of denominator has been the source of further variability in published estimates. Different studies have used: only the cancers found by screening; cancers found during the whole screening period, both screen-detected and interval; cancers diagnosed during the screening period and for the remainder of the women's lifetime. The panel focused on two estimates: the first from a population perspective using as the denominator the number of breast cancers, both invasive and ductal carcinoma in situ (DCIS), diagnosed throughout the rest of a woman's lifetime after the age that screening begins, and the second from the perspective of a woman invited to screening using the total number of breast cancers diagnosed during the screening period as the denominator. The panel thought that the best evidence came from three RCTs that did not systematically screen the control group at the end of the screening period and followed these women for several more years. The frequency of overdiagnosis was of the order of 11% from a population perspective, and about 19% from the perspective of a woman invited to screening. Trials that included systematic screening of the control group at the end of the active part of the trial were not considered to provide informative estimates of the frequency of overdiagnosis. Information from observational studies was also considered. One method that has been used is investigation of time trends in incidence rates of breast cancer for different age groups over the period that population screening was introduced. The published results of these studies varied greatly and have been interpreted as providing either reassurance or cause for alarm. So great was the variation in results that the panel conducted an exercise by varying the assumptions and statistical methods underlying these studies, using the same data sets; estimates of overdiagnosis rates were found to vary across the range of 0-36% of invasive breast cancers diagnosed during the screening period. The panel had no reason to favour one set of estimates over another, and concluded that this method could give no reliable estimate of the extent of overdiagnosis. Were it possible to distinguish at screening those cancers that would not otherwise have come to attention from those that, untreated, would lead to death, the overdiagnosis problem could be much reduced, at least in terms of unnecessary worry and treatment. Currently this is not possible, so neither the woman nor her doctor can know whether a screen-detected cancer is an 'overdiagnosed' case or not. In particular, DCIS, most often diagnosed at screening, does not inevitably equate to overdiagnosis - screen-detected DCIS, after wide local excision (WLE) only, is associated with subsequent development of invasive breast cancer in 10% of women within 10 years. The consequences of overdiagnosis matter, women are turned into patients unnecessarily, surgery and other forms of cancer treatment are undertaken, and quality of life and psychological well being are adversely affected. © 2013 Cancer Research UK. All rights reserved. Source

Partridge A.H.,Dana-Farber Cancer Institute | Rumble R.B.,American Society of Clinical Oncology | Carey L.A.,University of North Carolina at Chapel Hill | Come S.E.,Beth Israel Deaconess Medical Center | And 10 more authors.
Journal of Clinical Oncology

Recommendations: Endocrine therapy is preferable to chemotherapy as first-line treatment for patients with estrogen receptor-positive metastatic breast cancer unless improvement is medically necessary (eg, immediately life-threatening disease). Single agent is preferable to combination chemotherapy, and longer planned duration improves outcome but must be balanced against toxicity. There is no single optimal first-line or subsequent line chemotherapy, and choice of treatment will be determined by multiple factors including prior therapy, toxicity, performance status, comorbid conditions, and patient preference. The role of bevacizumab remains controversial. Other targeted therapies have not so far been shown to enhance chemotherapy outcome in HER2-negative breast cancer.Methods: A systematic review of randomized evidence (including systematic reviews and meta-analyses) from 1993 through to current was completed. Outcomes of interest included survival, progressionfree survival, response, quality of life, and adverse effects. Guideline recommendations were evidence based and were agreed on by the Expert Panel via consensus.Purpose: To identify optimal chemo- and targeted therapy for women with human epidermal growth factor 2 (HER2)-negative (or unknown) advanced breast cancer.Results: Seventy-nine studies met the inclusion criteria, comprising 20 systematic reviews and/or metaanalyses, 30 trials on first-line treatment, and 29 trials on second-line and subsequent treatment. These trials form the evidence base for the guideline recommendations. © 2014 by American Society of Clinical Oncology. Source

Bartlett J.,Ontario Cancer Institute | Canney P.,Beatson West of Scotland Cancer Center | Campbell A.,University of Warwick | Cameron D.,University of Edinburgh | And 17 more authors.
Clinical Oncology

The mortality from breast cancer has improved steadily over the past two decades, in part because of the increased use of more effective adjuvant therapies. Thousands of women are routinely treated with intensive chemotherapy, which can be unpleasant, is expensive and is occasionally hazardous. Oncologists have long known that some of these women may not need treatment, either because they have a low risk of relapse or because they have tumour biology that makes them less sensitive to chemotherapy and more suitable for early adjuvant endocrine therapy. There is an urgent need to improve patient selection so that chemotherapy is restricted to those patients who will benefit from it. Here we review the emerging technologies that are available for improving patient selection for chemotherapy. We describe the OPTIMA trial, which has just opened to recruitment in the UK, is the latest addition to trials in this area, and is the first to focus on the relative cost-effectiveness of alternate predictive assays. © 2012. Source

Stein R.C.,University College London | Dunn J.A.,University of Warwick | Bartlett J.M.S.,Ontario Cancer Institute | Campbell A.F.,University of Warwick | And 12 more authors.
Health Technology Assessment

Background: There is uncertainty about the chemotherapy sensitivity of some oestrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancers. Multiparameter assays that measure the expression of several tumour genes simultaneously have been developed to guide the use of adjuvant chemotherapy for this breast cancer subtype. The assays provide prognostic information and have been claimed to predict chemotherapy sensitivity. There is a dearth of prospective validation studies. The Optimal Personalised Treatment of early breast cancer usIng Multiparameter Analysis preliminary study (OPTIMA prelim) is the feasibility phase of a randomised controlled trial (RCT) designed to validate the use of multiparameter assay directed chemotherapy decisions in the NHS. Objectives: OPTIMA prelim was designed to establish the acceptability to patients and clinicians of randomisation to test-driven treatment assignment compared with usual care and to select an assay for study in the main RCT. Design: Partially blinded RCT with adaptive design. Setting: Thirty-five UK hospitals. Participants: Patients aged ≥ 40 years with surgically treated ER-positive HER2-negative primary breast cancer and with 1-9 involved axillary nodes, or, if node negative, a tumour at least 30 mm in diameter. Interventions: Randomisation between two treatment options. Option 1 was standard care consisting of chemotherapy followed by endocrine therapy. In option 2, an Oncotype DX® test (Genomic Health Inc., Redwood City, CA, USA) performed on the resected tumour was used to assign patients either to standard care [if ‘recurrence score’ (RS) was > 25] or to endocrine therapy alone (if RS was ≤ 25). Patients allocated chemotherapy were blind to their randomisation. Main outcome measures: The pre-specified success criteria were recruitment of 300 patients in no longer than 2 years and, for the final 150 patients, (1) an acceptance rate of at least 40%; (2) recruitment taking no longer than 6 months; and (3) chemotherapy starting within 6 weeks of consent in at least 85% of patients. Results: Between September 2012 and 3 June 2014, 350 patients consented to join OPTIMA prelim and 313 were randomised; the final 150 patients were recruited in 6 months, of whom 92% assigned chemotherapy started treatment within 6 weeks. The acceptance rate for the 750 patients invited to participate was 47%. Twelve out of the 325 patients with data (3.7%, 95% confidence interval 1.7% to 5.8%) were deemed ineligible on central review of receptor status. Interviews with researchers and recordings of potential participant consultations made as part of the integral qualitative recruitment study provided insights into recruitment barriers and led to interventions designed to improve recruitment. Patient information was changed as the result of feedback from three patient focus groups. Additional multiparameter analysis was performed on 302 tumour samples. Although Oncotype DX, MammaPrint®/BluePrint® (Agendia Inc., Irvine, CA, USA), Prosigna® (NanoString Technologies Inc., Seattle, WA, USA), IHC4, IHC4 automated quantitative immunofluorescence (AQUA®) [NexCourse BreastTM (Genoptix Inc. Carlsbad, CA, USA)] and MammaTyper® (BioNTech Diagnostics GmbH, Mainz, Germany) categorised comparable numbers of tumours into low-or high-risk groups and/or equivalent molecular subtypes, there was only moderate agreement between tests at an individual tumour level (kappa ranges 0.33-0.60 and 0.39-0.55 for tests providing risks and subtypes, respectively). Health economics modelling showed the value of information to the NHS from further research into multiparameter testing is high irrespective of the test evaluated. Prosigna is currently the highest priority for further study. Conclusions: OPTIMA prelim has achieved its aims of demonstrating that a large UK clinical trial of multiparameter assay-based selection of chemotherapy in hormone-sensitive early breast cancer is feasible. The economic analysis shows that a trial would be economically worthwhile for the NHS. Based on the outcome of the OPTIMA prelim, a large-scale RCT to evaluate the clinical effectiveness and cost-effectiveness of multiparameter assay-directed chemotherapy decisions in hormone-sensitive HER2-negative early breast would be appropriate to take place in the NHS. © Queen’s Printer and Controller of HMSO 2016. Source

Quinlan P.R.,Dundee Cancer Center | Quinlan P.R.,University of Nottingham | Groves M.,Dundee Cancer Center | Jordan L.B.,NHS Tayside | And 4 more authors.
Biopreservation and Biobanking

The challenges facing biobanks are changing from simple collections of materials to quality-assured fit-for-purpose clinically annotated samples. As a result, informatics awareness and capabilities of a biobank are now intrinsically related to quality. A biobank may be considered a data repository, in the form of raw data (the unprocessed samples), data surrounding the samples (processing and storage conditions), supplementary data (such as clinical annotations), and an increasing ethical requirement for biobanks to have a mechanism for researchers to return their data. The informatics capabilities of a biobank are no longer simply knowing sample locations; instead the capabilities will become a distinguishing factor in the ability of a biobank to provide appropriate samples. There is an increasing requirement for biobanking systems (whether in-house or commercially sourced) to ensure the informatics systems stay apace with the changes being experienced by the biobanking community. In turn, there is a requirement for the biobanks to have a clear informatics policy and directive that is embedded into the wider decision making process. As an example, the Breast Cancer Campaign Tissue Bank in the UK was a collaboration between four individual and diverse biobanks in the UK, and an informatics platform has been developed to address the challenges of running a distributed network. From developing such a system there are key observations about what can or cannot be achieved by informatics in isolation. This article will highlight some of the lessons learned during this development process. © Copyright 2015, Mary Ann Liebert, Inc. 2015. Source

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