Title: The Low Risk DCIS (ductal carcinoma in situ) Trial
Funder: Department of Health and Social Care

Abstract: BACKGROUND: The independent review of the UK National Health Service Breast Screening Programme reported recently on the benefits and harms of breast screening (The Lancet, Volume 380, Issue 9855, Pages 1778 - 1786, 17 November 2012). This concluded that breast screening saves lives but acknowledged the existence of overtreatment. Consequently, randomised trials were recommended to elucidate the appropriate treatment of screen-detected ductal carcinoma in situ (DCIS) and to gain a better understanding of its natural history. The LORIS trial aims to establish whether patients with newly diagnosed low risk DCIS can safely avoid surgery without detriment to their wellbeing (psychological and physical) and whether those patients who do require surgery can be identified by pathological and radiological means. DESIGN: LORIS is a multi-centre, randomised (1:1), controlled phase III trial of Surgery versus Active Monitoring in patients with low risk DCIS, incorporating a 2 year internal Feasibility Study. SETTING: NHS Breast Screening Clinics and Symptomatic Breast Clinics. TARGET POPULATION: Women with newly diagnosed, mammographically detected, asymptomatic, low risk DCIS (defined as low grade or low-intermediate grade, confirmed by Central Histopathology Review). HEALTH TECHNOLOGIES BEING ASSESSED: Effectiveness, cost effectiveness and acceptability to patients and clinicians of no surgical intervention for low risk DCIS. The trial addresses the possible current overtreatment of low risk DCIS. MEASUREMENT OF COST AND OUTCOMES: If non-inferiority of no surgery is shown, the trial will be immediately practice changing, saving hospital admission costs (breast conservation surgery, mastectomy, breast reconstruction, radiotherapy) but with minimal additional costs, as with or without surgery, long-term mammography is indicated. There are therefore clear potential healthcare savings to a non-surgical approach. It begins to address concerns aimed mainly at the breast screening service but applicable to equally to current treatments of asymptomatic mammogram-detected DCIS performed outside screening, where women are treated by target-driven surgery as urgent cancer patients. The radiological, pathological and translational data generated from this trial will assess the natural history of low risk DCIS and allow patients to make an informed choice and enable the selection of patients who can safely avoid surgery. The objective of the Feasibility Study is to demonstrate that enough eligible patients can be identified and recruited over the course of the trial to robustly answer the main trial objectives. The primary objective of the trial is ipsilateral invasive breast cancer free survival rate at 5 years. Secondary objectives are: time to development of ipsilateral invasive breast cancer, time to development of any invasive breast cancer, time to development of contralateral invasive breast cancer, overall survival, time to mastectomy, time to surgery, Quality of Life, Quality-Adjusted Life Years and assessment of predictive biomarkers. SAMPLE SIZE: The primary endpoint is ipsilateral invasive breast cancer free survival rate at 5 years. 932 patients are needed to show 2.5% non-inferiority. This includes the patients recruited during the Feasibility Study, plus a 10% allowance for non-adherence. The adherence rate will be reviewed following completion of the feasibility phase. The sample size will be adjusted accordingly should the drop-out rate be higher or lower than expected. The one-sided type I error is set at 5% and power is 80%. Assuming a 5 year ipsilateral invasive breast cancer free rate of 97.5% in the Surgery arm, to exclude a difference of less that 2.5% at 5 years. PROJECT TIMETABLE: Trial to open to recruitment in March 2014. Feasibility Study to complete by the end of Year 2 and any adjustments to patient information, recruitment strategy, trial processes to be made. Recruitment will continue until February 2020. Primary endpoint to be reported in 2025. Long term follow-up is essential, 10 years of annual mammograms are mandated or, inclusion within HTA mammographic follow-up trials.

Lay abstract: The breast cancer screening programmes in the United Kingdom currently invite women aged 50–70 years for screening mammography every 3 years. Since the screening programmes were established, there has been much debate over the degree of benefit and harm of screening programmes, and the balance between these. The expected major benefit is reduction in death 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. The Benefits and Harms of Breast Screening; An Independent Review was commissioned by the Department of Health to address these issues of debate and was published in October 2012 (The Lancet, Volume 380, Issue 9855, Pages 1778 - 1786, 17 November 2012). The reviewers found benefits and harms of the Programme and importantly established that this screening saves lives but also that over diagnosis exists. The panel estimated that for 10,000 UK women invited to screening from age 50 for 20 years, about 681 cancers will be found of which 129 will represent overdiagnosis, and 43 deaths from breast cancer will be prevented. In round terms, therefore, for each breast cancer death prevented, about three overdiagnosed cases will be identified and treated. The panel's review of overdiagnosis lead to their recommendation for further research into DCIS and in particular the need for the treatment of low grade DCIS. The surgical treatment of DCIS has remained unchanged since the 1950's, despite evidence that removing DCIS does not prevent invasive cancers. When diagnosed, DCIS is removed by surgery because of concern that it might turn into invasive cancer. This concern has never been explored within a randomised clinical trial. DCIS is almost always found only as a result of calcification on mammograms. Before breast screening, the incidence of DCIS was very low indeed. It is now a very common diagnosis, representing 20% of all breast 'cancers'. Women with DCIS are more likely to have a mastectomy than women with invasive cancer. Despite the treatment of all DCIS by surgery, the incidence of invasive breast cancer has increased. It appears that we may be diagnosing and treating women for a condition that may never become a clinical problem if undiagnosed. This is called 'overdiagnosis; and 'over-treatment'. The amount of DCIS detected is increasing with more sensitive digital mammogram techniques and its treatment is both a continuing economic burden to the NHS and an ethical dilemma for clinicians. There is agreement that not all untreated DCIS will become breast cancer, but, it is not known which DCIS can be safely left untreated. The current situation of operating on everyone with this diagnosis and labelling them with a diagnosis of cancer is no longer appropriate and is increasingly difficult for clinicians to justify and for 'patients' to accept. This LORIS trial will randomise consenting women presenting to Breast Units (mainly as a result of a screening abnormality) with low risk DCIS, to the current standard treatment which is surgery or to active monitoring with yearly mammograms and no surgery. Substantial cost savings can be made if surgery is found to be unnecessary. The processes involved in progression of DCIS to invasive disease are poorly understood and collecting samples from the current trial will provide a unique future resource to investigate this. It is expected that this trial will show that the invasive cancer rate is similar, with or without surgery, but, this trial is needed to be sure. A combination of tests done on biopsies by pathologists may well be able to inform us at the end of this trial, which patients do need surgery at diagnosis and which do not. A key element of the trial will be the Patient Reported Outcomes component which will serially capture information about the psychosocial aspects of DCIS management from patients in both trial arms. We will need to demonstrate that enough women are willing to accept randomisation into the trial to progress from a Feasibility Study of 60 patients to the main trial. A total of 932 patients are needed to show that in the Active Monitoring arm, the increased risk of developing an invasive cancer in the affected breast is no higher than 2.5% at 5 years. This has been determined as an acceptable threshold which would convince clinicians to change practice and offer monitoring as a standard treatment. Long-term follow-up will need to continue beyond the first analysis of this trial, as long term outcome data is essential to fully understand the natural history of this type of DCIS. There is significant inconsistency in pathology reporting of DCIS, particularly at the 'lower' end of the scale which includes Atypical Ductal Hyperplasia (ADH) (considered benign) through to low and intermediate grade DCIS. Both are described as cancers and are always treated by surgery and sometimes other treatments too, such as radiotherapy and endocrine therapies. Because of this inconsistency, all biopsies reported as low OR intermediate grade in the local hospital will be eligible for and subjected to Central Histopathology Review in this trial. At this review, all biopsies which the trial pathologists consider to be anything other than low grade or at low-intermediate grade will be declared ineligible. The study deliberately includes low risk rather than low grade DCIS to acknowledge both the inconsistency in current reporting, particularly the grey area between low and intermediate grades and to encompass the concept of dividing DCIS into high grade and non-high grade, which is currently gaining ground and appears to avoid the pitfalls of diagnostic inconsistency. At the end of this trial we should know; a) Is the invasive breast cancer rate the same with or without surgery i.e. is surgery necessary? b) Is it possible to predict by biopsy or molecular profiles and/or radiological features, who will progress to invasive breast cancer so that these patients get appropriate treatment to start with? c) What are the Patient Reported Outcomes of being diagnosed with a condition that, up until now, has been treated as cancer and having active monitoring instead? When this trial is reported, patients and clinicians will be able to make an informed choice about treatment options not currently available.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;6.4 SURGERY
Health categories: CANCER AND NEOPLASMS