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Circulating Tumour Cells (CTCs), the mechanism by which cancer spreads from the primary tumour to distant metastatic sites and cancer-associated thrombosis (CAT), a systemic hypercoagulable state found in many cancer patients, appear to have a symbiotic relationship. CTCs initiate coagulation and may contribute to CAT, and conversely coagulation facilitates the intravasation of CTCs into the systemic circulation, survival in the circulation and extravasation at distant sites. CTCs may be a strong contributor to CAT through direct or indirect activation of coagulation. Whilst the potential for patient-specific CAT risk calculated by a combination of CTC count and blood coagulation factor concentrations has been suggested, evidence of a two-way relationship of hypercoagulability and increased CTC invasiveness is emerging. Tissue factor, the main activator of the extrinsic pathway of coagulation, is particularly implicated. Targeting the CTC-CAT axis is a promising target for improving patient outcome. This review provides background on CAT and CTCs along with recent developments in the field.

Objective This study aims to prioritise the themes identified from the three gap analyses performed by a combination of scientists, clinicians, patients and members of the public to determine areas in breast cancer care where research is lacking. We also aimed to compare the priorities of areas of agreed research need between patients, the public, clinicians and scientists.Design A cross-section of patients, public, clinicians and scientists completed a prioritisation exercise to rank the identified themes where research is lacking in breast cancer care.Participants Patients, clinicians and scientists who have experienced, managed or worked in the field of breast cancer and members of the public.Methods The research areas identified in the Breast Cancer Campaign, Association of Breast Surgery and North West Breast Research Collaborative gap analyses were outlined as 22 themes in lay terminology. Patients, members of the public, clinicians and scientists were invited to complete the prioritisation exercise, on paper or electronically, ranking the themes from 1 to 22. Comparisons were made with arithmetic mean ranking.Results Of the 510 prioritisation exercises completed, 179 (35%) participants were patients, 162 (32%) public, 43 (8%) scientists and 122 (24%) clinicians. The theme ranked of highest priority overall was ‘better prevention’ (arithmetic mean rank 6.4 (SE 0.23)). ‘Better prevention’ was ranked top or second by patients, public and clinicians (7 (0.39), 4.7 (0.34) and 6.8 (0.5), respectively), however, scientists ranked this as their sixth most important factor (7.7 (0.92)). The public and clinicians had good agreement with patients (r=0.84 and r=0.75, respectively), whereas scientists had moderate agreement with patients (r=0.65). Certain themes were ranked significantly differently by participant groups. Compared with clinicians, patients prioritised research into ‘alternative to mammograms’, ‘diagnostic (cancer) blood test’ and ‘rare cancers’ (OR 2.1 (95% CI 1.3 to 3.5), p=0.002, OR 2.1 (95% CI 1.3 to 3.5), p=0.004 and OR 1.7 (95% CI 1.1 to 2.8), p=0.03). Compared with scientists, patients deprioritised ‘better laboratory models’ (OR 0.4 (95% CI 0.2 to 0.8), p=0.01).Conclusion This study demonstrates that patients, public, clinicians and scientists have different research priorities, with scientists being a particular outlier. This highlights the need to ensure the engagement of patients and public in research funding prioritisation decisions.

Background FAST-Forward aimed to identify a 5-fraction schedule of adjuvant radiotherapy delivered in 1 week that was non-inferior in terms of local cancer control and as safe as the standard 15-fraction regimen after primary surgery for early breast cancer. Published acute toxicity and 5-year results are presented here with other aspects of the trial. Design Multicentre phase III non-inferiority trial. Patients with invasive carcinoma of the breast (pT1-3pN0-1M0) after breast conservation surgery or mastectomy randomised (1 : 1 : 1) to 40 Gy in 15 fractions (3 weeks), 27 Gy or 26 Gy in 5 fractions (1 week) whole breast/chest wall (Main Trial). Primary endpoint was ipsilateral breast tumour relapse; assuming 2% 5-year incidence for 40 Gy, non-inferiority pre-defined as < 1.6% excess for 5-fraction schedules (critical hazard ratio = 1.81). Normal tissue effects were assessed independently by clinicians, patients and photographs. Sub-studies Two acute skin toxicity sub-studies were undertaken to confirm safety of the test schedules. Primary endpoint was proportion of patients with grade ≥ 3 acute breast skin toxicity at any time from the start of radiotherapy to 4 weeks after completion. Nodal Sub-Study patients had breast/chest wall plus axillary radiotherapy testing the same three schedules, reduced to the 40 and 26 Gy groups on amendment, with the primary endpoint of 5-year patient-reported arm/hand swelling. Limitations A sequential hypofractionated or simultaneous integrated boost has not been studied. Participants Ninety-seven UK centres recruited 4096 patients (1361:40 Gy, 1367:27 Gy, 1368:26 Gy) into the Main Trial from November 2011 to June 2014. The Nodal Sub-Study recruited an additional 469 patients from 50 UK centres. One hundred and ninety and 162 Main Trial patients were included in the acute toxicity sub-studies. Results Acute toxicity sub-studies evaluable patients: (1) acute grade 3 Radiation Therapy Oncology Group toxicity reported in 40 Gy/15 fractions 6/44 (13.6%); 27 Gy/5 fractions 5/51 (9.8%); 26 Gy/5 fractions 3/52 (5.8%). (2) Grade 3 common toxicity criteria for adverse effects toxicity reported for one patient. At 71-month median follow-up in the Main Trial, 79 ipsilateral breast tumour relapse events (40 Gy: 31, 27 Gy: 27, 26 Gy: 21); hazard ratios (95% confidence interval) versus 40 Gy were 27 Gy: 0.86 (0.51 to 1.44), 26 Gy: 0.67 (0.38 to 1.16). With 2.1% (1.4 to 3.1) 5-year incidence ipsilateral breast tumour relapse after 40 Gy, estimated absolute differences versus 40 Gy (non-inferiority test) were −0.3% (−1.0–0.9) for 27 Gy (p = 0.0022) and −0.7% (−1.3–0.3) for 26 Gy (p = 0.00019). Five-year prevalence of any clinician-assessed moderate/marked breast normal tissue effects was 40 Gy: 98/986 (9.9%), 27 Gy: 155/1005 (15.4%), 26 Gy: 121/1020 (11.9%). Across all clinician assessments from 1 to 5 years, odds ratios versus 40 Gy were 1.55 (1.32 to 1.83; p < 0.0001) for 27 Gy and 1.12 (0.94–1.34; p = 0.20) for 26 Gy. Patient and photographic assessments showed higher normal tissue effects risk for 27 Gy versus 40 Gy but not for 26 Gy. Nodal Sub-Study reported no arm/hand swelling in 80% and 77% in 40 Gy and 26 Gy at baseline, and 73% and 76% at 24 months. The prevalence of moderate/marked arm/hand swelling at 24 months was 10% versus 7% for 40 Gy compared with 26 Gy. Interpretation Five-year local tumour incidence and normal tissue effects prevalence show 26 Gy in 5 fractions in 1 week is a safe and effective alternative to 40 Gy in 15 fractions for patients prescribed adjuvant local radiotherapy after primary surgery for early-stage breast cancer. Future work Ten-year Main Trial follow-up is essential. Inclusion in hypofractionation meta-analysis ongoing. A future hypofractionated boost trial is strongly supported. Trial registration FAST-Forward was sponsored by The Institute of Cancer Research and was registered as ISRCTN19906132. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 09/01/47) and is published in full in Health Technology Assessment; Vol. 27, No. 25. See the NIHR Funding and Awards website for further award information. Plain language summary Patients diagnosed with early breast cancer are often recommended to have radiotherapy after surgery because research has shown that it lowers the risk of the cancer returning. However, it may cause some short- and long-term side effects. Previous clinical trials showed that the same, or even better, outcomes with a lower total dose of radiotherapy given in fewer, larger daily doses compared with older historical treatment schedules. The National Institute for Health and Care Research Health Technology Assessment Programme-funded FAST-Forward Trial aimed to see whether the number of doses could be reduced further without reducing the beneficial effects of radiotherapy. Between November 2011 and June 2014, 4096 patients agreed to take part in the FAST-Forward Main Trial testing three schedules of radiotherapy to the breast. Standard treatment given on 15 days over 3 weeks (Control Group) was compared with two different lower dose schedules where treatment was given on 5 days over 1 week (lower dose Test Groups). An additional 469 patients entered a sub-study where the gland area under the arm also received radiotherapy (Nodal Sub-Study). Main Trial 5-year results reported in April 2020 showed that the number of patients whose cancer had returned in the treated breast was low in all groups: around 2 in 100 (2.1%) for the Control Group, and 1.7% in the higher dose and 1.4% in the lower dose Test Groups. The majority of reported side effects assessed by patients and doctors up to 5 years after radiotherapy were mild for all treatment groups. Patients in the Control Group and in the lower dose Test Group experienced similar levels of side effects. More side effects were reported in the higher dose Test Group, although differences were small. Overall, the FAST-Forward findings suggest that the lower dose 1-week schedule gave similar results in terms of the cancer returning and side effects to the standard 3-week treatment and this schedule can now be used to help treat future patients. Scientific summary Background Breast cancer is the most common malignancy in women and the second leading cause of cancer death. After a diagnosis of early breast cancer, a combination of treatments is planned by a multidisciplinary team. This usually involves surgery to remove the cancer with additional radiotherapy (RT) and systemic therapies tailored to the stage and biology of the cancer, and to the individual patient’s characteristics and wishes. Meta-analyses confirm that RT after surgery for early breast cancer reduces local cancer relapse and breast cancer deaths. Randomised controlled trials involving over 8000 patients with long-term follow-up confirmed that hypofractionated RT [fewer larger fractions (Fr; daily doses)] can be at least as safe and effective as the historic standard of 50 Gray (Gy) in 25 fractions (5 weeks) if a lower total dose is used. The UK START trials contribute much of the global data for moderate hypofractionation. START-A maintained the 5-week treatment time across all randomised groups and included two doses of a 13-fraction regimen, enabling the investigators to make unconfounded estimates of the sensitivity to fraction size. START-B tested 40 Gy in 15 fractions over 3 weeks against 50 Gy in 25 fractions over 5 weeks. Five- and ten-year results for local tumour control and late-occurring normal tissue effects (NTE) assessed by patients, clinicians and from photographs were consistent with the hypothesis that breast cancer tissue and the dose-limiting normal tissues are similarly sensitive to fraction size. The START trials had a large effect on breast cancer RT practice in the UK and worldwide. A 15-fraction schedule has been the UK standard-of-care recommended by the National Institute for Health and Care Excellence since 2009, but was thought unlikely to represent the useful limits of hypofractionation for whole breast RT. The UK FAST trial compared 28.5 Gy in 5 fractions of 5.7 Gy or 30 Gy in 5 fractions of 6 Gy, both delivered once weekly over 5 weeks, to 50 Gy in 25 fractions. The first results of the FAST trial, subsequently confirmed with the 10-year results, identified a 5-fraction schedule estimated to be radiobiologically equivalent to the 25-fraction standard in terms of late NTE. This gave impetus to the investigation of 1-week 5-fraction schedules in the phase III FAST-Forward Trial. Objectives Main Trial: to identify a 5-fraction schedule of curative RT delivered in once-daily fractions (1 week) that is at least as effective and safe as the current UK standard 15-fraction (3-week) regimen after primary surgery for early breast cancer, in terms of local tumour control, adverse effects, patient-reported outcomes (PRO) and health economic (HE) consequences. Nodal Sub-Study: to show that a 5-fraction schedule of adjuvant RT to level I–III axilla and/or level IV axilla [supraclavicular fossa (SCF)] is non-inferior to a 15-fraction standard in terms of patient-reported arm swelling and function, and to contribute additional information to the endpoints of the Main Trial. Methods FAST-Forward is a UK-wide phase III randomised non-inferiority trial testing two 1-week schedules against the 3-week regimen. Patients with early breast cancer requiring adjuvant RT were randomly allocated (1 : 1 : 1) to 40 Gy in 15 fractions over 3 weeks, 27 Gy or 26 Gy in 5 fractions over 1 week to the whole breast or chest wall (Main Trial) plus the regional lymph nodes (Nodal Sub-Study). A sequential tumour bed RT boost to the conserved breast was allowed, with centres required to specify boost intention before randomisation. Primary endpoints were local relapse (Main Trial) and patient-reported arm/hand swelling (Nodal Sub-Study). Secondary endpoints were late NTE assessed by patients and clinicians, cancer and survival outcomes. The Main Trial target sample size was 4000 patients, providing 80% power (one-sided α = 0.025) to exclude an absolute increase of 1.6% in 5-year ipsilateral breast tumour relapse (IBTR) incidence for a 5-fraction schedule compared with control, assuming 2% 5-year incidence in the 40 Gy group. Eligibility for the Main Trial was patients with complete microscopic resection of early invasive breast cancer, following breast conservation surgery or mastectomy, prescribed local RT. Inclusion criteria was age ≥ 18 years, axillary staging and/or dissection, pT1-3 pN0-1 M0 disease, written informed consent, able to comply with follow-up; concurrent anti-human epidermal growth factor receptor-2 (HER-2) therapy and/or endocrine therapies were allowed. Age ≥ 65 years with pT1 G1/2 ER+ve/HER-2−ve pN0 M0 invasive disease was excluded from protocol v2.0 due to the very low risk of local cancer relapse. Exclusions included ipsilateral microinvasive disease and/or non-gradeable tumours, contralateral and/or previous ipsilateral breast cancer, concurrent cytotoxic chemotherapy (sequential neoadjuvant or adjuvant cytotoxic therapy allowed if ≥ 2 weeks between chemotherapy and RT) and RT to any regional lymph node area (excepting lower axilla included in standard tangential fields to breast/chest wall). The whole breast clinical target volume (CTV) was either determined retrospectively from field-based tangential fields or volumed prospectively. Post-mastectomy chest wall CTV encompassed post-surgical skin flaps and underlying soft tissues to the deep fascia; underlying muscle and rib cage excluded. The lymph node CTV included the axillary chain and/or the SCF (level IV axilla) either in entirety or levels specified by the clinician. The treatment plan was optimised with 3D dose compensation to achieve the dose constraints. A comprehensive quality assurance programme involved every RT centre before trial activation and continued throughout trial accrual. The RT planning packs for the Main Trial and Nodal Sub-Study are available from www.icr.ac.uk/fastforward. Patients were assessed by clinicians for IBTR and late NTE at annual follow-up visits. Late-onset NTE in ipsilateral breast or chest wall (breast distortion, shrinkage, induration and telangiectasia; and breast or chest wall oedema and discomfort) were graded by clinicians on a 4-point scale, interpreted as none, mild, moderate, or marked. Symptomatic rib fracture, symptomatic lung fibrosis, and ischaemic heart disease were recorded. In the PRO sub-study, questionnaires were administered at baseline (pre-randomisation), 3, 6, 12, 24 and 60 months. Patient assessments used a 4-point ordinal scale, as for the clinical assessments. In the photographic sub-study, photographs were taken at baseline (pre-RT), 2 and 5 years after RT and scored on a 3-point ordinal scale. In the acute toxicity sub-study, patients were assessed pre-treatment, then weekly for 6 weeks, or longer if there was higher than grade 1 toxicity still present. Two acute toxicity studies were performed; in the first study the scoring system included oedema, which is usually related to recent surgery, and also included patients with a boost. A second study was done without these confounding issues to more accurately assess the acute toxicity of the 1-week schedules compared with the 3-weekly standard. Acute reactions of the treated breast skin were graded using Radiation Therapy Oncology Group (RTOG) criteria for the first sub-study and standard common toxicity criteria for adverse effects (CTCAE) criteria for the second. The Nodal Sub-Study inclusion criteria required pT1-3 pN1-3a M0 disease and histological involvement of axillary lymph nodes with an indication for RT to level I-III axilla and/or level IV axilla. From 2018 the Nodal Sub-Study design was amended to a 2-group trial, with no further randomisation to Test Group 1 (27 Gy). All patients in the Nodal Sub-Study were asked to consent to the PRO sub-study and photographic assessments. The following additional PRO were included in the Nodal Sub-Study: shoulder stiffness, upper limb pain, sensorimotor symptoms and arm function. A HE evaluation was conducted to assess the cost-effectiveness of whole breast RT with 26 Gy/5 fractions over 1 week compared with the 3-week schedule of 40 Gy/15 fractions. We report the 5-year primary analysis of the Main Trial and a descriptive interim analysis of the Nodal Sub-Study up to 3 years’ follow-up; formal analysis of the Nodal Sub-Study will await 5 years’ follow-up. Results Between November 2011 and June 2014, 4110 patients were enrolled in the FAST-Forward Main Trial from 97 UK centres (47 RT and 50 referring centres); 14 patients subsequently withdrew consent. One hundred and ninety patients were recruited into acute toxicity study 1, 161 patients into acute toxicity study 2, 1798 patients into the PRO sub-study, 1737 patients into the photographic assessment sub-study, 3878 patients consented to donate a blood sample and 4077 patients consented to donate their primary tissue sample. Four hundred and sixty-nine patients were recruited to the Nodal Sub-Study. The demographic and clinical characteristics at baseline were well balanced between groups. In the Main Trial, after a median follow-up of 71.5 months IBTR was recorded in 79 patients (31 in the 40 Gy group, 27 in the 27 Gy group and 21 in the 26 Gy group); hazard ratios (HRs) versus 40 Gy in 15 fractions were 0.86 (95% confidence interval 0.51 to 1.44) for 27 Gy/5 fractions and 0.67 (0.38 to 1.16) for 26 Gy/5 fractions. Estimated 5-year cumulative incidence of IBTR was 2.1% for 40 Gy (expected incidence 2%), 1.7% for 27 Gy and 1.4% for 26 Gy. Estimated absolute differences in IBTR versus 40 Gy were –0.3% (–1.0 to 0.9) for 27 Gy and –0.7% (–1.3 to 0.3) for 26 Gy. As the upper confidence limits excluded an increase in IBTR of 1.6% or more so non-inferiority can be claimed for both 5-fraction schedules compared with 40 Gy/15 fractions. At least one annual clinical assessment of NTE was available in the Main Trial for 3975 (97.0%) of 4096 patients. At 5 years, any moderate or marked clinician-assessed NTE in the breast or chest wall was reported for 98 of 986 (9.9%) 40 Gy patients, 155 (15.4%) of 1005.27 Gy patients, and 121 of 1020 (11.9%) 26 Gy patients, with a significant difference between 40 Gy and 27 Gy (0.0003) but not between 40 Gy and 26 Gy (p = 0·17). Breast shrinkage was the most prevalent moderate or marked effect at 5 years, reported in 50 (5.5%) of 916.40 Gy patients, 78 (8.2%) of 948.27 Gy patients, and 65 (6.8%) of 954.26 Gy patients. Longitudinal analysis of all annual clinical assessments of NTE over follow-up showed a significantly increased risk of any moderate or marked effect in the breast or chest wall for the 27 Gy group compared with 40 Gy with no significant difference between 26 and 40 Gy. Comparing the two 5-fraction schedules, 26 Gy had significantly lower risk of any moderate or marked breast or chest wall NTE and breast shrinkage compared with 27 Gy. Estimates of 5-year cumulative incidence of any moderate or marked clinician-assessed NTE in the breast or chest wall were 26.8% for 40 Gy, 35.1% for 27 Gy and 28.5% for 26 Gy. Retrospective subgroup analyses in the Main Trial comparing IBTR in 26 Gy versus 40 Gy provide no evidence of a differential effect according to age, grade, pathological tumour size, nodal status, tumour bed boost, treatment with adjuvant chemotherapy, HER-2 status or in triple-negative patients. Confidence intervals for the HR overlap for the subgroups, although the number of events in these analyses was small, hence results should be interpreted with caution as the statistical power is low. Subgroup analysis in the Main Trial according to type of primary surgery was not possible as there was only one IBTR event post-mastectomy in a control group patient (out of 91) and none in the 173 patients treated with 5 fractions. The two acute toxicity sub-studies comprised a total of 350 patients. Incidence of grade 3+ acute skin toxicity according to RTOG criteria was 14% for 40 Gy/15 fractions, 10% for 27 Gy/5 fractions, and 6% for 26 Gy/5 fractions in sub-study 1. For sub-study 2, acute toxicity grade 3+ according to CTCAE was 0%, 2.4% and 0%, respectively. Grade 2 toxicity was more common in 40 Gy/15 fractions compared with the two 5-fraction schedules. Four hundred and sixty-nine patients from 28 RT and 22 referral centres (183 for 40 Gy/15 fractions, 104 for 27 Gy/5 fractions and 182 for 26 Gy/5 fractions) were entered into the Nodal Sub-Study. Compared with the Main Trial, as expected more patients had higher-grade disease and nearly half had a mastectomy. Axillary clearance was performed in around 50% of patients, with the remainder having some form of nodal sampling. At this interim review at 2 years patients reported moderate or marked hand/arm swelling in 10% (40 Gy), 7% (26 Gy) and 13% (27 Gy). Prevalence of clinician-assessed lymphodema at 3 years was 8% (40 Gy), 12% (26 Gy) and 11% (27 Gy). In the cost-effectiveness work the base case analysis, mean costs and quality-adjusted life-years (QALYs) for 40 Gy/15 fractions were £31,640 and 11.08 QALYs; for 26 Gy/5 fractions these were £29,638 and 11.12 QALYs. Therefore the 26 Gy/5 fractions regimen was expected to dominate with expected cost savings of £2002 (95% interval £1245 to £2804) and higher expected QALYs: 0.04 (95% interval −0.01 to 0.09). Across simulations there was a 99.9% chance that 26 Gy/5 fractions either dominated 40 Gy/15 fractions or had an incremental cost-effectiveness ratio below £15,000/QALY. Conclusion The 26 Gy/5 fractions 1-week schedule is non-inferior to 40 Gy/15 fractions over 3 weeks for IBTR. The 26 Gy dose level is comparable to 40 Gy/15 fractions in terms of NTE assessed by patients, clinicians and from photographs, and is comparable to NTE expected after 46–48 Gy in 2 Gy fractions. The 27 Gy/5 fractions regimen was non-inferior for IBTR but had statistically significantly higher levels of many late NTE compared with the 40 and 26 Gy schedules, with late NTE rates of comparable magnitude to 50 Gy/25 fractions, the historic standard schedule. Acute skin reactions reported within the trial are low, whichever regimen is used. Prevalence rates suggest that erythema after the 1-week schedule came on slightly quicker, is less intense and settles about 2 weeks earlier than after the 3-week schedule although no formal statistical analysis of this was performed. The mildness of the acute skin toxicity associated with the 5-fraction regimens was expected. Interim results from the Nodal Sub-Study at 2–3 years’ follow-up indicate no cause for concern of an excess in NTE for 26 Gy/5 fractions compared with 40 Gy/15 fractions. Low rates of IBTR and of moderate/marked late NTE can be attributed to improvements in all diagnostic and treatment modalities and to the commitment of patients to early diagnosis and randomised trials. Beyond its safety and effectiveness, the 26 Gy/5 fractions schedule is convenient and less expensive for patients and for health services. The 26 Gy/5 fractions schedule reduces the estimated healthcare fiscal cost of breast RT by over 50%. The 5-fraction regimen reduces the machine time required for breast RT patients, thus improving patient access for other groups of cancer patients within the NHS. Study registrations FAST-Forward is registered at www.isrctn.com, ISRCTN19906132. The Main Trial is published in Lancet 2020;395:1613–26. See the NIHR Journals Library website for further project information. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 09/01/47) and is published in full in Health Technology Assessment; Vol. 27, No. 25. See the NIHR Funding and Awards website for further award information.

Competing Interests: Competing interests: We have read and understood BMJ policy on declaration of interests and have the following interests to declare. TG is a member of the Academic and Research Committee for the Association of Breast Surgery, the Clinical Advisory Panel for Cancer Research UK, and National Audit of Primary Breast Cancer Audit Advisory Committee. RIC is a trustee and chair of the Academic and Research Committee for the Association of Breast Surgery, a committee member for the National Institute for Health and Care Excellence, joint lead investigator for the EndoNET Trial, and has received research support from SECA and Astra-Zeneca. DD and KH are the oncology and surgical leads for the National Audit of Primary Breast Cancer. KH is the chair of the EndoNet Trial Steering Committee. GKR is a committee member for the National Institute for Health and Care Excellence. TG, SS, SWK, and/DD are funded in part by Cancer Research UK (C16077/A29186, C8225/A21133).

Purpose: The introduction of breast screening in the UK led to an increase in the detection of non-invasive breast neoplasia, predominantly ductal carcinoma in situ (DCIS), a non-obligatory precursor of invasive breast cancer. The Sloane Project, a UK prospective cohort study of screen-detected non-invasive breast neoplasia, commenced in 2003 to evaluate the radiological assessment, surgical management, pathology, adjuvant therapy and outcomes for non-invasive breast neoplasia. Long-term follow-up and accurate data collection are essential to examine the clinical impact. Here, we describe the establishment, development and analytical processes for this large UK cohort study., Participants: Women diagnosed with non-invasive breast neoplasia via the UK National Health Service Breast Screening Programme (NHSBSP) from 01 April 2003 are eligible, with a minimum age of 46 years. Diagnostic, therapeutic and follow-up data collected via proformas, complement date and cause of death from national data sources. Accrual for patients with DCIS ceased in 2012 but is ongoing for patients with epithelial atypia/in situ neoplasia, while follow-up for all continues long term., Findings to Date: To date, patients within the Sloane cohort comprise one-third of those diagnosed with DCIS within the NHSBSP and are representative of UK practice. DCIS has a variable outcome and confirms the need for longer-term follow-up for screen-detected DCIS. However, the radiology and pathology features of DCIS can be used to inform patient management. We demonstrate validation of follow-up information collected from national datasets against traditional, manual methods., Future Plans: Conclusions derived from the Sloane Project are generalisable to women in the UK with screen-detected DCIS. The follow-up methodology may be extended to other UK cohort studies and routine clinical follow-up. Data from English patients entered into the Sloane Project are available on request to researchers under data sharing agreement. Annual follow-up data collection will continue for a minimum of 20 years., Competing Interests: Competing interests: KC was funded (May 2019 to October 2022) as part of the Cancer Research Grand Challenge PRECISION team (C38317/A24043), which is funded by Cancer Research UK and the Dutch Cancer Society. DD is funded by Cancer Research UK (grant C8225/A21133). EP received speaker’s honoraria (Roche), travel costs to speak at meeting (Roche), and participation in advisory group meetings for IPB advisors and Roche. SP participated in advisory boards for AstraZeneca, Roche and Exact Sciences, received money for speaking at meetings for Roche and Exact Sciences and is a member of the PRECISION consortium (C38317/A24043). AMS has participated in advisory boards for Exact Sciences and Veracyte. HS received travel and support to attend meetings of the CRUK Grand Challenge PRECISION Study (C38317/A24043). ES, AMT and MGW are members of the PRECISION consortium (C38317/A24043). BH, IS-H, AJM, OK, MS, CK, NS, JD-C, JL and SM have nothing to declare., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Background: The diagnosis, management and prognosis of microinvasive breast carcinoma remain controversial., Methods: We analysed the outcomes of patients with DCIS with and without microinvasion diagnosed between 2003 and 2012 within the Sloane project., Results: Microinvasion was recorded in 521 of 11,285 patients (4.6%), with considerable variation in reported incidence among screening units (0-25%). Microinvasion was associated with high-grade DCIS, larger DCIS size, comedo necrosis and solid, cribriform architecture (all P < 0.001). Microinvasion was more frequent in patients who underwent mastectomy compared with breast-conserving surgery (BCS) (6.9% vs 3.6%, P <  0.001), and in those undergoing axillary nodal surgery (60.4% vs 30.3%, P <  0.001) including the subset undergoing BCS (43.4% vs 8.5%, P < 0.001). Nodal metastasis rate was low and not statistically significant difference from the DCIS only group (P = 0.68). Following median follow-up of 110 months, 3% of patients had recurrent ipsilateral high-grade DCIS, and 4.2% developed invasive carcinoma. The subsequent ipsilateral invasion was of Grade 3 in 71.4% of patients with microinvasion vs 30.4% in DCIS without microinvasion (P = 0.02). Distant metastasis and breast cancer mortality were higher with microinvasion compared with DCIS only (1.2% vs 0.3%, P = 0.01 and 2.1% vs 0.8%; P = 0.005)., Conclusions: The higher breast cancer mortality with microinvasion indicates a more aggressive disease., (© 2022. The Author(s).)

Introduction: Shared learning is imperative in the assessment and safe implementation of new healthcare interventions. Magnetic seeds (Magseed®) potentially offer logistical benefit over wire localisation for non-palpable breast lesions but few data exist on outcomes comparing these techniques. A national registration study (iBRA-NET) was conducted to collate device outcomes. In order to share learning, thematic analysis was conducted to ascertain early clinical experiences of Magseed® and wire guided localisation and explore how learning events may be applied to improve clinical outcomes., Methods: A qualitative study of 27 oncoplastic surgeons, radiologists and physicians was conducted in January 2020 to ascertain the feasibility and challenges associated with Magseed® versus wire breast localisation surgery. Four focus groups were asked to discuss experiences, concerns and shared learning outcomes which were tabulated and analysed thematically., Results: Three key themes were identified comparing Magseed® and wire localisation of breast lesions relating to preoperative, intraoperative and postoperative learning outcomes. Percutaneous Magseed® detection, instrument interference and potential seed or wire dislodgement were the most common issues identified. Clinician experience suggested Magseed® index lesion identification was non-inferior to wire placement and improved the patient pathway in terms of scheduling and multi-site insertion., Conclusions: Prospective shared learning suggested Magseed® offered additional non-clinical benefits over wire localisation, improving the efficiency of the patient pathway. Recommendations for improving breast localisation technique, appropriate patient selection and clinical practice through shared learning are discussed that may aid other surgeons in the adoption of this relatively new technique., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Perianal abscess is common. Traditionally, postoperative perianal abscess cavities are managed with internal wound packing, a practice not supported by evidence. The aim of this randomized clinical trial (RCT) was to assess if non-packing is less painful and if it is associated with adverse outcomes., Methods: The Postoperative Packing of Perianal Abscess Cavities (PPAC2) trial was a multicentre, RCT (two-group parallel design) of adult participants admitted to an NHS hospital for incision and drainage of a primary perianal abscess. Participants were randomized 1:1 (via an online system) to receive continued postoperative wound packing or non-packing. Blinded data were collected via symptom diaries, telephone, and clinics over 6 months. The objective was to determine whether non-packing of perianal abscess cavities is less painful than packing, without an increase in perianal fistula or abscess recurrence. The primary outcome was pain (mean maximum pain score on a 100-point visual analogue scale)., Results: Between February 2018 and March 2020, 433 participants (mean age 42 years) were randomized across 50 sites. Two hundred and thirteen participants allocated to packing reported higher pain scores than 220 allocated to non-packing (38.2 versus 28.2, mean difference 9.9; P < 0.0001). The occurrence of fistula-in-ano was low in both groups: 32/213 (15 per cent) in the packing group and 24/220 (11 per cent) in the non-packing group (OR 0.69, 95 per cent c.i. 0.39 to 1.22; P = 0.20). The proportion of patients with abscess recurrence was also low: 13/223 (6 per cent) in the non-packing group and 7/213 (3 per cent) in the packing group (OR 1.85, 95 per cent c.i. 0.72 to 4.73; P = 0.20)., Conclusion: Avoiding abscess cavity packing is less painful without a negative morbidity risk., Registration Number: ISRCTN93273484 (https://www.isrctn.com/ISRCTN93273484)., Registration Number: NCT03315169 (http://clinicaltrials.gov)., (© The Author(s) 2022. Published by Oxford University Press on behalf of BJS Society Ltd.)

Background and Aim: The natural history of ductal carcinoma in situ (DCIS) is poorly understood. The aim of this cohort study was to determine the outcomes of women who had no surgery for screen-detected DCIS in the 6 months following diagnosis., Methods: English breast screening databases were retrospectively searched for women diagnosed with DCIS without invasive cancer at screening and who had no record of surgery within 6 months of diagnosis. These were cross-referenced with cancer registry data. Details of the potentially eligible women were sent to the relevant breast screening units for verification and for completion of data forms detailing clinical, radiological and pathological findings, non-surgical treatment and subsequent clinical course., Results: Data for 311 eligible women (median age 62 years) were available. 60 women developed invasive cancer, 56 ipsilateral and 4 contralateral. Ipsilateral invasion risk increased approximately linearly with time for at least 10 years. The 10-year cumulative risk of ipsilateral invasion was 9% (95% CI 4-21%), 39% (24-58%) and 36% (24-50%) for low, intermediate and high grade DCIS respectively and was higher in younger women, in those with larger DCIS lesions and in those with microinvasion. Most invasive cancers that developed were grade 2 or 3., Conclusion: The findings suggest that active surveillance may be a reasonable alternative to surgery in patients with low grade DCIS but that women with intermediate or high grade disease should continue to be offered surgery. This highlights the importance of reproducible grading of DCIS to ensure patients receive appropriate treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: The National Health Service (NHS) Breast Screening Programme aims to detect cancer earlier when treatment is more effective but can harm women by over diagnosing and overtreating cancers which would never have become symptomatic. As well as breast cancer, a spectrum of atypical epithelial proliferations (atypia) can also be detected as part of screening. This spectrum of changes, while not cancer, may mean that a woman is more likely to develop breast cancer in the future. Follow-up of atypia is not evidence based. We currently do not know which atypia should be detected to avoid future cancer. This study will explore how atypia develops into breast cancer in terms of number of women, time of cancer development, cancer type and severity, and whether this varies for different types of atypia., Methods and Analysis: The Sloane cohort study began in April 2003 with ongoing data collection including atypia diagnosed through screening at screening units in the UK. The database for England has 3645 cases (24 September 2020) of epithelial atypia, with follow-up from 1 to 15 years. The outcomes include subsequent invasive breast cancer and the nature of subsequent cancer. Descriptive statistics will be produced. The observed rates of breast cancer at 1, 3 and 6 years for types of atypia will be reported with CIs, to enable comparison to women in the general population. Time to event methods will be used to describe the time to breast cancer diagnosis for the types of atypia, including flexible parametric modelling if appropriate. Patient representatives from Independent Cancer Patients' Voice are included at every stage of the research., Ethics and Dissemination: The study has received research ethics approval from the University of Warwick Biomedical and Scientific Research Ethics Committee (BSREC 10/20-21, 8 October 2020), Public Health England office for data release approvals (ODR1718&#95;313) and approval from the English Breast Research Advisory Committee (BSPRAC&#95;031). The findings will be disseminated to breast screening clinicians (via journal publication and conference presentation), to the NHS Breast Screening Programme to update their guidelines on how women with atypia should be followed up, and to the general public., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at ICMJE | Disclosure of Interest and declare: DJ, KF, ST-P, NSt, NSh and SP receive funding from the NIHR Research for Patient Benefit Call (RfPB) for the conduct of this study. ST-P is funded by the NIHR through a career development fellowship (NIHR-CDF-2016-09-018). EP received a speaker’s honoraria and travel costs from Roche to speak at an advisory group meeting. EP participates as a IPB advisor at advisory group meetings. KC is funded as part of the Cancer Grand Challenges PRECISION team which is funded by Cancer Research UK and the Dutch Cancer Society. HS received travel and support to attend meetings of CRUK Grand Challenge Precision. SP is a member of the PRECISION Consortium, a recipient of a Cancer Research UK Grand Challenge Award, jointly funded by Cancer Research UK and the Dutch Cancer Society (KWF). AMS has participated in Advisory Boards for Exact Sciences and Veracyte. BH, SM, MGW, OK, JD-C, CK and AMT have nothing to declare., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)