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Abstract Background For patients with early breast cancer considered at very-low risk of local relapse, risks of radiotherapy may outweigh the benefits. Decisions regarding treatment omission can lead to patient uncertainty (decisional conflict), which may be lessened with patient decision aids (PDA). PRIMETIME (ISRCTN 41579286) is a UK-led biomarker-directed study evaluating omission of adjuvant radiotherapy in breast cancer; an embedded Study Within A Trial (SWAT) investigated whether PDA reduces decisional conflict using a cluster stepped-wedge trial design. Methods PDA diagrams and a video explaining risks and benefits of radiotherapy were developed in close collaboration between patient advocates and PRIMETIME trialists. The SWAT used a cluster stepped-wedge trial design, where each cluster represented the radiotherapy centre and referring peripheral centres. All clusters began in the standard information group (patient information and diagrams) and were randomised to cross-over to the enhanced information group (standard information plus video) at 2, 4 or 6 months. Primary endpoint was the decisional conflict scale (0–100, higher scores indicating greater conflict) which was assessed on an individual participant level. Multilevel mixed effects models used a random effect for cluster and a fixed effect for each step to adjust for calendar time and clustering. Robust standard errors were also adjusted for the clustering effect. Results Five hundred twenty-one evaluable questionnaires were returned from 809 eligible patients (64%) in 24 clusters between April 2018 and October 2019. Mean decisional conflict scores in the standard group (N = 184) were 10.88 (SD 11.82) and 8.99 (SD 11.82) in the enhanced group (N = 337), with no statistically significant difference [mean difference − 1.78, 95%CI − 3.82–0.25, p = 0.09]. Compliance with patient information and diagrams was high in both groups although in the enhanced group only 121/337 (36%) reported watching the video. Conclusion The low levels of decisional conflict in PRIMETIME are reassuring and may reflect the high-quality information provision, such that not everyone required the video. This reinforces the importance of working with patients as partners in clinical trials especially in the development of patient-centred information and decision aids.

Abstract Contralateral risk-reducing mastectomy (CRRM) rates have tripled over the last 2 decades. Reasons for this are multi-factorial, with those harbouring a pathogenic variant in the BRCA1/2 gene having the greatest survival benefit. On May 14th, 2013, Angelina Jolie shared the news of her bilateral risk-reducing mastectomy (BRRM), on the basis of her BRCA1 pathogenic variant status. We evaluated the impact of this news on rates of CRRM in women with increased risk for developing breast cancer after being diagnosed with unilateral breast cancer. The prospective cohort study included all women with at least a moderate lifetime risk of developing breast cancer who attended our family history clinic (1987–2019) and were subsequently diagnosed with unilateral breast cancer. Rates of CRRM were then compared between patients diagnosed with breast cancer before and after Angelina Jolie’s announcement (pre- vs. post-AJ). Of 386 breast cancer patients, with a mean age at diagnosis of 48 ± 8 years, 268 (69.4%) were diagnosed in the pre-AJ period, and 118 (30.6%) in the post-AJ period. Of these, 123 (31.9%) underwent CRRM, a median 42 (interquartile range: 11–54) days after the index cancer surgery. Rates of CRRM doubled following AJ’s news, from 23.9% pre-AJ to 50.0% post AJ (p

Abstract Background Breast cancer patients are at a four-fold increased risk of developing a venous thromboembolism (VTE), a major cause of death in this group. Conversely, coagulation factors promote tumour growth and metastasis. This has been evidenced in preclinical models, with an inhibitory effect of anticoagulants on cancer growth through proliferative, angiogenic, apoptotic, cancer stem cell and metastatic processes. The extrinsic clotting pathway is also more upregulated in patients in the relatively poorer prognosis oestrogen receptor (ER)-negative breast cancer subgroup, with increased tumour stromal expression of the coagulation factors Tissue Factor and thrombin. Rivaroxaban (Xarelto®, Bayer AG, Leverkusen, Germany) is a direct oral anticoagulant (DOAC). It is a Factor Xa inhibitor that is routinely prescribed for the prevention of stroke in non-valvular atrial fibrillation and for both VTE prophylaxis and treatment. This trial will assess the anti-proliferative and other anti-cancer progression mechanisms of Rivaroxaban in ER-negative early breast cancer patients. Methods This UK-based preoperative window-of-opportunity phase II randomised control trial will randomise 88 treatment-naïve early breast cancer patients to receive 20 mg OD Rivaroxaban treatment for 11 to 17 days or no treatment. Treatment will be stopped 24 h (range 18–36 h) prior to surgery or repeat core biopsy. All patients will be followed up for 2 weeks following surgery or repeat core biopsy. The primary endpoint is change in tumour Ki67. Secondary outcome measures include tumour markers of apoptosis and angiogenesis, extrinsic clotting pathway activation and systemic markers of metastasis, tumour load and coagulation. Discussion Laboratory evidence supports an anti-cancer role for anticoagulants; however, this has failed to translate into survival benefit when trialled in patients with metastatic disease or poor prognosis cancers, such as lung cancer. Subgroup analysis supported a potential survival benefit in better prognosis advanced disease patients. This is the first study to investigate the anti-cancer effects of anticoagulants in early breast cancer. Trial registration UK National Research Ethics Service (NRES) approval 15/NW/0406, MHRA Clinical Trials Authorisation 48380/0003/001-0001. The sponsor is Manchester University NHS Foundation Trust, and the trial is co-ordinated by Cancer Research UK Liverpool Cancer Trials Unit (LCTU). EudraCT 2014-004909-33 , registered 27 July 2015. ISRCTN14785273 .

Abstract Background Tumor stroma, of which fibroblasts are the most abundant cell, resembles a non‐healing wound, where a procoagulant environment creates a permissive milieu for cancer growth. We aimed to determine if tumor expression of coagulation factors (procoagulant phenotype), and systemic hypercoagulability, occur at the preinvasive (ductal carcinoma in situ; DCIS) stage and correlate with breast cancer subtype, disease‐free survival (DFS), and overall survival (OS). Methods In a prospective cohort of early breast cancer (DCIS, n = 76; invasive, n = 248) tumor, normal breast and plasma were examined. Fibroblast and epithelial expression of Tissue Factor (TF), thrombin, PAR1, PAR2, and plasma thrombin‐antithrombin (TAT) and D‐dimer were correlated with clinicopathological data, and 5‐year survival. Results Fibroblast expression of TF, thrombin, and PAR1 was increased in DCIS and invasive cancer compared to normal breast fibroblasts (P ≤ .003, all). Fibroblast TF, thrombin, PAR1, and PAR2 was increased in cancers with high Ki67, high grade, ER‐ (vs ER+), and HER2+ (vs HER2‐) (all P 3‐fold mortality risk compared to low TAT. Conclusion This demonstrates procoagulant phenotypic changes occur in fibroblasts at the preinvasive stage. Fibroblast procoagulant phenotype is associated with aggressive breast cancer subtypes and reduced survival. Coagulation may be a therapeutic target in breast cancer.

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.

Exposure to sub-lethal doses of ionising and non-ionising electromagnetic radiation can impact human health and well-being as a consequence of, for example, the side effects of radiotherapy (therapeutic X-ray exposure) and accelerated skin ageing (chronic exposure to ultraviolet radiation: UVR). Whilst attention has focused primarily on the interaction of electromagnetic radiation with cells and cellular components, radiation-induced damage to long-lived extracellular matrix (ECM) proteins has the potential to profoundly affect tissue structure, composition and function. This review focuses on the current understanding of the biological effects of ionising and non-ionising radiation on the ECM of breast stroma and skin dermis, respectively. Although there is some experimental evidence for radiation-induced damage to ECM proteins, compared with the well-characterised impact of radiation exposure on cell biology, the structural, functional, and ultimately clinical consequences of ECM irradiation remain poorly defined.

Abstract Background Breast cancer patients are at an increased risk of venous thromboembolism (VTE). However, current evidence as to whether VTE increases the risk of mortality in breast cancer patients is conflicting. We present data from a large cohort of patients from the UK and pool these with previous data from a systematic review. Methods Using the Clinical Practice Research Datalink (CPRD) dataset, we identified a cohort of 13,202 breast cancer patients, of whom 611 were diagnosed with VTE between 1997 and 2006 and 12,591 did not develop VTE. Hazard ratios (HR) were used to compare mortality between the two groups. These were then pooled with existing data on this topic identified via a search of the MEDLINE and EMBASE databases (until January 2015) using a random-effects meta-analysis. Results Within the CPRD, VTE was associated with increased mortality when treated as a time-varying covariate (HR = 2.42; 95% CI, 2.13–2.75), however, when patients were permanently classed as having VTE based on presence of a VTE event within 6 months of cancer diagnosis, no increased risk was observed (HR = 1.22; 0.93–1.60). The pooled HR from seven studies using the second approach was 1.69 (1.12–2.55), with no effect seen when restricted to studies which adjusted for key covariates. Conclusion A large HR for VTE in the time-varying covariate analysis reflects the known short-term mortality following a VTE. When breast cancer patients are fortunate to survive the initial VTE, the influence on longer-term mortality is less certain.

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.

Objective Internationally recognised specialist breast cancer scientists, clinicians and healthcare professionals have published breast cancer research gaps that are informing research funding priorities in the UK and worldwide. We aimed to determine the breast cancer research priorities of the public to compare with those identified by clinicians and scientists.Design We conducted a qualitative study and thematic analysis using ‘listening events’ where patients with breast cancer and public representatives used a patient’s breast cancer journey to identify research themes.Participants and setting Female participants were recruited from attendees at participating hospitals and support groups in the northwest of England, including patients, their family and friends as well as staff at a local retail centre.Intervention A framework approach was used to analyse transcribed discussions until thematic saturation was reached.Main outcome measures Breast cancer research priorities were identified from participant discussions and compared with the published gaps identified by scientists and healthcare professionals.Results Thematic saturation was reached after 27 female participants participated in listening events. Our participants consistently focused on improved methods of dissemination of information and improving education on the signs and symptoms of breast cancer. This was not highlighted by scientists or healthcare professionals. There was strong emphasis on quality of life-related issues such as side effects of treatment. There was some agreement between the priorities deduced by our study and those of the professionals in the areas of screening, prevention and breast reconstruction.Conclusion Our study identified some research themes that were not identified by scientists and healthcare professionals in two earlier landmark studies. This highlights the importance of including patients and public representatives when setting research priorities. The results should be used to guide investigators when planning future studies and for funding bodies in allocating resources for future projects.

Given the current postulated plasticity between epithelial and mesenchymal states of migratory cancer cells the detection of non-epithelial CTCs is an important scientific and clinical goal.We used the filtration-based ISET technology to enrich circulating tumour cells (CTCs) in early breast cancer blood samples and identify them using a morphology-based immunocytochemistry (ICC) approach.We found greater numbers of putative CTCs by this approach than by the cytokeratin-based CellSearch technology, but a high number of CTC false positives were identified in healthy volunteer samples which were not reduced in successive blood draws. Preliminary work using an oestrogen receptor (ER)-based multiplex ICC method in metastatic breast cancer ISET samples indicated a low number of ER+ CTCs even at this advanced stage.This work highlights the challenges in enumerating CTCs without conventional epithelial markers.