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Background: Mammographic screening programmes reduce breast cancer mortality, but detect many small tumours with favourable biological features which may not progress during a woman’s lifetime. Screen-detected cancers are treated with standard surgery and adjuvant therapies, with associated morbidities. There is a need to reduce overtreatment of good prognosis tumours and numerous studies have evaluated the omission of radiotherapy in this context. However, there is little evidence to support surgical de-escalation, although percutaneous minimally invasive treatment approaches have been described. Vacuum-assisted excision (VAE) is in widespread use for management of benign lesions and lesions of uncertain malignant potential. SMALL (ISRCTN 12240119) is designed to determine the feasibility of using this approach for treatment of small invasive tumours detected within the UK NHS Breast Screening Programme (BSP). Methods: SMALL is a phase III multicentre randomised trial comparing standard surgery with VAE for screen-detected good prognosis cancers. The main eligibility criteria are age ≥47 years, unifocal grade 1 tumours with maximum diameter 15mm, which are strongly ER/PR+ve and HER2-ve, with negative clinical/radiological axillary staging. Patients are randomised 2:1 in favour of VAE or surgery; with no axillary surgery in the VAE arm. Completeness of excision is assessed radiologically, and if excision is incomplete, patients undergo open surgery. Adjuvant radiotherapy and endocrine therapy are mandated in the VAE arm but may be omitted following surgery. Co-primary end-points are: 1. Non-inferiority comparison of the requirement for a second procedure following excision 2. Single arm analysis of local recurrence (LR) at 5 years following VAE Recruitment of 800 patients will permit demonstration of 10% non-inferiority of VAE for requirement of a second procedure. This ensures sufficient patients for single arm analysis of LR rates, where expected LR free survival is 99% at 5 years, with an undesirable survival probability after VAE of 97%. To ensure that the trial as a whole only has 5% alpha, the significance level for each co-primary outcome is set at 2.5% with 90% power. The Data Monitoring Committee will monitor LR events to ensure these do not exceed 3% per year. Secondary outcome measures include time to ipsilateral recurrence, overall survival, complications, quality of life and health economic analysis. A novel feature of SMALL is the integration of a QuinteT Recruitment Intervention (QRI), which aims to optimise recruitment to the study. Recruitment challenges are identified by analysing recruiter/patient interviews and audio-recordings of trial discussions, and by review of trial screening logs, eligibility and recruitment data and study documentation. Solutions to address these are developed collaboratively, including individual/group recruiter feedback and recruitment tips documents. Results: SMALL opened in December 2019, but recruitment halted in 2020 for 5 months due to COVID-19. At 7st July 2022, 142 patients had been randomised from 26 centres, with a randomisation rate of approximately 45%, and a per site recruitment rate of 0.4-0.5 patients/month, approaching the feasibility recruitment target of 144 patients. Drawing from preliminary QRI findings and insights from patient representatives, a recruitment tips document has been circulated (on providing balanced information about treatments, encouraging recruiters to engage with patient preferences, and explaining randomisation). Individual recruiter feedback has commenced, with wider feedback delivered across sites via recruitment training workshops. Conclusion: Despite pandemic-related challenges, SMALL has an excellent recruitment rate to date and is expected to have a global impact on treatment of breast cancer within mammographic screening programmes. SMALL is funded by the UK NIHR HTA programme, award 17/42/32 Citation Format: Stuart A. McIntosh, Charlotte E. Coles, David Dodwell, Kenneth Elder, Jessica Foster, Claire Gaunt, Amanda Kirkham, Iain Lyburn, Jenna Morgan, Sangeetha Paramasivan, Sarah E. Pinder, Sarah Pirrie, Shelley Potter, Tracy Roberts, Nisha Sharma, Hilary Stobart, Elizabeth Southgate, Sian Taylor-Phillips, Matthew Wallis, Daniel Rea. SMALL: Open Surgery versus Minimally invasive vacuum-Assisted excision for smaLL screen-detected breast cancer – a UK phase III randomised multi-centre trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT3-20-02.

Background:. Mammographic screening programmes have been shown to reduce breast cancer mortality. However, they detect many small tumours with favourable biological features which may not progress during a woman’s lifetime. These are treated with standard surgery and adjuvant therapies, which have associated morbidities. Thus, there is a need to reduce overtreatment of good prognosis tumours found by screening. Minimally invasive treatment approaches have been described but there is no prospective randomised evidence to support their routine use. Vacuum-assisted excision (VAE) is in widespread use for management of benign lesions and lesions of uncertain malignant potential. SMALL (ISRCTN 12240119) is designed to determine the feasibility of using this approach for treatment of small invasive tumours detected within the UK NHS Breast Screening Programme (BSP). Methods:. SMALL is a phase III multicentre randomised trial comparing standard surgery with VAE for screen-detected good prognosis breast cancers. The main eligibility criteria are age ≥47 years, screen-detected unifocal grade 1 tumours with maximum diameter 15mm, which are strongly ER/PR+ve and HER2-ve, with negative clinical/radiological axillary staging. Patients are randomised 2:1 in favour of VAE or surgery; with no axillary surgery in the VAE arm. Completeness of excision is assessed radiologically, and if excision is incomplete, patients undergo open surgery. Adjuvant radiotherapy and endocrine therapy are mandated in the VAE arm but may be omitted following surgery. Co-primary end-points are:1.Non-inferiority comparison of the requirement for a second procedure following excision2.Single arm analysis of local recurrence (LR) at 5 years following VAE. Recruitment of 800 patients over 4 years will permit demonstration of 10% non-inferiority of VAE for requirement of a second procedure. This ensures sufficient patients for single arm analysis of LR rates, where expected LR free survival is 99% at 5 years, with an undesirable survival probability after VAE of 97%. To ensure that the trial as a whole only has 5% alpha, the significance level for each co-primary outcome is set at 2.5% with 90% power. The Data Monitoring Committee will monitor LR events to ensure these do not exceed 3% per year. Secondary outcome measures include time to ipsilateral recurrence, overall survival, complications, quality of life and health economic analysis. A QuinteT Recruitment Intervention (QRI) is integrated throughout SMALL to optimise recruitment and informed consent. Recruitment challenges are identified by analysing recruiter/patient interviews and audio-recordings of trial discussions, and by review of screening, eligibility and recruitment data and study documentation. Solutions to address these are developed collaboratively, including individual/group recruiter feedback and recruitment tips documents. Results:. SMALL opened in December 2019, but recruitment halted in 2020 due to suspension of the NHS BSP for 5 months due to COVID-19. As of 1st July 2021, 55 patients had been approached in 10 centres, with 33 patients randomised (randomisation rate 60%). A further 23 centres are in set-up, with 8 suspended due to the pandemic. Drawing from preliminary QRI findings and insights from patient representatives, a recruitment tips document has been circulated (on introducing and discussing SMALL, providing balanced information. on treatment options and explaining randomisation). individual recruiter feedback has commenced, with wider feedback planned shortly. Conclusion:. Despite pandemic-related challenges, SMALL has an excellent recruitment rate to date and is expected to have a global impact on treatment of breast cancer within mammographic screening programmes. SMALL is funded by the UK NIHR HTA programme, award 17/42/32 Citation Format: Stuart A McIntosh, Charlotte E Coles, Carmel Conefrey, David Dodwell, Kenneth Elder, Jessica Foster, Claire Gaunt, Amanda Kirkham, Iain Lyburn, Jenna Morgan, Sangeetha Paramasivan, Sarah Pinder, Sarah Pirrie, Shelley Potter, Tracy Roberts, Nisha Sharma, Hilary Stobart, Elizabeth Southgate, Sian Taylor-Phillips, Matthew Wallis, Daniel Rea. SMALL - Open surgery versus minimally invasive vacuum-assisted excision for small screen detected breast cancer: A phase 3 randomised trial [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT1-06-02.

Purpose: It has been hypothesized that increased predisposition to breast cancer may correlate with radiosensitivity, and thus increased risk of toxicity following breast irradiation. This study investigated the relationship between common breast cancer risk variants and radiotherapy toxicity.Experimental Design: SNP genotypes were determined in female breast cancer patients from the RAPPER (Radiogenomics: Assessment of polymorphisms for predicting the effects of radiotherapy) study using the Illumina CytoSNP12 genome-wide array. A further 15,582,449 genotypes were imputed using the 1000 Genomes Project reference panel. Patient (n = 1,160) polygenic risk scores were generated by summing risk-allele dosages, both unweighted and weighted by published effect sizes for breast cancer risk. Regression models were used to test associations of individual variants and polygenic risk scores with acute and late toxicity phenotypes (telangiectasia, breast edema, photographically assessed shrinkage, induration, pigmentation, breast pain, breast sensitivity, and overall toxicity).Results: Genotypes of 90 confirmed breast cancer risk variants were accurately determined and polygenic risk scores were approximately normally distributed. Variant rs6964587 was associated with increased breast edema 5 years following radiotherapy (Beta, 0.22; 95% confidence interval, 0.09–0.34; P = 7 × 10−4). No other associations were found between individual variants or the unweighted (P > 0.17) or weighted (P > 0.13) polygenic risk score and radiotherapy toxicity. This study had >87% power to detect an association between the polygenic risk score (relative risk > 1.1) and toxicity.Conclusions: Cancer patients with a high polygenic predisposition to breast cancer do not have an increased risk of radiotherapy toxicity up to 5 years following radiotherapy but individual variants may increase risk. Clin Cancer Res; 22(6); 1413–20. ©2015 AACR.

Supplementary Table 1: The late toxicity endpoints recorded in the RAPPER breast cohorts Supplementary Table 2: RTOG acute toxicity grades definition Supplementary Table 3: Statistically significant non-genetic factors for acute and five-year toxicity Supplementary Table 4: Results from residual analyses of the effect of individual risk variants on acute and two-year toxicity Supplementary Table 5: Results from residual analyses of individual risk variants and five-year toxicity Supplementary Figures 1-9: QQ plots comparing expected and observed p-values for the associations between individual breast cancer risk SNPs and each toxicity endpoint Supplementary Figures 10-17: Scatter plots of individual breast cancer risk variants comparing their effect on breast cancer risk with their effects on each toxicity endpoint

Background: Adjuvant proton beam therapy (PBT) is increasingly available to patients with breast cancer. It achieves better planned dose distributions than standard photon radiotherapy and therefore may reduce the risks. However, clinical evidence is lacking. Methods: A systematic review of clinical outcomes from studies of adjuvant PBT for early breast cancer published 2000-2022 was undertaken. Early breast cancer was defined as when all detected invasive cancer cells are in the breast or nearby lymph nodes and can be removed surgically. Adverse outcomes were summarized quantitatively, and the prevalence of the most common ones estimated using meta-analysis. Results: Thirty-two studies (1452 patients) reported clinical outcomes after adjuvant PBT for early breast cancer. Median follow up ranged from 2-59 months. There were no published randomized trials comparing PBT with photon radiotherapy. Scattering PBT was delivered in seven studies (258 patients) starting 2003-2015 and scanning PBT in 22 studies (1041 patients) starting 2000-2019. Two studies (123 patients) starting 2011 used both PBT types. For one study (30 patients) PBT type was unspecified. Adverse events were less severe after scanning than after scattering PBT. They also varied by clinical target. For partial breast PBT, 498 adverse events were reported (8 studies, 358 patients). None were categorized as severe after scanning PBT. For whole breast or chest wall +/- regional lymph nodes PBT, 1344 adverse events were reported (19 studies, 933 patients). After scanning PBT, 4% (44/1026) of events were severe. The most prevalent severe outcome after scanning PBT was dermatitis which occurred in 5.7% (95% CI 4.2-7.6) of patients. Other severe adverse outcomes included infection, pain and pneumonitis (each ≤1%). Of the 141 reconstruction events reported (13 studies, 459 patients), the most prevalent after scanning PBT was prosthetic implant removal (34/181, 19%). Conclusions: This is a quantitative summary of all published clinical outcomes after adjuvant PBT for early breast cancer. Ongoing randomized trials will provide information on its longer-term safety compared with standard photon radiotherapy.

Purpose We estimated the cost-effectiveness of 4 radiotherapy modalities to treat early breast cancer in the UK. In a subgroup of patients eligible for all modalities, we compared whole-breast (WB) and partial breast (PB) radiotherapy delivered in either 15 (WB15F, PB15F) or 5 fractions (WB5F, PB5F). In a subgroup ineligible for PB radiotherapy, we compared WB15F to WB5F. Methods We developed a Markov cohort model to simulate lifetime healthcare costs and quality-adjusted life years (QALYs) for each modality. This was informed by the clinical analysis of two non-inferiority trials (FAST Forward and IMPORT LOW) and supplemented with external literature. The primary analysis assumed that radiotherapy modality influences health only through its impact on locoregional recurrence and radiotherapy-related adverse events. Results In the primary analysis, PB5F had the least cost and greatest expected QALYs. WB5F had the least cost and the greatest expected QALYs in those only eligible for WB radiotherapy. Applying a cost-effectiveness threshold of £15,000/QALY, there was a 62% chance that PB5F was the cost-effective alternative in the PB eligible group, and there was a 100% chance that WB5F was cost-effective in the subgroup ineligible for PB radiotherapy. Conclusions Hypofractionation to 5 fractions and partial breast radiotherapy modalities offer potentially important benefits to the UK health system.

Purpose: Our aim was to test whether updated polygenic risk scores (PRS) for susceptibility to cancer affect risk of radiation therapy toxicity. Methods and Materials: Analyses included 9,717 patients with breast (n=3,078), prostate (n=5,748) or lung (n=891) cancer from Radiogenomics and REQUITE Consortia cohorts. Patients underwent potentially curative radiation therapy and were assessed prospectively for toxicity. Germline genotyping involved genome-wide single nucleotide polymorphism (SNP) arrays with nontyped SNPs imputed. PRS for each cancer were generated by summing literature-identified cancer susceptibility risk alleles: 352 breast, 136 prostate, and 24 lung. Weighted PRS were generated using log odds ratio (ORs) for cancer susceptibility. Standardized total average toxicity (STAT) scores at 2 and 5 years (breast, prostate) or 6 to 12 months (lung) quantified toxicity. Primary analysis tested late STAT, secondary analyses investigated acute STAT, and individual endpoints and SNPs using multivariable regression. Results: Increasing PRS did not increase risk of late toxicity in patients with breast (OR, 1.000; 95% confidence interval [CI], 0.997-1.002), prostate (OR, 0.99; 95% CI, 0.98-1.00; weighted PRS OR, 0.93; 95% CI, 0.83-1.03), or lung (OR, 0.93; 95% CI, 0.87-1.00; weighted PRS OR, 0.68; 95% CI, 0.45-1.03) cancer. Similar results were seen for acute toxicity. Secondary analyses identified rs138944387 associated with breast pain (OR, 3.05; 95% CI, 1.86-5.01; P = 1.09 × 10 –5) and rs17513613 with breast edema (OR, 0.94; 95% CI, 0.92-0.97; P = 1.08 × 10 –5). Conclusions: Patients with increased polygenic predisposition to breast, prostate, or lung cancer can safely undergo radiation therapy with no anticipated excess toxicity risk. Some individual SNPs increase the likelihood of a specific toxicity endpoint, warranting validation in independent cohorts and functional studies to elucidate biologic mechanisms.

In the care of patients with operable breast cancer, there has been a shift toward increasing use of neoadjuvant therapy. There are benefits to neoadjuvant therapy, such as monitoring for response, as well as an increased rate of breast conservation and reduction of potential morbidity associated with breast surgery, including axillary management. Among patients with highly proliferative tumors, such as HER2-positive or triple-negative breast cancer, those with residual disease are at higher risk of recurrence, which informs the recommended systemic therapy in the adjuvant setting. For instance, in patients with residual disease after neoadjuvant chemotherapy and HER2-targeted therapy, there is a role for adjuvant trastuzumab emtansine for those with residual disease at the time of surgery. The same holds true regarding the role of adjuvant capecitabine in patients with residual disease after neoadjuvant chemotherapy. With the added complexities of treating patients in the era of the COVID-19 outbreak, additional considerations are critical, including initiation of surgery within an appropriate time from completion of neoadjuvant therapy. National consensus guidelines on time to surgery must be developed to improve measurement and comparison across systems. In addition, there is emerging radiation treatment management research addressing a number of factors, including hypofractionation, role of proton beam therapy, safe omission of radiotherapy, and preoperative radiotherapy with or without drug combination. In this article, the multidisciplinary approach of treating patients with operable breast cancer is highlighted, with updates and future considerations described.

Background The B-MaP-C study aimed to determine alterations to breast cancer (BC) management during the peak transmission period of the UK COVID-19 pandemic and the potential impact of these treatment decisions. Methods This was a national cohort study of patients with early BC undergoing multidisciplinary team (MDT)-guided treatment recommendations during the pandemic, designated ‘standard’ or ‘COVID-altered’, in the preoperative, operative and post-operative setting. Findings Of 3776 patients (from 64 UK units) in the study, 2246 (59%) had ‘COVID-altered’ management. ‘Bridging’ endocrine therapy was used (n = 951) where theatre capacity was reduced. There was increasing access to COVID-19 low-risk theatres during the study period (59%). In line with national guidance, immediate breast reconstruction was avoided (n = 299). Where adjuvant chemotherapy was omitted (n = 81), the median benefit was only 3% (IQR 2–9%) using ‘NHS Predict’. There was the rapid adoption of new evidence-based hypofractionated radiotherapy (n = 781, from 46 units). Only 14 patients (1%) tested positive for SARS-CoV-2 during their treatment journey. Conclusions The majority of ‘COVID-altered’ management decisions were largely in line with pre-COVID evidence-based guidelines, implying that breast cancer survival outcomes are unlikely to be negatively impacted by the pandemic. However, in this study, the potential impact of delays to BC presentation or diagnosis remains unknown.

The United Kingdom has been severely affected by the coronavirus disease 2019 (COVID-19) pandemic. As the National Health Service (NHS) has urgently prioritized management of this outbreak, the UK clinical oncology community has had to adapt rapidly to maintain cancer services and training. These unprecedented times have altered countless aspects of cancer care, education, and research, providing a legacy that will extend well beyond the pandemic that catalyzed them. This editorial focuses on 3 key themes that distinguish the United Kingdom from many other countries.

Background: PRIMETIME is a UK-led prospective biomarker directed cohort study aiming to identify a group of breast cancer patients who can safely avoid radiotherapy following breast conserving surgery. This group is deemed to be at such a low risk of local relapse that the potential benefits of radiotherapy are unlikely to outweigh the risks. The uncertainty patients face regarding healthcare decisions is known as ‘decisional conflict’ which may increase when a component of standard of care is removed. Patient decision aids (PDA) are interventions which help patients to weigh up the risks and benefits of treatments. Evidence suggests PDA reduce decisional conflict. The study within a trial (SWAT) concept enables trialists to conduct research embedded within a larger trial in an economic and efficient manner. A SWAT testing whether the introduction of a PDA video reduces decisional conflict was conducted within the PRIMETIME study. The method development of the PRIMETIME SWAT is described. Methods: The SWAT was embedded within PRIMETIME after PRIMETIME had opened to recruitment. All eligible patients approached for the PRIMETIME study were eligible for the PRIMETIME SWAT. The SWAT utilised a cluster stepped-wedge trial design. Each cluster consisted of the radiotherapy centre and any peripheral centres referring into that radiotherapy centre. At the outset of the SWAT, all sites utilised the standard written information when discussing the trial with patients as had been envisaged in the original protocol. At pre-specified time-points each cluster “crossed over” to additionally incorporate the PDA video in the information provided to patients eligible for PRIMETIME. Decisional conflict was assessed in clusters prior to and following implementation of the PDA. The PDA was designed in collaboration with PRIMETIME patient advocates to be used in addition to the standard written information, explaining the same risks and benefits of radiotherapy but using an enhanced video format. Access to the PDA was restricted for healthcare professionals as well as patients until the cluster had crossed over to the intervention group to ensure that healthcare professionals did not alter the way in which they presented the study having watched the video. The primary endpoint was reduction in decisional conflict as measured on the decisional conflict scale. Discussion: The eligible population for the SWAT was greater than the population of the main PRIMETIME study (i.e. including patients who declined PRIMETIME), to try and obtain a SWAT sample representative of the general population. The cluster aspect of the stepped-wedge design ensured all patients in a cluster would receive uniform information which would simplify processes for sites and avoid cross-contamination between patients. The stepped-wedge aspect enabled all clusters to have access to the PDA by the end of the trial. The PDA was designed to complement the standard written information and explain the risks and benefits of radiotherapy in a different format using a video. If PDA are found to reduce decisional conflict within treatment de-escalation trials, this will provide the evidence to increase resources into the development of PDAs in future trials. Citation Format: Indrani Subarna Bhattacharya, Joanne S Haviland, Ada Balasopoulou, Liba Stones, Hilary Stobart, Lesley Turner, Penelope Hopwood, Judith M Bliss, Charlotte E Coles. Method development for a ‘Study within a Trial’ using a cluster stepped wedge trial design: Evaluating a patient decision aid video on patients’ decisional conflict in the PRIMETIME study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-12-10.

Introduction: Potential advantages of neoadjuvant systemic therapy (NST) include downstaging disease to minimise surgery, and in vivo assessment of tumour sensitivity to therapeutic drugs. Considerable variation in NST use remains, however, and it is unclear whether pathological response rates reflect those reported in trials, or whether downstaging achieved impacts on surgical decision-making. The NeST prospective multicentre study will address these questions through investigating patterns of care in the UK. Methods: Women undergoing NST as their primary breast cancer treatment (chemotherapy (CT), endocrine (ET) and targeted therapies) in UK centres between December 2017 and November 2018 were included. Anonymised data was collected at 37 participating centres, and uploaded to REDCap. Results: 1179 patients received neoadjuvant treatment during the study period. 41% had HER2+ disease, 28% TNBC and 31% ER+ HER2- disease. 48% were node positive and 52% node negative. Cited indications for neoadjuvant treatment were (more than one option applicable to each patient): Downstaging (mastectomy to breast conservation) 37% Facilitate dual antiHER2 therapy 33% Inoperable disease 19% Improved cosmesis (reduced volume of excision) 17% Facilitate BRCA testing 9% Inflammatory breast cancer 6% In patients recommended to receive NST, the MDT decision was for neoadjuvant CT in 87% of cases and neoadjuvant ET in 13%. For ER+ disease, the commonest reasons for prescribing CT were high grade disease and pre-menopausal status. The majority were treated with anthracycline-taxane combinations. 21% of TNBC patients were treated with platinum-containing regimens. In HER2+ disease, 54% were treated with dual antiHER2 therapies/chemotherapy, with 10% receiving chemotherapy/single antiHER2 agent (trastuzumab). Centres were asked to indicate primary breast surgical treatment recommended prior to/without NST. At abstract submission, this data was available for 887 patients. 31 had inoperable disease. A total of 477 were considered to require mastectomy, with disease not amenable to breast conservation surgery (BCS). A further 379 patients were considered candidates for BCS. Data on final surgical procedure was available for 765 patients. Of those patients determined suitable only for mastectomy at diagnosis, 123 underwent BCS as their primary operation - a downstaging rate of 26%. The overall mastectomy rate in this cohort was 48%, with 33% having mastectomy and 15% mastectomy with immediate reconstruction. Pathological response data was available in 672 patients, with an overall pathological complete response (pCR) rate of 29% (defined as no residual invasive or in situ disease). pCR rate according to molecular subtype was 37% for HER2+ disease, 35% for TNBC and 7% for ER+, HER2-ve disease. The pCR rate in patients downstaged from mastectomy to BCS was 27%. Conclusions: This UK national prospective study suggests that surgical downstaging remains a key indication for the use of NST. This is reflected in the fact that 26% of patients in this series were downstaged from an original surgical plan for mastectomy, with NST enabling BCS in these patients. However, based on this data it appears that surgical downstaging is no more likely in those with pCR compared to those without a pCR. Additional indications for NST are emerging, according to disease biology. There is widespread use of dual antiHER2 targeted therapies in this setting, with increasing use of platinum-containing regimens for TNBC. Neoadjuvant CT continues to be frequently used in the treatment of ER+ disease, despite known low pCR rates in this context, which are again confirmed. Low rates of neoadjuvant ET use are reported. Data collection is ongoing; updated data will be presented in December 2019. Citation Format: Stuart A McIntosh, Gareth W Irwin, Finian Bannon, Charlotte Coles, Ellen Copson, Ramsey Cutress, Rajiv Dave, Margaret Grayson, Chris Holcombe, Sheeba Irshad, Ciara O'Brien, Rachel O'Connell, Carlo Palmieri, Abeer M Shaaban, Nisha Sharma, Jagdeep Singh, Ian Whitehead, Shelley Potter. National utilisation of neoadjuvant systemic therapy and impact on surgical treatment - A prospective multi-centre cohort study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-16-04.

Background: PRIMETIME is a UK-led prospective biomarker-directed cohort study aiming to identify a group of breast cancer patients who can safely avoid radiotherapy following breast conserving surgery. This group is deemed to be at such a low risk of local relapse that the potential benefits of radiotherapy are unlikely to outweigh the risks. The uncertainty patients face regarding healthcare decisions is known as decisional conflict. Patient decision aids (PDA) are interventions which help patients to weigh up the risks and benefits of treatments. Evidence suggests PDA reduce decisional conflict. A study within a trial (SWAT) concept which enables trialists to conduct research embedded within a larger trial was used to investigate if the introduction of a PDA video reduces decisional conflict within PRIMETIME. Methods: The PDA video was designed to be used in addition to the standard written information and developed in close collaboration with PRIMETIME patient advocates. The PRIMETIME SWAT was implemented using a cluster stepped-wedge trial design. Each cluster was defined as the radiotherapy centre and peripheral centres referring into that centre. All clusters began in the standard information group (receiving written information) and then crossed over to the enhanced information group (receiving written information and PDA video) at either 2, 4 or 6 months. The primary endpoint was a reduction in decisional conflict following PDA implementation. Decisional conflict was assessed using the validated decisional conflict scale questionnaire (0-100 scale with greater scores indicating more decisional conflict) in the standard and enhanced information groups. The target sample size was 288 patients from 24 clusters, to provide 84% power (alpha 0.05) with an effect size of 0.55 (assuming standard deviation, SD=18) across the 0-1 range of possible intra-class correlation values. For the primary endpoint an estimate of the difference in mean decisional conflict pre- and post-implementation of the PDA video was obtained from a multilevel mixed effects linear regression model. Results: In an interim analysis conducted on 2nd May 2019, 318 evaluable questionnaires were returned from 463 eligible patients (69%) recruited across 24 clusters; 158 questionnaires from the standard and 160 questionnaires from the enhanced group. 60/130 (53%) patients in the enhanced information group (with available data) reportedly did not watch the PDA video. The mean decisional conflict score in the standard group [158 patients] was 10.73 (SD=11.63) and 8.43 (10.83) in the enhanced group [160 patients]. There was a reduction in decisional conflict in the enhanced compared with the standard group, however the effect size was small and unlikely to be clinically significant [estimated difference in means = -2.50 (-4.73- -0.28), p=0.03, effect size=0.11]. The final analysis will be conducted after the last cluster has crossed over to the enhanced group in October 2019. Conclusions: A SWAT using a cluster stepped-wedge trial design testing the implementation of a PDA video on patient’s decisional conflict was conducted across multiple UK centres participating in PRIMETIME. The average decisional conflict scores were low therefore there is less scope for obtaining further reductions, and the difference we observed was not clinically significant. The low baseline scores may reflect the PRIMETIME study population who are at low risk of local recurrence. Almost half of patients reportedly did not watch the video; this may be due to the standard written information being sufficient to fulfil the needs of this patient population. Citation Format: Indrani Subarna Bhattacharya, Joanne Haviland, Ada Balasopoulou, Liba Stones, Hilary Stobart, Lesley Turner, Penelope Hopwood, Charlotte E Coles, Judith M Bliss. Does the addition of a patient decision aid video reduce decisional conflict in patients considering a de-escalation of radiotherapy trial? Results from the PRIMETIME study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-12-04.

Introduction: Approximately 55,000 women in the United Kingdom are diagnosed with new breast cancer annually. Since emerging in December 2019, SARS-CoV-2 (coronavirus disease 2019, COVID-19) has become a global pandemic, affecting healthcare delivery worldwide. In response to the pandemic, multiple guidelines were issued to assist with rationalising breast cancer care. The primary aim of the B-MaP-C study is to audit and describe breast cancer management of patients newly diagnosed with breast cancer during the COVID-19 pandemic against pre-COVID-19 management practice in the UK. The implications of changes to management will be determined and the impact of a COVID-19 diagnosis on the patient's breast cancer management will be determined. Methods and analysis: This is a multi-centre collaborative audit of consecutive breast cancer patients undergoing treatment decisions during the acute and recovery phases of the COVID-19 pandemic. All patients with newly diagnosed primary breast cancer, whose treatment was decided in a multidisciplinary meeting from the 16th March 2020, are eligible for inclusion. Ethics and dissemination: As this is an audit ethical approval is not required. Each participating centre is required to register the study locally and obtain local governance approvals prior to commencement of data collection. Local audit data will be available to individual participating units for governance purposes. The results of the data analysis will be submitted for publication, as well as disseminated via the ABS newsletter and a webinar. All data will be presented at national and international conferences, circumstances permitting. Registration details: Each participating centre received local governance audit registration.

High-quality randomised clinical trials testing moderately fractionated breast radiotherapy have clearly shown that local control and survival is at least as effective as with 2 Gy daily fractions with similar or reduced normal tissue toxicity. Fewer treatment visits are welcomed by patients and their families, and reduced fractions produce substantial savings for health-care systems. Implementation of hypofractionation, however, has moved at a slow pace. The oncology community have now reached an inflection point created by new evidence from the FAST-Forward fivefraction randomised trial and catalysed by the need for the global radiation oncology community to unite during the COVID-19 pandemic and rapidly rethink hypofractionation implementation. The aim of this paper is to support equity of access for all patients to receive evidence-based breast external beam radiotherapy and to facilitate the translation of new evidence into routine daily practice. The results from this European Society for Radiotherapy and Oncology Advisory Committee in Radiation Oncology Practice consensus state that moderately hypofractionated radiotherapy can be offered to any patient for whole breast, chest wall (with or without reconstruction), and nodal volumes. Ultrafractionation (five fractions) can also be offered for non-nodal breast or chest wall (without reconstruction) radiotherapy either as standard of care or within a randomised trial or prospective cohort. The consensus is timely; not only is it a pragmatic framework for radiation oncologists, but it provides a measured proposal for the path forward to influence policy makers and empower patients to ensure equity of access to evidence-based radiotherapy.

Background SMALL (ISRCTN 12240119) is a novel UK phase III multicentre randomised trial comparing vacuum-assisted excision (VAE) to surgery for small screen-detected breast cancers with biologically favourable characteristics. Acceptance by the clinical community and recruitment to SMALL was anticipated to be challenging as it involves randomisation, surgical de-escalation and minimally-invasive percutaneous treatment (VAE). A QuinteT Recruitment Intervention (QRI) has therefore been integrated throughout SMALL’s recruitment period, with the aim of optimising recruitment and informed consent. Methods The QRI in SMALL has involved the analysis of: a) screening log data b) written views from recruiters on the two treatments and their advantages/disadvantages c) in-depth semi-structured interviews with members of the Trial Management Group (TMG) and clinician-recruiters and d) audio-recordings of recruitment discussions with potentially eligible patients. Recruitment challenges were identified and addressed through the provision of written recruitment tips documents, and group and individual feedback sessions with recruiters. Results There was widespread support for the concept of the SMALL trial within the clinical community. Recruiters recognised the pioneering role of SMALL as the only current surgical de-escalation randomised trial in screen-detected breast cancer. Key recruitment challenges revolved around i) healthcare professionals (HCPs) who met patients early in the pathway providing information indicating that they were being referred for surgery (without mentioning SMALL or VAE), ii) concerns around the balance of de-escalation/escalation of different treatment modalities (e.g. some clinicians may prefer to de-escalate radiotherapy in preference to surgery in low-risk patients), iii) challenges in articulating equipoise in a surgical de-escalation trial, iv) patient preferences (primarily for surgery) and recruiter discomfort in exploring/addressing such preferences and v) fewer eligible patients than anticipated. QRI actions to overcome these issues included developing a tips document for HCPs meeting patients early in the pathway, highlighting the need to refrain from making treatment recommendations. A more generic tips document was also developed emphasising the importance of the early introduction of the study, provision of balanced information about both treatments, encouraging recruiters to engage with patients’ concerns and preferences, and adequate explanation of randomisation. Group and individual feedback sessions focussed on two key areas – articulating equipoise through balanced information provision, and considering optimal ways to explore patient preferences where they are expressed. Despite the many set-up and recruitment challenges that arose from opening at the start of the pandemic, SMALL has recruited 142 patients to date from 23 sites, with an approached to randomised patient ratio of ~50%. Conclusion SMALL is a novel surgical de-escalation study in breast cancer, which will provide critical evidence to support reductions in treatment of good prognosis disease. Using a range of qualitative methodology, the QRI has identified both broad support for the study within the clinical community, but has also identified barriers to recruitment at both clinician and patient level. These challenges have been addressed employing a range of methods, and the recruitment level and approach/randomised ratio shows the overall acceptability of this study to patients. Further work will involve interviews with patients, with a focus on their views on de-escalation, and further recruiter feedback sessions. Taken together, theis data will help inform the development and design of future de-escalation and treatment optimisation studies in breast cancer. SMALL is funded by the UK NIHR HTA programme, award 17/42/32 Citation Format: Stuart A. McIntosh, Charlotte E. Coles, David Dodwell, Kenneth Elder, Jessica Foster, Claire Gaunt, Amanda Kirkham, Iain Lyburn, Jenna Morgan, Sarah E. Pinder, Sarah Pirrie, Shelley Potter, Tracy Roberts, Nisha Sharma, Hilary Stobart, Elizabeth Southgate, Sian Taylor-Phillips, Matthew Wallis, Daniel Rea, Sangeetha Paramasivan. Recruitment challenges in a UK surgical de-escalation study: preliminary qualitative research findings from the SMALL trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-05-17.

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.

'No abstract'

We report on the third Assisi Think Tank Meeting (ATTM) on breast cancer, a brainstorming project which involved European radiation and clinical oncologists who were dedicated to breast cancer research and treatment. Held on February 2020, the ATTM aimed at identifying key clinical questions in current clinical practice and "grey" areas requiring research to improve management and outcomes. Before the meeting, three key topics were selected: 1) managing patients with frailty due to either age and/or multi-morbidity; 2) stereotactic ra-diation therapy and systemic therapy in the management of oligometastatic disease; 3) contralateral breast tumour prevention in BCRA-mutated patients. Clinical practice in these areas was investigated by means of an online questionnaire. In the lapse period between the survey and the meeting, the working groups reviewed data, on-going studies and the clinical challenges which were then discussed in-depth and subjected to intense brainstorming during the meeting; research protocols were also proposed. Methodology, outcome of discussions, conclusions and study proposals are summarized in the present paper. In conclusion, this report presents an in-depth analysis of the state of the art, grey areas and controversies in breast cancer radiation therapy and dis-cusses how to confront them in the absence of evidence-based data to guide clinical decision-making.

Bolus serves as a tissue equivalent material that shifts the 95-100% isodose line towards the skin and subcutaneous tissue. The need for bolus for all breast cancer patients planned for postmastectomy radiation therapy (PMRT) has been questioned. The work was initiated by the faculty of the European SocieTy for Radiotherapy & Oncology (ESTRO) breast cancer courses and represents a multidisciplinary international breast cancer expert collaboration to optimize PMRT. Due to the lack of randomised trials evaluating the benefits of bolus, we designed a stepwise project to evaluate the existing evidence about the use of bolus in the setting of PMRT to achieve an international consensus for the indications of bolus in PMRT, based on the Delphi method. (c) 2021 Elsevier B.V. All rights reserved. Radiotherapy and Oncology 164 (2021) 115-121

BackgroundNeoadjuvant systemic therapy (NST) is increasingly used in the treatment of breast cancer, yet it is clear that there is significant geographical variation in its use in the UK. This study aimed to examine stated practice across UK breast units, in terms of indications for use, radiological monitoring, pathological reporting of treatment response, and post-treatment surgical management.MethodsMultidisciplinary teams (MDTs) from all UK breast units were invited to participate in the NeST study. A detailed questionnaire assessing current stated practice was distributed to all participating units in December 2017 and data collated securely usingREDCap. Descriptive statistics were calculated for each questionnaire item.ResultsThirty-nine MDTs from a diverse range of hospitals responded. All MDTs routinely offered neoadjuvant chemotherapy (NACT) to a median of 10% (range 5–60%) of patients. Neoadjuvant endocrine therapy (NET) was offered to a median of 4% (range 0–25%) of patients by 66% of MDTs. The principal indication given for use of neoadjuvant therapy was for surgical downstaging. There was no consensus on methods of radiological monitoring of response, and a wide variety of pathological reporting systems were used to assess tumour response. Twenty-five percent of centres reported resecting the original tumour footprint, irrespective of clinical/radiological response. Radiologically negative axillae at diagnosis routinely had post-NACT or post-NET sentinel lymph node biopsy (SLNB) in 73.0 and 84% of centres respectively, whereas 16% performed SLNB pre-NACT. Positive axillae at diagnosis would receive axillary node clearance at 60% of centres, regardless of response to NACT.DiscussionThere is wide variation in the stated use of neoadjuvant systemic therapy across the UK, with general low usage of NET. Surgical downstaging remains the most common indication of the use of NAC, although not all centres leverage the benefits of NAC for de-escalating surgery to the breast and/or axilla. There is a need for agreed multidisciplinary guidance for optimising selection and management of patients for NST. These findings will be corroborated in phase II of the NeST study which is a national collaborative prospective audit of NST utilisation and clinical outcomes.BackgroundNeoadjuvant systemic therapy (NST) is increasingly used in the treatment of breast cancer, yet it is clear that there is significant geographical variation in its use in the UK. This study aimed to examine stated practice across UK breast units, in terms of indications for use, radiological monitoring, pathological reporting of treatment response, and post-treatment surgical management.MethodsMultidisciplinary teams (MDTs) from all UK breast units were invited to participate in the NeST study. A detailed questionnaire assessing current stated practice was distributed to all participating units in December 2017 and data collated securely usingREDCap. Descriptive statistics were calculated for each questionnaire item.ResultsThirty-nine MDTs from a diverse range of hospitals responded. All MDTs routinely offered neoadjuvant chemotherapy (NACT) to a median of 10% (range 5–60%) of patients. Neoadjuvant endocrine therapy (NET) was offered to a median of 4% (range 0–25%) of patients by 66% of MDTs. The principal indication given for use of neoadjuvant therapy was for surgical downstaging. There was no consensus on methods of radiological monitoring of response, and a wide variety of pathological reporting systems were used to assess tumour response. Twenty-five percent of centres reported resecting the original tumour footprint, irrespective of clinical/radiological response. Radiologically negative axillae at diagnosis routinely had post-NACT or post-NET sentinel lymph node biopsy (SLNB) in 73.0 and 84% of centres respectively, whereas 16% performed SLNB pre-NACT. Positive axillae at diagnosis would receive axillary node clearance at 60% of centres, regardless of response to NACT.DiscussionThere is wide variation in the stated use of neoadjuvant systemic therapy across the UK, with general low usage of NET. Surgical downstaging remains the most common indication of the use of NAC, although not all centres leverage the benefits of NAC for de-escalating surgery to the breast and/or axilla. There is a need for agreed multidisciplinary guidance for optimising selection and management of patients for NST. These findings will be corroborated in phase II of the NeST study which is a national collaborative prospective audit of NST utilisation and clinical outcomes.

TPS614 Background: Mammographic screening programmes reduce breast cancer mortality but detect many small tumours with favourable biology which may not progress. These are treated with surgery and adjuvant therapies, but associated morbidities mean there is a need to reduce overtreatment. Minimally invasive treatments such as vacuum-assisted excision (VAE) have been described but there is no prospective randomised evidence to support their routine use. SMALL (ISRCTN 12240119) is designed to establish the feasibility of using VAE to treat small tumours detected within the UK NHS Breast Screening Programme (BSP). Methods: Phase III multicenter randomized trial comparing surgery with VAE for screen-detected good prognosis cancers. Eligibility criteria are age ≥47 years, unifocal grade 1 tumors (maximum diameter 15mm), strongly ER/PR+ve and HER2-ve, with negative axillary staging. Patients are randomized 2:1 to VAE or surgery, with no axillary surgery in the VAE arm. Excision is assessed radiologically, and if incomplete, patients undergo surgery. Adjuvant radiotherapy and endocrine therapy are mandated in the VAE arm. Coprimary end-points are: (1) Non-inferiority comparison of the requirement for a second procedure. (2) Single-arm analysis of local recurrence (LR) at 5 years after VAE. Recruitment of 800 patients will permit demonstration of 10% non-inferiority of VAE for requirement of a second procedure, ensuring sufficient patients for single arm analysis of LR rates, where expected LR free survival is 99% at 5 years, with an undesirable survival probability after VAE of 97%. The DMC will monitor LR events to ensure these do not exceed 3% per year. Secondary outcome measures include time to ipsilateral recurrence, overall survival, complications, quality of life and health economic analysis. A QuinteT Recruitment Intervention (QRI) is integrated throughout SMALL to optimize recruitment and informed consent. Recruitment challenges are identified by analyzing recruiter/patient interviews, audio-recordings of trial discussions, and by review of screening, eligibility and recruitment data and study documentation. Solutions are developed collaboratively, including recruiter feedback and recruitment tips documents. Results: SMALL opened in December 2019, but recruitment halted for 5 months due to COVID-19. At 11th February 2022, 91 patients had been recruited from 22 centers, with an approached/consented ration of 50%. Drawing from preliminary QRI findings, a recruitment tips document has been circulated (on discussing SMALL, providing balanced information on treatment options and explaining randomization). Individual recruiter feedback has commenced, with wider feedback planned shortly. Conclusion: Despite pandemic-related challenges, SMALL has excellent recruitment to date and is expected to have a global impact on treatment of screen-detected breast cancer. Clinical trial information: 12240119.

Highlights • Moderately hypofractionated radiation therapy (mHF-RT) for breast cancer patients is applied very variably in clinical practice worldwide. • mHF-RT to the breast, chest wall (with or without breast reconstruction), and regional lymph nodes is a safe and effective alternative to conventionally fractionated regimens. • The use of mHF-RT can help during health crises like the COVID-19 pandemic, to compensate the potential backlog of patients whose radiation therapy was delayed., Post-operative radiation therapy (RT) reduces loco-regional recurrence rates and mortality in most patients with non-metastatic breast cancer. The aim of this critical review is to provide an overview of the applicability of moderately hypofractionated RT for breast cancer patients, focusing on factors influencing clinical decision-making. An international group of radiation oncologists agreed to assess, integrate, and interpret the existing evidence into a practical report to guide clinicians in their daily management of breast cancer patients. We conclude that moderately hypofractionated RT to the breast, chest wall (with/without breast reconstruction), and regional lymph nodes is at least as safe and effective as conventionally fractionated regimens and could be considered as the treatment option for the vast majority of the patients.For those who are still concerned about its generalised application, we recommend participating in ongoing trials comparing moderately hypofractionated RT to conventionally fractionated RT for breast cancer patients in some clinical circumstances.

PURPOSE: Numerous publications during the COVID-19 pandemic recommended the use of hypofractionated radiation therapy. This project assessed aggregate changes in the quality of the evidence supporting these schedules to establish a comprehensive evidence base for future reference and highlight aspects for future study. METHODS AND MATERIALS: Based on a systematic review of published recommendations related to dose fractionation during the COVID-19 pandemic, 20 expert panelists assigned to 14 disease groups named and graded the highest quality of evidence schedule(s) used routinely for each condition and also graded all COVID-era recommended schedules. The American Society for Radiation Oncology quality of evidence criteria were used to rank the schedules. Process-related statistics and changes in distributions of quality ratings of the highest-rated versus recommended COVID-19 era schedules were described by disease groups and for specific clinical scenarios. RESULTS: From January to May 2020 there were 54 relevant publications, including 233 recommended COVID-19-adapted dose fractionations. For site-specific curative and site-specific palliative schedules, there was a significant shift from established higher-quality evidence to lower-quality evidence and expert opinions for the recommended schedules (P = .022 and P < .001, respectively). For curative-intent schedules, the distribution of quality scores was essentially reversed (highest levels of evidence "pre-COVID" vs "in-COVID": high quality, 51.4% vs 4.8%; expert opinion, 5.6% vs 49.3%), although there was variation in the magnitude of shifts between disease sites and among specific indications. CONCLUSIONS: A large number of publications recommended hypofractionated radiation therapy schedules across numerous major disease sites during the COVID-19 pandemic, which were supported by a lower quality of evidence than the highest-quality routinely used dose fractionation schedules. This work provides an evidence-based assessment of these potentially practice-changing recommendations and informs individualized decision-making and counseling of patients. These data could also be used to support radiation therapy practices in the event of second waves or surges of the pandemic in new regions of the world.

BACKGROUND: We aimed to identify a five-fraction schedule of adjuvant radiotherapy (radiation therapy) delivered in 1 week that is non-inferior in terms of local cancer control and is as safe as an international standard 15-fraction regimen after primary surgery for early breast cancer. Here, we present 5-year results of the FAST-Forward trial.METHODS: FAST-Forward is a multicentre, phase 3, randomised, non-inferiority trial done at 97 hospitals (47 radiotherapy centres and 50 referring hospitals) in the UK. Patients aged at least 18 years with invasive carcinoma of the breast (pT1-3, pN0-1, M0) after breast conservation surgery or mastectomy were eligible. We randomly allocated patients to either 40 Gy in 15 fractions (over 3 weeks), 27 Gy in five fractions (over 1 week), or 26 Gy in five fractions (over 1 week) to the whole breast or chest wall. Allocation was not masked because of the nature of the intervention. The primary endpoint was ipsilateral breast tumour relapse; assuming a 2% 5-year incidence for 40 Gy, non-inferiority was predefined as ≤1·6% excess for five-fraction schedules (critical hazard ratio [HR] of 1·81). Normal tissue effects were assessed by clinicians, patients, and from photographs. This trial is registered at isrctn.com, ISRCTN19906132.FINDINGS: Between Nov 24, 2011, and June 19, 2014, we recruited and obtained consent from 4096 patients from 97 UK centres, of whom 1361 were assigned to the 40 Gy schedule, 1367 to the 27 Gy schedule, and 1368 to the 26 Gy schedule. At a median follow-up of 71·5 months (IQR 71·3 to 71·7), the primary endpoint event occurred in 79 patients (31 in the 40 Gy group, 27 in the 27 Gy group, and 21 in the 26 Gy group); HRs versus 40 Gy in 15 fractions were 0·86 (95% CI 0·51 to 1·44) for 27 Gy in five fractions and 0·67 (0·38 to 1·16) for 26 Gy in five fractions. 5-year incidence of ipsilateral breast tumour relapse after 40 Gy was 2·1% (1·4 to 3·1); estimated absolute differences versus 40 Gy in 15 fractions were -0·3% (-1·0 to 0·9) for 27 Gy in five fractions (probability of incorrectly accepting an inferior five-fraction schedule: p=0·0022 vs 40 Gy in 15 fractions) and -0·7% (-1·3 to 0·3) for 26 Gy in five fractions (p=0·00019 vs 40 Gy in 15 fractions). At 5 years, any moderate or marked clinician-assessed normal tissue effects 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. Across all clinician assessments from 1-5 years, odds ratios versus 40 Gy in 15 fractions were 1·55 (95% CI 1·32 to 1·83, pINTERPRETATION: 26 Gy in five fractions over 1 week is non-inferior to the standard of 40 Gy in 15 fractions over 3 weeks for local tumour control, and is as safe in terms of normal tissue effects up to 5 years for patients prescribed adjuvant local radiotherapy after primary surgery for early-stage breast cancer.FUNDING: National Institute for Health Research Health Technology Assessment Programme.

The current COVID-19 pandemic challenges oncologists to profoundly re-organize oncological care in order to dramatically reduce hospital visits and admissions and therapy-induced immune-related complications without compromising cancer outcomes. Since COVID-19 is a novel disease, guidance by scientific evidence is often unavailable, and impactful decisions are inevitably made on the basis of expert opinions. Here we report how the seven comprehensive cancer centers of Cancer Core Europe have organized their healthcare systems at an unprecedented scale and pace to make their operations 'pandemic proof'. We identify and discuss many commonalities, but also important local differences, and pinpoint critical research priorities to enable evidence-based remodeling of cancer care during the COVID-19 pandemic. Also, we discuss how the current situation offers a unique window of opportunity for assessing the effects of de-escalating anticancer regimens, which may fast-forward the development of more-refined and less-toxic treatments. By sharing our joint experiences, we offer a roadmap for proceeding and aim to mobilize the global research community to generate the data that are critically needed to offer the best possible care to patients.

Aims:\ud Radiotherapy clinical trials are integral to the development of new treatments to improve the outcomes of patients with cancer. A collaborative study by the National Cancer Research Institute Clinical and Translational Radiotherapy Research Working Group and the National Institute for Health Research was carried out to understand better if and why inefficiencies occur in the set-up of radiotherapy trials in the UK.\ud \ud Materials and methods:\ud Two online surveys collected information on the time taken for UK radiotherapy trials to reach key milestones during set-up and the research support currently being provided to radiotherapy centres to enable efficient clinical trial set-up. Semi-structured interviews with project managers and chief investigators identified better ways of working to improve trial set-up in the future.\ud \ud Results:\ud The timelines for the set-up of 39 UK radiotherapy trials were captured in an online survey showing that the median time from grant approval to trial opening was 600 days (range 169–1172). There were 38 responses from radiotherapy centres to a survey asking about the current support provided for radiotherapy research. Most of these centres have more than one type of staff member dedicated to supporting radiotherapy research. The most frequent barrier to radiotherapy trial set-up identified was lack of physicists' time and lack of time for clinical oncologists to carry out research activities. Four main themes around trial set-up were identified from semi-structured interviews: the importance of communication and building relationships, the previous experience of the chief investigator and clinical trials units, a lack of resources and having the time and personnel required to produce trial documentation and to process trial approval requests.\ud \ud Conclusions: \ud This unique, collaborative project has provided up to date information about the current landscape of trial set-up and research support in the UK and identified several avenues on which to focus future efforts in order to support the excellent radiotherapy trial work carried out across the UK.

Background: FAST-Forward aims to identify a 5-fraction (Fr) schedule of adjuvant radiotherapy (radiation therapy) delivered in 1 week which is non-inferior for local cancer control and as safe as an international standard 15Fr regimen after primary surgery for early breast cancer. Five-year results are presented. Methods: FAST-Forward (ISRCTN19906132) randomised (1:1:1) patients with invasive carcinoma of the breast (pT1-3 pN0-1 M0) after breast conservation surgery or mastectomy to 40Gy in 15Fr (3 weeks), 27Gy or 26Gy in 5Fr (1 week) to whole breast/chest wall. Primary endpoint was ipsilateral breast tumour relapse (IBTR); assuming 2% 5-year incidence for 40Gy, non-inferiority was pre-defined as < 1.6% excess for 5Fr schedules (critical hazard ratio HR=1.81). Normal tissue effects (NTE) were assessed by clinicians, patients and photographs. Findings: 4096 consenting patients (1361 40Gy, 1367 27Gy, 1368 26Gy) were recruited November 2011-June 2014 from 97 UK centres. At 71 months median follow-up, 79 IBTR events were reported (40Gy: 31, 27Gy: 27, 26Gy: 21); HRs (95%CI) versus 40Gy/15Fr were 27Gy/5Fr: 0.86 (0.51,1.44), 26Gy/5Fr: 0.67 (0.38,1.16). Five-year incidence of IBTR after 40Gy was 2.1% (1.4,3.1); estimated absolute differences versus 40Gy/15Fr were -0.3% (-1.0,0.9) for 27Gy/5Fr (p=0.0022 for non-inferiority) and -0.7% (-1.3,0.3) for 26Gy/5Fr (p=0.00019). 5-year prevalence of any clinician-assessed moderate/marked breast NTE after 40Gy: 98/986 (9.9%), 27Gy: 155/1005 (15.4%), 26Gy: 121/1020 (11.9%). Across all clinician assessments from 1-5 years, odds ratios versus 40Gy/15Fr were 1.55 (1.32,1.83, p

Purpose Post mastectomy radiation therapy (PMRT) reduces locoregional recurrence (LRR) and breast cancer mortality for selected patients. Bolus overcomes the skin-sparing effect of external-beam radiotherapy, ensuring adequate dose to superficial regions at risk of local recurrence (LR). This systematic review summarizes the current evidence regarding the impact of bolus on LR and acute toxicity in the setting of PMRT. Results 27 studies were included. The use of bolus led to higher rates of acute grade 3 radiation dermatitis (pooled rates of 9.6% with bolus vs. 1.2% without). Pooled crude LR rates from thirteen studies (n = 3756) were similar with (3.5%) and without (3.6%) bolus. Conclusions Bolus may be indicated in cases with a high risk of LR in the skin, but seems not to be necessary for all patients. Further work is needed to define the role of bolus in PMRT.

[No Abstract]

AIMS: These multidisciplinary guidelines aim to provide clinically helpful, evidence-based recommendations on the surgical management of the axilla in patients who have received neo-adjuvant chemotherapy for early breast cancer.MATERIALS & METHODS: Following a review of published evidence, a writing group representing all disciplines quorate within a breast cancer multidisciplinary meeting prepared the guidelines.KEY RECOMMENDATIONS: In patients presenting with clinically node negative axillae, sentinel node biopsy (SNB) may be performed prior to or on completion of neo-adjuvant chemotherapy (NACT). In patients presenting with clinically node positive axillae, SNB may be safely considered following completion of NACT. Four nodes should be removed with dual mapping. If evidence of complete pathological response of previous metastases is seen, axillary radiotherapy may be offered. If residual cancer (isolated tumour cells, micro- or macrometastes) is seen within the SNB, offer axillary node dissection.

Background: Risk factors for local recurrence after mastectomy in ductal carcinoma in situ (DCIS) emerged as a grey area during the second “Assisi Think Tank Meeting” (ATTM) on Breast Cancer. Aim: To review practice patterns of post-mastectomy radiation therapy (PMRT) in DCIS, identify risk factors for recurrence and select suitable candidates for PMRT. Methods: A questionnaire concerning DCIS management, focusing on PMRT, was distributed online via SurveyMonkey. Results: 142 responses were received from 15 countries. The majority worked in academic institutions, had 5–20 years work-experience and irradiated 5 cm, skin- or nipple- sparing mastectomy. Moderate hypofractionation was the most common schedule, except after immediate breast reconstruction (57% conventional fractionation). Conclusions: The present survey highlighted risk factors for PMRT administration, which should be further evaluated.

Over the past decade, breast cancer has overtaken cervical cancer to become the most common cancer among women in India, as in most Western nations. In addition to the high incidence, the morbidity and mortality associated with this malignancy are disproportionately higher in India. Although some efforts are being made to increase awareness about this disease, a large majority of Indian patients present with advanced disease. Here, important institutional data and treatment outcomes are reviewed and compared with data from the West. Additionally, we highlight recent efforts in setting up collaborative multicentre trials in breast cancer in India and suggest some ways forward to improve outcomes.

Highlights • Seroma was not associated with patient-reported breast appearance change after breast radiotherapy. • Haematoma and smoking were significant risk factors for patient-reported breast appearance change. • Seroma prevalence in our study was lower than previous reports., Background Seroma describes a collection of serous fluid within a cavity, occurring following surgery. Seroma is associated with normal tissue effects (NTE) following breast radiotherapy, as reported by clinicians and on photographs. This study investigates the association between seroma and the NTE breast appearance change collected using patient-reported outcome measures (PROMs) in IMPORT HIGH, as well as investigating the association between breast appearance change and patient/tumour/treatment factors. Methods Case–control methodology was used for seroma analysis within IMPORT HIGH. Cases were patients reporting moderate/marked breast appearance change and controls reported none/mild changes at year-3. One control was selected at random for each case. Seromas were graded as not visible/subtle or visible/highly visible on CT radiotherapy planning scans. Logistic regression tested associations, adjusting for patient/tumour/treatment factors. Results 1078/1149 patients consented to PROMs, of whom 836 (78%) reported whether they had 3-year breast appearance change; 231 cases and 231 controls were identified. 304/462 (66%) patients received chemotherapy. Seroma prevalence was 20% (41/202) in cases and 16% (32/205) in controls, and less frequent in patients receiving adjuvant chemotherapy [10% (24/246) compared with 29% (40/138) without]. Visible seroma was not significantly associated with breast appearance change [OR 1.38 (95%CI 0.83–2.29), p = 0.219]. Larger tumour size, haematoma, current smoking and body image concerns at baseline were independent risk factors. Conclusions Seroma was not associated with patient-reported breast appearance change, but haematoma and smoking were significant risk factors. Lack of association may be related to lower prevalence of seroma compared with previous reports, perhaps reflecting patients receiving adjuvant chemotherapy in whom seroma resolves prior to radiotherapy.