Weight control and energy restriction could improve survival in patients with advanced breast cancer (ABC) but randomised data are lacking. A randomised screening trial was conducted to assess an intermittent energy restricted diet and resistance exercise intervention (IER + RE) vs RE alone (RE) on progression free survival (PFS), toxicity and Quality of Life (QoL) during chemotherapy for ABC. Sixty-eight women were randomised to IER + RE (n = 35) or RE (n = 33) with one-sided significance assessed at the 20% threshold. The primary end point was PFS secondary endpoints included chemotherapy toxicity, weight change and QoL. The adjusted hazard rate for progression comparing IER + RE vs RE was 0.729 (0.391–1.361) and the median PFS 42.0 vs 26.1 weeks respectively (p = 0.160). Toxicity was low and comparable between groups. Comparing IER + RE vs RE alone at cycle 3 the median (interquartile range) changes were: weight –1.8 kg (–4.2 to –0.7) vs +0.2 kg (–0.74, 2.59) (p < 0.001), FACT-B + 4.0 (–0.8, 11) vs +1.0 (–4.0, 4.0) (p = 0.031) and Hospital Anxiety Depression Score –2.0 (–3.5, +0.5) vs +1.0 (–2, 3.5) (p = 0.022). IER + RE improved PFS and QoL without evidence of harms warranting a further larger randomised study in ABC. https://www.isrctn.com/ISRCTN12841416 .

BACKGROUND:Understanding healthcare professionals' (HCPs) experiences of caring for women with false-positive screening test results in the National Health Service Breast Screening Programme (NHSBSP) is important for reducing the impact of such results. METHODS:Interviews were undertaken with 12 HCPs from a single NHSBSP unit, including advanced radiographer practitioners, breast radiographers, breast radiologists, clinical nurse specialists (CNSs), and a radiology healthcare assistant. Data were analysed thematically using Template Analysis. RESULTS:Two themes were produced: (1) Gauging and navigating women's anxiety during screening assessment was an inevitable and necessary task for all participants. CNSs were perceived as particularly adept at this, while breast radiographers reported a lack of adequate formal training. (2) Controlling the delivery of information to women (including amount, type and timing of information). HCPs reported various communication strategies to facilitate women's information processing and retention during a distressing time. CONCLUSIONS:Women's anxiety could be reduced through dedicated CNS support, but this should not replace support from other HCPs. Breast radiographers may benefit from more training to emotionally support recalled women. While HCPs emphasised taking a patient-centred communication approach, the use of other strategies (e.g., standardised scripts) and the constraints of the 'one-stop shop' model pose challenges to such an approach. PATIENT AND PUBLIC CONTRIBUTION:During the study design, two Patient and Public Involvement members (women with false-positive-breast screening test results) were consulted to gain an understanding of patient perspectives and experiences of being recalled specifically in the NHSBSP. Their feedback informed the formulations of the research aim, objectives and the direction of the interview guide.

Abstract Background Wire-guided localisations (WGL) of breast cancers have been the gold-standard for pre-operative localisation of non-palpable breast cancers for many years but have significant limitations. Newer localisation techniques have been introduced including Radio Frequency ID tags (RFID) and magnetic seeds which aim to overcome these limitations. The UK iBRA-net group have designed a multi-centre platform study aiming to compare the safety and effectiveness of wire, RFID, magnetic seeds, and radar-based localisation. A second aim was the qualitative assessment of shared learning as users gained experience. Methods A UK national multi-centre prospective observational platform study was designed to compare a control arm of WGL for women undergoing breast conserving surgery with two interventional arms of RFID tags and magnetic seeds. Patient data were collected between August 2018 and July 2022 in UK centres. The primary outcome was accurate excision of the index lesion at the time of surgery. Secondary outcomes were defined as; resection margins, breast reoperation rate (planned and unplanned), complications, cancellation rate on day of surgery, and duration of the surgery. To account for lesion size in the assessment of excision weight, we used size as a denominator over two dimensions, reporting this as weight/size2, in g/mm2. Data was collected prospectively on a secure REDcap database following approval from local audit departments. To calculate the sample size a power calculation was employed, with n=950 patients per group the upper limit of the observed one-sided 95% confidence interval for the difference between identification rates (intervention vs WGL) is expected to be less than 0.9% with 80% power, assuming the two methods both have an expected identification rate of 99.4%. Simple summary statistics were calculated for each outcome and data were tested for distribution and differences between groups using unpaired t-tests, Mann-Whitney U tests, and Chi squared tests as appropriate. Analyses were conducted using Stata® IC version 14 (StataCorp, College Station, Texas, USA). Results Data were accrued from 3484 patients in 55 units. This included 1293 patients having WGL, 1188 RFID tags, and 1003 magnetic seeds. RFID had a lower rate of identification of the index lesion compared to magnetic seed and wire (97.9% vs. 99.8% vs. 99.1% respectively). When comparing the reasons behind failure of the primary outcome, the majority were not thought to be related to the modality of localisation. Data from 1560 patients with unifocal, unilateral breast lesions were included in subgroup analysis, excluding those having neo-adjuvant chemotherapy and those having therapeutic mammoplasty. Positive margins were lower in RFID excisions compared to wire (11.2% vs. 15% respectively, p< 0.05), whereas magnetic seed were equivalent (11.2 % vs 13.3%, P=0.22). Routine cavity shaves were performed in 64.5% of WGL vs 48.3% of RFID vs 64.3% of magnetic guided excisions. There was no difference in specimen weight/size2 (0.138 WGL vs. 0.131 RFID vs. 0.15 magnetic seed). Re-excision (for positive or close margins) was equivalent across the three groups (13.2% of wire vs 15% of RFID vs 12.3% of magnetic seed guided excisions, p=0.3). There have been four shared learning educational events focussing on three key themes relating to preoperative, intraoperative, and postoperative learning outcomes in addition to 130 database shared learning entries. This may aid other surgeons as they adopt these techniques. Conclusions All three localisation devices demonstrate high levels of localisation accuracy. There was a higher rate of device dislodgement in the RFID group, which was also identified in the shared learning events. However, re-excision rates were equivalent across the three groups. This study has demonstrated a robust platform for the comparative evaluation of new localisation technologies and of sharing learning and experience. Citation Format: Rachel Foster, James Harvey, Rajiv Dave, Anthony Maxwell, Senthurun Mylvaganam, Matthew Gardiner, Sue Down, Nicola Barnes, Mihir Chandarana, Shelley Potter, Yazan Masannat, Chris Holcombe, Tahir Masudi, Amtul Carmichael, Robert Milligan, Jenna Morgan. The IBRAnet localisation study; a UK National multi-centre cohort study comparing the safety and effectiveness of guidewire, RFID, and magnetic seed- guided localisation for impalpable breast lesions [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-23-04.

Background Risk stratification as a routine part of the NHS Breast Screening Programme (NHSBSP) could provide a better balance of benefits and harms. We developed BC-Predict, to offer women when invited to the NHSBSP, which collects standard risk factor information; mammographic density; and in a sub-sample, a Polygenic Risk Score (PRS). Methods Risk prediction was estimated primarily from self-reported questionnaires and mammographic density using the Tyrer–Cuzick risk model. Women eligible for NHSBSP were recruited. BC-Predict produced risk feedback letters, inviting women at high risk (≥8% 10-year) or moderate risk (≥5–<8% 10-year) to have appointments to discuss prevention and additional screening. Results Overall uptake of BC-Predict in screening attendees was 16.9% with 2472 consenting to the study; 76.8% of those received risk feedback within the 8-week timeframe. Recruitment was 63.2% with an onsite recruiter and paper questionnaire compared to <10% with BC-Predict only ( P < 0.0001). Risk appointment attendance was highest for those at high risk (40.6%); 77.5% of those opted for preventive medication. Discussion We have shown that a real-time offer of breast cancer risk information (including both mammographic density and PRS) is feasible and can be delivered in reasonable time, although uptake requires personal contact. Preventive medication uptake in women newly identified at high risk is high and could improve the cost-effectiveness of risk stratification. Trial registration Retrospectively registered with clinicaltrials.gov (NCT04359420).

Background: Disparity between mammographic and pathological sizing of DCIS can lead to surgical overtreatment, with poor cosmetic outcomes of breast conservation surgery (BCS) or inappropriate mastectomy versus undertreatment, with subsequent need for re-excision. In addition, where mammographic size is smaller than pathological size, this may reflect an increased risk of mammographically occult residual disease post surgery; where pathological size is smaller than mammographic size there is a possibility of pathological underestimation or missed positive margins, with both scenarios resulting in increased risk of recurrence. Methods: The Sloane Project, within the UK NHS Breast Screening Programme, is a prospective cohort study of screen detected DCIS (2003-2012), with recurrence data for a median follow-up of 9 years. The NHS Breast Screening Programme screens women from age 50-70. We assessed factors associated with mammographic/pathology disparity, leading to i) 'downsizing' from pre-operative mammographic size estimation to final surgically resected pathological size or ii) 'upsizing' from pre-operative mammographic size to surgically resected pathological size. We defined 'downsizing' as pathological size <10mm or <5mm (largest diameter) smaller than mammographic size and 'upsizing' as pathological size >10mm or >5mm larger than mammographic size. Ipsilateral recurrence rates were determined in patients with mammographic/pathology disparity (downsized or upsized) compared to those with accurate preoperative sizing. Results: Using a 10mm size disparity, among 10829 patients, DCIS was downsized (pathological size smaller than mammographic size) in 26%, upsized in 19% and similar in 54%. Mastectomy was associated with marked mammographic/pathology disparity, with a 3.90RR of downsizing (p<0.0001, 95% C.I 3.52,4.31) and a 4.72RR of upsizing (p<0.0001,95% C.I 4.23, 5.27). Presence of microcalcification was associated with mammographic/pathology disparity, yielding a 1.29 RR of downsizing (p=0.0034, 95% C.I. 1.09,1.54) and 1.53 RR of upsizing (p<0.0001, 95% C.I. 1.25,1.88). Casting or linear calcification (compared to granular or punctate) was associated with a 2-fold RR of downsizing. For each 1mm increase in mammographic size, the relative risk (RR) of downsizing increased by 1.07 times (p<0.0001, 95% CI 1.073,1.080). A 1.01 RR of downsizing for every 1 year younger (p=0.0002, 95% CI 1.01,1.02), contrasted with a 1.44 RR of upsizing with high mammographic density. The results remained similar when patients prescribed endocrine therapy or radiotherapy were excluded. Re-excision (but not completion mastectomy) is associated with increased recurrence, with recurrence occurring in 237 of 5157 not requiring re-excision but 99 of 1488 requiring re-excision; RR: 1.45 (1.15-1.82). Conclusion: Large mammographic size, microcalcification casting features and young age (size overestimation) versus microcalcification and high density (size underestimation) should be considered in selecting surgery for DCIS. Mammographic/pathology disparity of only 5mm, whether this leads to downsizing or upsizing, is associated with an increased risk of ipsilateral recurrence after breast conservation. Table 1.In patients undergoing breast conservation, impact of 10mm and 5 mm mammographic/pathology disparity on ipsilateral recurrence rateTotalIpsilateral recurrence, n (%)RR (CI)Change in size of >10mmNo change3062158 (5.2%)1downsized111666 (5.9%)1.15 (0.87-1.51)upsized52036 (6.9%)1.34 (0.95-1.90)unknown19112 (6.3%)1.22 (0.69-2.15)TOTAL4889272 (5.6%)Change in size of >5mmNo change2783118 (4.2%)1downsized1953115 (5.9%)1.39 (1.08-1.78)upsized139580 (5.7%)1.35 (1.03-1.78)unknown23814 (5.9%)1.39 (0.81-2.38)TOTAL6369327 (5.1%) Citation Format: Cliona Clare Kirwan, Bridget Hilton, Karen Clements, Hilary Stobart, Matthew Wallis, Senthurun Mylvaganam, Elena Provenzano, Anthony Maxwell, Nisha Sharma, Abeer Shaaban, David Dodwell, Joanne Dulson-Cox, Elinor Sawyer, Olive Kearins, Samantha Brace-McDonnell, Sarah Pinder, Alastair M Thompson. Predictors of inaccurate pre-operative size assessment of screen detected DCIS and impact on recurrence rates [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 P1-22-01.

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

Background The variable natural history of ductal carcinoma in situ (DCIS) is poorly understood. The aim of this retrospective cohort study was to determine the outcomes of women who were diagnosed through the English National Health Service Breast Screening Programme (NHS BSP) and had no surgery for screen-detected DCIS. Method English NHS BSP databases were searched for women diagnosed with DCIS without invasive cancer on needle biopsy between 1 April 2001 and 31 March 2018 inclusive, who had no record of surgery within 6 months of diagnosis. These were cross-referenced with cancer registry data for further treatment, event information and mortality records. Details of potentially eligible women were sent to the relevant breast screening units for verification and for completion of data forms detailing clinical, radiological and pathological findings, non-surgical treatment, subsequent clinical course and outcomes. Results Data for 311 eligible women (median age 62 years) were included, with median follow-up (primary DCIS diagnosis to either surgery, development of invasive disease, death or last known to be alive) of 4.1 years (range 0.5 to 17.4 years). The median age at diagnosis was 64 years (range 47 to 90 years). Sixty (19%) women developed invasive breast cancer, 56 ipsilateral and 4 contralateral. Twenty-two women (7%) underwent surgery for DCIS (>6 months after diagnosis) and 86 (28%) died of other causes. Women with high or intermediate grade DCIS were significantly more likely to develop ipsilateral invasive breast cancer (iIBC) than those with low grade DCIS. 28/123 (23%) with high grade DCIS, 21/105 (20%) with intermediate grade DCIS, 5/76 (7%) with low grade DCIS and 2/7 (29%) with an unknown grade of DCIS developed iIBC. Ipsilateral invasion risk increased approximately linearly with time for at least 10 years. Women who developed iIBC were significantly younger than those who did not. This was driven primarily by a strong association among those with high grade DCIS. There was no significant difference in age between those with intermediate and low grade DCIS respectively who did or did not develop iIBC. The median baseline size of DCIS in women who developed iIBC was higher than in women who did not develop iIBC, both overall and in each of the three grade categories (median sizes - high grade 38 mm vs 29 mm, p=0.19; intermediate grade 35 mm vs 18 mm, p=0.31; low grade 18 mm vs 15 mm, p=0.38). This reached statistical significance for all grades combined: 37 mm (range 3-95) v 20 mm (range 3-200), p=0.02. Of the 262 women with a known microinvasion status, 8/25 (32%) with definite or possible microinvasion were subsequently diagnosed with ipsilateral invasive cancer compared to 38/237 (16%) without microinvasion (p=0.027). There was no significant association on univariable analysis between risk of iIBC and microcalcification as the predominant radiological feature (iIBC and microcalcification 47/258 vs iIBC and other radiological feature 7/46; p=0.83), the presence of histological necrosis (iIBC and necrosis, 14/89 vs iIBC and no necrosis, 31/157; p=0.49) or the use of ET (iIBC and ET 11/67 vs iIBC and no ET 45/244; p=0.86). Of the 51 invasive cancers that developed with a known grade, 46 (90%) were grade 2 or 3. Conclusion The findings suggest that women diagnosed with high or intermediate grade DCIS and those with microinvasion should continue to be offered surgery. For those with low grade DCIS there is a need for shared decision-making in the choice of surgery or active surveillance based on a discussion of the risks and benefits of the options as currently understood, and in the light of the low reproducibility of DCIS grading. Citation Format: Karen Clements, Anthony Maxwell, Bridget Hilton, Matthew Wallis, Cliona Kirwan, Hilary Stobart, Elena Provenzano, Nisha Sharma, Janet Litherland, Abeer Shaaban, David Dodwell, Joanne Dulson-Cox, Elinor Sawyer, Senthurun Mylvaganam, Olive Kearins, Samantha Brace-McDonnell, Sarah Pinder, Alastair Thompson. A longitudinal cohort study of outcomes in 311 women with unresected ductal carcinoma in situ detected through the English breast screening programme [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 P1-22-06.

Background/objectives The natural history of microinvasive carcinoma of the breast (one or more foci of invasion of 1mm or less) and its optimal management remain controversial. We analysed the frequency and outcome of patients with DCIS plus microinvasion within a large prospective cohort of screen-detected DCIS. Methods Patients with screen-detected DCIS diagnosed between 2003 and 2012 with or without microinvasion in the final surgical specimen were identified from the UK Sloane Project database. Comprehensive imaging, surgical, pathology, oncology and subsequent outcome data were collected with a median follow-up of 9 years. Results Among 11285 DCIS patients diagnosed in the UK, microinvasion was reported in 521 (4.6%). The frequency of reported microinvasion varied considerably among screening units (0-25%) but overall decreased from 7% in 2003/04 to 3% in 2011/12.As reported elsewhere, microinvasion was significantly associated with high grade DCIS (5.9% of 7182 cases) compared to 2.9% of intermediate grade and <1% of low grade DCIS (p<0.001, Chi square test). Microinvasion was associated with larger DCIS size (p<0.001) 2.2% of DCIS <10mm, 3.9% of DCIS 10-20mm, 5.8% of DCIS 20-30mm, 5.2% of DCIS 30-40mm and 8.0% of DCIS >40mm had microinvasive foci reported. Microinvasion was also associated with the presence of comedo necrosis (p<0.001), and solid (p<0.001), cribriform (p<0.001) or flat (p=0.03) DCIS architecture.Microinvasion was identified more frequently in patients who underwent mastectomy (6.9%) than in those who had breast conserving surgery (BCS) (3.6%; p<0.001). Axillary nodal surgery was more commonly performed for microinvasion (60.4% compared to 30.3%) including for patients undergoing BCS (43.4% vs 8.5% of all patients with BCS; p<0.001). The rate of nodal metastasis was, however, low and not statistically significantly different between those with and without microinvasion (0.4% and 0.1% respectively, p=0.27).Patients with microinvasion who underwent BCS were also more likely to receive radiotherapy (p<0.001). There was no significant association between the presence or absence of microinvasion with margin status or width. Subsequent events data for England showed that microinvasion was associated with a low rate of ipsilateral subsequent events, with 2.3% of patients having recurrent DCIS and 4.2% developing invasive carcinoma. This was not statistically significantly different from DCIS without microinvasion. All subsequent ipsilateral DCIS events in patients with microinvasion were of high grade. The majority (71.4%) of subsequent ipsilateral invasive carcinomas were of grade 3 compared with only 30.4% of grade 3 carcinomas in patients with DCIS without microinvasion (p=0.02). Breast cancer mortality was significantly higher in women whose tumours showed microinvasion (2.1%) compared with those without it (0.8%; p=0.005). Conclusions Microinvasion was most commonly identified within high-grade DCIS and in larger DCIS lesions, and was associated with comedo necrosis. Its pathological reporting decreased over a 10-year period, but there was significant variation between departments, which requires further evaluation. Patients with DCIS plus microinvasion were more likely to have undergone mastectomy, axillary node surgery and to receive radiotherapy after BCS. Microinvasive breast carcinoma was associated with a low rate of subsequent in situ/invasive events and had a good prognosis but, nevertheless, a higher breast cancer mortality than DCIS without microinvasion. Citation Format: Abeer M Shaaban, Bridget Hilton, Karen Clements, David Dodwell, Nisha Sharma, Cliona Kirwan, Elinor Sawyer, Anthony Maxwell, Matthew Wallis, Hilary Stobart, Senthurun Mylvaganam, Janet.Litherland Litherland, Samantha Brace-Mcdonnell, Joanne Dulson-Cox, Olive Kearins, Elena Provenzano, Sarah Pinder, Alastair Thompson. The diagnosis and prognosis of ductal carcinoma in situ (DCIS) with microinvasion - Results from the United Kingdom Sloane project [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 P3-12-36.

PURPOSE:There is great promise in breast cancer risk stratification to target screening and prevention. It is unclear whether adding gene panels to other risk tools improves breast cancer risk stratification and adds discriminatory benefit on a population basis.METHODS:In total, 10,025 of 57,902 women aged 46 to 73 years in the Predicting Risk of Cancer at Screening study provided DNA samples. A case-control study was used to evaluate breast cancer risk assessment using polygenic risk scores (PRSs), cancer gene panel (n = 33), mammographic density (density residual [DR]), and risk factors collected using a self-completed 2-page questionnaire (Tyrer-Cuzick [TC] model version 8). In total, 525 cases and 1410 controls underwent gene panel testing and PRS calculation (18, 143, and/or 313 single-nucleotide polymorphisms [SNPs]).RESULTS:Actionable pathogenic variants (PGVs) in BRCA1/2 were found in 1.7% of cases and 0.55% of controls, and overall PGVs were found in 6.1% of cases and 1.3% of controls. A combined assessment of TC8-DR-SNP313 and gene panel provided the best risk stratification with 26.1% of controls and 9.7% of cases identified at <1.4% 10-year risk and 9.01% of controls and 23.3% of cases at ≥8% 10-year risk. Because actionable PGVs were uncommon, discrimination was identical with/without gene panel (with/without: area under the curve = 0.67, 95% CI = 0.64-0.70). Only 7 of 17 PGVs in cases resulted in actionable risk category change. Extended case (n = 644)-control (n = 1779) series with TC8-DR-SNP143 identified 18.9% of controls and only 6.4% of stage 2+ cases at <1.4% 10-year risk and 20.7% of controls and 47.9% of stage 2+ cases at ≥5% 10-year risk.CONCLUSION:Further studies and economic analysis will determine whether adding panels to PRS is a cost-effective strategy for risk stratification.

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

Background and aim: The natural history of ductal carcinoma in situ (DCIS) is poorly understood. The aim of this cohort study was to determine the outcomes of women who had no surgery for screen-detected DCIS in the 6 months following diagnosis. Methods: English breast screening databases were retrospectively searched for women diagnosed with DCIS without invasive cancer at screening and who had no record of surgery within 6 months of diagnosis. These were cross-referenced with cancer registry data. Details of the potentially eligible women were sent to the relevant breast screening units for verification and for completion of data forms detailing clinical, radiological and pathological findings, non-surgical treatment and subsequent clinical course. Results: Data for 311 eligible women (median age 62 years) were available. 60 women developed invasive cancer, 56 ipsilateral and 4 contralateral. Ipsilateral invasion risk increased approximately linearly with time for at least 10 years. The 10-year cumulative risk of ipsilateral invasion was 9% (95% CI 4 -21%), 39% (24-58%) and 36% (24-50%) for low, intermediate and high grade DCIS respectively and was higher in younger women, in those with larger DCIS lesions and in those with microinvasion. Most invasive cancers that developed were grade 2 or 3. Conclusion: The findings suggest that active surveillance may be a reasonable alternative to surgery in patients with low grade DCIS but that women with intermediate or high grade disease should continue to be offered surgery. This highlights the importance of reproducible grading of DCIS to ensure patients receive appropriate treatment. (c) 2022 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Purpose The introduction of breast screening in the UK led to an increase in the detection of non-invasive breast neoplasia, predominantly ductal carcinoma in situ (DCIS), a non-obligatory precursor of invasive breast cancer. The Sloane Project, a UK prospective cohort study of screen-detected non-invasive breast neoplasia, commenced in 2003 to evaluate the radiological assessment, surgical management, pathology, adjuvant therapy and outcomes for non-invasive breast neoplasia. Long-term follow-up and accurate data collection are essential to examine the clinical impact. Here, we describe the establishment, development and analytical processes for this large UK cohort study.Participants Women diagnosed with non-invasive breast neoplasia via the UK National Health Service Breast Screening Programme (NHSBSP) from 01 April 2003 are eligible, with a minimum age of 46 years. Diagnostic, therapeutic and follow-up data collected via proformas, complement date and cause of death from national data sources. Accrual for patients with DCIS ceased in 2012 but is ongoing for patients with epithelial atypia/in situ neoplasia, while follow-up for all continues long term.Findings to date To date, patients within the Sloane cohort comprise one-third of those diagnosed with DCIS within the NHSBSP and are representative of UK practice. DCIS has a variable outcome and confirms the need for longer-term follow-up for screen-detected DCIS. However, the radiology and pathology features of DCIS can be used to inform patient management. We demonstrate validation of follow-up information collected from national datasets against traditional, manual methods.Future plans Conclusions derived from the Sloane Project are generalisable to women in the UK with screen-detected DCIS. The follow-up methodology may be extended to other UK cohort studies and routine clinical follow-up. Data from English patients entered into the Sloane Project are available on request to researchers under data sharing agreement. Annual follow-up data collection will continue for a minimum of 20 years.

Introduction Obesity and overweight are strong potentially modifiable risk factors for postmenopausal breast and endometrial cancer. Bariatric surgery can achieve considerable weight loss and risk reduction of weight-related cancer but is unlikely to be a feasible cancer prevention strategy. Total diet replacement (TDR) can also lead to significant weight reduction. This study aims to examine the cellular and molecular changes in breast and endometrial tissue in high-risk women following TDR-induced weight loss, as well as longer-term adherence to a 12-month TDR weight loss intervention.Methods and analysis PROBE-TDR (PRevention Of Breast and Endometrial cancer using Total Diet Replacement) is a prospective, non-blinded, randomised controlled trial of 47 women at increased risk of breast and/or endometrial cancer. Randomisation is 2:1 to either an immediate 12-month TDR weight loss programme (n=31) or delayed dietary intervention (control) (n=16). The TDR programme includes an initial 12-week period of TDR (850 kcal/day) followed by a 40-week food-based diet, based on the nutritional principles of a Mediterranean diet, as either continued weight loss (~1500 kcal/day) or weight loss maintenance (~2000 kcal/day). Menstrual phase-matched biopsies of the breast and endometrium will be assessed at baseline and at the end of the 12-week TDR in the immediate diet group, compared with women randomised to the control group following their usual diet. The trial will also assess longer-term adherence and weight loss success across the 12-month programme in both the immediate and control groups.Ethics and dissemination Approval for this study has been obtained from the Health Research Authority and Health and Care Research Wales (approval 20/NW/0095). Results will be published in peer-reviewed journals, presented at conferences and shared with trial participants.Trial registration number International Standard Randomised Controlled Trial Number Registry (ISRCTN15358157).

Background The luminal progenitor (LP) population in the normal breast is under the control of paracrine progesterone signalling and likely represents the cell of origin of estrogen receptor negative (ER-) BC. Exogenous progestins, as contraception or menopausal hormone replacement therapy (HRT), increase the risk of ER- and ER+ BC. We sought to examine the effect antagonism of progesterone signalling on the tissue composition and cellular hierarchy of normal human breast and thus the potential for progesterone receptor antagonism in breast cancer prevention. Methods BC-APPS1 is a single arm phase 2 pilot study in which premenopausal women at increased familial BC risk underwent vacuum assisted biopsy (VAB) in the luteal phase of the menstrual cycle prior to commencing a 12 week course of the selective progesterone receptor modulator (SPRM) ulipristal acetate (UA; 5mg daily). VAB was repeated in the final week of therapy. The primary endpoint of BC-APPS1 was change in epithelial Ki67 assessed by immunohistochemistry. Secondary endpoints included toxicity and additional tissue endpoints including immunofluorescence (IF) staining of LP markers, 2D mixed luminal/basal and 3D (mammosphere) colony formation assays, LP fraction by FACS (CD49f+/EPCAM+ cells), single cell and bulk RNAseq, epithelium/stromal laser capture microdissection-based proteomics and tissue stiffness analyses. Baseline samples were compared to a historic cohort of normal risk (n=25) and high risk (n=41) samples for IF analyses. Results Between 03/2016 and 03/2019 26 women were recruited to BC-APPS1 and 24 underwent paired biopsies. The trial met its primary endpoint with a significant reduction in median Ki67 between baseline (4.89%; IQR 4.36-10.42) and 12 weeks (2.41%; IQR 1.57-3.24; p<0.0001). Study procedures were well tolerated with minimal drug toxicity (all G1/2). 2 women discontinued UA due to anxiety: 1 drug induced and 1 induced following development of a small haematoma following VAB1. FACS analysis (n=17) demonstrated significant reduction in the LP proportion with UA treatment (median baseline 44.7% IQR 28.1-55.2 and 12 weeks 25.4% IQR 17.2-37.8; p<0.01). Breast tissue from high-risk women had increased expression of PR+ (10.8% vs 4.5%; p<0.01) and dual Sox9+Ki67+ cells (4.8% vs 0.8%, p<0.01). The Sox9+Ki67+ population reduced significantly with UA therapy in BC-APPS1 (4.4% vs 1.3%, p<0.05). In functional analyses both mammosphere and mixed luminal/basal colony formation reduced with UA treatment and single cell RNAseq (n=8 pairs) and epithelium/stromal laser capture microdissection-based proteomics (n=5 pairs) identified stromal components and remodelling as key pathways perturbed by UA treatment. Tissue stiffness, assessed by atomic force microscopy and previously shown to be positively associated with %mammographic density, was significantly reduced with UA treatment. Conclusions: High risk women have increased surrogate markers of BC risk including proliferating luminal progenitor cells which can be reduced by short term SPRM treatment with UA. Treatment is generally well tolerated and SPRM therapy is an attractive candidate for BC prevention. Longer term studies are warranted and stromal remodelling and breast tissue stiffness data suggest that mammographic density should be investigated as a potential surrogate biomarker of activity. Citation Format: Sacha Howell, Alice Greenhalgh, Robert Pedley, Suad Alghamdi, Amanda Caruso, Mujtaba Ansari, Tiago Moreira, Sue Astlet, Anthony Maxwell, Yit Lim, Hayley Brookes, Faiza Idries, Anthony Howell, D Gareth Evans, Michael Sherratt, Andrew Gilmore, Elaine Harkness, Walid Khaled, Alecia-Jane Twigger, Matt Roberts, Robert Clarke, Bruno Simoes. Results from the breast cancer - anti progestin prevention study 1 (BC-APPS1) trial - a novel approach in breast cancer prevention [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 P1-10-01.

Background: Breast cancer is often detected at later stages, indicating a significant need for additional screening methods. Mammography has limitations in breast cancer detection, for example young age, mammographic high density (categories C and D), small tumors and breast cancer classifications such as invasive lobular carcinomas. Syantra DX Breast Cancer is a new whole blood test that detects the presence of breast cancer by evaluating the expression of 12 novel genes through a custom qPCR process with proprietary software that includes machine learning-derived algorithms. Methodology: Whole blood samples (2.5 ml) were collected and analyzed with Syantra DX Breast Cancer as part of the ongoing IDBC prospective international clinical study (NCT04495244). The study is designed to demonstrate test performance in 2,100 participants. Women aged 30 to 75 years with a normal screening mammogram or physical exam (for the controls), or a BI-RADs 3 – 5 score on a screening mammogram were enrolled. A total of 1,107 participants (240 asymptomatic breast cancer, 867 non-cancer) were recruited and evaluated. All blood samples were collected pre-biopsy. For this interim analysis, 383 samples (132 cancer, 251 non-cancer) were used for machine learning-based model development and initial testing using a cross-validation approach. A set of 724 samples, with 695 evaluable samples (blind test set: 96 cancer, 599 non-cancer) were used for independent testing. All samples in the test set were randomized and blinded by the Alberta Cancer Research Biobank. Clinical performance metrics are reported for the blind test set with 99.5% confidence intervals (CI) computed through an exact binomial test. Results: In the blind test set, 59% of breast cancer subjects were Stage 1 and 25% stage 2. For molecular subtype, 75% were hormone receptor positive, 10% were HER2 positive, and 5% were triple negative. For subjects with invasive breast cancer, the average tumor size was 29 mm (CI: 19 – 38 mm). For the entire test set, Syantra DX Breast Cancer demonstrated an inferred accuracy of 92.2% (CI: 88.9% – 94.6%) with a specificity of 94.3% (CI: 91.0% – 96.4%) and sensitivity of 79.2% (CI: 65.5% – 88.4%) for cancer detection (Table 1). Higher performance was observed in the group of study women under 50 with an inferred specificity of 99.0% and a sensitivity of 91.7% (Table 1). Evaluation of performance in women with extremely dense breast tissue (category D; n=52) revealed an inferred specificity of 95.3% (CI: 77.4% – 99.2%) and sensitivity of 88.9% (CI: 42.6% – 98.9%). This analysis also showed that small tumors less than 10 mm (n=19) were detected by the test, with a sensitivity of 68.4%. Conclusions: Interim data from the IDBC study demonstrated the clinical utility of the Syantra DX Breast Cancer test for use in early screening. Syantra DX Breast Cancer is the first blood test to show strong performance for women under 50, as well for those with very high breast density, and therefore provides a promising screening option to supplement current imaging approaches. Table 1. Performance Metrics of the Syantra DX Breast Cancer TestAgeNumber of participants (n)AccuracySpecificitySensitivity< 50Normal: 19298.5% (CI: 93.8% – 99.7%)99.0% (CI: 94.2% – 99.8%)91.7% (CI: 51.1% – 99.1%)Cancer: 12≥ 50Normal: 40789.6% (CI: 85.1% – 92.9%)92.1% (CI: 87.5% – 95.1%)77.4% (CI: 62.5% – 87.5%)Cancer: 84Entire cohortNormal: 59992.2% (CI: 88.9% – 94.6%)94.3% (CI: 91.0% – 96.4%)79.2% (CI: 65.5% – 88.4%)Cancer: 96 Citation Format: Nigel Bundred, Kenneth Fuh, Nasimeh Asgarian, Shannon Brown, Danielle Simonot, Xiuling Wang, Robert Shepherd, May Lynn Quan, Bobbi Jo Docktor, Anthony Maxwell, Cliona Kirwan, Alan Hollingsworth (retired), Donald Morris, Kristina Rinker. A whole blood assay to identify breast cancer: Interim analysis of the international identify breast cancer (IDBC) study evidence supporting the Syantra DX breast cancer test [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 P2-01-02.

Background Wire localization is historically the most common method for guiding excision of non-palpable breast lesions, but there are limitations to the technique. Newer technologies such as magnetic seeds may allow some of these challenges to be overcome. The aim was to compare safety and effectiveness of wire and magnetic seed localization techniques. Methods Women undergoing standard wire or magnetic seed localization for non-palpable lesions between August 2018 and August 2020 were recruited prospectively to this IDEAL stage 2a/2b platform cohort study. The primary outcome was effectiveness defined as accurate localization and removal of the index lesion. Secondary endpoints included safety, specimen weight and reoperation rate for positive margins. Results Data were accrued from 2300 patients in 35 units; 2116 having unifocal, unilateral breast lesion localization. Identification of the index lesion in magnetic-seed-guided (946 patients) and wire-guided excisions (1170 patients) was 99.8 versus 99.1 per cent (P = 0.048). There was no difference in overall complication rate. For a subset of patients having a single lumpectomy only for lesions less than 50 mm (1746 patients), there was no difference in median closest margin (2 mm versus 2 mm, P = 0.342), re-excision rate (12 versus 13 per cent, P = 0.574) and specimen weight in relation to lesion size (0.15 g/mm(2)versus 0.138 g/mm(2), P = 0.453). Conclusion Magnetic seed localization demonstrated similar safety and effectiveness to those of wire localization. This study has established a robust platform for the comparative evaluation of new localization devices.