UK NHS Breast Screening Programme Research Articles

Abstract PS01-10: Surgical margins in breast conserving surgery (BCS) for ductal carcinoma in-situ (DCIS) and clinical outcomes: significant associations with increased recurrence and overall survival

Abstract Background: Optimal surgical margin in breast conserving surgery (BCS) for DCIS are not established, largely due to an absence of accurate margin data. A margin width of 2mm was adopted by the American College of Surgeons (ACS). The UK Association of Breast Surgery (ABS) recommended a 1mm margin. Conducting a randomized controlled trial to answer this question is unfeasible; therefore we used retrospective histological margin data from available datasets to assess whether there is an association between margin width and time to recurrence (TTR). Methods: Patients were included if aged >18 years with a new diagnosis of DCIS alone, between 2003-2014, within UK NHS Breast Screening Programme (BSP). Primary treatment included BCS and a minimum histological excision margin width recorded. Exclusion criteria included: i) prior history of DCIS; ii) prior history of invasive cancer or its diagnosis within 3 months of initial surgical treatment for DCIS. Data was extracted from English Cancer Registries (CR), ABS and Sloane audits. TTR was defined as time from diagnosis to local or distant recurrence. Cox regression was used to compare TTR by surgical margin width utilising a range of thresholds, with focus on < 1mm vs ≥1mm; < 2mm vs ≥2mm and ≥1- < 2mm vs ≥2mm. Patients with 0mm margin or where categorized as “clear/not stated” were excluded from these analyses. Models were adjusted for age group, DCIS grade and size, ER status, number of BCSs, radiotherapy (RT) received, diagnosis year and CR centre. Overall survival (OS) was a secondary endpoint. Results: 17,260 patients diagnosed with DCIS having BCS as definitive surgery were identified between 2003-2014; 679 (5%), 2105 (15%), 1339 (10%) and 9744 (70%) with recorded margins of >0- < 1mm, ≥1- < 2mm, ≥2- < 3mm and ≥3mm, respectively. 10,253 (59%) patients received RT and in 7,007 (41%) RT receipt was unknown. Overall, 14,004 (81%), 3,052 (18%) and 201 (1%) patients had one, two and ≥3 BCSs respectively; there was no significant change in these percentages over time (p=0.2 Cuzick test). Median follow-up time for the cohort was 8.2 years (IQR: 6.1-11.2). 2221 (13%) patients had a subsequent event: 1741/2221 (78%) invasive recurrence and 480/2221 (22%) DCIS alone. The annual event rate over 15 years of follow-up was relatively consistent at 1.2% per annum (pa) for margins ≥2mm versus 1.8% pa for margins < 2mm. A shorter TTR was observed for patients with surgical margins < 1mm vs ≥1mm (adjusted HR=1.30; 95%CI: 1.05-1.62; p=0.02); < 2mm vs ≥2mm (adjusted HR=1.20; 95%CI: 1.06-1.36; p=0.004) and ≥1- < 2mm vs ≥2mm (adjusted HR=1.20; 95%CI: 1.04-1.40; p=0.02). Margins >2mm did not appear to significantly improve TTR (adjusted HR=0.96; 95%CI: 0.85-1.08; p=0.50 for ≥5mm vs ≥2- < 5mm). Models also showed that risk of recurrence increased as the number of BCSs increased (adjusted HR=1.25; 95%CI: 1.10-1.43: p< 0.001 for 2 vs 1 and adjusted HR=2.03; 95%CI: 1.36-3.03: p< 0.001 for 3+ vs 1). In total, 1552 (9%) patients had died. OS appeared reduced for patients with surgical margins < 2mm vs ≥2mm (adjusted HR=1.25 (1.07-1.45); p=0.005) and for ≥1- < 2mm vs ≥2mm (adjusted HR=1.28 (1.07-1.54); p=0.008). Margins <2mm did not appear to significantly improve OS further (adjusted HR=1.06; 95%CI: 0.92-1.21; p=0.43 for ≥5mm vs ≥2- < 5mm). Conclusion: Patients with DCIS with histological margins of < 2mm, adjusted for other clinical factors, have significantly worse TTR and OS rates compared to margins ≥2mm; the increased annual event rate is consistent out to 15 years. More than 1 BCS is also associated with an increased risk of recurrence. These findings are important for the treatment of patients with DCIS. Citation Format: John Robertson, D Mark Sibbering, Sikhuphukile Ndebele-Mahati, Olive Kearins, Sarah Pinder, Ashu Gandhi, Judith Bliss, Lucy Kilburn. Surgical margins in breast conserving surgery (BCS) for ductal carcinoma in-situ (DCIS) and clinical outcomes: significant associations with increased recurrence and overall survival [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 PS01-10.

Abstract PO4-18-09: SMALL: Open Surgery versus Minimally invasive vacuum-Assisted excision for smaLL screen-detected breast cancer – a UK phase III randomised multi-centre trial

Abstract Background: Mammographic screening programmes reduce breast cancer mortality but detect many small good-prognosis tumours which may not progress. Screen-detected cancers are currently treated with standard surgery and adjuvant therapies, with associated morbidities. There is a need to reduce overtreatment of good prognosis tumours and numerous studies are evaluating omission of radiotherapy in low-risk disease. 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 lesions of uncertain malignant potential and benign lesions. SMALL (ISRCTN 12240119) is designed to determine the feasibility of using this approach to treat small invasive tumours detected within the UK NHS Breast Screening Programme. Methods: SMALL is a phase III multicentre randomised trial comparing standard surgery with VAE for screen-detected cancers. Main eligibility criteria are age ≥47 years, unifocal grade 1 tumours with maximum diameter 15mm, strongly ER/PR+ve and HER2-ve, with negative axillary staging. Patients are randomised 2:1 to VAE or surgery, with no axillary surgery in the VAE arm. Completeness of excision is assessed radiologically, and if excision is incomplete, patients undergo 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 6th July 2023, 39 centres are open, with 300 patients randomised from 32 of these, with a randomisation rate of approximately 45%, and a per site recruitment rate of 0.4-0.5 patients/month. Despite the pandemic, SMALL achieved the internal pilot feasibility targets and continues to recruit to the main study, with estimated completion of recruitment in June 2025. 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 and wider feedback is being delivered across sites via recruitment training workshops. Conclusion: Despite pandemic-related challenges, SMALL has excellent recruitment 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 McIntosh, Charlotte Coles, David Dodwell, Kenneth Elder, Jessica Foster, Claire Gaunt, Amanda Kirkham, Iain Lyburn, Sangeetha Paramasivan, Jenna Morgan, Sarah Pinder, 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 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-18-09.

SMALL: Open surgery versus minimally invasive vacuum-assisted excision for small screen-detected breast cancer—A UK phase III randomised multi-centre trial.

TPS625 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 multicentre randomised trial comparing surgery with VAE for screen-detected good prognosis cancers. Eligibility criteria are age ≥47 years, unifocal grade 1 tumours (maximum diameter 15mm), strongly ER/PR+ve and HER2-ve, with negative axillary staging. Patients are randomised 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. Co-primary 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%. 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, 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: At 10th February 2023, 231 patients had been recruited from 32 centres, (~45% of eligible patients), with per site recruitment of 0.4-0.5 patients/month. Based on preliminary QRI findings, a recruitment tips document has been circulated (on discussing SMALL, providing balanced information on treatment options and explaining randomisation), with individual recruiter feedback underway and wider feedback planned shortly. Conclusion: SMALL has excellent recruitment to date, confirming feasibility and acceptability, and is expected to have a global impact on treatment of screen-detected breast cancer. Clinical trial information: ISRCTN12240119 .

Abstract OT3-20-02: SMALL: Open Surgery versus Minimally invasive vacuum-Assisted excision for smaLL screen-detected breast cancer – a UK phase III randomised multi-centre trial

Abstract 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.

SMALL: Open surgery versus minimally invasive vacuum-assisted excision for small screen-detected breast cancers.

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.

Abstract P1-22-01: Predictors of inaccurate pre-operative size assessment of screen detected DCIS and impact on recurrence rates

Abstract 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.

Abstract OT1-06-02: SMALL - Open surgery versus minimally invasive vacuum-assisted excision for small screen detected breast cancer: A phase 3 randomised trial

Abstract 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.

Testing a breast cancer prevention and a multiple disease prevention weight loss programme amongst women within the UK NHS breast screening programme\u2014a randomised feasibility study

BackgroundExcess weight and unhealthy behaviours (e.g. sedentariness, high alcohol) are common amongst women including those attending breast screening. These factors increase the risk of breast cancer and other diseases. We tested the feasibility and acceptability of a weight loss/behaviour change programme framed to reduce breast cancer risk (breast cancer prevention programme, BCPP) compared to one framed to reduce risk of breast cancer, cardiovascular disease (CVD) and diabetes (T2D) (multiple disease prevention programme, MDPP).MethodsWomen aged 47-73 years with overweight or obesity (n = 1356) in the NHS Breast Screening Programme (NHSBSP) were randomised (1:2) to be invited to join a BCPP or a MDPP. The BCPP included personalised information on breast cancer risk and a web and phone weight loss/behaviour change intervention. The MDPP also included an NHS Health Check (lipids, blood pressure, HbA1c and personalised feedback for risk of CVD [QRISK2] and T2D [QDiabetes and HbA1c]). Primary outcomes were uptake and retention and other feasibility outcomes which include intervention fidelity and prevalence of high CVD and T2D risk. Secondary outcomes included change in weight.ResultsThe BCPP and MDPP had comparable rates of uptake: 45/508 (9%) vs. 81/848 (10%) and 12-month retention; 33/45 (73%) vs. 53/81 (65%). Both programmes had a high fidelity of delivery with receipt of mean (95% CI) 90 (88-98% of scheduled calls, 91 (86-95%) of scheduled e-mails and 89 (76-102) website entries per woman over the 12-month period. The MDPP identified 15% of women with a previously unknown 10-year CVD QRISK2 of ≥ 10% and 56% with 10-year Qdiabetes risk of ≥ 10%. Both groups experienced good comparable weight loss: BCPP 26/45 (58%) and MDPP 46/81 (57%) with greater than 5% weight loss at 12 months using baseline observation carried forward imputation.ConclusionsBoth programmes appeared feasible. The MDPP identified previously unknown CVD and T2D risk factors but does not appear to increase engagement with behaviour change beyond a standard BCPP amongst women attending breast screening. A future definitive effectiveness trial of BCPP is supported by acceptable uptake and retention, and good weight loss.Trial registrationISRCTN91372184, registered 28 September 2014.

Radiological audit of interval breast cancers: Estimation of tumour growth rates

IntroductionThis multicentre, retrospective study aimed to establish correlation between estimated tumour volume doubling times (TVDT) from a series of interval breast cancers with their clinicopathological features. The potential impact of delayed diagnosis on prognosis was also explored. Materials and methodsInterval cancers, where screening mammograms demonstrated changes that were retrospectively classified as either uncertain or suspicious, were reviewed from five screening units within the UK NHS Breast Screening Programme (NHSBSP). Data collected included the time interval between screening mammogram and cancer diagnosis, the size of the initial mammographic abnormality and of the subsequent cancer, demographics, mammographic density and tumour biology. We estimated volume doubling times and the estimated change in size and node status, which would have followed if these cancers had been detected at the previous screen. Results306 interval cancers meeting the inclusion criteria were identified. Average time from screening to diagnosis was 644 days (SD 276 days). 19% were diagnosed in the first twelve months, 42% in the subsequent twelve months and 39% thereafter. Overall average estimated TVDT was 167 days (95% CI 151–186). Significant differences were noted with age (p = 0.01), grade (p < 0.001) and ER status (p < 0.001) with women under 60, grade 3 cancers and ER negative cancers having shorter TVDTs. HER2 positive tumours had shorter doubling times than HER2 negative, but this difference was not statistically significant. It was estimated that diagnosing these cancers at the previous screen would have increased ten-year survival from 82% to 86%. ConclusionHigh grade, ER negativity and younger age were associated with shorter durations of TVDT. The role of HER2 status on interval cancer growth rate requires further assessment. It is likely that the delayed diagnosis of interval cancers confers a 4% reduction in ten-year survival.

Effectiveness of a small breast screening programme: 25 year evaluation (25 year breast screening evaluation).

Objective:To evaluate mammography screening quality on the Island of Jersey over a 25-year period from Jan 1990 to end March 2015 from females invited between ages 50 to 75 using a 2 yearly screening interval. Jersey had a population of only around 67,000 at onset, rising to around 100,000 at the end of the 25 years.Methods:An analysis was performed of key routinely collected measures that are important to determining if a screening programme is on course to reduce breast cancer mortality such as uptake, recall rates, screen detected cancer and interval cancer rates. Further supporting indicators including grade, stage and comparative deaths from breast cancer in screen detected and not screen detected females were also assessed.Results:Over the 25-year period 19,768 females were invited to screening and 16,866 attended, giving an uptake of 85.2%. There were 501 screen detected cancers of which 400 were invasive, and 101 DCIS. 125 interval cancers presented outside screening over the 25 years. The annual recall rate over the last 20 years was <6% for prevalent round and 4% for incident round screening. Based on the standardized detection ratio (SDR) and uptake, the estimated reduction in mortality from breast cancer was calculated as 40.2%.Conclusions:Recommended population sizes for breast units range from a quarter to half a million people. For very small units like Jersey serving smaller populations, rigorous quality control is essential to maintain credibility. Despite the small size of the programme evidence shows a similar detection rate to the UK NHS Breast screening programme was achieved. In small programmes careful monitoring of rates of uptake, recall, cancer detection and interval rates are required over adequate time periods together with supporting information to show that small units can achieve national standards and detection rates necessary to reduce breast cancer mortality.Advances in knowledge:Running a small breast cancer screening programme is challenging for quality control. The impact on mortality can be predicted for small screening programmes despite their size. 10-year group survival in screen detected invasive breast cancer >90%. Interval cancers are more advanced than screen detected invasive cancers, so high suspicion is still required in breast symptoms after "normal" screen result. Mortality in lapsed/ceased attenders suggest that extending age range could be beneficial.

Breast screening interval and the characteristics of screen-detected cancers

There is little evidence regarding the optimum interval between mammograms in a population breast cancer screening programme. The UK NHS Breast Screening Programme employs a 3-year interval, unlike other countries which screen more frequently. This study uses variations in the screening interval within a single large UK screening service to examine possible relationships between screening interval and screen-detected cancer characteristics.

Effect of mammographic screening from age 40 years on breast cancer mortality in the UK Age trial at 17 years' follow-up: a randomised controlled trial

Age-specific effects of mammographic screening, and the timing of such effects, are a matter of debate. The results of the UK Age trial, which compared the effect of invitation to annual mammographic screening from age 40 years with commencement of screening at age 50 years on breast cancer mortality, have been reported at 10 years of follow-up and showed no significant difference in mortality between the trial groups. Here, we report the results of the UK Age trial after 17 years of follow-up. Women aged 39-41 from 23 UK NHS Breast Screening Programme units years were randomly assigned by individual randomisation (1:2) to either an intervention group offered annual screening by mammography up to and including the calendar year of their 48th birthday or to a control group receiving usual medical care (invited for screening at age 50 years and every 3 years thereafter). Both groups were stratified by general practice. We compared breast cancer incidence and mortality by time since randomisation. Analyses included all women randomly assigned who could be traced with the National Health Service Central Register and who had not died or emigrated before entry. The primary outcome measures were mortality from breast cancer (defined as deaths with breast cancer coded as the underlying cause of death) and breast cancer incidence, including in-situ, invasive, and total incidence. Because there is an interest in the timing of the mortality effect, we analysed the results in different follow-up periods. This trial is registered, number ISRCTN24647151. Between Oct 14, 1990, and Sept 25, 1997, 160 921 participants were randomly assigned; 53 883 women in the intervention group and 106 953 assigned to usual medical care were included in this analysis. After a median follow-up of 17 years (IQR 16·8-18·8), the rate ratio (RR) for breast cancer mortality was 0·88 (95% CI 0·74-1·04) from tumours diagnosed during the intervention phase. A significant reduction in breast cancer mortality was noted in the intervention group compared with the control group in the first 10 years after diagnosis (RR 0·75, 0·58-0·97) but not thereafter (RR 1·02, 0·80-1·30) from tumours diagnosed during the intervention phase. The overall breast cancer incidence during 17 year follow-up was similar between the intervention group and the control group (RR 0·98, 0·93-1·04). Our results support an early reduction in mortality from breast cancer with annual mammography screening in women aged 40-49 years. Further data are needed to fully understand long-term effects. Cumulative incidence figures suggest at worst a small amount of overdiagnosis. National Institute for Health Research Health Technology Assessment programme and the American Cancer Society. Past funding was received from the Medical Research Council, Cancer Research UK, the UK Department of Health, and the US National Cancer Institute.

The TOMMY trial: a comparison of TOMosynthesis with digital MammographY in the UK NHS Breast Screening Programme--a multicentre retrospective reading study comparing the diagnostic performance of digital breast tomosynthesis and digital mammography with digital mammography alone.

Digital breast tomosynthesis (DBT) is a three-dimensional mammography technique with the potential to improve accuracy by improving differentiation between malignant and non-malignant lesions. The objectives of the study were to compare the diagnostic accuracy of DBT in conjunction with two-dimensional (2D) mammography or synthetic 2D mammography, against standard 2D mammography and to determine if DBT improves the accuracy of detection of different types of lesions. Women (aged 47-73 years) recalled for further assessment after routine breast screening and women (aged 40-49 years) with moderate/high of risk of developing breast cancer attending annual mammography screening were recruited after giving written informed consent. All participants underwent a two-view 2D mammography of both breasts and two-view DBT imaging. Image-processing software generated a synthetic 2D mammogram from the DBT data sets. In an independent blinded retrospective study, readers reviewed (1) 2D or (2) 2D + DBT or (3) synthetic 2D + DBT images for each case without access to original screening mammograms or prior examinations. Sensitivities and specificities were calculated for each reading arm and by subgroup analyses. Data were available for 7060 subjects comprising 6020 (1158 cancers) assessment cases and 1040 (two cancers) family history screening cases. Overall sensitivity was 87% [95% confidence interval (CI) 85% to 89%] for 2D only, 89% (95% CI 87% to 91%) for 2D + DBT and 88% (95% CI 86% to 90%) for synthetic 2D + DBT. The difference in sensitivity between 2D and 2D + DBT was of borderline significance (p = 0.07) and for synthetic 2D + DBT there was no significant difference (p = 0.6). Specificity was 58% (95% CI 56% to 60%) for 2D, 69% (95% CI 67% to 71%) for 2D + DBT and 71% (95% CI 69% to 73%) for synthetic 2D + DBT. Specificity was significantly higher in both DBT reading arms for all subgroups of age, density and dominant radiological feature (p < 0.001 all cases). In all reading arms, specificity tended to be lower for microcalcifications and higher for distortion/asymmetry. Comparing 2D + DBT to 2D alone, sensitivity was significantly higher: 93% versus 86% (p < 0.001) for invasive tumours of size 11-20 mm. Similarly, for breast density 50% or more, sensitivities were 93% versus 86% (p = 0.03); for grade 2 invasive tumours, sensitivities were 91% versus 87% (p = 0.01); where the dominant radiological feature was a mass, sensitivities were 92% and 89% (p = 0.04) For synthetic 2D + DBT, there was significantly (p = 0.006) higher sensitivity than 2D alone in invasive cancers of size 11-20 mm, with a sensitivity of 91%. The specificity of DBT and 2D was better than 2D alone but there was only marginal improvement in sensitivity. The performance of synthetic 2D appeared to be comparable to standard 2D. If these results were observed with screening cases, DBT and 2D mammography could benefit to the screening programme by reducing the number of women recalled unnecessarily, especially if a synthetic 2D mammogram were used to minimise radiation exposure. Further research is required into the feasibility of implementing DBT in a screening setting, prognostic modelling on outcomes and mortality, and comparison of 2D and synthetic 2D for different lesion types. Current Controlled Trials ISRCTN73467396. This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 19, No. 4. See the HTA programme website for further project information.

Correlation between Fine-Needle Aspiration Cytology and Histology for Palpable Breast Masses in a Nigerian Tertiary Health Institution.

Background. Management of breast lumps can be challenging in resource poor settings. Fine-needle aspiration cytology (FNAC) especially when used with cell block can help improve affordability for the patients. Objective. To determine the diagnostic accuracy of FNAC of palpable breast lesions within a 5-year period. Methods. The findings obtained from FNAC of palpable breast lumps seen at the FNAC clinic of our department from January 2007 to December 2011 were retrieved and correlated with findings on histology of excisional biopsies. Results. A total of 1790 patients had FNAC of breast lumps during the 5-year period; 436 of them subsequently had biopsies. Our results compare favourably with the measures of test performance of the UK NHS Breast Screening Programme shown in brackets: absolute sensitivity 95.4% (>70%), complete sensitivity 99.2% (>90%), full specificity 88.9% (>65%), positive predictive value 99.6% (>99%), false-negative rate 0.8% (<4%), false-positive rate 0.4% (<0.5%), inadequate rate 3.2% (<15%), and suspicious rate 10.2% (<15%). Conclusion. Breast FNACs compare very well with histology of excisional biopsies and in experienced hands are extremely useful in the management of breast lumps. Further studies assessing the diagnostic accuracy of FNAC and cell blocks in our setting are recommended.

Variations in the management of the axilla in screen-detected Ductal Carcinoma In Situ: Evidence from the UK NHS Breast Screening Programme audit of screen detected DCIS

The diagnosis and surgical management of screen-detected Ductal Carcinoma In Situ (DCIS) remains controversial including a range of axillary approaches and consequent morbidity. This study examined the management of the axilla in all patients with DCIS presenting through the United Kingdom National Health Service Breast Screening Programme (UK NHS BSP).Retrospective analysis of the UK NHS BSP identified 26,696 women initially diagnosed with DCIS over the 8 years 1 April 2003–31 March 2011. The final breast pathology of these women was upgraded to invasive ductal cancer in 5564 (20.8%) women or micro-invasive cancer in 1031 (3.9%) women. At first operation, 5290 (26.3%) of the 20,094 women who had a final post-operative diagnosis of DCIS only underwent axillary surgery (72.4% at the time of mastectomy, 23.8% breast conservation surgery, 3.8% axillary surgery alone). Performance of axillary surgery reflected increasing tumour size, micro-invasion or increasing nuclear grade for the final diagnosis of DCIS.More extensive nodal surgery was performed in those undergoing mastectomy; 10.8% of women had more than 8 nodes removed. Overall, 12.0% of women with invasive cancer, 1.7% with micro-invasion, and 0.2% with DCIS alone, were ultimately node positive.Improved pre-operative sampling of DCIS, axillary assessment by ultrasound with needle biopsy for suspected metastases, risk stratification for sentinel node biopsy (for high grade or extensive DCIS) and avoiding axillary clearance for a pre-operative diagnosis of DCIS alone should reduce unnecessary axillary surgery. Standards using such criteria for axillary surgery in screen-detected DCIS should be integrated into the NHS BSP.

TOMMY Trial (a comparison of tomosynthesis with digital mammography in the UK NHS breast screening programme) setting up a multicentre imaging trial

Digital breast tomosynthesis (DBT) has the potential to improve the accuracy of standard digital mammography (DM) [1]. The TOMMY Trial is a multicentre, multireader, retrospective matched comparison of the diagnostic performance of DBT and DM.

A randomised controlled trial of an intervention to promote early presentation of breast cancer in older women: effect on breast cancer awareness.

Background:There is virtually no evidence for the effectiveness of interventions to promote early presentation in breast cancer. We aimed to test the efficacy of an intervention to equip older women with the knowledge, skills, confidence and motivation to detect symptoms and seek help promptly, with the aim of promoting early presentation with breast cancer symptoms.Methods:We randomised 867 women aged 67–70 years attending for their final routine appointment on the UK NHS Breast Screening Programme to receive: a scripted 10-min interaction with a radiographer plus a booklet, a booklet alone or usual care. The primary outcome was whether or not a woman was breast cancer aware based on knowledge of breast cancer symptoms and age-related risk, and reported breast checking.Results:At 1 month, the intervention increased the proportion who were breast cancer aware compared with usual care (interaction arm: 32.8% vs 4.1%; odds ratio (OR): 24.0, 95% confidence interval (CI): 7.7–73.7; booklet arm: 12.7% vs 4.1%; OR: 4.4, 95% CI: 1.6–12.0). At 1 year, the effects of the interaction plus booklet, and the booklet, on breast cancer awareness were largely sustained, although the interaction plus booklet remained much more effective.Conclusions:An intervention to equip older women with the knowledge, skills, confidence and motivation to detect breast cancer symptoms and seek help promptly increases breast cancer awareness at 1 year. Future research will evaluate whether the intervention promotes early presentation and reduces breast cancer mortality.

A randomised controlled trial of an intervention to promote early presentation of breast cancer in older women: effect on breast cancer awareness

AbstractThere is virtually no evidence for the effectiveness of interventions to promote early presentation in breast cancer. We tested the efficacy of an intervention to equip older women with the knowledge, skills, confidence and motivation to detect symptoms and seek help promptly, with the aim of promoting early presentation with breast cancer symptoms. We randomised 867 women aged 67 to 70 attending for their final routine appointment on the UK NHS Breast Screening Programme to receive: a scripted ten-minute interaction with a radiographer plus a booklet; a booklet alone; or usual care. The primary outcome was whether or not a woman was breast cancer aware based on knowledge of breast cancer symptoms and age-related risk; and reported breast checking. At one month, the intervention increased the proportion who were breast cancer aware compared with usual care (interaction arm: 32.8% versus 4.1%; odds ratio 24.0, 95% confidence interval 7.7 to 73.7; booklet arm: 12.7% versus 4.1%; odds ratio 4.4, 95% confidence interval 1.6 to 12.0). At one year, the effects of the interaction plus booklet, and the booklet, on breast cancer awareness were largely sustained, although the interaction plus booklet remained much more effective. Future research will evaluate whether the intervention promotes early presentation and reduces breast cancer mortality.

Mammography—oncogenecity at low doses

Controversy exists regarding the biological effectiveness of low energyx-rays used for mammography breast screening. Recent radiobiology studieshave provided compelling evidence that these low energy x-rays may be4.42 ± 2.02 times more effective in causing mutational damage than higher energy x-rays.These data include a study involving in vitro irradiation of a human cell line using amammography x-ray source and a high energy source which matches the spectrum ofradiation observed in survivors from the Hiroshima atomic bomb. Current radiation riskestimates rely heavily on data from the atomic bomb survivors, and a direct comparisonbetween the diagnostic energies used in the UK breast screening programme and those usedfor risk estimates can now be made. Evidence highlighting the increase in relative biologicaleffectiveness (RBE) of mammography x-rays to a range of x-ray energies implies that therisks of radiation-induced breast cancers for mammography x-rays are potentiallyunderestimated by a factor of four. A pooled analysis of three measurementsgives a maximal RBE (for malignant transformation of human cells in vitro) of4.02 ± 0.72 for 29 kVp (peak accelerating voltage) x-rays compared to high energy electrons and higherenergy x-rays.For the majority of women in the UK NHS breast screening programme, it is shown thatthe benefit safely exceeds the risk of possible cancer induction even when this higherbiological effectiveness factor is applied. The risk/benefit analysis, however, implies theneed for caution for women screened under the age of 50, and particularly for those with afamily history (and therefore a likely genetic susceptibility) of breast cancer.In vitro radiobiological data are generally acquired at high doses, and there are differentextrapolation mechanisms to the low doses seen clinically. Recent low dose in vitro datahave indicated a potential suppressive effect at very low dose rates and doses. Whilstmammography is a low dose exposure, it is not a low dose rate examination, andprotraction of dose should not be confused with fractionation. Although there is potentialfor a suppressive effect at low doses, recent epidemiological data, and several internationalradiation risk assessments, continue to promote the linear no-threshold (LNT) model.Finally, recent studies have shown that magnetic resonance imaging (MRI) is moresensitive than mammography in detecting invasive breast cancer in women with a geneticsensitivity. Since an increase in the risk associated with mammographic screening wouldblur the justification of exposure for this high risk subgroup, the use of other (non-ionising)screening modalities is preferable.

Results from the UK NHS breast screening programme 2000–05

To present results from the UK NHS breast screening programme (NHSBSP) for the six-year period from 1 April 1999 to 31 March 2005, and to compare these with targets. Data are collected annually from all UK screening units on standard KC62 return forms. The prevalence of screen-positive cancer (cancer detection rate) has increased at both rounds during the six-year period. At the incident round, cancer detection rates increased by 24%, from 5.4 per 1000 in 2000 to 6.7 per 1000 in 2005 and the detection of small cancers (< or = 10 mm) has increased by 40%. Generally, quality measures in the programme continue to improve. However, while rates of recall at the incident screen decreased from 3.8% in 2000 to 3.6% in 2005, at the prevalent round, in 2005, 22% of units continued to recall more than 10% of women to assessment. The results suggest that the performance of the programme continues to improve. In the future, analysis of data on interval cancers will assist the interpretation of cancer detection rates.