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

Background: 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 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 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:. 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.

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 40mm had microinvasive foci reported. Microinvasion was also associated with the presence of comedo necrosis (p 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.

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 Detection of circulating tumour DNA (ctDNA) in patients (pts) who have completed treatment for early-stage triple negative breast cancer (TNBC) is associated with a very high risk of future relapse. Identifiying those at high risk of subsequent relapse may allow tailoring of further therapy to delay or prevent recurrence. The c-TRAK TN trial assessed the utility of prospective ctDNA surveillance in pts treated for TNBC and the activity of pembrolizumab (P) in pts with ctDNA detected.. Methods c-TRAK TN, a multi-centre phase II trial with integrated prospective screening component, enrolled pts with early-stage TNBC and either residual disease following neoadjuvant chemotherapy, or tumour size >20mm and/or axillary lymph node involvement if adjuvant chemotherapy was given. Tumour tissue was sequenced to identify somatic mutations suitable for tracking using personalised digital PCR ctDNA assays (BioRad QX200). Pts had “active” ctDNA surveillance via blood sample testing every 3 months to 12 months (potential up to 18 months if samples missed due to COVID) during which time if ctDNA was detected (ctDNA+) pts could be randomised 2:1 to P (200mg i.v. q 3 weeks for 1 year) or observation (Obs). Pts and clinicians were blinded to ctDNA+ results unless they were allocated P, when staging scans were done and those free of clinical recurrence started treatment. Following advice from the Independent Data Monitoring Committee, the Obs arm closed on 16/06/2020 with all subsequent ctDNA+ pts allocated P. Following the completion of active ctDNA surveillance, 3-monthly visits continued to 24 months to be analysed retrospectively. The aim was to recruit 150 pts to ctDNA surveillance, assuming 30% would be ctDNA+ within 12 months, allowing ctDNA+ rate to be estimated with a 2-sided 95%CI of +/- 7.3%. Co-primary endpoints are i) rates of ctDNA detection by 12 and 24 months from start of ctDNA surveillance; ii) rates of sustained ctDNA clearance on P defined as absence of detectable ctDNA, or disease recurrence 6 months after starting P.. Results 208 pts were registered between 30/01/18 and 06/12/19, 185 had tumour sequenced, 171 (92.4%) had trackable mutations, and 161 entered ctDNA surveillance. The rate of ctDNA detection by 12 months after start of surveillance was 27.3% (44/161, 95% CI 20.6-34.9). ctDNA+ rates from baseline, 3, 6, 9 and 12 month ctDNA samples were 23/161 (14.3%), 6/115 (5.2%), 6/99 (5.1%), 7/84 (8.3%), and 2/84 (2.4%) respectively. An additional 2 pts were ctDNA+ on COVID extended active surveillance at 15 (1/51, 2%) or 18 months (1/11, 9%). 7 pts relapsed without prior ctDNA detection. 45 pts entered the therapeutic component of the trial (initially 31 to P and 14 to Obs). 1 Obs pt was re-allocated to P. Of pts allocated to P, 72% (23/32) had metastatic disease at time of ctDNA detection on staging scans (75% (12/16) who were ctDNA+ at baseline and 69% (11/16) at other timepoints). 4 pts declined to start P, largely due to COVID concerns. Of the 5 pts who commenced P, at the time of analysis none achieved sustained ctDNA clearance and 4 had recurred. In pts allocated to Obs, median time to recurrence was 4.1 months (95% CI: 3.2-not-defined).. Conclusion The c-TRAK TN trial is to our knowledge the first study to assess the proof-of-principle of whether ctDNA assays have clinical utility in guiding further therapy in TNBC. Relatively few pts commenced P treatment precluding assessment of potential activity. At enrollment, patients had a relatively high of rate of undiagnosed metastatic disease when imaged. Our findings have implications for future trial design, emphasizing the importance of early start of ctDNA testing, and more sensitive and/or more frequent ctDNA testing regimes. Citation Format: Nicholas Turner, Claire Swift, Ben Jenkins, Lucy Kilburn, Maria Coakley, Matthew Beaney, Lisa Fox, Katie Goddard, Isaac Garcia-Murillas, Peter Hall, Catherine Harper-Wynne, Tamas Hickish, Sarah Kernaghan, Iain Macpherson, Alicia Okines, Carlo Palmieri, Sophie Perry, Katrina Randle, Claire Snowdon, Hilary Stobart, Andrew Wardley, Duncan Wheatley, Simon Waters, Matthew Winter, Judith Bliss. Primary results of the cTRAK TN trial: A clinical trial utilising ctDNA mutation tracking to detect minimal residual disease and trigger intervention in patients with moderate and high risk early stage triple negative breast cancer [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 GS3-06.

Background The presence or absence of residual disease following neoadjuvant systemic anti-cancer therapy (neoSACT) for HER2-positive early breast cancer (HER2+ EBC) provides powerful prognostic information that may guide subsequent adjuvant treatment for the individual patient. Pathological complete response (pCR) following neoSACT identifies a population with excellent outcomes in whom the balance of toxicity associated with the current treatment pathway may be disproportionate to the absolute clinical benefit. Aims HER2-RADiCAL seeks to reduce the burden of toxicity and healthcare costs of treating HER2+ EBC by testing the hypothesis that pCR can be used as a functional response biomarker to select patients who can safely receive less intensive therapy, including avoiding anthracyclines, with minimal or no loss of efficacy in the population. Trial design and eligibility criteria HER2-RADiCAL is a response-directed interventional cohort (single-arm) study embedded within a real-world data driven clinical pathway model. Participants will be registered within 6 weeks of completion of breast cancer surgery. The main eligibility criteria include clinical stage T1N1 or T2N0-1 at diagnosis and locally-determined pCR (ypT0/Tis ypN0) after standard of care taxane-based (non-anthracycline) neoadjuvant chemotherapy, trastuzumab and pertuzumab. After registration participants will continue to receive trastuzumab to complete a total of 9 cycles including those (neo-)adjuvant cycles administered prior to study entry. Participants will receive no further pertuzumab nor any adjuvant chemotherapy. Statistical methods The primary clinical endpoint is relapse free interval. Recruitment of 720 participants over 3 years will provide 90% power to exclude an event rate >6.5% at 3 years. Secondary endpoints include relapse-free survival, invasive breast cancer-free survival, invasive disease-free survival, distant recurrence-free interval, breast cancer-free interval, treatment pathway adherence and cost-effectiveness. Real-world data driven clinical pathway model Health economic modelling will compare the protocol-driven study cohort with two comparator pathways: a non-response adapted maximum therapy pathway (the standard clinical pathway prior to the study) and a real-world representative pathway taken from 4-nation UK National Health Service data at the beginning and end of the study. Patient and public involvement Patient advocates have shaped the research by confirming that the main outcomes being evaluated are important to patients and that the interventional cohort design, with power to exclude an absolute risk of recurrence outwith a 2-3% margin of historical control data, is acceptable and preferable to a randomised controlled trial, which would take longer to get answers and need many more patients to be included. They have been involved in protocol design, including methodology, sample collection and patient follow-up, and their input has shaped the patient information materials and consent forms. Patient advocates will have an ongoing key role in overseeing the progress of the study as members of the Trial Management Group, and they will also have an important role in communicating the study results to patients and the public. Current status HER2-RADiCAL is planned to open at ~40 UK sites commencing in September 2021. Citation Format: Iain Macpherson, Stuart McIntosh, Lucy Kilburn, Holly Tovey, Sarah Kernaghan, Katie Goddard, Indrani Bhattacharya, Clinton Boyd, Charlotte Coles, Cliona Kirwan, Mairead Mackenzie, Ciara O’Brien, Alistair Ring, Claire Snowdon, Hilary Stobart, Duncan Wheatley, Andrew Wardley, Abeer Shaaban, Peter Hall, David Cameron, Judith Bliss. The HER2-RADiCAL study (Response ADaptive CAre pLan) - Tailoring treatment for HER2 positive early breast cancer [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 OT2-05-01.

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

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

BACKGROUND: Ductal carcinoma in situ (DCIS) was virtually unknown before breast screening and now accounts for up to 25% of all ‘breast cancers’ detected. Over 50,000 women are diagnosed annually with DCIS in the US alone; most receive treatments intended for women with invasive breast cancer which may offer no benefit and are associated with physical and psychological complications, and financial burdens. Observational studies show a majority of DCIS never becomes invasive, even if left untreated. Lack of prospective data and concerns about “overtreatment” are now being addressed by PRECISION - an international consortium of clinicians, scientists and patient advocates - collaborating to understand the biological nature of DCIS and how it evolves. Our goal is to develop tests that distinguish between women with DCIS who will likely develop breast cancer and should be treated, and those who can safely avoid treatment. Patient advocates are fully integrated into PRECISION as well as 3 prospective randomized clinical trials - LORD (EU), LORIS (UK) and COMET (US) – aiming to produce evidence to show whether or not Active Surveillance has equivalent outcomes to surgery for low-risk DCIS. These trials are critical because PRECISION uses biospecimens from each trial, in addition to other DCIS cohorts around the world. PATIENT ADVOCATE AIMS: • Help foster teams that contribute to better outcomes for women with DCIS. • Assist in designing effective informational tools for providers, organizations, and the public. • Understand international differences in health services, medical culture, and patient expectations, and recommend improvements. • Measure the value of patient involvement in PRECISION research. • Raise awareness and communicate about ongoing research and (over)treatment of DCIS. METHODS: The PRECISION Patient Advocate Involvement Panel (PAIP) includes representatives from each country: NL, UK, and US. PAIP members provide encouragement that helps to shape ongoing projects into a cohesive team, while encouraging new synergistic projects that can potentially improve clinical practice. The PAIP actively participates in the Steering Group, all Work Packages (WPs), and a variety of internal and external communications. This includes making posters and presentations at international conferences, preparing for PRECISION reviews, creating website and newsletter content, giving interviews, co-authoring publications, and developing social media campaigns to raise awareness. RESULTS: The PAIP has: a) helped build collaborations between institutions; b) developed public-facing information about PRECISION and the 3 clinical trials; c) offered patient-oriented ideas and feedback to all WPs; d) helped resolve international contract barriers; e) helped identify additional DCIS cohorts; f) suggested ideas to improve recruitment for the clinical trials; g) given feedback on surveys and co-authored publications; h) built relationships with postdocs and PhD students; and i) engaged public and clinician audiences on DCIS dilemmas in each country. Additional ongoing PAIP work includes engaging in research to reduce pathology report DCIS grade discordance within and between countries (a critical issue for women diagnosed with DCIS). CONCLUSIONS: There is a need to better understand DCIS subtypes, stratify associated risks for invasive cancer, synergize accurate communication about DCIS, and improve pathology standards within and between countries. The PAIP will continue to work closely with researchers and communicate evidence that answers important questions related to risk factors for women who may or may not need treatment for DCIS. *PRECISION is sponsored by a Cancer Research UK Grand Challenge Award, which is also funded by the Dutch Cancer Society. Citation Format: Deborah Collyar, Donna Pinto, Hilary Stobart, Ellen Verschuur, Marja van Oirsouw, on behalf of the PRECISION Project. How patient advocates and researchers work together in PRECISION* to identify low-risk ductal carcinoma in situ (DCIS) that may not need aggressive treatment [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-16-04.

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

Introduction: Ductal carcinoma in situ (DCIS) is considered a non-obligate precursor of invasive ductal carcinoma. With the aim of preventing a subsequent invasive cancer, all DCIS lesions are currently treated with surgical excision often supplemented with radiotherapy (RT). To prevent DCIS over- or undertreatment, a reliable marker of DCIS invasiveness risk is urgently needed. Methods: We studied two large DCIS cohorts: the Sloane cohort, a prospective breast screening cohort from the UK (median follow-up of 11 years), and a Dutch population-based cohort (NKI, median follow-up of 13 years). FFPE tissue specimens from patients with pure primary DCIS after breast-conserving surgery (BCS) +/- RT that did develop a subsequent ipsilateral event (DCIS or invasive) were considered as cases, whereas patients that did not develop any form of recurrence up to the last follow-up or death were considered as controls. We performed copy number analysis (CNA) and RNAseq analysis on 229 cases (80 DCIS only recurrences) and 344 controls. Results: DCIS was classified into the PAM50 subtypes using RNAseq data which revealed an enrichment of luminal A phenotype in DCIS that did not recur (P = 0.01, Fisher Exact test). No single copy number aberration was more common in cases compared to controls. RNAseq data did not reveal any genes significantly over/under-expressed in cases versus controls after FDR correction. However, by limiting the analysis to samples that had not had RT and excluding pure DCIS recurrences, we could develop a penalized Cox model from RNAseq data. The model was trained on weighted samples (to correct for the biased sampling of the case-control dataset) from the NKI series with double loop cross-validation. The genes were selected using the Elastic net framework of penalization. Using this predicted hazard ratio, the samples were split into high, medium, and low-risk quantiles, with a recurrence risk of 23%, 7% and 2%, respectively at 5 years (p = 10-10, Wald test). The NKI-trained predictor was independently validated in the Sloane No RT no DCIS recurrence cohort (p = 0.02, Wald test). GSEA analysis revealed proliferation hallmarks enriched in the recurrence predictor (FDR = 0.058). The RNAseq predictor was more predictive of recurrence than PAM50, clinical features (Grade, Her2 and ER) and the 12-gene Oncotype DCIS score (p < 0.001, permutation test using the Wald statistic) in both the NKI and Sloane series. Conclusion: Genomic profiling of two independent series of DCIS with outcome data did not reveal any clear associations with recurrence until analysis was limited to a set of samples who had not had radiotherapy and DCIS recurrences were excluded. We then identified an RNAseq-based classifier that could differentiate primary DCIS in low-, medium-, and high-risk groups, and validated it in an independent cohort. This classifier, if validated in other datasets, will allow us to identify women who do not need intensive treatment for their DCIS. Citation Format: Maria Roman Escorza, Michael Sheinman, Tycho Bismeijer, Ahmed A. Ahmed, Vandna Shah, Jeffrey R. Marks, Lorraine M. King, Anargyros Megalios, Lindy L. Visser, Marlous Hoogstrat, Helen R. Davies, Tapsi Kumar, Deborah Collyar, Hilary Stobart, Sarah Pinder, Nicholas N. Navin, Andrew Futreal, Serena Nik-Zainal, E. Shelley Hwang, Esther H. Lips, Alastair Thompson, Lodewyk F.A. Wessels, Jelle Wesseling, Elinor J. Sawyer. Genomic predictor can discriminate between high- and low-risk DCIS [abstract]. In: Proceedings of the AACR Special Conference on Rethinking DCIS: An Opportunity for Prevention?; 2022 Sep 8-11; Philadelphia, PA. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_1): Abstract nr PR002.

With the widespread adoption of breast cancer screening the incidence of pure ductal carcinoma in situ (DCIS) has increased. As DCIS is considered a non-obligate precursor of invasive ductal carcinoma most women with pure DCIS are treated with breast conserving surgery (BCS) +/- radiotherapy. However, for many this is likely to be overtreatment as only a minority will develop a subsequent ipsilateral recurrence. Studies also show that only ~60% of these ipsilateral recurrences are invasive disease with the remainder being pure DCIS. To predict which women are most likely to benefit from interventions, there is a need to identify biomarkers that are associated with invasive recurrence. Our aim was to assess whether copy number aberrations (CNAs) could be used to identify DCIS that was likely to recur as invasive disease or remain recurrence-free during long-time follow up. We performed somatic copy number profiling on 309 pure DCIS samples that had not developed an ipsilateral event (controls), 198 that had developed subsequent ipsilateral invasive disease (INV-cases) and 58 that had developed subsequent ipsilateral pure DCIS (DCIS-cases). The samples were obtained from two large nation-wide cohorts: the Sloane cohort, a prospective breast screening cohort from the UK with a median follow up of 12.5 years and a Dutch population based cohort, with a median follow up of 13 years. CNAs were assessed using the CytoSNP array or low pass whole genome sequencing and analyzed using GISTIC. Integrative cluster (IntClust) subtyping revealed that only 5 subtypes were well represented in DCIS compared to 10 in invasive disease and the distribution of clusters between INV-cases and controls was similar with the exception of IntClust 4, which was significantly more common in controls (P= 0.025, Fishers exact test). IntClust 4 is characterized to have low levels of genomic instability and a CNA-devoid. INV-cases were globally more aberrant than controls (P = 0.006, Wilcoxon test) as assessed by the chromosomal instability index (CIN) score. GISTIC identified 17 recurrent amplifications, 21 recurrent gains and 22 recurrent losses in the whole cohort. Six of these regions were more common in INV-cases compared to controls: amplifications at 17q24.1 and 8p11.23, losses at 1p36.13 and 11q23.2 ​and gains at 17q21.33​ and 16p (Nominal P < 0.05 and FDR < 0.1, Fishers exact test). Subgroup analysis of ER+, Her2- INV-cases versus controls revealed an additional differential CNA, amplification at 11q13.3 more common in cases. DCIS-cases had similar CNAs to INV-cases and were more aberrant than controls in terms of CIN score (P < 0.037, Wilcoxon test) but not as aberrant as INV-cases. In conclusion, we have identified potential CNAs that are associated with invasive recurrence. Further analysis will integrate gene expression with copy number data to identify which genes are being targeted by these CNAs in order to identify pathways important in progression of DCIS. Citation Format: Ahmed A. Ahmed, Maria Roman-Escorza, Tycho Bismeijer, Michael Sheinman, Vandna Shah, Rana Shami, Jeffrey R. Marks, Lorraine M. King, Anargyros Megalios, Lindy L. Visser, Marlous Hoogstraat, Helen R. Davies, Tapsi Kumar, Deborah Collyar, Hilary Stobart, Sarah Pinder, Nicholas N. Navin, Andrew Futreal, Serena Nik-Zainal, E. Shelley Hwang, Lodewyk F. Wessels, Esther H. Lips, Alastair Thompson, Jelle Wesseling, Elinor J. Sawyer. Copy number analysis of pure DCIS and association with recurrence [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5108.

Background Early introduction and international collaboration of patient advocates is essential in the investigation of safe treatment of DCIS. This diagnosis has increased since the introduction of screening. The treatment of low risk DCIS has been the subject of debate, controversy, anxiety and cost to women and health services globally. There has been much "public" as well as "professional" discussion leading to considerable distress. Some surgeons have concerns about carrying out unnecessary surgery on patients with low risk DCIS, but this is current best practice due to lack of credible evidence that monitoring can be safe. Some women feel their "lives were saved" whilst others feel "mutilated" by "unnecessary” surgery. These women cannot know the true harm or benefit of the treatment which they receive without evidence from clinical trials and biological/molecular research. Aims · To provide evidence of the value of patient involvement. · To encourage recruitment in "difficult to recruit studies" by educating the public, patients and clinicians. · To assist in the design of effective information tools. · To increase liaison between advocates internationally to understand differences in culture, health services, and patient expectation. Methods The PRECISION team includes 2 patient advocates from each of the DCIS randomized trials (LORIS in the UK, LORD in the Netherlands and COMET in the US). Our group will liaise with other groups involved in the wider efforts around DCIS. We will take part in media interviews and public debates to raise awareness and the need for evidence to change practice to reduce overtreatment of low riskDCIS. We will work with our researcher colleagues in each PRECISION work project, join the PRECISION steering group, and liaise together via regular calls. Importantly, we will encourage awareness amongst clinicians to emphasize that patients wish to be informed about available trials, and that not to do so is denying patient choice. Results An increase in interest and recruitment can be measured and the influence of early involvement of patient advocates can be demonstrated so that the model can be used in other trials. The biology is intricate, scientific and exciting but it is crucial that the outcome is available and understood by all women and their physicians worldwide. The results will be promoted by patient advocates through publications, social media and patient groups. Advocates will appear as co-authors on scientific publications. CONCLUSIONS With the increase in international clinical trials, there is a need for further understanding of the differences in practice and patient need in different hospitals - as well as in different countries. We will show the value of our collaboration by demonstrating the results of patient advocate involvement in the PRECISION program. * The PRECISION Team is a Cancer Research UK Grand Challenge Award 2017 winning team and will be jointly funded by Cancer Research UK and the Dutch Cancer Society. Citation Format: Verschuur E, Collyar D, Oirsouw Mv, Pinto D, Stobart H, Wilcox M, On Behalf of the PRECISION Project. Patient advocates are partners in global breast research: Value is recognised by early advocate involvement in the PREvent ductal carcinoma in situ invasive overtreatment now (PRECISION) study and related trials [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-17-02.

Introduction: Ductal Carcinoma In Situ (DCIS) is a proliferation of neoplastic cells confined to the ducto-lobular system. Due to uncertainty which DCIS lesions progress to invasive breast cancer women with DCIS receive surgery and radiotherapy. The PRECISION (PREvent ductal carcinoma In Situ Invasive Overtreatment Now) initiative intends to improve the management of DCIS including reduction of unnecessary treatment. Histological high grade is an unfavorable prognostic indicator used to guide treatment decisions, and used as an exclusion criterion for DCIS trials that randomize between active surveillance and standard treatment. Hence, accurate assessment of grade is important in current clinical practice. Pathologists within PRECISION setup this study to compare histological parameters of four retrospective DCIS cohorts from three different countries to investigate interobserver variability particularly in grading of DCIS. Method: Tissue slides from two population-based cohorts (UK Sloane cohort n=110; Dutch DCIS cohort n= 110) and two hospital based cohorts (Duke n=110; MDACC n=95) were included, leading to a total of 425 slides. All slides were reviewed by 9 breast pathologists originating from the UK, US and the Netherlands (NL) using the digital software platform Slidescore. The slides included were a representative selection of histological grades from all cases in these respective studies (see table 1 for distribution). Kappa (κ) values were calculated based on a generalized linear mixed model using the ordinal package in R. Results: The distribution of grade according to the majority opinion and originally assigned during diagnosis is shown in table 1. The cohort from NL demonstrated less grade 1 lesions according to the majority opinion compared to originally assigned grade. Table 2 shows the κ values of all evaluated histological variables. DCIS grade 1,2,3, grade 1/2 vs 3, necrosis and calcification show moderate agreement (κ between 0.4-0.6). Lymphocytic infiltrate, periductal fibrosis and mitoses demonstrate poor agreement (κ between 0.2-0.4). Conclusion: Histological factors including DCIS grade 1/2/3 and DCIS grade 1/2 versus 3 show only moderate agreement in this study using whole slide images. Preliminary analyses show no differences in κ values with the inclusion of country of the pathologist. However, the distribution of grade differs between the grading originally assigned and determined by majority opinion. Since clinical decisions are based on histological variables, it is important to realize that interobserver variability play a part in the diagnostic process. We are currently reviewing con- versus discordant cases and discussing how pathology guidelines can be improved. In addition, we are exploring whether artificial intelligence-based methods could be used to standardize grading of DCIS. Table 1. Distribution of grade of all slides and slides from participating centers. Slides were excluded if the majority opinion was equally divided between two grades or if originally grade 1-2/2-3 was assigned.Origin of tissue slidesGrade 1 (n)Grade 2 (n) Grade 3 (n)Excluded nAll tissue slides (n=425)Distribution according to majority opinion12% (49)40% (163)48% (197)16Distribution originally assigned12% (36)36% (111)53% (165)113Slides from Netherlands Cancer Institute (n=110)Distribution according to majority opinion6% (6)31% (33)64% (68)3Distribution originally assigned17% (19)33% (36)50% (55)0Slides from Sloane (n=110)Distribution according to majority opinion20% (20)51% (52)29% (30)8Distribution originally assigned11% (12)31% (34)58% (64)0Slides from Duke (n=110)Distribution according to majority opinion9% (10)44% (47)47% (50)3Distribution originally assigned5% (5)45% (41)50% (46)18Slides from MDAnderson (n=95)Distribution according to majority opinion14% (13)33% (31)53% (49)2Distribution originally assignedTo be collected Table 2. Kappa values of evaluated histological parametersVariableModel based weighted kappa (κma)95% confidence intervalDCIS grade 1/2/30.500.440.57DCIS grade 1/2 vs 30.520.440.60DCIS grade 1 vs 2/30.450.400.50DCIS grade low vs high0.520.440.59Necrosis absent vs present (manually dichotomized)0.550.510.59Calcification absent vs present0.510.480.55Lymphocytic infiltrate0.470.390.55Periductal fibrosis0.350.300.40Mitoses0.340.250.42 Citation Format: Maartje van Seijen, Katarzyna Jóźwiak, Sarah E Pinder, Allison Hall, Savitri Krishnamurthy, Jeremy SJ Thomas, Laura Collins, Jonathan Bijron, Joost Bart, Danielle Cohen, Wen Ng, Hilary Stobart, Jan Hudecek, Esther H Lips, Jelle Wesseling. Variability in ductal carcinoma in situ grading among an international group of pathologists [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-02-05.

The Breast Cancer Campaign Tissue Bank (BCCTB) was initiated in 2010 after the charity Breast Cancer Campaign heard from breast cancer experts that insufficient high quality breast cancer tissue was preventing research which would impact people with breast cancer1. The charity decided to involve patient advocates in the development of the BCCTB from the beginning. Two advocates reviewed the initial applications to form the BCCTB. These included both single and multi-centre applications so they suggested that, rather than choosing one centre to form the Bank, the charity consider a collaboration of centres. Throughout the development of the BCCTB, the patient advocates asked the ‘elephant in the room’ questions and brought a different perspective. They also helped to design the Bank's processes, including the consent process and asking that all tissue applicants produce a lay summary of their research. There are now two advocates on the Board which provides strategic direction to the BCCTB. The advocates have equal status to other Board members. There are also three advocates on the Tissue Access Committee which controls the use of tissue in the Bank. Lay summaries of projects have to be approved by all advocates before an application can proceed. This means that no precious tissue is released without the approval of a lay person, who can ensure maximum patient benefit will be achieved from any research. The Bank's data return policy was also driven by the patient advocates who were keen that the tissues donated were used to their maximum benefit. This has resulted in the first publication from BCCTB2 Patient advocates have been involved in promoting the use of tissue from the bank presenting at conferences and at BCCTB road shows. Patient advocates have also been involved in asking potential donors to consent to donate to the tissue bank. The involvement of patient advocates in the development and oversight of the BCCTB has shown researchers that patient and public involvement works. The advocates can also help promote the Bank and the benefits of tissue donation to both professionals and lay groups. The patient advocates involved in the Breast Cancer Campaign Tissue Bank are members of the charity Independent Cancer Patients’ Voice 1. Thompson P, Brennan K, Cox A, Gee J, Harcourt D, Harris A, Harvie M, Holen I, Howell A, Nicholson R, Steel M, Streuli C. Evaluation of the current knowledge limitations in breast cancer research: a gap analysis. Breast Cancer Res 2008: 10(2); R26. 2. Speirs V, Morgan A. Investment biobanking – increased returns on tissue samples. Nat Rev Clin Onc 2013; 10:128-129. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-10-01.