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Background: Multi-parameter tumor gene expression assays (MPAs) are used to estimate individual patient risk and guide chemotherapy use in hormone-sensitive, HER2-negative early breast cancer. The TAILORx trial supports MPA use in a node-negative population. Evidence for MPA use in postmenopausal node-positive breast cancer has been provided by the RxPONDER trial interim analysis but this relies on the absence of superiority in an analysis where >50% of events were unrelated to breast cancer. There is much uncertainty about MPA use for premenopausal patients. OPTIMA (Optimal Personalised Treatment of early breast cancer usIng Multi-parameter Analysis) (ISRCTN42400492) is a prospective international randomized controlled trial designed to validate MPAs as predictors of chemotherapy sensitivity in a largely node-positive breast cancer population. Methods: OPTIMA is a partially blinded study with an adaptive two-stage design. The trial recruits women and men age 40 or older with resected ER-positive, HER2-negative invasive breast cancer and up to 9 involved axillary lymph nodes. Randomization is to standard management (chemotherapy and endocrine therapy) or to MPA-directed treatment using the Prosigna (PAM50) test. Those with a Prosigna tumor Score (ROR_PT) >60 receive standard management whilst those with a low score (≤60) tumor are treated with endocrine therapy alone. Endocrine therapy for pre-menopausal women includes ovarian suppression for all participants unless they experience a chemotherapy-induced menopause. Adjuvant abemaciclib is permitted. The trial will be analyzed for (1) non-inferiority of recurrence according to randomization and (2) cost-effectiveness. The key secondary outcome is non-inferiority of recurrence for patients with low ROR_PT score tumors. The efficacy analyses will be performed Per Protocol using Invasive Breast Cancer Free Survival (IBCFS) as the primary outcome measure to limit the risk of a false non-inferiority conclusion. Recruitment of 4500 patients over 8 years will permit demonstration of up to 3% non-inferiority of test-directed treatment with at least 83% power, assuming 5-year IBCFS is 87% with standard management. An integrated qualitative recruitment study addresses challenges to consent and recruitment, building on experience from the feasibility study which found that a multidisciplinary approach is important for recruitment success. OPTIMA is strongly supported by a patient group which has helped design all patient documents and which is represented on the TMG. Results: The OPTIMA main trial opened in January 2017 and has continued to recruit throughout the COVID-19 pandemic. Overall recruitment as of 1 July 2022 was 2814 (2593 from UK, 221 from Norway). Patient characteristics are well balanced between the trial arms. Currently 95% of randomized participants are eligible for inclusion in the PP analysis. 66% of the MPA-directed arm participants have been allocated to endocrine therapy only. The test failure rate is < 1%. Conclusion: OPTIMA will provide robust unbiased evidence on test-directed chemotherapy safety for both postmenopausal and premenopausal women with 1-3 involved nodes as well as for patients with 4-9 involved nodes and for patients treated with abemaciclib. Funding: OPTIMA is funded by the UK NIHR HTA Programme (10/34/501) and in Norway by KLINBEFORSK and the Norwegian Cancer Society. Views expressed are those of the authors and not those of the HTA Programme, NIHR, NHS or the Department of Health. Trial Inquiries: OPTIMA@warwick.ac.uk Patient characteristics Citation Format: Robert Stein, Andreas Makris, Iain Macpherson, Luke Hughes-Davies, Andrea Marshall, Georgina Dotchin, David A. Cameron, Belinda E. Kiely, Caroline Wilson, Anne Armstrong, Helena M. Earl, Christopher J. Poole, Janice Tsang, Bjørn Naume, Daniel Rea, Hege Ohnstad, Peter S. Hall, Stuart A. McIntosh, Bethany Shinkins, Christopher McCabe, Adrienne Morgan, John MS Bartlett, Janet A. Dunn. OPTIMA, a prospective randomized trial to validate the clinical utility and cost-effectiveness of gene expression test-directed chemotherapy decisions in high clinical risk early breast cancer. [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 OT3-32-01.

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.

PURPOSE: There is currently no standardised definition for patients at high risk of recurrence of HER2-negative early breast cancer (eBC, stages 1–3) after surgery. Recognising that the assessment of high risk is often multifactorial, the aim of this modified Delphi panel was to establish expert UK consensus on this definition, separately considering HR-positive and triple-negative (TN) patients. METHODS: A total of 45 UK-based clinicians, including breast cancer oncologists and surgeons, were invited to participate. The number of respondents in each of three rounds was 29, 24 and 22 respectively. Statements were developed using the results from a targeted literature review and the guidance of a lead clinician, and comprised free-text, single-choice or numerical formats. The first round aimed to determine which factors are currently used in clinical practice to assess risk of recurrence in the populations of interest. In the subsequent rounds, the objective was to establish thresholds indicative of high risk in a 10-year timeframe for each of the factors retained in Round 1. Between each round, statements were refined, considering the distribution of responses and free-text notes provided by participants. Consensus for single-choice questions was set at a pre-defined threshold of ≥70% of respondents. RESULTS: Consensus was achieved on the need to assess age, tumour size, tumour grade, number of positive nodes, presence of inflammatory breast cancer and one or more risk prediction tools to define high risk of recurrence in all HER2-negative patients. In HR-positive patients, there was agreement on the use of one or more tumour profiling tests and biomarkers to define high risk of recurrence. However, there was no consensus on biomarker use in TN patients, and support for specific biomarkers (such as Ki-67) was conflicting for both sub-populations based on the analysis of free-text notes. Similarly, while there was consensus on the use of pCR status/residual disease to indicate high risk in TN patients, this factor failed to reach consensus for the HR-positive sub-population. Germline BRCA status and menopausal status were not considered to be key factors for risk of recurrence in either biological subtype. In the second and third rounds, thresholds indicative of high recurrence risk were agreed; it should be noted that the free-text responses provided by the participants frequently highlighted that many of the factors should be considered along a continuous scale when assessing the risk of individual patients. In HR-positive patients, these thresholds included: age < 35 years, tumour size >5 cm (each when considered independently from other risk factors); tumour grade 3 (independently or in combination with other factors); number of positive lymph nodes ≥4 when considered independently or ≥1 in combination with other factors. For patients with TN tumours, the following thresholds reached consensus, whether considered independently or in combination with other factors: tumour size >2 cm, tumour grade 3, number of positive lymph nodes ≥1. In several cases, however, no consensus could be reached on the appropriate threshold indicating high risk of recurrence. In the HR-positive sub-population, these included thresholds for age and tumour size, when considered in combination with other factors. In the TN sub-population, this included age, whether independently or in combination with other factors. CONCLUSIONS: The expert consensus reached in this panel highlights that an integrated model is important in assessing recurrence risk in eBC and that definitions of high risk differ according to biological subtype. The results may serve as a valuable reference point for clinicians to use in assessing risk of disease recurrence and in making treatment decisions after surgery in the HER2-negative eBC population. FUNDING: AstraZeneca UK Ltd. Writing support: Costello Medical. Citation Format: Ellen R. Copson, Jean E. Abraham, Jeremy P. Braybrooke, Stuart A. McIntosh, Caroline O. Michie, Carlo Palmieri, Rebecca Roylance, Saiqa Spensley. Expert consensus on the definition of high risk of recurrence in HER2-negative early breast cancer: a modified Delphi panel [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 P3-05-39.

Purpose Epidemiological studies have indicated a higher prevalence of hypothyroidism in breast cancer patients, possibly related to shared risk factors and breast cancer treatments. However, few studies have evaluated how hypothyroidism impacts survival outcomes in breast cancer patients. We aimed to determine the association between hypothyroidism and breast cancer-specific and all-cause mortality. Methods We conducted a population-based study using the Scottish Cancer Registry to identify women diagnosed with breast cancer between 2010 and 2017. A matched comparison cohort of breast cancer-free women was also identified. Using hospital diagnoses and dispensed prescriptions for levothyroxine, we identified hypothyroidism diagnosed before and after breast cancer diagnosis and determined associations with breast cancer-specific and all-cause mortality. Cox proportional hazards regression was used to calculate hazard ratios (HR) and 95% confidence intervals (CI) adjusted for potential confounders. Results A total of 33,500 breast cancer patients were identified, of which 3,802 had hypothyroidism before breast cancer diagnosis and 565 patients went on to develop hypothyroidism after. Breast cancer patients had higher rates of hypothyroidism compared with cancer-free controls (HR 1.14, 95% CI 1.01–1.30). Among breast cancer patients, we found no association between hypothyroidism (diagnosed before or after) and cancer-specific mortality (before: HR 0.99, 95% CI 0.88–1.12, after: HR 0.97, 95% CI 0.63–1.49). Similar associations were seen for all-cause mortality. Conclusion In a large contemporary breast cancer cohort, there was little evidence that hypothyroidism, either at diagnosis or diagnosed after breast cancer, was associated with cancer-specific or all-cause mortality.

Supplementary Data from Combined Perioperative Lapatinib and Trastuzumab in Early HER2-Positive Breast Cancer Identifies Early Responders: Randomized UK EPHOS-B Trial Long-Term Results

Supplementary Figure from Combined Perioperative Lapatinib and Trastuzumab in Early HER2-Positive Breast Cancer Identifies Early Responders: Randomized UK EPHOS-B Trial Long-Term Results

Purpose:EPHOS-B aimed to determine whether perioperative anti-HER2 therapy inhibited proliferation and/or increased apoptosis in HER2-positive breast cancer.Patients and Methods:This randomized phase II, two-part, multicenter trial included newly diagnosed women with HER2-positive invasive breast cancer due to undergo surgery. Patients were randomized to: part 1 (1:2:2), no treatment (control), trastuzumab or lapatinib; part 2 (1:1:2) control, trastuzumab, or lapatinib and trastuzumab combination. Treatment was given for 11 days presurgery. Coprimary endpoints were change in Ki67 and apoptosis between baseline and surgery tumor samples (biologic response: ≥30% change). Central pathology review scored residual cancer burden (RCB). Relapse-free survival (RFS) explored long-term effects.Results:Between November 2010 and September 2015, 257 patients were randomized (part 1: control 22, trastuzumab 57, lapatinib 51; part 2: control 29, trastuzumab 32, combination 66). Ki67 response was evaluable for 223 patients: in part 1 Ki67 response occurred in 29/44 (66%) lapatinib versus 18/49 (37%) trastuzumab (P = 0.007) and 1/22 (5%) control (P < 0.0001); in part 2 in 36/49 (74%) combination versus 14/31 (45%) trastuzumab (P = 0.02) and 2/28 (7%) control (P < 0.0001). No significant increase in apoptosis after 11 days was seen in treatment groups. Six patients achieved complete pathologic response (pCR, RCB0) and 13 RCB1, all but two in the combination group. After 6 years median follow-up, 28 (11%) had recurrence and 19 (7%) died. No recurrences or deaths were observed among patients who achieved a pCR. Ki67% falls ≥50% associated with fewer recurrences (P = 0.002).Conclusions:Early response after short duration anti-HER2 dual therapy identifies cancers dependent on the HER2 pathway providing a strategy for exploring risk-adapted individualized treatment de-escalation.

PDF file - 2823K, Supplementary Figure 1. Estrogen metabolites cause DNA double strand breaks in S- phase cells. Supplementary Figure 2. BRCA1 supresses estrogen metabolite mediated DSBs and is required for their repair. Supplementary Figure 3. Estrogen and its metabolites induce DNA DSBs in a dose and time dependent manner. Supplementary Figure 4. BRCA1 suppresses estrogen metabolites induced DNA damage in BRCA1 mutant breast cancer cells. Supplementary Figure 5. BRCA1 and BRCA2 are required for repair of estrogen metabolite induced DSBs in MCF10A and MCF7 breast cells. Supplementary Figure 6. BRCA1, but not BRCA2, suppresses estrogen metabolite mediated DNA damage by repressing CYP1A1 expression in breast cells.

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Germline mutations in BRCA1 predispose carriers to a high incidence of breast and ovarian cancers. BRCA1 functions to maintain genomic stability through critical roles in DNA repair, cell-cycle arrest, and transcriptional control. A major question has been why BRCA1 loss or mutation leads to tumors mainly in estrogen-regulated tissues, given that BRCA1 has essential functions in all cell types. Here, we report that estrogen and estrogen metabolites can cause DNA double-strand breaks (DSB) in estrogen receptor-α–negative breast cells and that BRCA1 is required to repair these DSBs to prevent metabolite-induced genomic instability. We found that BRCA1 also regulates estrogen metabolism and metabolite-mediated DNA damage by repressing the transcription of estrogen-metabolizing enzymes, such as CYP1A1, in breast cells. Finally, we used a knock-in human cell model with a heterozygous BRCA1 pathogenic mutation to show how BRCA1 haploinsufficiency affects these processes. Our findings provide pivotal new insights into why BRCA1 mutation drives the formation of tumors in estrogen-regulated tissues, despite the general role of BRCA1 in DNA repair in all cell types. Cancer Res; 74(10); 2773–84. ©2014 AACR.

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

Purpose A James Lind Alliance priority setting partnership was developed to identify research priorities in breast cancer surgery from individuals with lived experience, at high genetic risk of breast cancer, and healthcare professionals (HCPs). Methods ‘Uncertainties’ were collected using an online survey. Following an evidence check and development of summary questions, an interim survey asked participants to rank their top 10 research priorities from the question list. Top-ranked questions from patient/carer, high-risk and professional groups were carried forward for discussion to a final online prioritisation workshop. Results 260 participants (101 patients/carers, 156 HCPs) submitted 940 uncertainties via the initial survey. These were analysed thematically into 128 summary questions in six topic areas. Following evidence checking, 59 questions were included in the interim survey which was completed by 572 respondents. Marked differences were seen in questions prioritised by patients/carers, HCPs and women at high-risk. The top eight priorities in patient/carer and professional groups and top two priorities for high-risk women were carried forward to the online workshop at which 22 participants discussed and agreed the final top 10. Key themes included de-escalation of breast and axillary surgery, factors impacting the development/detection of locoregional recurrence and optimal provision of support for informed treatment decision-making. Conclusion The top 10 research priorities in breast cancer surgery have been agreed. However, the observed differences in research priorities identified by patients and professional groups were not anticipated. Top priorities from both groups should inform future UK breast cancer surgical research, to ensure that it addresses questions that are important to breast cancer community as a whole.

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.

Introduction\ud \ud Evidence based guidelines for the optimal management of breast cancer locoregional recurrence (LRR) are limited, with potential for variation in clinical practice. This national practice questionnaire (NPQ) was designed to establish the current practice of UK breast multidisciplinary teams (MDTs) regarding LRR management.\ud \ud \ud \ud Methods\ud \ud UK breast units were invited to take part in the MARECA study MDT NPQ. Scenario-based questions were used to elicit preference in pre-operative staging investigations, surgical management, and adjuvant therapy.\ud \ud \ud \ud Results\ud \ud 822 MDT members across 42 breast units (out of 144; 29%) participated in the NPQ (February–August 2021). Most units (95%) routinely performed staging CT scan, but bone scan was selectively performed (31%).\ud \ud \ud \ud For patients previously treated with breast conserving surgery (BCS) and radiotherapy, few units (7%) always/usually offered repeat BCS. However, in the absence of radiotherapy, most units (90%) always/usually offered repeat BCS. For patients presenting with isolated local recurrence following previous BCS and SLNB (sentinel lymph node biopsy), most units (95%) advocated repeat SLNB. Where SLNs could not be identified, 86% proceeded to a four-node axillary sampling procedure.\ud \ud \ud \ud For ER positive, HER2 negative, node negative local recurrence, 10% of units always/usually offered chemotherapy. For ER positive, HER2 negative, node positive local recurrence, this recommendation increased to 64%. For triple negative breast cancer local recurrence, 90% of units always/usually offered chemotherapy.\ud \ud \ud \ud Conclusion\ud \ud This survey has highlighted where consistencies and variations exist in the multidisciplinary management of breast cancer LRR. However, further research is required to determine how these management patterns influence patient outcomes, which will further refine optimal treatment pathways.

Objective: The aim of this study was to evaluate vacuum-assisted excision (VAE) for percutaneous treatment of breast cancers. Methods: This is a retrospective analysis of 1061 vacuum-assisted biopsies (VAB) and VAE for the diagnostic purpose of suspicious breast lesions in a breast unit between April 13, 2017 and November 28, 2020. In total, 116 cases with complete data from VAB/VAE and surgical excision were evaluated. Excision following VAB/VAE was defined as complete resection (CR) if there was no residual tumor, minimal residual disease (MRD) if residual tumor was ≤3 mm, gross residual disease (GRD) if residual tumor was ≥3 mm, and upgrade from DCIS on VAB/VAE to invasive cancer. CR and MRD were combined as potentially resected and treated percutaneously (PRTP). The GRD and those with an upgrade to invasion were determined not suitable for percutaneous treatment. Results: The median age was 55.6 years (20–91; SD 12.27), and the median tumor size on imaging was 11.6 mm (4–88; SD 10.59). Of the 116 tumors, 29 (25%) were CR, 18 (15.5%) were MRD, 64 (55.2%) were GRD, and 5 (4.3%) were upgraded from DCIS to invasion. There were 47 (40.5%) tumors that were PRTP, of which 10 (21.3%) were DCIS and 37 (78.7%) were invasive diseases (12 pure invasive carcinoma [IC], 24 IC + DCIS, and 1 DCIS with microinvasion). In multivariate analysis, a VAE procedure (p=0.008, odds ratio [OR]: 4.4, 95%CI) with low/intermediate nuclear grade (p=0.000, OR: 12.5, 95%CI) and final T≤10 mm (p=0.000, OR: 50.1, 95%CI) were associated with PRTP. In this retrospective analysis, the probability of PRTP of low/intermediate grade tumors smaller than 10 mm undergoing VAE was 84.58%. Conclusion: These data suggest that low/intermediate grade pT1a/b breast tumors can be completely excised with percutaneous VAE. Based on this, small (≤10 mm) IC of low/intermediate grade could be considered for entry to prospective randomized trials of VAE for local treatment, with a long-term follow-up to assess recurrence rates. Standardization of the procedure should be recommended.

Therapeutic mammaplasty (TM) may be an alternative to mastectomy, but few well designed studies have evaluated the success of this approach or compared the short-term outcomes of TM with mastectomy with or without immediate breast reconstruction (IBR). Data from the national iBRA-2 and TeaM studies were combined to compare the safety and short-term outcomes of TM and mastectomy with or without IBR.The subgroup of patients in the TeaM study who underwent TM to avoid mastectomy were identified, and data on demographics, complications, oncology and adjuvant treatment were compared with those of patients undergoing mastectomy with or without IBR in the iBRA-2 study. The primary outcome was the percentage of successful breast-conserving procedures in the TM group. Secondary outcomes included postoperative complications and time to adjuvant therapy.A total of 2916 patients (TM 376; mastectomy 1532; mastectomy and IBR 1008) were included in the analysis. Patients undergoing TM were more likely to be obese and to have undergone bilateral surgery than those having IBR. However, patients undergoing mastectomy with or without IBR were more likely to experience complications than the TM group (TM: 79, 21·0 per cent; mastectomy: 570, 37·2 per cent; mastectomy and IBR: 359, 35·6 per cent; P 0·001). Breast conservation was possible in 87·0 per cent of patients who had TM, and TM did not delay adjuvant treatment.TM may allow high-risk patients who would not be candidates for IBR to avoid mastectomy safely. Further work is needed to explore the comparative patient-reported and cosmetic outcomes of the different approaches, and to establish long-term oncological safety.La mamoplastia terapéutica (therapeutic mammaplasty, TM) puede ser una alternativa a la mastectomía, pero hay pocos estudios bien diseñados que hayan evaluado el éxito de esta estrategia o hayan comparado los resultados a corto plazo de la TM con la mastectomía con o sin (+/-) reconstrucción mamaria inmediata (immediate breast reconstruction, IBR). Para comparar la seguridad y los resultados a corto plazo de la TM y la mastectomía +/- IBR se combinaron los datos de los estudios nacionales iBRA-2 y TeaM. MÉTODOS: En el estudio TeaM se identificó el subgrupo de pacientes al que se realizó una TM para evitar la mastectomía y se compararon los datos demográficos, las complicaciones, los resultados oncológicos y el tratamiento adyuvante con las pacientes sometidas a mastectomía +/- IBR del estudio iBRA-2. La variable principal fue el porcentaje de éxito de la cirugía conservadora de mama en el grupo TM. Las variables secundarias fueron las complicaciones postoperatorias y el intervalo de tiempo hasta el inicio del tratamiento adyuvante.Se incluyeron en el análisis 2.916 pacientes (TM n = 376; mastectomía n = 1.532; IBR n = 1.008). La TM era más frecuente en pacientes obesas o en las sometidas a cirugía bilateral en comparación con las pacientes con IBR. Sin embargo, las pacientes sometidas a una mastectomía +/- IBR tenían más probabilidades de desarrollar complicaciones que las del grupo TM (TM n = 79, 21,0%; mastectomía n = 570, 37,2%; mastectomía y IBR n = 359, 35,6%; P 0,001). La conservación de la mama fue posible en el 87% de las pacientes con TM y el procedimiento no retrasó el inicio del tratamiento adyuvante. CONCLUSIÓN: La TM puede permitir que pacientes de alto riesgo que no serían candidatas a IBR eviten la mastectomía de una forma segura. Se necesitan más trabajos para comparar los resultados percibidos por las pacientes y los estéticos de las diferentes estrategias terapéuticas y establecer la seguridad oncológica a largo plazo.

Introduction BRCA1 mutation carriers have a significant lifetime risk of breast cancer, with their primary risk-reduction option being bilateral mastectomy. Preclinical work from our laboratory demonstrated that in BRCA1-deficient breast cells, oestrogen and its metabolites are capable of driving DNA damage and subsequent genomic instability, which are well-defined early events in BRCA1-related cancers. Based on this, we hypothesise that a chemopreventive approach which reduces circulating oestrogen levels may reduce DNA damage and genomic instability, thereby providing an alternative to risk-reducing surgery. Methods and analysis 12 premenopausal women with pathogenic BRCA1 mutations and no previous risk-reducing surgery will be recruited from family history clinics. Participants will be allocated 1:1 to two arms. All will undergo baseline breast biopsies, blood and urine sampling, and quality of life questionnaires. Group A will receive goserelin 3.6 mg/28 days by subcutaneous injection, plus oral anastrozole 1 mg/day, for 12 weeks. Group B will receive oral tamoxifen 20 mg/day for 12 weeks. Following treatment, both groups will provide repeat biopsies, blood and urine samples, and questionnaires. Following a 1-month washout period, the groups will cross over, group A receiving tamoxifen and group B goserelin and anastrozole for a further 12 weeks. After treatment, biopsies, blood and urine samples, and questionnaires will be repeated. DNA damage will be assessed in core biopsies, while blood and urine samples will be used to measure oestrogen metabolite and DNA adduct levels. Ethics and dissemination This study has ethical approval from the Office for Research Ethics Committees Northern Ireland (16/NI/0055) and the Medicines and Healthcare products Regulatory Agency (MHRA) (reference: 32485/0032/001–0001). The investigational medicinal products used in this trial are licensed and in common use, with well-documented safety information. Dissemination of results will be via high-impact journals and relevant national/international conferences. A copy of the results will be offered to the participants and be made available to patient support groups. Trial registration number EudraCT: 2016-001087-11; Pre-results.

© 2018 Elsevier Ltd The 2013 Breast Cancer Campaign gap analysis established breast cancer research priorities without a specific focus on surgical research or the role of surgeons on breast cancer research. This Review aims to identify opportunities and priorities for research in breast surgery to complement the 2013 gap analysis. To identify these goals, research-active breast surgeons met and identified areas for breast surgery research that mapped to the patient pathway. Areas included diagnosis, neoadjuvant treatment, surgery, adjuvant therapy, and attention to special groups (eg, those receiving risk-reducing surgery). Section leads were identified based on research interests, with invited input from experts in specific areas, supported by consultation with members of the Association of Breast Surgery and Independent Cancer Patients' Voice groups. The document was iteratively modified until participants were satisfied that key priorities for surgical research were clear. Key research gaps included issues surrounding overdiagnosis and treatment; optimising treatment options and their selection for neoadjuvant therapies and subsequent surgery; reducing rates of re-operations for breast-conserving surgery; generating evidence for clinical effectiveness and cost-effectiveness of breast reconstruction, and mechanisms for assessing novel interventions; establishing optimal axillary management, especially post-neoadjuvant treatment; and defining and standardising indications for risk-reducing surgery. We propose strategies for resolving these knowledge gaps. Surgeons are ideally placed for a central role in breast cancer research and should foster a culture of engagement and participation in research to benefit patients and health-care systems. Development of infrastructure and surgical research capacity, together with appropriate allocation of research funding, is needed to successfully address the key clinical and translational research gaps that are highlighted in this Review within the next two decades.