Background The frequency of mammographic surveillance for women after diagnosis of breast cancer varies globally. The aim of this study was to evaluate whether less than annual mammography was non-inferior in terms of breast cancer-specific survival in women aged 50 years or older. Methods Mammo-50 was a multicentre, randomised, phase 3 trial of annual versus less frequent mammography (2-yearly after conservation surgery; 3-yearly after a mastectomy) for women aged 50 years or older at initial diagnosis of invasive or non-invasive breast cancer and who were recurrence free 3 years post curative surgery. The trial was conducted at 114 National Health Service hospitals in the UK. Participants were randomly assigned (1:1) to annual or less frequent mammograms at 3 years post curative surgery and were followed up for 6 years. The co-primary outcomes were breast cancer-specific survival and cost-effectiveness. The cost-effectiveness analysis will be reported elsewhere. Breast cancer-specific survival was assessed in the intention-to-treat population. Secondary outcomes were recurrence-free interval, overall survival, and referrals back to the hospital system. 5000 women provided 90% power to detect a 3% absolute non-inferiority margin for breast cancer-specific survival with 25% one-sided significance. The trial was registered with the ISRCTN registry, ISRCTN48534559; recruitment is complete but longer-term followup is ongoing. Findings Between April 22, 2014, and Sept 28, 2018, 5235 women were randomly assigned to annual mammography (n=2618) or less frequent mammography (n=2617). 3858 (736%) women were aged 60 years or older, 4202 (803%) had undergone conservation surgery, 4576 (874%) had invasive disease, 1159 (221%) had node positive disease, and 4330 (827%) had oestrogen receptor-positive tumours. With a median of 57 years follow-up (IQR 50-60; 87 years post curative surgery), 343 women died, including 116 who died of breast cancer (61 in the annual mammography group and 55 in the less frequent mammography group). 5-year breast cancer-specific survival was 981% (95% CI 975-986) in the annual mammography group and 983% (978-988) in the less frequent mammography group (hazard ratio 092, 95% CI 064-132), demonstrating non-inferiority of less frequent mammography at the pre- specified 3% margin (non-inferiority p<00001). 5-year recurrence-free interval was 941% (95% CI 931-949) in the annual mammography group and 945% (935-953) in the less frequent mammography group. Overall survival at 5 years was 947% (95% CI 938-955%) and 945% (935-953), respectively. 224 (649%) of 345 breast cancer events were detected from emergency admissions or symptomatic referrals back to the hospital system, including 108 (617%) of 175 in the annual mammography group and 116 (682%) of 170 in the less frequent mammography group. Interpretation For patients aged 50 years or older and at 3 years post diagnosis, less frequent mammograms were non-inferior compared with annual mammograms for breast cancer-specific survival, recurrence-free interval, and overall survival, and should be considered for this population.

Abstract Background In ATNEC trial, cT1-3N1M0 patients receive NACT followed by SNB/TAD. If the sentinel nodes(SNs) have converted to benign(ypN0), patients are randomly assigned to Axillary Treatment vs no Axillary Treatment. The study promotes standardized node marking procedures and includes a radiotherapy quality assurance program. Objectives – This study prospectively evaluates practice patterns, NACT response, adoption of node marking, rates of marked node identification, and breast conservation rates in the ongoing ATNEC trial across 70 centers in the UK. The trial aims to recruit 1900 patients. Materials and Methods Data from 196 randomized patients (median age: 54 [range: 28-79] years; median BMI: 26.5 [range: 17.6-51.1]) from December 2021 to June 28, 2023, across 70 UK centers were analyzed. These patients presented with cT1-3N1M0 breast cancer, received NACT, and exhibited no residual nodal disease (ypN0) on SNB/TAD. Results Among the randomised patients 54%(106) were post-menopausal, 71%(140) underwent breast conserving surgery(BCS) and 29%(56) mastectomy. At presentation, 12% (23) had T3, 63% (124) had T2, and 23% (46) had T1 tumors. Grade 3 tumors accounted for 70% (138) of cases. Among the patients, 60% (117) were HER2 positive, 31% (61) were triple negative, and 9% (18) were HER2 negative (ER or PgR positive). Anthracycline and taxane-based NACT were administered to 57% (106), while 38% (71) received a platinum-containing regimen. During SNB/TAD, a median of 4 nodes (interquartile range, 3-5) were removed. Among 184 patients with node marking data, 74% (136) had the involved node marked. The marked node was successfully removed in 94% (128) of these patients. Clip/coil only, Magseed and black dye were the commonest techniques used for node marking. The marked node was the sentinel node in 83% (106) of cases. Among 185 randomized patients with post-NACT response data, 68% (125) achieved a complete pathological response (pCR) in the breast, while 8% (15) had DCIS only and 22% (41) had invasive cancer. Among 105 patients with complete breast tumor response on imaging, 15% (16) had residual DCIS or invasive cancer. In the subset of patients with partial response or stable breast tumors on imaging (69 patients), 46% (32) had no residual tumor on histology (ypT0). Furthermore, 14% (26) exhibited partial or stable disease in the axilla on imaging but achieved complete pathological response on histology. Conclusions HER2-positive and triple-negative breast cancer cases predominate among patients undergoing NACT in the UK. Although 68% achieved a complete pCR (ypT0) in the breast, rates of BCS remain low. Notably, around 75% of randomized patients underwent node marking, with an intra-operative identification rate of 94%, demonstrating the successful implementation of node marking in the UK through the ATNEC trial. Citation Format: Amit Goyal, Andrea Marshall, Sophie Nicholls, Natalie Hammonds, Beatrix Elsberger, Duncan Wheatley, Janice Rose, Helen-Teresa Edwards, Abeer Shaaban, Roeum Butt, Gareth Jackson, Tara Homer, Luke Vale, Samreen Ahmed, Shama Puri, Sophie Gasson, Julie Bruce, Helen Higgins, Janet Dunn. Practice patterns and outcomes in the ongoing neoadjuvant ATNEC trial: node marking, response to NACT and breast conservation rates [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-23-05.

Abstract Introduction: Annual surveillance mammograms for an unspecified period, after treatment for early breast cancer, are widely practised in USA and Europe and represent a significant healthcare cost. Current UK guidelines recommend annual mammograms up to 5 years, then reverts to 3 year screening without specified risk stratification. Further evidence is needed to determine the optimum frequency and duration of mammographic surveillance. Methods: A multi-centre, randomised controlled, phase III trial of annual mammography versus 2-yearly for conservation surgery and 3-yearly mammograms for mastectomy patients up to 9 years. Women were eligible if aged 50 years or over at initial diagnosis of breast cancer (invasive or DCIS), and recurrence free 3 years post curative surgery. Primary outcome was breast cancer specific survival (BCSS). Secondary outcomes include recurrence free interval (RFI) and overall survival (OS). BCSS event was defined as deaths from breast cancer and RFI as any locoregional or distant invasive recurrence or new breast primary. 5000 women were needed to detect a 3% absolute non-inferiority (NI) margin for BCSS with 2.5% one-sided alpha and at least 85% power. Analyses were carried out on intention-to-treat basis. Results: 5235 women were randomised between April 2014 and September 2018. 4347 (83%) women were aged 55-75 years, 4203 (80%) had undergone conservation surgery, 4564 (87%) had invasive disease, 1162 (22%) had node positive disease, 4330 (83%) had ER positive tumours and 3812 (73%) were taking hormone therapy at the time of randomisation. Patient characteristics were balanced across arms. With a median of 5.4 years follow-up (interquartile range 4.6-5.9), 319 women have died; 104 of breast cancer (53 on annual arm; 51 on less frequent arm). BCSS at 5 years was 98.2% (95% CI 97.5-98.6%) on annual arm and 98.3% (95% CI 97.7-98.8%) on less frequent arm. Hazard ratio (HR) was 1.04 (95% CI 0.71 -1.54), demonstrating non-inferiority of less frequent mammograms at the 3% margin (NI p< 0.0001; critical value 2.71) and the 1% margin (NI p=0.02; critical value 1.56). 320 (6%) women had a new invasive breast cancer event (55 loco-regional recurrences, 85 new breast primaries, 139 distant recurrences and 41 with multiple invasive events); 164 on the annual arm compared to 156 on the less frequent arm. Five-year RFI was 94.2% (95% CI 93.2-95.1%) for the annual arm and 94.4% (95% CI 93.4-95.3%) for the less frequent arm; HR= 1.03; (95% CI 0.83-1.28) demonstrating non-inferiority at a 2% margin (NI p=0.006; critical value 1.36). OS at 5 years was 94.9% (95% CI 93.9-95.7%) on the annual arm and 94.3% (95% CI 93.3-95.2%) on the less frequent arm. Hazard ratio (HR) was 1.18 (95% CI 0.94 -1.47), demonstrating non-inferiority of less frequent mammograms at the 3% margin (NI p=0.003; critical value 1.61) and the 2.5% margin (NI p=0.02; critical value 1.51). A total of 14987 mammograms have been performed on the annual arm and 8047 on the less frequent arm. 1967 (75%) of 2618 women on the annual arm complied with their allocated schedule compared to 1775 (68%) of 2617 women on the less frequent arm. COVID-19 pandemic affected compliance; it is estimated that 345 (7%) women missed mammograms during the pandemic. A sensitivity analysis was performed on the 72% of women who fully complied with their scheduled mammograms as per protocol, and again NI was demonstrated for BCSS, RFI and OS. Conclusions: For patients aged 50 or older and 3 years post diagnosis, Mammo-50 demonstrated that less frequent mammograms were no worse than annual mammograms. These results provide evidence for less frequent mammographic surveillance for this patient population. Citation Format: Janet Dunn, Peter Donnelly, Nada Elbeltagi, Andrea Marshall, Alastair Thompson, Riccardo Audisio, Sarah Pinder, David Cameron, Amy Campbell, Sue Hartup, Lesley Turner, Annie Young, Helen Higgins, Eila Watson, Sophie Gasson, Peter Barrett-Lee, Claire Hulme, Bethany Shinkins, Peter Hall, Andy Evans. Mammographic surveillance in early breast cancer patients aged 50 years or over: results of the Mammo-50 non-inferiority trial of annual versus less frequent mammography [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr GS03-02.

Abstract Introduction: There is a lack of evidence or consensus on the optimum frequency and duration of mammographic surveillance and follow-up for breast cancer patients aged 50 years and older at diagnosis. Mammo-50 will provide clinicians with valuable, risk-adjusted information to guide their future practice and is due to report December 2023. Quality of life (QoL) was assessed in a sub-study of the main trial. Methods: A multi-centre, randomised controlled, phase III trial of annual mammography versus 2-yearly for conservation surgery and 3-yearly for mastectomy patients with an observational cohort to explore reasons for non-participation. The trial randomised 5235 women between April 2014 and September 2018 and a further 915 registered in the cohort; 90% of women agreed to participate in the QoL sub-study. QoL questionnaires were completed at trial entry (3 years post-surgery) and then annually for up to 10 years. The distress thermometer was used as a patient reported measure of distress and concerns throughout the trial. The trial team contacted the patient’s clinical care team informing them of the reasons causing patients’ high levels of distress. Results: A total of 4521 (74%) women completed the distress thermometer at baseline. Of these, 289 (6.4%) reported high levels of distress (score 8-10), 825 (18.2%) medium levels of distress (score 5-7), 2033 (45.0%) low levels of distress (1-4) and 1374 (30.4%) reported no distress. Levels of distress were similar across clinical characteristics including surgery type, disease type and ER status, but differed for hormone therapy use (p=0.004). Women who had stopped hormone therapy tended to have higher levels of distress than those who had never had hormone therapy or for whom hormone therapy was ongoing. The most common reasons for causing high levels of distress (score, 8-10) in the 289 patients were sleep problems and/or nightmares (135 (47%)), fatigue, exhaustion or extreme tiredness (132 (46%)), worry, fear or anxiety (111 (38%)), hot flushes (94 (33%)), pain (89 (31%)), memory or concentration (84 (29%)) and sadness or depression (84 (29%)) of patients. Conclusions: Within the Mammo-50 trial, 6.4% of women reported high levels of distress upon trial entry. A quarter of women reported high/medium levels of distress with sleep, fatigue, worry, hot flushes, memory and sadness/depression being the main concerns. Levels of distress were highest in those women who had stopped hormone therapy. These results have been fed back to the UK NCRI breast cancer symptom management group whose remit it is to identify and provide guidelines for supporting women with unmet needs. Acknowledgement and disclaimer: This study is funded by the NIHR HTA programme (project ref. 11/25/03). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. Citation Format: Amy F. Campbell, Andrea Marshall, Janet A. Dunn, Peter K. Donnelly, Andy J. Evans, Nada I. Elbeltagi, David A. Cameron, Riccardo A. Audisio, Lesley Turner, Eila Watson, Sophie J. Gasson, Annie M. Young, Alastair M. Thompson, Mammo-50 Trial Management Group. Mammo-50: Mammographic surveillance in early breast cancer patients aged over 50 years – patient reported outcomes 3 years post diagnosis [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 P5-08-04.

TPS615 Background: Neoadjuvant chemotherapy (NACT) results in eradication of cancer in the axillary nodes in 40-70% of patients. This raises questions about the benefit of further axillary treatment in patients with no evidence of residual nodal disease (ypN0) post NACT. Methods: Design: ATNEC is a phase 3, randomized (1:1), multi-center UK trial, with embedded economic evaluation. Patients with proven axillary node metastases on needle biopsy receive NACT followed by sentinel node biopsy (SNB). If the sentinel nodes have converted to benign (ypN0), ATNEC randomly assigns patients to axillary treatment (nodal radiotherapy [ART] or axillary nodal clearance [ALND]) vs no further axillary treatment. Stratification: Institution, type of surgery (breast conserving surgery vs mastectomy), receptor status (triple negative vs HER2 positive vs ER positive and/or PR positive and HER2 negative).Inclusion criteria: Age ≥ 18; Male or female; T1-3N1M0 breast cancer at diagnosis (pre-NACT); FNA or core biopsy confirmed axillary nodal metastases at presentation; ER and HER2 status evaluated on primary tumor; Received standard NACT as per local guidelines; Imaging of the axilla to assess response to NACT;Dual tracer SNB post-NACT and at least 3 nodes removed (sentinel nodes and marked node): If a single tracer is used, the patient is eligible if the involved node is marked pre-NACT and at least 3 nodes removed (including the marked node), If axillary node sampling is performed following failed localization of sentinel nodes, patient is eligible if at least 3 nodes removed (including the marked node), If node is not marked, or marked node is not removed, patient is eligible if the histology report shows evidence of down-staging with complete pathological response in at least one node and at least 3 nodes removed; No evidence of nodal metastases post NACT (ypN0). Exclusion criteria: Bilateral invasive breast cancer; SNB prior to NACT; Previous ipsilateral axillary nodal surgery; Previous cancer within last 5 years or concomitant malignancy. Aims: To assess whether omitting further axillary treatment (ALND & ART) for patients with early-stage breast cancer and axillary nodal metastases on needle biopsy - who after NACT have no residual nodal disease on SNB (ypN0) - is non-inferior to axillary treatment in terms of disease-free survival, and reduces lymphoedema at 5 years. Statistical methods: All analyses will be carried out on an intention-to-treat basis to preserve randomization, avoid bias from exclusions and preserve statistical power. Radiotherapy Quality Assurance: Study has in-built radiotherapy QA program that will be coordinated by National Radiotherapy Trials QA (RTTQA) group. Target accrual: 1,900 Status: Recruiting. As of 11-Feb-2022, 39 sites open, 87 patients enrolled, 31 randomized. Clinical trial information: NCT04109079.

Background: Clinical trials are key to improving outcomes in metastatic breast cancer (MBC). However, participation is low. Little data exists regarding the attitudes and experiences of patients in relation to clinical research. This study co-developed by a patient living with MBC and researchers aims to explore the experiences and issues related to accessing and participating in clinical research. Material and Method: A mixed methods study consisting of an online survey and qualitative interviews. Participants responded to an online questionnaire which contained closed and open questions, this was live between 17th May 2021 and 30th November 2021. Qualitative interviews from a sample of patients who gave their consent were carried out between 15th August 2021 and 22nd November 2021. Descriptive statistical analysis of the quantitative results from the closed questions and thematic analysis of the qualitative data generated by the open-ended questions and interviews were utilised. Data were extracted on 1st December 2021. Results: 768 eligible responses were received (765 female, 2 male, 1 unknown gender). The greatest proportion of responders were aged 51-60 years (37%), 92% were white (n=708) and 45% employed (n=345). 31% (n=235) were diagnosed with MBC within the last year with 14% (n=107) >5 years ago. 86% (n=660) knew what a clinical trial was. With 23% (n=173) reported an oncologist raising trial participation while 32% (n=243) of patients raising participation with their oncologist. Responses to such inquiries varied from positive and supportive to ‘vague and dismissive’. Accessing new treatments (96%, n=737) and playing a more active role in own health (81%, n=619) would encourage trial participation while being unsure of potential benefits (43%, n=333) was the commonest reason for possible non-participation. Preferred sources of information on trials were a consultant (80%, n=612), nurse (61%, n=467) or trial database (29%, n=220). 36% (n=276) were willing to travel for a study increasing to 56% (n=430) if travel costs were covered, and 43% (n=306) would travel worldwide for a study. £0 to over £100 per month for travel was reported to be affordable. Of the 14% (107 of 768) who had taken part in clinical trials; 72% (n=77) found it a positive experience. Free text responses indicated this was related to additional/longer monitoring. The lack of information relating to trials was a recurring theme. 21 participants were interviewed for the qualitative sub study, with three complementary themes emerging from these namely (1) information about clinical trials/research, (2) barriers to participation and (3) research priorities. Conclusion: This large UK study provides insights into the experiences and attitudes of patients with MBC in relation to clinical research. It demonstrates that patients are keen to be involved in research but face barriers to inclusions. Key messages include the need to develop patient facing trial databases, the importance of clinical staff in the provision of study information and a willingness to travel for a trial but the need for financial support. Addressing the issues identified in this survey are key to ensuring MBC patients not only have opportunities to participate in clinical research but also the ability to take these opportunities up. Citation Format: Lesley Stephen, Janet A. Dunn, Claire Balmer, Sophie J. Gasson, Nada I. Elbeltagi, Ellen R. Copson, Carlo Palmieri. A UK study exploring the attitudes and experience of patients living with metastatic breast cancer with regard to clinical research: A patient advocate-academic collaborative study [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 P4-07-37.

Background: For patients who are node positive at presentation and are found to have a complete nodal tumour response (ypN0) post-neoadjuvant chemotherapy (NACT), we do not yet know whether local axillary therapy can be modified based on the response to NACT. ATNEC addresses whether axillary treatment can be de-escalated, post-surgery, in T1-3N1M0 breast cancer patients who have no residual nodal disease post-NACT. Methods: Design: ATNEC is a phase III, randomized (1:1), multi-centre trial, with embedded economic evaluation. Patients with proven axillary node metastases on needle biopsy receive NACT followed by sentinel node biopsy (SNB). If the sentinel nodes have converted to ypN0, ATNEC randomizes patients to axillary treatment (nodal radiotherapy [ART] or axillary nodal clearance [ANC]) vs. no further axillary treatment. Stratification: Institution, type of surgery (breast conserving surgery vs mastectomy), receptor status (triple negative vs HER2 positive vs ER positive and/or PR positive and HER2 negative). Inclusion criteria: • Age ≥ 18 • Male or female • T1-3N1M0 breast cancer at diagnosis (pre-NACT) • FNA or core biopsy confirmed axillary nodal metastases at presentation • ER and HER2 status evaluated on primary tumour • Received standard NACT as per local guidelines • Imaging of the axilla to assess response to NACT • Dual tracer SNB post-NACT and at least 3 nodes removed (sentinel nodes and marked node). o If a single tracer is used, the patient is eligible if the involved node is marked pre-NACT and at least 3 nodes removed (including the marked node) o If axillary node sampling is performed following failed localization of sentinel nodes, patient is eligible if at least 3 nodes removed (including the marked node). o If node is not marked, or marked node is not removed, patient is eligible if the histology report shows evidence of down-staging with complete pathological response in at least one node of the 3 removed nodes. • No evidence of nodal metastases post-NACT (ypN0) Exclusion criteria: • Bilateral invasive breast cancer • SNB prior to NACT • Previous ipsilateral axillary nodal surgery • Previous cancer within last 5 years or concomitant malignancy Aims: To assess whether omitting further axillary treatment (ART or ANC) for patients with early stage breast cancer and axillary nodal metastases on needle biopsy - who post NACT have no residual nodal disease on SNB (ypN0) - is non-inferior to axillary treatment in terms of disease-free survival, and whether lymphoedema is reduced at 5 years. Statistical methods: All analyses will be carried out on an intention-to-treat basis to preserve randomization, avoid bias from exclusions and preserve statistical power. Radiotherapy Quality Assurance: ATNEC has in-built radiotherapy QA coordinated by National Radiotherapy Trials QA (RTTQA) group. The RTQA monitors trial protocol compliance ensuring clinical outcomes reflect differences in randomization schedules rather than departures from the protocol. ATNEC is the only trial in the UK that offers QA for IMC radiotherapy. Screening Data: ATNEC collects screening data to monitor acceptance rates and reasons why patients decline the trial to identify ways to improve recruitment. Screening data until 30-Jun-22 shows that 69% of eligible patients were approached (244/354) and, of those approached, 45% were consented (109/244). For the 81 patients who declined, the most common reasons were; preference for axillary treatment (31%), preference for no axillary treatment (10%), no reason documented (23%) and ineligibility (21%). ClinicalTrials.gov: NCT04109079 Target accrual: 1900 Target sites: 100 Trial Status: Recruiting. As of 30-Jun-22: 52 sites open, 158 patients enrolled, 54 randomised. ATNEC is open to new sites and international collaboration. Citation Format: Amit Goyal, Sophie Nicholls, Andrea Marshall, Natalie Hammonds, Duncan Wheatley, Beatrix Elsberger, Janice Rose, Helen-Teresa Edwards, Roeum Butt, Abeer Shaaban, Shama Puri, Samreen Ahmed, Tara Homer, Luke Vale, Julie Bruce, Sophie J. Gasson, Helen Higgins, Janet A. Dunn. ATNEC: A multicentre, randomized trial investigating whether axillary treatment can be avoided in T1-3N1M0 breast cancer patients with no residual cancer in the axillary lymph nodes after neoadjuvant chemotherapy [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 OT1-09-02.

OBJECTIVE:This research took a co-design approach to develop a social intervention to support people affected by a cancer diagnosis to be physically active. METHODS:We conducted semi-structured interviews with five key stakeholder groups: (1) adults with a recent breast or prostate cancer diagnosis; (2) family and friends of cancer patients; (3) healthcare professionals; (4) physical activity providers; and (5) cancer charity representatives. Inductive content analysis was used to identify themes in the data. We then worked with a subset of participants to co-develop the intervention. RESULTS:Participants welcomed the idea of a social approach to a physical activity intervention. Input was received on the timing and format of delivery, how to communicate about physical activity to cancer patients and their family and friends and the types of physical activity that would be appropriate. Our findings suggest that interventions need to be flexible in terms of timing and delivery and offer a wide range of physical activity options. These findings directly informed the co-development of 'All Together Active'. CONCLUSION:All Together Active is designed to support cancer patients and their family and friends to be active throughout treatment and beyond, benefiting their physical and mental health.

Background: ACOSOG Z1071 demonstrated the reliability of sentinel node biopsy (SNB) at assessing residual nodal disease post-neoadjuvant chemotherapy (NACT), in patients with nodal metastasis at presentation. However, we do not know whether local axillary therapy can be modified based on NACT response.

Background: For patients who are node positive to start at presentation and are found to have a complete nodal tumour response (ypN0) post neoadjuvant chemotherapy (NACT), we do not yet know whether local axillary therapy can be modified based on the response to NACT. ATNEC randomised trial specifically address axillary management following NACT in patients with proven axillary node metastases. Methods: Design: ATNEC is a phase III, randomised (1:1), multi-centre trial, with embedded economic evaluation. Patients with proven axillary node metastases on needle biopsy receive NACT followed by sentinel node biopsy (SNB). If the sentinel nodes have converted to benign (ypN0), ATNEC randomly assigns patients to axillary treatment (nodal radiotherapy or axillary nodal clearance) vs. no axillary treatment (without further surgery). Aims: To assess whether, omitting further axillary treatment (ALND and ART) for patients with early stage breast cancer and axillary nodal metastases on needle biopsy - who after NACT have no residual nodal disease on SNB - is non-inferior to axillary treatment in terms of disease free survival, and reduces the risk of lymphoedema at 5 years. Stratification: Institution, type of surgery (breast conserving surgery [BCS] vs mastectomy), receptor status (triple negative vs HER2 positive vs ER status positive and/or PR status positive and HER2 negative). Inclusion criteria:. • Age ≥ 18. • Male or female. • T1-3N1M0 breast cancer at diagnosis (pre-NACT). • FNA or core biopsy confirmed axillary nodal metastases at presentation. • ER and HER2 status evaluated on primary tumour. • Received standard NACT as per local guidelines. • Imaging assessment of the axilla at completion of NACT. • Dual tracer SNB after NACT and at least 3 nodes removed (sentinel nodes and marked node). o If a single tracer is used, the patient is eligible if the involved node is marked before NACT and at least 3 nodes removed (including the marked node). o If axillary node sampling is performed following failed localisation of sentinel nodes, patient is eligible if at least 3 nodes removed (including the marked node). o If node is not marked, or marked node is not removed, patient is eligible if the histology report shows evidence of down-staging with complete pathological response in at least one node and at least 3 nodes removed. • No evidence of nodal metastases post NACT (ypN0). Exclusion criteria:. • Bilateral invasive breast cancer. • SNB prior to NACT. • Previous ipsilateral axillary nodal surgery. • Previous cancer within last 5 years or concomitant malignancy. Radiotherapy Quality Assurance: ATNEC has in-built radiotherapy QA programme that is coordinated by National Radiotherapy Trials QA (RTTQA) group. Target accrual: 1900 Number of sites: 100 Trial Status: Recruiting. Trial is open to new sites. Disclaimer: This study is funded by the National Institute for Health Research (NIHR) Health Technology Assessment (HTA) programme (Reference - HTA NIHR128311). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. Citation Format: Amit Goyal, Sophie Cramp, Andrea Marshall, Duncan Wheatley, Natalie Hammonds, Shama Puri, Tara Homer, Luke Vale, Roeum Butt, Romaana Mir, Janice Rose, Helen Teresa Edwards, Samreen Ahmed, Abeer Shaaban, Beatrix Elsberger, Julie Bruce, Sophie Gasson, Valerie Speirs, Jacqui Shaw, Helen Higgins, Janet Dunn. ATNEC: A multi-centre, randomised trial investigating whether axillary treatment can be avoided in T1-3N1M0 breast cancer patients with no residual cancer in the lymph glands after neoadjuvant chemotherapy (clinicaltrials.gov: nct04109079) [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 OT1-04-01.

Abstract Background: Neoadjuvant chemotherapy (NACT) results in eradication of cancer in the axillary lymph nodes in 40% to 70% of patients. This has raised questions about the benefit of further axillary treatment in these patients with no evidence of residual disease in the lymph nodes. Trial design: A multi-centre phase III randomised controlled trial with embedded economic evaluation in which participants will be randomised in a 1:1 ratio. Study participants: T1-3N1M0 breast cancer patients aged 18 years or older, with needle biopsy proven nodal metastases, who after NACT have no residual cancer in the lymph nodes on dual tracer sentinel node biopsy and removal of at least 3 lymph nodes (sentinel nodes and marked involved node). Intervention: Participants in the experimental group will not receive further axillary treatment (axillary lymph node dissection [ALND] or axillary radiotherapy [ART]), after NACT and surgery. Participants in the control group will receive further axillary treatment (ALND or ART) after NACT and surgery, as per local guidelines. Stratification: Institution, type of breast surgery (breast conserving surgery (BCS) vs mastectomy), receptor status (triple negative vs HER2 positive vs ER status positive and/or PR status positive and HER2 negative) Eligible participants will be/should have:•Age ≥ 18•Male or female •T1-3N1M0 breast cancer at diagnosis (prior to NACT) •FNA or core biopsy confirmed axillary nodal metastases at presentation •Oestrogen receptor and HER2 status evaluated on primary tumour •Received standard NACT as per local guidelines (Patients undergoing neoadjuvant endocrine therapy as part of another clinical trial are eligible) •Ultrasound of the axilla at completion of NACT •Undergo dual tracer sentinel node biopsy after NACT and at least 3 nodes removed (sentinel nodes and marked node). If axillary node sampling is performed following failed localisation of sentinel nodes, patient will be eligible if at least 3 nodes removed (including the marked node) •No evidence of nodal metastases post NACT (isolated tumour cells, micro or macro metastasis) Participants will be excluded if they have any one of the following:•Bilateral invasive breast cancer•Sentinel node biopsy prior to NACT•Marked node not removed except where at least one node removed showsoevidence of down-staging with complete pathological response e.g. fibrosis or scarring and at least 3 nodes removed•Previous axillary surgery on the same body side as the scheduled targeted sampling•Any previous cancer within last 5 years or concomitant malignancy except basal or squamous cell carcinoma of the skin, in situ carcinoma of the cervix oin situ or stage 1 melanoma, contra- or ipsilateral in situ breast cancer Specific aims: To assess whether, omitting further axillary treatment (ALND and ART) for patients with early stage breast cancer and axillary nodal metastases on needle biopsy, who after NACT have no residual cancer in the lymph nodes on sentinel node biopsy, is non-inferior to axillary treatment in terms of disease free survival (DFS), and reduces the risk of lymphoedema at 5 years.Statistical methods: All analyses will be carried out on an intention-to-treat basis to preserve randomisation, avoid bias from exclusions and preserve statistical power. Target accrual: 1900, Number of sites: ~100 ClinicalTrials.gov: NCT04109079 Contact information: atnec@warwick.ac.uk Disclaimer: This study is funded by the National Institute for Health Research (NIHR) Health Technology Assessment (HTA) programme (Reference - HTA NIHR128311). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. Citation Format: Amit Goyal, Sophie Cramp, Duncan Wheatley, Andrea Marshall, Shama Puri, Tara Homer, Luke Vale, Romaana Mir, Zohal Nabi, Janice Rose, Helen Teresa Edwards, Samreen Ahmed, Abeer Shaaban, Beatrix Elsberger, Julie Bruce, Sophie Gasson, Valerie Speirs, Jacqui Shaw, Helen Higgins, Janet Dunn. Axillary management in T1-3N1M0 breast cancer patients with needle biopsy proven nodal metastases at presentation after neoadjuvant chemotherapy - ATNEC (ClinicalTrials.gov NCT04109079) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-04-01.

TPS600 Background: Neoadjuvant chemotherapy (NACT) results in eradication of cancer in the axillary nodes in 40% to 70% of patients. This raises questions about the benefit of further axillary treatment in those patients with no evidence of residual nodal disease (ypN0) after NACT. Methods: Design: ATNEC is a phase 3, randomised (1:1), multi-centre trial, with embedded economic evaluation, comparing standard axillary treatment (axillary lymph node dissection [ALND] or axillary radiotherapy [ART]) with no further axillary treatment in T1-3N1M0 breast cancer patients with needle biopsy proven axillary nodal metastases, who after NACT have no residual nodal disease (ypN0) on dual tracer sentinel node biopsy (SNB) and removal of at least 3 nodes (sentinel nodes and marked involved node). Stratification: Institution, type of surgery (breast conserving surgery vs mastectomy), receptor status (triple negative vs HER2 positive vs ER positive and/or PR positive and HER2 negative). Inclusion criteria are: Age ≥ 18, Male or female, T1-3N1M0 breast cancer at diagnosis (pre-NACT), FNA or core biopsy confirmed axillary nodal metastases at presentation, ER and HER2 status evaluated on primary tumour, received standard NACT as per local guidelines, ultrasound of the axilla at completion of NACT, dual tracer SNB after NACT and at least 3 nodes removed (sentinel nodes and marked node), no evidence of nodal metastases post NACT (ypN0). Exclusion criteria are: bilateral invasive breast cancer, SNB prior to NACT, marked node not removed except where at least one node removed shows evidence of down-staging with complete pathological response e.g. fibrosis/scarring and at least 3 nodes removed, previous ipsilateral axillary surgery, previous cancer within last 5 years or concomitant malignancy except basal or squamous cell carcinoma of the skin, in situ carcinoma of the cervix, in situ or stage 1 melanoma, contra- or ipsilateral in situ breast cancer. Aims: To assess whether, omitting further axillary treatment (ALND and ART) for patients with early stage breast cancer and axillary nodal metastases on needle biopsy - who after NACT have no residual nodal disease on SNB (ypN0) - is non-inferior to axillary treatment in terms of disease free survival, and reduces the risk of lymphoedema at 5 years. Statistical methods: All analyses will be carried out on an intention-to-treat basis to preserve randomisation, avoid bias from exclusions and preserve statistical power. Radiotherapy quality assurance: Study has in-built radiotherapy QA programme that will be co-ordinated by National Radiotherapy Trials QA (RTTQA) group. Target accrual: 1900. Trial status: Recruiting. Number of sites: 100. Clinical trial information: NCT04109079.

BackgroundThe addition of adjuvant trastuzumab to chemotherapy has significantly improved outcomes for people with human epidermal growth factor receptor 2 (HER2)-positive, early, potentially curable breast cancer. Twelve months’ trastuzumab, tested in registration trials, was adopted as standard adjuvant treatment in 2006. Subsequently, similar outcomes were demonstrated using 9 weeks of trastuzumab. Shorter durations were therefore tested for non-inferiority.ObjectivesTo establish whether or not 6 months’ adjuvant trastuzumab is non-inferior to 12 months’ in the treatment of HER2-positive early breast cancer using a primary end point of 4-year disease-free survival.DesignThis was a Phase III randomised controlled non-inferiority trial.SettingThe setting was 152 NHS hospitals.ParticipantsA total of 4088 patients with HER2-positive early breast cancer who it was planned would receive both chemotherapy and trastuzumab took part.InterventionRandomisation (1 : 1) to 6 months’ or 12 months’ trastuzumab treatment.Main outcomesThe primary end point was disease-free survival. The secondary end points were overall survival, cost-effectiveness and cardiac function during treatment with trastuzumab. Assuming a 4-year disease-free survival rate of 80% with 12 months’ trastuzumab, 4000 patients were required to demonstrate non-inferiority of 6 months’ trastuzumab (5% one-sided significance, 85% power), defining the non-inferiority limit as no worse than 3% below the standard arm. Costs and quality-adjusted life-years were estimated using a within-trial analysis and a lifetime decision-analytic model.ResultsBetween 4 October 2007 and 31 July 2015, 2045 patients were randomised to 12 months’ trastuzumab and 2043 were randomised to 6 months’ trastuzumab. Sixty-nine per cent of patients had ER-positive disease; 90% received anthracyclines (49% with taxanes; 41% without taxanes); 10% received taxanes without anthracyclines; 54% received trastuzumab sequentially after chemotherapy; and 85% received adjuvant chemotherapy (58% were node negative). At 6.1 years’ median follow-up, with 389 (10%) deaths and 566 (14%) disease-free survival events, the 4-year disease-free survival rates for the 4088 patients were 89.5% (95% confidence interval 88.1% to 90.8%) in the 6-month group and 90.3% (95% confidence interval 88.9% to 91.5%) in the 12-month group (hazard ratio 1.10, 90% confidence interval 0.96 to 1.26; non-inferiorityp = 0.01), demonstrating non-inferiority of 6 months’ trastuzumab. Congruent results were found for overall survival (non-inferiorityp = 0.0003) and landmark analyses 6 months from starting trastuzumab [non-inferiorityp = 0.03 (disease-free-survival) andp = 0.006 (overall survival)]. Six months’ trastuzumab resulted in fewer patients reporting adverse events of severe grade [365/1929 (19%) vs. 460/1935 (24%) for 12-month patients;p = 0.0003] or stopping early because of cardiotoxicity [61/1977 (3%) vs. 146/1941 (8%) for 12-month patients;p < 0.0001]. Health economic analysis showed that 6 months’ trastuzumab resulted in significantly lower lifetime costs than and similar lifetime quality-adjusted life-years to 12 months’ trastuzumab, and thus there is a high probability that 6 months’ trastuzumab is cost-effective compared with 12 months’ trastuzumab. Patient-reported experiences in the trial highlighted fatigue and aches and pains most frequently.LimitationsThe type of chemotherapy and timing of trastuzumab changed during the recruitment phase of the study as standard practice altered.ConclusionsPERSEPHONE demonstrated that, in the treatment of HER2-positive early breast cancer, 6 months’ adjuvant trastuzumab is non-inferior to 12 months’. Six months’ treatment resulted in significantly less cardiac toxicity and fewer severe adverse events.Future workOngoing translational work investigates patient and tumour genetic determinants of toxicity, and trastuzumab efficacy. An individual patient data meta-analysis with PHARE and other trastuzumab duration trials is planned.Trial registrationCurrent Controlled Trials ISRCTN52968807, EudraCT 2006-007018-39 and ClinicalTrials.gov NCT00712140.FundingThis project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full inHealth Technology Assessment; Vol. 24, No. 40. See the NIHR Journals Library website for further project information.