500 Background: Tumor gene expression tests are widely used to assist adjuvant chemotherapy decisions for women with early breast cancer (EBC). OPTIMA (Optimal Personalised Treatment of early breast cancer using Multi-parameter Analysis) is an international RCT comparing chemotherapy decisions made with the Prosigna (PAM50) gene expression test with standard treatment in mostly node-positive patients. Methods: Women and men aged >40 recommended to receive chemotherapy for ER+ HER2- EBC with 0-9 involved axillary nodes and T size >30mm if node negative were eligible. Randomization was between standard chemotherapy followed by endocrine therapy (CET) or to a Prosigna test directed chemotherapy decision. Patients with Prosigna ROR score > 60 tumors were assigned CET whilst those with low ROR score (≤60) tumors received endocrine therapy (ET) alone. ET for premenopausal women included ovarian function suppression (OFS) in the absence of chemotherapy-induced ovarian insufficiency. ROR scores were not disclosed, and patients receiving CET were blinded to their randomization. OPTIMA was designed to demonstrate non-inferiority (NI) of 5-year invasive breast cancer free survival (IBCFS) in the test-directed arm with a 3% margin in the per protocol (PP) population using a 5% 1-sided alpha. Control arm testing allowed treatment comparison within the low ROR score population at a 3.5% NI margin. Results: From 16 th Jan 2017 to 12 th Dec 2025 4429 patients were randomized, 2215 to the control arm and 2214 to the test-directed arm of whom 2061 (93%) and 2097 (95%) were included in the respective PP group. Patient characteristics in the PP population were well-balanced; 62% were postmenopausal, 37% premenopausal and 0.8% male. 73% had pN1/pN1sn, 8% had pN0/pN1mi and 19% had pN2 tumors. 68% had low ROR score tumors. With a median follow-up of 3.9 years (interquartile range 2.0-5.9), 280 IBCFS events occurred (141 on control arm; 139 on test directed arm) of which 66% were distant recurrences. The 5-year IBCFS rate in the control arm was 91.5% [95% CI 89.7- 92.9%] and 90.4% [95% CI 88.6- 92.0%] in the test-directed arm, Hazard Ratio (HR) 0.99 [90% CI 0.81- 1.20], NI p = 0.013, thereby meeting the pre-defined NI margin. The corresponding 5-year IBCFS rates for the low ROR score population were 94.9% [95% CI 92.9- 96.4%] and 93.7% [95% CI 91.8- 95.2%] for the two arms respectively, HR 1.06 [90% CI 0.78- 1.46] NI p = 0.0051 again demonstrating non-inferiority. There was no significant outcome heterogeneity between subgroups including for menopausal and nodal status. Conclusions: The OPTIMA trial demonstrates that women and men with ER+ HER2- EBC and ROR score ≤60 tumors can safely avoid chemotherapy. It provides evidence for the utility of test-directed chemotherapy in premenopausal women treated with OFS and patients with high levels of nodal involvement. Clinical trial information: ISRCTN42400492.

Introduction Up to 40% of women with breast cancer will require a mastectomy, and breast reconstruction is routinely offered to restore symmetry. While not all women want, or are suitable for, breast reconstruction, many want to be symmetrical following breast cancer surgery. For these women, contralateral mastectomy for ‘flat symmetry’ is a good alternative, but in the UK, access to contralateral ‘symmetrising’ mastectomy (CSM) is highly variable. Many women seeking this option describe feeling frustrated, unsupported and having to ‘fight’ to access care, while clinicians express concerns about decisional regret. The FLAME (FLat symmetry After Mastectomy for brEast cancer) study aims to work with key stakeholders to co-develop a consensus-based pathway to improve access and outcomes for women seeking CSM as an alternative to breast reconstruction after a unilateral mastectomy for breast cancer.Methods and analysis Pathway development will be underpinned by the Medical Research Council (MRC) framework for the development of complex interventions, informed by the Behaviour Change Wheel and Capability, Opportunity, Motivation—Behaviour framework, complemented by Intervention Mapping. There will be six key stages: (1) creation of a logic model of the issues that need to be addressed with the CSM pathway using a systematic literature review, national practice surveys and qualitative interviews with key stakeholders; (2) definition of the logic model of change objectives (performance objectives, change determinants and change objectives); (3) pathway design informed by appropriate behaviour change techniques; (4) co-development of the pathway in a co-design workshop involving key stakeholders; (5) co-development of an implementation plan and (6) future evaluation.Ethics and dissemination Ethical approval has been obtained from the University of Bristol Research Ethics Review Committee (ref: 27961). Written and verbal informed consent will be obtained from all participants before the interview study and again from individuals participating in the workshop. Findings will be presented at national/international meetings and published in peer-reviewed journals. Dissemination materials will be co-produced with key stakeholders and shared widely with professional associations and patient support organisations to promote uptake and implementation.

Improved outcomes, particularly the marked reduction in locoregional recurrence, and the increasing numbers of survivors of early breast cancer, have led to the wish to reduce treatment morbidity, without compromising long-term outcomes.Trials to assess reduced breast and axillary surgery, radiotherapy and endocrine therapy have all been conducted and led to new standards of care and reduced toxicity.In some cases, however, implementation of research findings has been compromised by a relative lack of quality control in trials, substitution of a de-escalated treatment by an alternative, a lack of patient-relevant endpoints and the difficulties in the design and powering of ‘non-inferiority’ trials.We summarize the current landscape of care and clinical research in this area, explore the problems identified in some studies and suggest how they may be mitigated.

Background: In the UK, all patients with newly diagnosed invasive breast cancer have axillary staging with an axillary USS +/- biopsy of abnormal/equivocal nodes and currently UK NICE guidelines recommend axillary node clearance (ANC) for allpatients with biopsy proven node positive breast cancer having primary surgery, irrespective of the number of nodes involved (∼20% of all patients). This highly morbid procedure leads to life-long complications in 1 in 3 patients including lymphoedema and chronic pain which dramatically impact quality of life. ANC aims to reduce locoregional recurrence (LRR) and improve breast cancer survival but there is no evidence to support these benefits for patients with limited nodal involvement (cN0, radiologically detected disease). These patients would meet the criteria for omission of ANC based on eligibility for the ACOSOG Z0011 trial, but this approach has not been adopted in the UK due to concerns regarding false negative sentinel node biopsy (SNB) in node positive patients. Targeted axillary dissection (TAD) which combines removal of the localised biopsy proven involved node(s) in combination with a SNB may offer an alternative to ANC, effectively addressing concerns regarding false negative rates while reducing the risk of life-changing complications The TADPOLE study aims to determine if TAD is a clinically and cost-effective alternative to ANC in patients with low volume node positive breast cancer having primary surgery. Methods: TADPOLE is a multicentre pragmatic phase 3 randomised controlled trial comparing TAD and ANC in breast cancer patients with low volume nodal disease having primary surgery. All patients with cN0 biopsy proven low volume axillary nodal disease will be eligible to participate. Excluded will be patients with >3 nodes on USS, those who have recurrent disease, previous axillary surgery or neoadjuvant systemic therapy. Participants will be randomised 2:1 to TAD or ANC. Surgical quality assurance (QA) processes will promote standardised introduction of ‘primary’ TAD in the UK and ensure procedure fidelity within the trial. Participants will have adjuvant therapy as per standard of care but axillary radiotherapy (ART) will be prohibited in the TAD group. Robust radiotherapy quality assurance (RTTQA) will be embedded throughout. The co-primary end-points are: i) Patient reported and objective lymphoedema at 12 months ii) Single arm analysis of LRR at 5 years in the TAD cohort. Recruitment of 390 patients in the TAD arm will be required to detect a 50% reduction in lymphoedema at 12 months with 90% power and a type 1 error of 5% and exclude an undesirable LRR of <5% in the TAD cohort at 5 years with one sided 2.5% alpha and 90% power. Inflating for multiplicity and allowing for 5% dropout and 5% crossover a total of 861 patients (574 TAD:287 ANC) will be required for the trial. 40 UK breast units will recruit to the trial. An embedded qualitative study will optimise recruitment and a SWAT (study within a trial) will optimise the inclusion of non-English speaking participants. Results: Consensus work with UK breast surgeons to agree how to standardise axillary surgery within the trial is underway and will underpin the surgical QA within TADPOLE. The trial will commence recruitment early 2025 and include a 9 month internal pilot phase. Recruitment is planned for 28 months with a target of 1 participant/centre/m at 40 sites. Conclusion: TADPOLE has been designed with extensive patient and public involvement and will address the top UK breast surgery research priority identified in the James Lind Alliance Priority Setting Process. If TAD causes less lymphoedema and is oncologically safe, TADPOLE will change practice, improving outcomes for thousands of patients with node positive breast cancer each year. Citation Format: Shelley Potter, Kerry Avery, Ramsey Cutress, David Dodwell, Nisha Sharma, Katherine Fairhurst, Tim Robinson, Indrani Bhattacharya, Natalie Blencowe, Hannah Markham, Elsa Marques, Lucy Culliford, Petra Baji, Kirsty Roberts, Jessica Harris, Sophie Rees, Adrienne Morgan, Margaret Perkins, Stuart A McIntosh. TADPOLE: A multicentre, pragmatic, phase III randomised controlled trial comparing Targeted Axillary Dissection vs axillary node clearance in patients with POsitive axillary Lymph nodes in Early breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P3-08-16.

DAG illustrating the assumed relationships between covariates, exposure and endometrial cancer.

Results for the main analysis investigating the association between MetS, and MetS components and endometrial cancer risk.

STROBE Statement—Checklist of items that should be included in reports of cohort studies

Tumours with genomic instability display enhanced immunogenicity and potential for response to immune checkpoint blockade (ICB). Interestingly, chemotherapy mediated DNA damage can also stimulate the immune system through activation of the cGAS/STING innate immune pathway and therefore, improve clinical outcomes in combination with ICB. Here we set out to compare the ability of classically used chemotherapies to activate innate immunity, as well as characterise the mechanism(s) behind it. We identified topoisomerase 2 (TOP2) poisons, such as anthracyclines, as the most effective activators of cGAS/STING, leading to a potent type I interferon response. Mechanistically, we demonstrate that abortive TOP2cc repair intermediates (dsDNA fragments containing 5’-phosphotyrosyl residues) get encapsulated within micronuclei and activate cGAS, which can be blocked with antimitotic agents (e.g. taxanes). Crucially, we discovered that these 5’-phosphotyrosyl linked fragments are resistant to nuclease degradation by the cytoplasmic nuclease TREX1, which stabilises them, resulting in robust cGAS/STING mediated inflammation. Finally, using in vivo modelling, we confirmed that Top2 poisons enhance anti-tumour responses to ICB in comparison to taxanes. In line with this, using pre and on-treatment breast tumour biopsies, we have shown that anthracycline-based chemotherapy induces a robust type I interferon response in breast tumours, driving tumour lymphocytic infiltration. Moreover, following anthracycline treatment with taxane treatment results in supression of lymphocytic infiltration in these same tumours. Collectively, our findings reveal that TOP2 poison mediated DNA lesions enhance cGAS substrate availability by impairing cytoplasmic dsDNA degradation, highlighting their ability to drive anti-tumour immune responses and enhance the therapeutic efficacy of ICB. Citation Format: Kienan Savage, Eliana M. Barros, Richard D.A. Wilkinson, Guido Zagnoli-Viera, Stuart A. McIntosh, Katrina M. Lappin, Oliver Barker, Ieuan L. Morgan, Eileen E. Parkes, Marc A. Fuchs, Nuala McCabe, Roger A. Greenberg, Tim Harrison, Keith W. Caldecott, Richard D. Kennedy. CHEMOTHERAPEUTIC TOPOISOMERASE 2 POISONS GENERATE TREX1 RESISTANT DNA FRAGMENTS THAT INDUCE A POTENT cGAS/STING RESPONSE [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P2-02-02.

Background: Effects of CDK7 in cancer include: enhanced oncogene transcription; anti-apoptotic gene upregulation; cell cycle acceleration via CDK phosphorylation; and estrogen receptor activation, driving resistance to hormonal therapy. Thus, CDK7 inhibition represents a potential anticancer strategy. Samuraciclib (CT7001), a once-daily oral CDK7 inhibitor, combined with the SERD fulvestrant had a favorable safety profile and clinical activity in patients with HR+/HER2− advanced breast cancer (BC) previously treated with a CDK4/6i [Coombes, 2023]. Patients with no detectable TP53 mutation in baseline ctDNA appeared to have better outcomes. Oral SERDs are of interest due to their pharmacokinetic (PK) properties and convenient administration. The oral SERD elacestrant significantly improves progression-free survival (PFS) versus standard-of-care endocrine therapy in ER+/HER2− advanced or metastatic BC previously treated with a CDK4/6 inhibitor, and particularly ESR1-mutant tumors [Bardia et al. SABCS 2022]. Non-clinical data indicate that the biology underlying the samuraciclib/SERD combination translates from fulvestrant to elacestrant, in addition to overcoming other resistance mechanisms. Thus, clinical evaluation of this combination is warranted [data on file]. Methods: The phase 1b/2 SUMIT-ELA open-label dose escalation and expansion study (NCT05963997) is evaluating the safety, efficacy, and PK of samuraciclib combined with elacestrant, both dosed QD. Eligible patients (n=48) are ≥18 years, have histologically or cytologically confirmed ER+/HER2− advanced or mBC not amenable to resection or radiotherapy of curative intent, have received an AI + CDK4/6i in the adjuvant or advanced setting, are receiving a LHRH agonist if pre/perimenopausal, and have RECIST v1.1 measurable or evaluable disease. All patients undergo baseline Guardant360 ctDNA analysis to assess ESR1 and TP53 mutation status. Prior SERD, mTOR inhibitor, or chemotherapy for advanced BC are not permitted. Patients undergo RECIST v1.1 evaluation at baseline, every 8 weeks until week 48, and every 12 weeks thereafter. The primary endpoints are identification of tolerable combination doses of samuraciclib and elacestrant (phase 1b) and 6-month PFS rate (phase 2). Secondary endpoints are tolerability, clinical benefit rate at 24 weeks, ORR, DoR, best percentage change in tumor size, PK, and associations between ESR1 and TP53 mutation and efficacy/safety. Results: The following cohorts (C) have been recruited and dosed with samuraciclib + elacestrant as follows: C1 (240+300 mg, n=6); C2 (360+300 mg, n=6); and C3 (360+400 mg, n=5). Dose escalation is complete and C4 expansion at the recommended top doses of both compounds is recruiting (360 mg samuraciclib + 400 mg elacestrant). Co-dosing of samuraciclib and elacestrant had no significant impact on the exposure of either agent. The most frequent all-grade treatment-related AEs were diarrhea, nausea, vomiting, asthenia, and abdominal pain. One subject in C1 (53-year-old female; TP53wt, ESR1wt; liver metastasis) experienced a confirmed partial response with a 37% reduction in the size of target lesions. Conclusions: The most frequent treatment-related AEs were similar to the known safety profiles from both previous samuraciclib and elacestrant studies. With no drug-drug interactions between the treatments, further study of combination treatment in expansion C4 is supported. Preliminary signs of antitumor activity were observed. Citation Format: Francois-Clement Bidard, Maxime Brunet, Amita Patnaik, Cécile Vicier, Raquel Gomez, Sacha Howell, Luisa Sanchez, Erin Roesch, Mario Campone, Agostina Stradella, Simon Lord, Carlos Garay, Paolo Mazzei, Glen Clack, Stuart McIntosh, William Gradishar. Cyclin-dependent kinase 7 (CDK7) inhibitor samuraciclib combined with selective estrogen receptor degrader (SERD) elacestrant in advanced HR+ breast cancer after CDK4/6i: dose escalation data from the Phase 1b/2 SUMIT-ELA study [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P2-07-22.

Introduction Mammographic screening identifies many women with small breast cancers with favourable biological features, which have an excellent prognosis. Some of these may never have become clinically apparent without screening and are commonly described as ‘overdiagnosed’ cancers. Despite this, all patients with screen-detected cancers are currently treated with surgical excision and sentinel lymph node biopsy, although this may represent overtreatment. There is, therefore, a need for less invasive approaches to reduce treatment burden for patients while maintaining current excellent oncological outcomes. Vacuum-assisted excision (VAE) may represent such an alternative treatment approach, and the SMALL (Open Surgery versus Minimally invasive-vacuum Assisted excision for smaLL screen-detected breast cancer) trial aims to investigate the use of VAE for the safe de-escalation of surgical treatment for such excellent prognosis invasive breast cancers.Methods SMALL is a prospective, multicentre, randomised phase III trial of VAE versus surgery in patients with small, biologically favourable screen-detected invasive breast cancer. SMALL has an innovative hybrid design with coprimary endpoints. These include a randomised non-inferiority comparison of surgical re-excision rates following initial treatment, and a single-arm analysis of local recurrence at 5 years following VAE. Secondary outcomes include complication rates, overall survival, quality of life and a health economic analysis. The trial includes a QuinteT Recruitment Intervention to support recruitment.Ethics and dissemination Ethical approval was obtained from the Office for Research Ethics (Northern Ireland) for all UK sites. Results will be submitted for publication in a peer-reviewed journal, presented, shared with patient partners and with relevant professional organisations to inform future guideline development for the management of screen-detected breast cancer.Trial registration number ISRCTN12240119.

Percentage change in Ki67 between pretreatment (baseline) and surgery for part 1 (A) and part 2 (B); Kaplan–Meier estimates by treatment group for relapse free survival (C) and overall survival (D). A, Waterfall plots for part 1 and part 2: for each patient, bar height represents percentage change at surgery from baseline. Percentage change was calculated as [(surgery score + 0.1) − (pretreatment score + 0.1)]/[(pretreatment score + 0.1)]*100. The constant of 0.1 was added to accommodate cases with a value of 0%. Negative values represent decrease from baseline, positive values represent increase from baseline. pCR in breast: patients with pCR (no disease in ether breast or nodes) plus two additional patients with 0% breast cellularity but nodal involvement are represented as bars of height −120% at the left of the figures and noted “pCR in breast;” any existing Ki67 values for these patients have been excluded of the main analysis; in a sensitivity analysis, we imputed a value of −100% change for these patients (Appendix 2). Small triangles indicate patients with RCB1. Disease recurrences are also indicated at the top of each figure with circles and crosses. B, RFS is represented in the time interval of up to 6 years after randomization, as no RFS event occurred later. Overall survival is represented in the fully observed range of values. Log-rank test comparing concurrently randomized treatment groups are reported in the figures. In the figure, trastuzumab and control part 1 and part 2 groups are combined to improve readability. C, control; L, lapatinib; T, trastuzumab; T+L, combination; P1, part 1; P2, part 2; all, P1&P2; P, P value.

Association of perioperative changes in biological markers with RFS (A) by categories of Ki67 relative change, (B) by categories of Ki67 absolute change, (C) by baseline TILs, (D) by surgery TILs. RFS is represented in the time interval 0 to 6 years, as no RFS events occurred beyond 6 years from randomization. All treatment groups are combined; log-rank tests are stratified by treatment group (P = P value). For A and B, a value of −100% Ki67 change (ΔKi67) has been imputed for patients with a pCR in breast. For B, we have categorized both baseline and surgery Ki67 into high if ≥10% or low if <10%. No patient increased Ki67 from low to high after 11 days of perioperative treatment. Because of small number of patients in the “low–low” group, we have compared patients with “high” value at surgery with patients with “low” value at surgery.

e12570 Background: Accurate information about locoregional (LR) treatments following neoadjuvant systemic therapy (NST) for breast cancer is essential for interpretation of oncological outcomes, but reporting is currently poor. We aimed to develop a core outcome set (COS) to improve quality and consistency of LR outcome reporting in trials. Methods: The COS was developed in three phases according to COS-STAD guidance: 1. Generation of a long list of relevant outcome domains from a systematic literature review and stakeholder interviews. 2. Prioritisation of outcome domains using two rounds of an online Delphi survey. 3. An in-person consensus meeting to agree the final COS. Results: In total, 159 unique LR outcomes were identified from phase 1 and categorised into 101 (69 surgical/32 RT) outcomes for survey inclusion. 470 international participants (206 surgeons/144 medical oncologists/98 radiation oncologists) took part in survey Round 1, of whom 336 (71.5%) (153 surgeons/90 medical oncologists/ 77 radiation oncologists) participated in Round 2. After Round 2, 31 outcomes, combined into 15 summary outcomes, were scored as ‘consensus in’, 60 as ‘consensus out’ and 10 as ‘no consensus’. 23 professionals and 5 patient advocates attended the consensus meeting, where ‘consensus in’/’consensus out’ items were ratified, and ‘no consensus’ items discussed. A final 15 item COS for LR outcome reporting was agreed and ratified (Table). Conclusions: A COS for LR treatment reporting in NST trials has been robustly developed using an internationally collaborative approach. Widespread implemention will improve the quality and value of future breast cancer NST trials. Final COS 1 Type of breast and axillary surgery planned before starting NST 2 Proportion of patients not having surgery after NST due to disease progression, treatment toxicities or other comorbidities 3 Number/proportion of patients with a complete response to NST not having surgery to the breast and/or axilla, and how response was assessed 4 How response to NST in the breast and axilla was assessed 5 Type of initial breast and axillary surgery performed after NST 6 Proportion of patients with involved margins after initial and final surgery, and number of procedures required 7 Total number of excised and involved axillary lymph nodes, with extent of involvement 8 Further axillary treatment in patients with ypN+ disease after sentinel node biopsy/targeted axillary dissection (SLNB/TAD) 9 Proportion of patients in whom breast and/or axillary surgery was downstaged 10 Proportion of patients having radiation therapy 11 Indications for radiation therapy at trial level 12 Details of breast/chest wall and nodal targets 13 Details of dose and fractionation to breast/chest wall and nodal areas 14 Receipt of boost; indications for boost (at trial level) 15 Morbidity of locoregional treatments (short/long term as defined in protocol)

Criteria for each of the definitions of MetS used in the study

Characteristics of population with no missing MetS components (study population) and those excluded for having at least one missing MetS components