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Breast cancer results in a three- to four-fold increased risk of venous thromboembolism (VTE), which is associated with reduced patient survival. Despite this, the mechanisms underpinning breast cancer-associated thrombosis remain poorly defined. Tumor cells can trigger endothelial cell (EC) activation resulting in increased von Willebrand factor (VWF) secretion. Importantly, elevated plasma VWF levels constitute an independent biomarker for VTE risk. Moreover, in a model of melanoma, treatment with low molecular weight heparin (LMWH) negatively regulated VWF secretion and attenuated tumor metastasis.To investigate the role of VWF in breast cancer metastasis and examine the effect of LMWH in modulating EC activation and breast tumor transmigration.von Willebrand factor levels were measured by ELISA. Primary ECs were used to assess tumor-induced activation, angiogenesis, tumor adhesion, and transendothelial migration.Patients with metastatic breast cancer have markedly elevated plasma VWF:Ag levels that also correlate with poorer survival. MDA-MB-231 and MCF-7 breast cancer cells induce secretion of VWF, angiopoietin-2, and osteoprotegerin from ECs, which is further enhanced by the presence of platelets. Vascular endothelial growth factor-A (VEGF-A) plays an important role in modulating breast cancer-induced VWF release. Moreover, VEGF-A from breast tumor cells also contributes to a pro-angiogenic effect on ECs. VWF multimers secreted from ECs, in response to tumor-VEGF-A, mediate adhesion of breast tumor cells along the endothelium. LMWH inhibits VWF-breast tumor adhesion and transendothelial migration. Our findings highlight the significant crosstalk between tumor cells and the endothelium including increased VWF secretion which may contribute to tumor metastasis.

BackgroundWomen with breast pain constitute >20% of breast clinic attendees.AimTo investigate breast cancer incidence in women presenting with breast pain and establish the health economics of referring women with breast pain to secondary care.Design and settingA prospective cohort study of all consecutive women referred to a breast diagnostic clinic over 12 months.MethodWomen were categorised by presentation into four distinct clinical groups and cancer incidence investigated.ResultsOf 10 830 women, 1972 (18%) were referred with breast pain, 6708 (62%) with lumps, 480 (4%) with nipple symptoms, 1670 (15%) with ‘other’ symptoms. Mammography, performed in 1112 women with breast pain, identified cancer in eight (0.7%). Of the 1972 women with breast pain, breast cancer incidence was 0.4% compared with ∼5% in each of the three other clinical groups. Using ‘breast lump’ as reference, the odds ratio (OR) of women referred with breast pain having breast cancer was 0.05 (95% confidence interval = 0.02 to 0.09, PConclusionThis study shows that referring women with breast pain to a breast diagnostic clinic is an inefficient use of limited resources. Alternative management pathways could improve capacity and reduce financial burden.

Background The B-MaP-C study aimed to determine alterations to breast cancer (BC) management during the peak transmission period of the UK COVID-19 pandemic and the potential impact of these treatment decisions. Methods This was a national cohort study of patients with early BC undergoing multidisciplinary team (MDT)-guided treatment recommendations during the pandemic, designated ‘standard’ or ‘COVID-altered’, in the preoperative, operative and post-operative setting. Findings Of 3776 patients (from 64 UK units) in the study, 2246 (59%) had ‘COVID-altered’ management. ‘Bridging’ endocrine therapy was used (n = 951) where theatre capacity was reduced. There was increasing access to COVID-19 low-risk theatres during the study period (59%). In line with national guidance, immediate breast reconstruction was avoided (n = 299). Where adjuvant chemotherapy was omitted (n = 81), the median benefit was only 3% (IQR 2–9%) using ‘NHS Predict’. There was the rapid adoption of new evidence-based hypofractionated radiotherapy (n = 781, from 46 units). Only 14 patients (1%) tested positive for SARS-CoV-2 during their treatment journey. Conclusions The majority of ‘COVID-altered’ management decisions were largely in line with pre-COVID evidence-based guidelines, implying that breast cancer survival outcomes are unlikely to be negatively impacted by the pandemic. However, in this study, the potential impact of delays to BC presentation or diagnosis remains unknown.

Women with breast cancer-related genetic pathogenic variants (e.g., BRCA1 , BRCA2 ) or with a strong family history carry lifetime risks of developing breast cancer of up to 80 to 90 percent. A significant proportion of these women proceed to bilateral risk-reducing mastectomy. The authors aimed to document the surgical morbidity of risk-reducing mastectomy and establish whether a diagnosis of breast cancer at the time of surgery impacted outcomes.Clinical details of 445 women identified as having a greater than 25 percent lifetime risk of developing breast cancer who underwent risk-reducing mastectomy and breast reconstruction were interrogated for surgical outcomes such as planned, unplanned, and emergency procedures; complication rates; length of stay; and longevity of breast reconstruction. These outcome measures were recorded in women diagnosed with breast cancer perioperatively (cancer group) and those without malignancy (benign group).Median follow-up was similar in both groups (benign group, 70 months; cancer group, 73 months). Patients were older in the cancer group than in the benign group (43 years versus 39 years; p0.001). Women in the cancer group required more planned procedures to complete reconstruction than those in the benign group (four versus two; p = 0.002). Emergency procedures, unplanned surgical interventions (e.g., capsulectomy), and postreconstruction complication rates were similar between groups. One in five women overall required revision surgery. Patients with autologous reconstructions had a revision rate of 1.24 per 1000 person-years compared with 2.52 per 1000 person-years in the implant reconstruction group.Women contemplating risk-reducing mastectomy can be reassured that this is a safe and effective procedure but will likely take multiple interventions. This knowledge should be integral to obtaining informed consent.Risk, II.

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.

Introduction Tamoxifen is a widely used hormonal based therapy for breast cancer in the adjuvant and metastatic setting, prolonging overall and recurrence-free survival. There has been increasing interest in the potential for novel “off-target” effects of tamoxifen and its metabolite N-desmethyltamoxifen across a number of cancer types. We aim to review the current literature regarding the potential use of tamoxifen in other primary malignancies. Method A qualitative systematic review was performed according to the PRISMA guidelines using pre-set search criteria across the PubMed, Cochrane and Scopus databases from 1985 to 2019. Additional results were generated from included papers references. Results A total of 324 papers were identified, of which 47 were included; a further 29 articles were obtained from additional referencing to give a total of 76 articles. Clinical trials have demonstrated benefits with the use of tamoxifen in isolation and combination, specifically in patients with advanced non-resectable malignancy, however results are not consistent across the literature. In vivo data consistently suggests that off target effects of tamoxifen are mediated through the ceramide pathway or through inhibition of protein kinase C (PKC). Conclusions With increased focus upon the potential of repurposing drugs, tamoxifen may be a candidate for repurposing in the wider cancer setting. There is evidence to suggest that the ceramide or PKC pathway could act as a therapeutic target for tamoxifen or alternative chemotherapeutics and merits further investigation.

Background Tumor stroma, of which fibroblasts are the most abundant cell, resembles a non‐healing wound, where a procoagulant environment creates a permissive milieu for cancer growth. We aimed to determine if tumor expression of coagulation factors (procoagulant phenotype), and systemic hypercoagulability, occur at the preinvasive (ductal carcinoma in situ; DCIS) stage and correlate with breast cancer subtype, disease‐free survival (DFS), and overall survival (OS). Methods In a prospective cohort of early breast cancer (DCIS, n = 76; invasive, n = 248) tumor, normal breast and plasma were examined. Fibroblast and epithelial expression of Tissue Factor (TF), thrombin, PAR1, PAR2, and plasma thrombin‐antithrombin (TAT) and D‐dimer were correlated with clinicopathological data, and 5‐year survival. Results Fibroblast expression of TF, thrombin, and PAR1 was increased in DCIS and invasive cancer compared to normal breast fibroblasts (P ≤ .003, all). Fibroblast TF, thrombin, PAR1, and PAR2 was increased in cancers with high Ki67, high grade, ER‐ (vs ER+), and HER2+ (vs HER2‐) (all P 3‐fold mortality risk compared to low TAT. Conclusion This demonstrates procoagulant phenotypic changes occur in fibroblasts at the preinvasive stage. Fibroblast procoagulant phenotype is associated with aggressive breast cancer subtypes and reduced survival. Coagulation may be a therapeutic target in breast cancer., In a large prospective cohort study (n = 324) of breast cancer patients, increased expression of markers of coagulation (Tissue Factor, thrombin and their respective receptors PAR2 and PAR1) are localized to fibroblasts, increased in aggressive breast cancer subtypes, and correlate with reduced overall survival. The phenotypic change in fibroblasts to a procoagulant state occurs at the preinvasive (DCIS) stage, implying an epithelial‐stromal communication across the basement membrane in DCIS creates a procoagulant stromal milieu and potentially an environment to facilitate invasion.

Introduction The Sloane Project is a prospective cohort study, including 50% of United Kingdom screen detected ductal carcinoma in situ (DCIS) (2003-2012). We sought to examine the trends in surgical management over time for screen detected DCIS. Methods Trends in type of breast surgery were compared with DCIS radiology, pathology and breast size. Results Of 9945 patients with complete data undergoing surgical excision, 2274 (22.9%) underwent mastectomy as their first procedure, of whom 1581 (69.5%) had a simple mastectomy. Among 7877 undergoing attempted breast conserving surgery (BCS), 83 (1%) had therapeutic mammoplasty (TM). The 4:1 attempted BCS:mastectomy ratio remained consistent over time. Of attempted BCS, 882 (11.2%) were ultimately converted to mastectomy (28.9% reconstructed). Over the decade, preoperative radiological estimation of DCIS remained constant at 26mm, however pathological DCIS size steadily increased from 22.4mm (2003-4) to 25.3 (2011-12). There was no corresponding increase in mastectomy, completion mastectomy or re-excision rates. Mean tumour size excised at BCS was 19.3mm (mean), at TM was 32.4mm and at mastectomy was 39.8mm. The rates of simple mastectomy (vs reconstruction) decreased from 77.7% to 61.2% while there was a small increase in TMs (from 0.2% (2 patients) [2003-4] to 1.7% (15 patients) [2011-12]). There was a statistically (but small [8%] clinically) significant difference in mean breast volume for BCS compared to mastectomy patients (1068ml vs 988ml respectively, Student’s t-test p Conclusion Breast size and pathological size, but not radiological size of screen detected DCIS increased between 2003 and 2012, but BCS rates remained consistent. Interestingly, breast size had no apparent influence on type of surgery, although the decrease in simple mastectomy suggests breast reconstruction increased over time. Citation Format: Cliona Clare Kirwan, Sheila Stallard, Senthurun Mylvaganam, Bridget Hilton, Karen Clements, Shan Cheung, Alistair Thompson. Surgical management of DCIS during the UK Sloane audit project [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-16-03.

Introduction: Approximately 55,000 women in the United Kingdom are diagnosed with new breast cancer annually. Since emerging in December 2019, SARS-CoV-2 (coronavirus disease 2019, COVID-19) has become a global pandemic, affecting healthcare delivery worldwide. In response to the pandemic, multiple guidelines were issued to assist with rationalising breast cancer care. The primary aim of the B-MaP-C study is to audit and describe breast cancer management of patients newly diagnosed with breast cancer during the COVID-19 pandemic against pre-COVID-19 management practice in the UK. The implications of changes to management will be determined and the impact of a COVID-19 diagnosis on the patient's breast cancer management will be determined. Methods and analysis: This is a multi-centre collaborative audit of consecutive breast cancer patients undergoing treatment decisions during the acute and recovery phases of the COVID-19 pandemic. All patients with newly diagnosed primary breast cancer, whose treatment was decided in a multidisciplinary meeting from the 16th March 2020, are eligible for inclusion. Ethics and dissemination: As this is an audit ethical approval is not required. Each participating centre is required to register the study locally and obtain local governance approvals prior to commencement of data collection. Local audit data will be available to individual participating units for governance purposes. The results of the data analysis will be submitted for publication, as well as disseminated via the ABS newsletter and a webinar. All data will be presented at national and international conferences, circumstances permitting. Registration details: Each participating centre received local governance audit registration.

Circulating Tumour Cells (CTCs), the mechanism by which cancer spreads from the primary tumour to distant metastatic sites and cancer-associated thrombosis (CAT), a systemic hypercoagulable state found in many cancer patients, appear to have a symbiotic relationship. CTCs initiate coagulation and may contribute to CAT, and conversely coagulation facilitates the intravasation of CTCs into the systemic circulation, survival in the circulation and extravasation at distant sites. CTCs may be a strong contributor to CAT through direct or indirect activation of coagulation. Whilst the potential for patient-specific CAT risk calculated by a combination of CTC count and blood coagulation factor concentrations has been suggested, evidence of a two-way relationship of hypercoagulability and increased CTC invasiveness is emerging. Tissue factor, the main activator of the extrinsic pathway of coagulation, is particularly implicated. Targeting the CTC-CAT axis is a promising target for improving patient outcome. This review provides background on CAT and CTCs along with recent developments in the field.

Although cancer-associated thrombosis (CAT) is relatively uncommon in breast cancer compared to other solid cancers, as breast cancer is the most commonly diagnosed cancer in women worldwide, the financial and personal cost of breast cancer associated thrombosis (BrCAT) is significant. This increasing risk of BrCAT over time parallels modern developments in breast cancer management. This review comprehensively reports the evidence for BrCAT in the context of modern breast cancer treatments. The risk of BrCAT is most pronounced within the first 3 months to year of diagnosis. The risk of BrCAT increases with operating time, paralleling the increasing frequency of immediate breast reconstruction. Systemic therapies such as chemotherapy and tamoxifen have well recognised thrombogenic effects, that are exacerbated by surgery and supplementary treatments such as colony-stimulating factors, steroids, and bisphosphonates however risk assessment tools are not designed specifically for this lower-VTE risk cancer. Cyclin-dependent kinases 4 and 6 (CDK4/6) Inhibitors, used in metastatic breast cancer, with trials ongoing in early disease, appear to have a class thrombogenic effect, although there is no increase CAT risk with other breast cancer targeted therapies. Given the numerous prothrombotic treatments facing patients within the first year of diagnosis, from surgery, chemotherapy, targeted therapies and endocrine therapy, a more personalised approach considering the additive effects of each individual patient's pathway, as well as their pre-existing risk factors, needs to be considered.

Exposure to sub-lethal doses of ionising and non-ionising electromagnetic radiation can impact human health and well-being as a consequence of, for example, the side effects of radiotherapy (therapeutic X-ray exposure) and accelerated skin ageing (chronic exposure to ultraviolet radiation: UVR). Whilst attention has focused primarily on the interaction of electromagnetic radiation with cells and cellular components, radiation-induced damage to long-lived extracellular matrix (ECM) proteins has the potential to profoundly affect tissue structure, composition and function. This review focuses on the current understanding of the biological effects of ionising and non-ionising radiation on the ECM of breast stroma and skin dermis, respectively. Although there is some experimental evidence for radiation-induced damage to ECM proteins, compared with the well-characterised impact of radiation exposure on cell biology, the structural, functional, and ultimately clinical consequences of ECM irradiation remain poorly defined.

Approximately 60% of implant-based breast reconstructions (IBBR) are performed with an acellular dermal matrix (ADM), for which, reliable, good quality long-term outcome data is limited. In a retrospective multicentre cohort study, we aimed to determine long-term aesthetic and quality of life outcomes of IBBR with ADM (Strattice™) compared to a submuscular technique. Methods Capsular contracture (Baker III/IV capsule) was determined by clinical examination by an independent researcher. Quality of life was assessed using BREAST-Q and aesthetic outcome by photographic assessment from a breast surgeon, breast care nurse and lay person, blinded to reconstruction type. Results We recruited 117 (51 bilateral) patients with ADM reconstructions, median follow-up 62 months (range 29–113) and 49 patients (16 bilateral) with submuscular reconstructions, median follow-up 76 months (range 38–111). 17 (10.1%) ADM reconstructions were Baker 3/4 compared to six (9.2%) submuscular (p = 0.85). Of the Baker 1/2 reconstructions six (3.6%) ADM and eight (13.6%) submuscular had previously undergone revision surgery to correct capsular contracture (p = 0.01). Combining both findings gave an estimated rate of capsular contracture of 13.6% in the ADM group and 21.2% in the submuscular (p = 0.14). A higher mean score for satisfaction with breasts was demonstrated when comparing ADM to submuscular (62 and 55, respectively; p = 0.01) but no significant difference in other BREAST-Q domains. The mean ‘general satisfaction’ score was higher in the ADM group for all three photograph assessors. Conclusion This study provides evidence of improved aesthetic outcome and reduction in capsular contracture with ADM reconstruction when compared to submuscular, consistent over long-term follow-up.

Background For patients with early breast cancer considered at very-low risk of local relapse, risks of radiotherapy may outweigh the benefits. Decisions regarding treatment omission can lead to patient uncertainty (decisional conflict), which may be lessened with patient decision aids (PDA). PRIMETIME (ISRCTN 41579286) is a UK-led biomarker-directed study evaluating omission of adjuvant radiotherapy in breast cancer; an embedded Study Within A Trial (SWAT) investigated whether PDA reduces decisional conflict using a cluster stepped-wedge trial design. Methods PDA diagrams and a video explaining risks and benefits of radiotherapy were developed in close collaboration between patient advocates and PRIMETIME trialists. The SWAT used a cluster stepped-wedge trial design, where each cluster represented the radiotherapy centre and referring peripheral centres. All clusters began in the standard information group (patient information and diagrams) and were randomised to cross-over to the enhanced information group (standard information plus video) at 2, 4 or 6 months. Primary endpoint was the decisional conflict scale (0–100, higher scores indicating greater conflict) which was assessed on an individual participant level. Multilevel mixed effects models used a random effect for cluster and a fixed effect for each step to adjust for calendar time and clustering. Robust standard errors were also adjusted for the clustering effect. Results Five hundred twenty-one evaluable questionnaires were returned from 809 eligible patients (64%) in 24 clusters between April 2018 and October 2019. Mean decisional conflict scores in the standard group (N = 184) were 10.88 (SD 11.82) and 8.99 (SD 11.82) in the enhanced group (N = 337), with no statistically significant difference [mean difference − 1.78, 95%CI − 3.82–0.25, p = 0.09]. Compliance with patient information and diagrams was high in both groups although in the enhanced group only 121/337 (36%) reported watching the video. Conclusion The low levels of decisional conflict in PRIMETIME are reassuring and may reflect the high-quality information provision, such that not everyone required the video. This reinforces the importance of working with patients as partners in clinical trials especially in the development of patient-centred information and decision aids.

Introduction: Breast cancer patients have a four-fold increased risk of developing a venous thromboembolism and those that do have a significantly increased risk of mortality despite adjusting for cancer stage. Tissue Factor (TF) is expressed by breast cancer-associated fibroblasts as well as breast cancer epithelial cells, and at significantly higher levels than by normal breast fibroblasts. TF signals via PAR-1 and PAR-2 to induce proliferation, invasion, angiogenesis and metastasis. Rivaroxaban is a licensed oral anticoagulant that inhibits the TF-Factor VIIa-Factor Xa complex and could therefore be repurposed to target the procoagulant tumour microenvironment in breast cancer. We hypothesise that a procoagulant microenvironment will induce breast cancer progression in vitro and that these promoting effects will be inhibited by anticoagulants, including Rivaroxaban. Methods: Lentivirally transduced TF over-expressing fibroblasts (TFF) and their control (CF) or conditioned media (TFFCM and CFCM), were cultured with oestrogen receptor positive (MCF-7), triple negative (MDA-MB-231) and HER2 positive (BT474) breast cancer cells, in the presence or absence of Rivaroxaban or anti-TF antibody 10H10. Proliferation (sulforhodamine-B/EdU assay), migration (scratch/transwell assay) and stem cell activity (mammosphere forming efficiency (MFE) assay) were assessed. The underlying mechanism was analysed with western blotting and quantitative PCR. The TFFCM and CFCM were analysed with cytokine arrays, enzyme-linked immunosorbent assays (ELISA) and mass spectrometry whilst the TFF and CF were analysed using RNA sequencing. Results: 3D co-culture of MCF-7s with TFF as compared to CF promoted cancer cell migration (p=0.04) and stem cell activity (MFE: p Citation Format: Emma L Blower, John Castle, Angelica Santiago-Gomez, Robert Clarke, Cliona C Kirwan. Rivaroxaban targets the procoagulant tumour microenvironment in vitro and thereby inhibits breast cancer progression [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 P5-06-09.

While it is known that histologically involved margins lead to a higher local recurrence rate, re-excision of anterior margins is less common than that of radial margins. However, there are minimal long-term data on the oncological safety of non-surgical management of anterior margins. A retrospective study was performed of all patients who underwent breast conserving surgery for breast cancer between 2000 and 2008 at two tertiary referral centres. A close margin was defined as disease within two mm of the resection margin (including disease at the margin). 6922 patients underwent surgery for invasive or in situ breast cancer of whom 277 patients had a close anterior margin alone after breast conserving surgery. Two hundred and twenty patients had non-surgical management of their margins, while 57 had re-excision surgery. Overall, there were 4/57 local recurrences in the surgical management group and 12/220 in the non-surgical management group. The local recurrence-free survival rate at 5 years was 98.2% (1 recurrence, 95% CI 87.8–99.7) in the surgical management group and 97.2% (6 recurrences, 95% CI 93.8–98.7) in the non-surgical management group. At 10 years, the rates were 92.2% (4 recurrences, 95% CI 80.3–97.0) in the surgical management group and 93.9% (12 recurrences, 95% CI 89.4–96.5) in the non-surgical management group. There was no significant difference found in the local recurrence rate between management groups (HR 1.24, 95% CI 0.40, 3.85; p = 0.71). Local recurrence rates are acceptable and similar in both the surgically and non-surgically managed groups. Non-surgical management of close anterior margins appears oncologically safe when combined with appropriate adjuvant therapy.

Introduction Implant based reconstruction accounts for approximately 85% of reconstructions in the UK and 80% in the US with an increase in use of acellular dermal matrices (ADM) e.g. Strattice™. There is little long-term data on the outcomes of ADM reconstructions and its efficacy. Our aim was to establish the most comprehensive long-term surgical, cost-effectiveness, quality of life and cosmetic outcomes in three large UK reconstructive centres. Methods All women who had undergone immediate implant based breast reconstruction with Strattice™ or a submuscular technique between 2009 and 2015 across three tertiary centres in the UK were invited for prospective clinical (examination and tonometry), cosmetic and quality of life assessment. An eight year retrospective review of case notes, theatre database and implant log was performed. Results 601 patients underwent 837 reconstructions. 589 Strattice™-assisted (331 therapeutic, 258 risk reduction) and 248 submuscular (152 therapeutic, 96 risk reduction). Revision surgery was performed in 43% of Strattice™-assisted reconstructions and 35% of submuscular within the follow-up period (p=0.034). Strattice™-assisted reconstructions were revised significantly sooner than submuscular, median time to first revision of 12 months vs. 21 months (p At a median time of 58 months from initial procedure, 10% in the Strattice™-assisted group and 14% in the submuscular had significant capsular contracture (Baker 3/4). At the time of assessment 7% of the Strattice™-assisted group and 17% of the submuscular had already undergone revision surgery for capsular contracture. Therefore, overall there was significantly more capsular contracture in the submuscular group (17% vs. 31%, p=0.047). There was no difference between the mean (of the four quadrant readings) breast tonometry reading between the two groups (0 hard – 10 soft). The median reading was 5.3 in the Strattice™-assisted group, 5.4 in the submuscular and 6.6 in native breasts. Those with Baker 1/2 had a median reading of 5.4 compared to 4.8 in those with a Baker 3/4 capsule. Quality of life was equivalent between the two groups at a median time of 58 months. There was no difference in median Breast Q score for satisfaction with breasts, Strattice™-assisted 62 vs. submuscular 58 or satisfaction with outcome 67 vs. 75. The mean cost of the index reconstructive procedure was less in the Strattice™-assisted group (£3634 vs. £4230) but there were no significant differences in long-term cost. Conclusion Long-term clinical outcomes support the use of Strattice™ in breast reconstruction. It reduces capsular contracture and enables patients to have their surgery in one rather than two procedures. The increased revision rate in the Strattice-assisted group was multi-faceted e.g. patient request to upsize and correction of contouring defects. Strattice™ reduces healthcare cost. Citation Format: Wilson RL, Kirwan CC, O'Donoghue JM, Linforth RA, Johnson RK, Harvey JR. The long-term outcomes of the BROWSE multicentre cohort study comparing Strattice™-assisted implant based reconstruction and submuscular reconstruction [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-16-03.

Introduction Cancer is likened to a non-healing wound. There is limited evidence on the expression of wound healing tissue inflammatory markers, CD68(pan-macrophage marker), HO-1(tumour cell marker) and FAP(cancer-associated fibroblast marker) in human breast cancer. Method In 201 invasive breast cancer and 58 DCIS patients, CD68+TAM expression, tumour HO-1 and fibroblast FAP expression, quantified by immunohistochemistry(dichotomised: high/present vs low/absent), was correlated with tumour factors (grade, proliferation(Ki67), ER, HER2); demographic factors, behavioural factors (smoking, alcohol) and survival status(DFS, OS) Result High CD68+macrophage expression was increased in invasive breast cancer, compared to DCIS, and normal tissue distant from the tumour(59%,41%and 6% respectively; p Conclusion Tumour inflammation as assessed by CD68+TAM expression shows utility in identifying aggressive breast cancer sub-types. The association reported between CD68+TAM density and alcohol intake suggests a possible mechanism for alcohol as a risk factor for breast cancer. The prognostic value of HO-1 and FAP expression demonstrated here suggests a functional role of these wound healing markers in breast cancer. HO-1:Heme-oxygenase-1; FAP:Fibroblast activation protein; TAM:Tumour associated macrophage; DCIS: Ductal carcinoma in situ Take-home message Wound healing pathways of inflammation may be implicated in early breast cancer development

Contralateral risk-reducing mastectomy (CRRM) rates have tripled over the last 2 decades. Reasons for this are multi-factorial, with those harbouring a pathogenic variant in the BRCA1/2 gene having the greatest survival benefit. On May 14th, 2013, Angelina Jolie shared the news of her bilateral risk-reducing mastectomy (BRRM), on the basis of her BRCA1 pathogenic variant status. We evaluated the impact of this news on rates of CRRM in women with increased risk for developing breast cancer after being diagnosed with unilateral breast cancer. The prospective cohort study included all women with at least a moderate lifetime risk of developing breast cancer who attended our family history clinic (1987–2019) and were subsequently diagnosed with unilateral breast cancer. Rates of CRRM were then compared between patients diagnosed with breast cancer before and after Angelina Jolie’s announcement (pre- vs. post-AJ). Of 386 breast cancer patients, with a mean age at diagnosis of 48 ± 8 years, 268 (69.4%) were diagnosed in the pre-AJ period, and 118 (30.6%) in the post-AJ period. Of these, 123 (31.9%) underwent CRRM, a median 42 (interquartile range: 11–54) days after the index cancer surgery. Rates of CRRM doubled following AJ’s news, from 23.9% pre-AJ to 50.0% post AJ (p p p = 0.040), and to increase with the estimated lifetime risk of breast cancer (p p = 0.015) on univariable analysis. After adjusting for these factors, the step-change increase in CRRM rates post-AJ remained significant (odds ratio: 9.61, p

ObjectiveInternationally recognised specialist breast cancer scientists, clinicians and healthcare professionals have published breast cancer research gaps that are informing research funding priorities in the UK and worldwide. We aimed to determine the breast cancer research priorities of the public to compare with those identified by clinicians and scientists.DesignWe conducted a qualitative study and thematic analysis using ‘listening events’ where patients with breast cancer and public representatives used a patient’s breast cancer journey to identify research themes.Participants and settingFemale participants were recruited from attendees at participating hospitals and support groups in the northwest of England, including patients, their family and friends as well as staff at a local retail centre.InterventionA framework approach was used to analyse transcribed discussions until thematic saturation was reached.Main outcome measuresBreast cancer research priorities were identified from participant discussions and compared with the published gaps identified by scientists and healthcare professionals.ResultsThematic saturation was reached after 27 female participants participated in listening events. Our participants consistently focused on improved methods of dissemination of information and improving education on the signs and symptoms of breast cancer. This was not highlighted by scientists or healthcare professionals. There was strong emphasis on quality of life-related issues such as side effects of treatment. There was some agreement between the priorities deduced by our study and those of the professionals in the areas of screening, prevention and breast reconstruction.ConclusionOur study identified some research themes that were not identified by scientists and healthcare professionals in two earlier landmark studies. This highlights the importance of including patients and public representatives when setting research priorities. The results should be used to guide investigators when planning future studies and for funding bodies in allocating resources for future projects.

Background: \ud Preoperative and perioperative aromatase inhibitor (POAI) therapy has the potential to improve outcomes in women with operable oestrogen receptor-positive primary breast cancer. It has also been suggested that tumour Ki67 values after 2 weeks (Ki672W) of POAI predicts individual patient outcome better than baseline Ki67 (Ki67B). The POETIC trial aimed to test these two hypotheses.\ud \ud Methods: \ud POETIC was an open-label, multicentre, parallel-group, randomised, phase 3 trial (done in 130 UK hospitals) in which postmenopausal women aged at least 50 years with WHO performance status 0–1 and hormone receptor-positive, operable breast cancer were randomly assigned (2:1) to POAI (letrozole 2·5 mg per day orally or anastrozole 1 mg per day orally) for 14 days before and following surgery or no POAI (control). Adjuvant treatment was given as per UK standard local practice. Randomisation was done centrally by computer-generated permuted block method (variable block size of six or nine) and was stratified by hospital. Treatment allocation was not masked. The primary endpoint was time to recurrence. A key second objective explored association between Ki67 (dichotomised at 10%) and disease outcomes. The primary analysis for clinical endpoints was by modified intention to treat (excluding patients who withdrew consent). For Ki67 biomarker association and endpoint analysis, the evaluable population included all randomly assigned patients who had paired Ki67 values available. This study is registered with ClinicalTrials.gov, NCT02338310; the European Clinical Trials database, EudraCT2007-003877-21; and the ISRCTN registry, ISRCTN63882543. Recruitment is complete and long-term follow-up is ongoing.\ud \ud Findings: \ud Between Oct 13, 2008, and April 16, 2014, 4480 women were recruited and randomly assigned to POAI (n=2976) or control (n=1504). On Feb 6, 2018, median follow-up was 62·9 months (IQR 58·1–74·1). 434 (10%) of 4480 women had a breast cancer recurrence (280 [9%] POAI; 154 [10%] control), hazard ratio 0·92 (95% CI 0·75–1·12); p=0·40 with the proportion free from breast cancer recurrence at 5 years of 91·0% (95% CI 89·9–92·0) for patients in the POAI group and 90·4% (88·7–91·9) in the control group. Within the POAI-treated HER2-negative subpopulation, 5-year recurrence risk in women with low Ki67B and Ki672W (low–low) was 4·3% (95% CI 2·9–6·3), 8·4% (6·8–10·5) with high Ki67B and low Ki672W (high–low) and 21·5% (17·1–27·0) with high Ki67B and Ki672W (high–high). Within the POAI-treated HER2-positive subpopulation, 5-year recurrence risk in the low–low group was 10·1% (95% CI 3·2–31·3), 7·7% (3·4–17·5) in the high–low group, and 15·7% (10·1–24·4) in the high–high group. The most commonly reported grade 3 adverse events were hot flushes (20 [1%] of 2801 patients in the POAI group vs six [

Summary Background Many women with increased lifetime risk of developing breast cancer, due to pathogenic gene variants or family history, choose to undergo bilateral risk reducing mastectomies (BRRM). Patient reported outcome measures (PROMS) are an increasingly important part of informed consent but are little studied in women undergoing BRRM. Methods We used a validated PROMS tool for breast reconstruction (BREAST-Q) in 297 women who had BRRM and breast reconstruction, 81% of whom had no malignancy (Benign Group, BG) and 19% in whom a perioperative breast cancer was diagnosed (Cancer Group, CG). 128 women also completed a Hospital Anxiety & Depression Score (HADS) questionnaire to test if preoperative HADS score could predict PROMS outcomes. Results Women in the CG had lower PROMS scores for satisfaction with their breasts, nipple reconstruction and sexual wellbeing. Both groups reported equal satisfaction with BRRM outcome and psychosocial well-being. Physical well-being PROMS of the abdomen and chest were high in women in both groups as were scores for satisfaction with the care they received. The CG group reported suboptimal quality of patient information. A higher presurgical HADS anxiety score predicted less favourable postoperative psychosocial well-being despite similar levels of satisfaction with aesthetic outcome. Conclusion We show a high degree of patient reported satisfaction by woman undergoing BRRM and reconstruction. There was a negative association with a cancer diagnosis on quality of life PROMS and higher preoperative anxiety levels negatively affected postoperative psychosocial well-being. These important findings should be part of the informed consent process during preoperative counselling.

BackgroundBreast cancer patients are at a four-fold increased risk of developing a venous thromboembolism (VTE), a major cause of death in this group. Conversely, coagulation factors promote tumour growth and metastasis. This has been evidenced in preclinical models, with an inhibitory effect of anticoagulants on cancer growth through proliferative, angiogenic, apoptotic, cancer stem cell and metastatic processes. The extrinsic clotting pathway is also more upregulated in patients in the relatively poorer prognosis oestrogen receptor (ER)-negative breast cancer subgroup, with increased tumour stromal expression of the coagulation factors Tissue Factor and thrombin.Rivaroxaban (Xarelto®, Bayer AG, Leverkusen, Germany) is a direct oral anticoagulant (DOAC). It is a Factor Xa inhibitor that is routinely prescribed for the prevention of stroke in non-valvular atrial fibrillation and for both VTE prophylaxis and treatment. This trial will assess the anti-proliferative and other anti-cancer progression mechanisms of Rivaroxaban in ER-negative early breast cancer patients.MethodsThis UK-based preoperative window-of-opportunity phase II randomised control trial will randomise 88 treatment-naïve early breast cancer patients to receive 20 mg OD Rivaroxaban treatment for 11 to 17 days or no treatment. Treatment will be stopped 24 h (range 18–36 h) prior to surgery or repeat core biopsy. All patients will be followed up for 2 weeks following surgery or repeat core biopsy.The primary endpoint is change in tumour Ki67. Secondary outcome measures include tumour markers of apoptosis and angiogenesis, extrinsic clotting pathway activation and systemic markers of metastasis, tumour load and coagulation.DiscussionLaboratory evidence supports an anti-cancer role for anticoagulants; however, this has failed to translate into survival benefit when trialled in patients with metastatic disease or poor prognosis cancers, such as lung cancer. Subgroup analysis supported a potential survival benefit in better prognosis advanced disease patients. This is the first study to investigate the anti-cancer effects of anticoagulants in early breast cancer.Trial registrationUK National Research Ethics Service (NRES) approval 15/NW/0406, MHRA Clinical Trials Authorisation 48380/0003/001-0001. The sponsor is Manchester University NHS Foundation Trust, and the trial is co-ordinated by Cancer Research UK Liverpool Cancer Trials Unit (LCTU). EudraCT2014-004909-33, registered 27 July 2015.ISRCTN14785273.

Purpose:Fulvestrant, the first-in-class selective estrogen receptor (ER) degrader (SERD), is clinically effective in patients with ER+ breast cancer, but it has administration and pharmacokinetic limitations. Pharmacodynamic data suggest complete ER degradation is not achieved at fulvestrant's clinically feasible dose. This presurgical study (NCT03236974) compared the pharmacodynamic effects of fulvestrant with AZD9496, a novel, orally bioavailable, nonsteroidal, potent SERD, in treatment-naïve patients with ER+ HER2− primary breast cancer awaiting curative intent surgery.Patients and Methods:Patients were randomized 1:1 to receive AZD9496 250 mg twice daily from day 1 for 5–14 days, or fulvestrant 500 mg on day 1. On-treatment imaging-guided core tumor biopsies were taken between day 5 and 14 and compared with pretreatment diagnostic biopsies. The primary objective was to compare the effects of AZD9496 and fulvestrant on ER expression. Secondary objectives included changes in progesterone receptor (PR) and Ki-67 pharmacokinetic/pharmacodynamic relationships and safety.Results:Forty-six women received treatment (AZD9496 n = 22; fulvestrant n = 24); 35 paired biopsies were evaluable (AZD9496 n = 15; fulvestrant n = 20). The least square mean estimate for ER H-score reduction was 24% after AZD9496 versus 36% after fulvestrant treatment (P = 0.86). AZD9496 also reduced PR H-scores (−33.3%) and Ki-67 levels (−39.9%) from baseline, but was also not superior to fulvestrant (PR: −68.7%, P = 0.97; Ki-67: −75.4%, P = 0.98). No new safety findings were identified.Conclusions:This was the first presurgical study to demonstrate that an oral SERD affects its key biological targets. However, AZD9496 was not superior to fulvestrant at the dose tested.

BACKGROUND: We aimed to identify a five-fraction schedule of adjuvant radiotherapy (radiation therapy) delivered in 1 week that is non-inferior in terms of local cancer control and is as safe as an international standard 15-fraction regimen after primary surgery for early breast cancer. Here, we present 5-year results of the FAST-Forward trial.METHODS: FAST-Forward is a multicentre, phase 3, randomised, non-inferiority trial done at 97 hospitals (47 radiotherapy centres and 50 referring hospitals) in the UK. Patients aged at least 18 years with invasive carcinoma of the breast (pT1-3, pN0-1, M0) after breast conservation surgery or mastectomy were eligible. We randomly allocated patients to either 40 Gy in 15 fractions (over 3 weeks), 27 Gy in five fractions (over 1 week), or 26 Gy in five fractions (over 1 week) to the whole breast or chest wall. Allocation was not masked because of the nature of the intervention. The primary endpoint was ipsilateral breast tumour relapse; assuming a 2% 5-year incidence for 40 Gy, non-inferiority was predefined as ≤1·6% excess for five-fraction schedules (critical hazard ratio [HR] of 1·81). Normal tissue effects were assessed by clinicians, patients, and from photographs. This trial is registered at isrctn.com, ISRCTN19906132.FINDINGS: Between Nov 24, 2011, and June 19, 2014, we recruited and obtained consent from 4096 patients from 97 UK centres, of whom 1361 were assigned to the 40 Gy schedule, 1367 to the 27 Gy schedule, and 1368 to the 26 Gy schedule. At a median follow-up of 71·5 months (IQR 71·3 to 71·7), the primary endpoint event occurred in 79 patients (31 in the 40 Gy group, 27 in the 27 Gy group, and 21 in the 26 Gy group); HRs versus 40 Gy in 15 fractions were 0·86 (95% CI 0·51 to 1·44) for 27 Gy in five fractions and 0·67 (0·38 to 1·16) for 26 Gy in five fractions. 5-year incidence of ipsilateral breast tumour relapse after 40 Gy was 2·1% (1·4 to 3·1); estimated absolute differences versus 40 Gy in 15 fractions were -0·3% (-1·0 to 0·9) for 27 Gy in five fractions (probability of incorrectly accepting an inferior five-fraction schedule: p=0·0022 vs 40 Gy in 15 fractions) and -0·7% (-1·3 to 0·3) for 26 Gy in five fractions (p=0·00019 vs 40 Gy in 15 fractions). At 5 years, any moderate or marked clinician-assessed normal tissue effects in the breast or chest wall was reported for 98 of 986 (9·9%) 40 Gy patients, 155 (15·4%) of 1005 27 Gy patients, and 121 of 1020 (11·9%) 26 Gy patients. Across all clinician assessments from 1-5 years, odds ratios versus 40 Gy in 15 fractions were 1·55 (95% CI 1·32 to 1·83, pINTERPRETATION: 26 Gy in five fractions over 1 week is non-inferior to the standard of 40 Gy in 15 fractions over 3 weeks for local tumour control, and is as safe in terms of normal tissue effects up to 5 years for patients prescribed adjuvant local radiotherapy after primary surgery for early-stage breast cancer.FUNDING: National Institute for Health Research Health Technology Assessment Programme.

BACKGROUND Prepectoral implant-based breast reconstruction with acellular dermal matrix has become an increasingly popular option for selected patients. There are no randomized data to demonstrate short- or long-term outcomes. Cohort studies to date have demonstrated safety, but risk factors for complications are unknown. METHODS This was a prospective cohort study of all patients undergoing prepectoral implant-based breast reconstruction between 2013 and 2019. Clinical factors and those related to reconstruction were analysed in relation to complications and implant loss using univariable and multivariable logistic regression. RESULTS A total of 469 reconstructions were undertaken in 289 women; the majority of reconstructions were performed using a one-stage direct-to-implant technique with acellular dermal matrix. Median follow-up was 21 (range 2-71) months. Minor complications were seen after 11·2 per cent of reconstructions, major complications after 5·9 per cent, and the rate of implant loss by 3 months was 3·1 per cent. In the final multivariable model, sentinel node biopsy (odds ratio (OR) 5·06, 95 per cent c.i. 2·00 to 12·80), axillary clearance (OR 6·67, 1·17 to 37·94) and adjuvant radiotherapy (OR 7·11, 1·60 to 31·61) were independent risk factors for development of a major complication, and sentinel node biopsy (OR 4·32, 1·23 to 15·22) for implant loss. CONCLUSION Prepectoral implant-based breast reconstruction has acceptable medium-term results but careful patient selection is advised.

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.

Background: FAST-Forward aims to identify a 5-fraction (Fr) schedule of adjuvant radiotherapy (radiation therapy) delivered in 1 week which is non-inferior for local cancer control and as safe as an international standard 15Fr regimen after primary surgery for early breast cancer. Five-year results are presented. Methods: FAST-Forward (ISRCTN19906132) randomised (1:1:1) patients with invasive carcinoma of the breast (pT1-3 pN0-1 M0) after breast conservation surgery or mastectomy to 40Gy in 15Fr (3 weeks), 27Gy or 26Gy in 5Fr (1 week) to whole breast/chest wall. Primary endpoint was ipsilateral breast tumour relapse (IBTR); assuming 2% 5-year incidence for 40Gy, non-inferiority was pre-defined as < 1.6% excess for 5Fr schedules (critical hazard ratio HR=1.81). Normal tissue effects (NTE) were assessed by clinicians, patients and photographs. Findings: 4096 consenting patients (1361 40Gy, 1367 27Gy, 1368 26Gy) were recruited November 2011-June 2014 from 97 UK centres. At 71 months median follow-up, 79 IBTR events were reported (40Gy: 31, 27Gy: 27, 26Gy: 21); HRs (95%CI) versus 40Gy/15Fr were 27Gy/5Fr: 0.86 (0.51,1.44), 26Gy/5Fr: 0.67 (0.38,1.16). Five-year incidence of IBTR after 40Gy was 2.1% (1.4,3.1); estimated absolute differences versus 40Gy/15Fr were -0.3% (-1.0,0.9) for 27Gy/5Fr (p=0.0022 for non-inferiority) and -0.7% (-1.3,0.3) for 26Gy/5Fr (p=0.00019). 5-year prevalence of any clinician-assessed moderate/marked breast NTE after 40Gy: 98/986 (9.9%), 27Gy: 155/1005 (15.4%), 26Gy: 121/1020 (11.9%). Across all clinician assessments from 1-5 years, odds ratios versus 40Gy/15Fr were 1.55 (1.32,1.83, p

Additional file 1. SPIRIT 2013 Checklist: Recommended items to address in a clinical trial protocol and related documents.

Significance: Colorectal cancer (CRC), results in a hypercoagulable state which manifests clinically as venous thromboembolism (VTE), often presenting as a deep vein thrombosis (DVT) or pulmonary embolism (PE). The consequences of VTE in CRC can be devastating, resulting in long-term morbidity and are a frequent cause of death, even amongst those who would have otherwise had a favourable cancer prognosis. The incidence of VTE in all cancers is increasing, whilst the exact incidence of VTE in CRC is likely to be underestimated. All cancer treatments increase the risk of VTE in an already at risk population. Critical issues: CRC-associated VTE is a challenging entity to manage with recurrences occurring more frequently in cancer patients, despite anticoagulation. Anticoagulation, whether treatment or prophylactic, increases the risk of bleeding, especially in patients with cancer. Although strong evidence underpins the initial management of cancer-associated VTE, there is uncertainty with regard optimum treatment duration. For VTE prevention, extended (28 days), pharmacological thromboprophylaxis post CRC surgery is internationally recommended. Pharmacological thromboprophylaxis is not routinely recommended for nonhospitalised patients receiving chemotherapy. Future directions: There is growing evidence of a symbiotic relationship between cancer biology and the clotting system. Tissue factor (TF), the initiator of the clotting pathway, promotes cancer via clotting dependent and independent mechanisms. Clotting pathway factors, including TF, may have utility as biomarkers in CRC, for assessment of VTE risk in addition to cancer prognosis. The clotting system may also be a target for potential anti-cancer therapies, either via existing anticoagulants or experimental direct TF inhibitors.

Introduction The most recent meta-analysis published, containing only studies from 2011 onwards, reports acellular dermal matrix (ADM) assisted breast reconstructions are associated with a significant increase in risk of infection, seroma and mastectomy flap necrosis but not implant loss when compared to submuscular reconstructions. We hypothesised that implant loss associated with ADM-assisted reconstruction did not exclusively occur within the first 30 days after surgery and studies with short-term follow-up may underestimate the risk. We aimed to determine with long-term follow-up at what time point explantation occurs after Strattice™ ADM-assisted reconstruction and if it differs from traditional submuscular implant based reconstruction. Methods A retrospective case note review was completed for all immediate implant based reconstructions performed between 1st January 2009 and 31st December 2015 in a single tertiary centre in England. Implant losses, the timings and causes of loss were determined. Results In total there were 510 immediate implant based reconstructions performed in 373 patients, of which 135 were submuscular and 375 ADM-assisted. In the ADM group a total of 22 (5.9%) implants were lost as a complication of their primary surgery. 14 implants were lost due to infection and eight due to wound breakdown. Implants were lost over a range of 14-661 days, median 76 days. Implant loss occurred within 30 days in six (27%), In the submuscular group a total of 11 (8.1%) implants were lost as a complication of their primary surgery. Six implants were lost due to infection and five due to wound breakdown. Implants were lost over a range of 12-274 days, median 49 days. Implant loss occurred within 30 days in four (36%), Comparing the two groups there were no differences in total implant loss rate or time to implant loss. Conclusions Implant loss within the first 3 months of ADM-assisted breast reconstruction is 3.5%; however, implant loss can occur more than 90 days after ADM-assisted breast reconstruction. Patients and clinicians should be aware that the risk of explantation continues for up to two years post-operatively with an ADM-assisted reconstruction whereas with submuscular coverage there were no implant losses beyond nine months follow-up. There were no differences in explantation rates between submuscular and ADM-assisted breast reconstructions. Citation Format: Wilson RL, Kirwan CC, Johnson RK, Harvey JR. Long term risk of explantation with Strattice™ assisted breast reconstruction, is it any different to submuscular reconstruction? [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-14-05.

Background Experimental evidence (Fisher et al, 1989) & a small clinical trial (IMPACT) respectively suggested peri-operative endocrine therapy (ET) may improve long-term disease-related outcome in patients undergoing primary surgery for ER positive (ER+) breast cancer (BC) & that tumor Ki67 levels after 2 weeks of peri-operative aromatase inhibitor (POAI) therapy might offer an effective way of predicting outcome & the need for additional adjuvant treatment. POETIC (*Peri-Operative Endocrine Therapy - Individualising Care) is a phase III randomized controlled trial designed to test these hypotheses & provide data to determine whether 2 week Ki67 improves prediction beyond that by baseline Ki67 of the group who have a higher risk of relapse in the first years after diagnosis in spite of best current standard of care. Patients & methods Postmenopausal patients with ER+ BC were randomised 2:1 to either, POAI (centre choice: letrozole 2.5mg or anastrozole 1mg daily) for 14 days prior to & 14 days following surgery or no POAI (Control). Randomization was stratified by treating center; adjuvant treatment was per UK routine practice. Tissue samples were collected at baseline & surgery (FFPE) for blinded Ki67 testing. Primary endpoint was Time to Recurrence (TTR: time from randomization to loco-regional or distant recurrence or BC death). A secondary endpoint was Ki67 at baseline & after 2 weeks of AI. Results Between 2008 & 2014, 4480 patients (2976 AI, 1504 Control) were randomized from 130 UK centers. Median age was 67 (IQR 62-75), 18% had grade 3 tumors, 39% were node positive and 61% had tumor size>2cm. For adjuvant ET 314 patients (7.2%) received tamoxifen (Tam), 3695 (84.6%) an AI, 251 (5.7%) Tam changing to AI and 109 (2.5%) changing from AI to Tam. On 8 August 2017, median follow-up was 60.7 months (IQR 49.5 to 72.2). 408/4480 (9.1%) patients have had a TTR event; 263 (8.8%) allocated to POAI compared to 145 (9.6%) controls: HR=0.91 (95%CI: 0.74, 1.12) Log-rank p=0.37. Adjusted HR=0.91 (95%CI: 0.74, 1.11). The relationship of Ki67 (baseline & after 2 weeks) with TTR in both the POAI & control groups will be presented for the overall ER+ population & HER2 defined sub-groups. Discussion There was no significant evidence that four weeks of POAI improved TTR compared with no POAI. POETIC will provide definitive evidence on the role of 2 week POAI-treated Ki67 to inform future practice & trials in terms of the potential to identify a group of patients for whom current standard of care appears insufficient in the few years post diagnosis. Citation Format: Robertson JFR, Dowsett M, Bliss JM, Morden JP, Wilcox M, Evans A, Holcombe C, Horgan K, Kirwan C, Mallon E, Sibbering M, Skene A, Vidya R, Cheang M, Banerji J, Kilburn L, Dodson A, Smith I. Peri-operative aromatase inhibitor treatment in determining or predicting longterm outcome in early breast cancer – The POETIC* Trial (CRUK/07/015) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr GS1-03.

Fulvestrant, the first-in-class selective estrogen receptor (ER) degrader (SERD), is clinically effective in patients with ERPatients were randomized 1:1 to receive AZD9496 250 mg twice daily from day 1 for 5-14 days, or fulvestrant 500 mg on day 1. On-treatment imaging-guided core tumor biopsies were taken between day 5 and 14 and compared with pretreatment diagnostic biopsies. The primary objective was to compare the effects of AZD9496 and fulvestrant on ER expression. Secondary objectives included changes in progesterone receptor (PR) and Ki-67 pharmacokinetic/pharmacodynamic relationships and safety.Forty-six women received treatment (AZD9496This was the first presurgical study to demonstrate that an oral SERD affects its key biological targets. However, AZD9496 was not superior to fulvestrant at the dose tested.

Purpose Circulating tumour cells (CTCs) are a marker of poor prognosis and are associated with increased risk of venous thromboembolism in metastatic breast cancer (MBC). We aimed to determine if the presence of CTCs and plasma markers of hypercoagulability [thrombin–antithrombin III (TAT), fibrinogen and d-dimer] are biomarkers of survival in MBC. Methods/patients In a prospective study of MBC patients, CTC (CellSearch®) enumeration and plasma TAT, fibrinogen and d-dimer measured prior to commencement of treatment for disease progression were correlated to overall survival. Results At study completion, of 50 MBC patients recruited (median age 59 years, range 36–82), 40 patients had died (median survival 417 days, range 58–2141). CTCs (≥ 1/7.5 ml) were identified in 16 patients (median number of cells per 7.5 ml, 3 (range 1–31) and were associated with systemic hypercoagulability (medians TAT: 8.1 vs. 5.2 ng/ml, p = 0.03; fibrinogen: 4.3 vs. 3.1 g/l, p = 0.03; d-dimer: 1327 vs. 683 ng/ml, p = 0.0001). At 1 year, of 16 patients with ≥ 1 CTC, 7 had died (44%), compared to 5 of 26 (19%) patients in the no-CTC group. The presence of ≥ 1 CTC was associated with a trend for reduced overall survival (median 455 days vs. 614 days, p = 0.15). Plasma TAT inversely correlated with survival and was significantly higher in patients dying within 1 year (median 9.8 vs. 5.2 ng/ml, p = 0.004) whilst d-dimer showed a trend for reduced 1-year survival (median 1211 vs. 817 ng/ml, p = 0.06). MBC patients with combined high d-dimer (≥ 895 ng/ml) and CTC positivity (≥ 1/7.5 ml whole peripheral blood) had significantly reduced survival (p = 0.04). Conclusions The correlation between CTCs, hypercoagulability and reduced survival in MBC suggests the coagulation system supports tumour cell metastasis and is, therefore, a potential therapeutic target. Electronic supplementary material The online version of this article (10.1007/s12094-019-02197-6) contains supplementary material, which is available to authorized users.

INTRODUCTIONIdiopathic mastalgia (benign breast pain of unknown origin) is often poorly managed because of its subjective nature and unclear aetiology. Mastalgia is a reason for up to 50% of breast outpatient referrals. Existing systematic reviews discuss dated treatment options that provide limited symptomatic relief. METHODSA systematic review was conducted for aetiology and treatment of idiopathic mastalgia in accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidance. Databases such as PubMed, MEDLINE, Cochrane Database and the Clinical Trial Registry were searched (February 2016). RESULTSReassurance plus bra-fitting advice provides relief for most women. If symptoms persist, addition of topical non-steroidal anti-inflammatory drugs (NSAIDs) provides relief in 70–92% of women. There is some benefit in reducing dietary coffee and fat intake. Medical treatments have serious side-effects (often androgenic or menopausal) and should be considered only in cases resistant to simpler measures. Dopamine agonists are useful, but less effective than endocrine treatments such as Danazol or Tamoxifen. Of the Selective Oestrogen Receptor Modulator drugs, Ormeloxifene appears most effective, but is not licenced in the United Kingdom. Relaxation therapy, acupuncture and kinesiology may be useful but currently lack good evidence of effectiveness. DISCUSSIONFirst-line management of breast pain should be explanation, reassurance and a bra-fitting advice. Subsequent drug therapy should be balanced against its side-effects; topical NSAIDs and Ormeloxifene show greatest benefit with least side-effects. Newer agents (Ormeloxifene) currently being used for mastalgia in India could be considered in the developed world.

Highlights • Seroma was not associated with patient-reported breast appearance change after breast radiotherapy. • Haematoma and smoking were significant risk factors for patient-reported breast appearance change. • Seroma prevalence in our study was lower than previous reports., Background Seroma describes a collection of serous fluid within a cavity, occurring following surgery. Seroma is associated with normal tissue effects (NTE) following breast radiotherapy, as reported by clinicians and on photographs. This study investigates the association between seroma and the NTE breast appearance change collected using patient-reported outcome measures (PROMs) in IMPORT HIGH, as well as investigating the association between breast appearance change and patient/tumour/treatment factors. Methods Case–control methodology was used for seroma analysis within IMPORT HIGH. Cases were patients reporting moderate/marked breast appearance change and controls reported none/mild changes at year-3. One control was selected at random for each case. Seromas were graded as not visible/subtle or visible/highly visible on CT radiotherapy planning scans. Logistic regression tested associations, adjusting for patient/tumour/treatment factors. Results 1078/1149 patients consented to PROMs, of whom 836 (78%) reported whether they had 3-year breast appearance change; 231 cases and 231 controls were identified. 304/462 (66%) patients received chemotherapy. Seroma prevalence was 20% (41/202) in cases and 16% (32/205) in controls, and less frequent in patients receiving adjuvant chemotherapy [10% (24/246) compared with 29% (40/138) without]. Visible seroma was not significantly associated with breast appearance change [OR 1.38 (95%CI 0.83–2.29), p = 0.219]. Larger tumour size, haematoma, current smoking and body image concerns at baseline were independent risk factors. Conclusions Seroma was not associated with patient-reported breast appearance change, but haematoma and smoking were significant risk factors. Lack of association may be related to lower prevalence of seroma compared with previous reports, perhaps reflecting patients receiving adjuvant chemotherapy in whom seroma resolves prior to radiotherapy.

The B-MaP-C study aimed to determine alterations to breast cancer (BC) management during the peak transmission period of the UK COVID-19 pandemic and the potential impact of these treatment decisions.This was a national cohort study of patients with early BC undergoing multidisciplinary team (MDT)-guided treatment recommendations during the pandemic, designated 'standard' or 'COVID-altered', in the preoperative, operative and post-operative setting.Of 3776 patients (from 64 UK units) in the study, 2246 (59%) had 'COVID-altered' management. 'Bridging' endocrine therapy was used (n = 951) where theatre capacity was reduced. There was increasing access to COVID-19 low-risk theatres during the study period (59%). In line with national guidance, immediate breast reconstruction was avoided (n = 299). Where adjuvant chemotherapy was omitted (n = 81), the median benefit was only 3% (IQR 2-9%) using 'NHS Predict'. There was the rapid adoption of new evidence-based hypofractionated radiotherapy (n = 781, from 46 units). Only 14 patients (1%) tested positive for SARS-CoV-2 during their treatment journey.The majority of 'COVID-altered' management decisions were largely in line with pre-COVID evidence-based guidelines, implying that breast cancer survival outcomes are unlikely to be negatively impacted by the pandemic. However, in this study, the potential impact of delays to BC presentation or diagnosis remains unknown.