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The Oncotype DX® Breast Recurrence Score assay can guide recommendations made to patients with oestrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-) breast cancer regarding post-surgery adjuvant therapy. Standard practice is to order the test in the post-operative setting on a specimen from the excised invasive carcinoma. However, it has been shown to be technically possible to perform the test on the diagnostic core biopsy. By testing the diagnostic core biopsy in the pre-operative setting, the wait for excised invasive carcinoma Recurrence Score results could be reduced allowing patients to be more accurately counselled regarding their treatment pathway sooner with any adjuvant treatment recommendations expedited. This would allow for more efficient streaming of follow up appointments. The aim of this study is to compare the impact on the patient treatment pathway of performing the Oncotype DX® test on the diagnostic core biopsy pre-operatively (intervention) as opposed to the excised invasive carcinoma (control). This parallel group randomised controlled trial aims to recruit 330 newly diagnosed patients with grade 2 or grade 3, ER+, HER2-, invasive intermediate risk early-stage breast cancer. Participants will be randomised 2:1 to the preoperative testing of the diagnostic core biopsy compared to the post-operative testing of the excision specimen. The primary endpoint is number of clinical touchpoints between treating team and patient from initial approach until offer and prescription of the first adjuvant treatment. Secondary endpoints include time from diagnosis to offer and prescription of the first adjuvant treatment, patient-reported anxiety scores and health cost impact analysis collected at baseline, following the post-operative clinic and following the offer of adjuvant treatment, and number of alterations in treatment sequence from original planned surgical treatment to neoadjuvant therapy. The study was registered on ISRCTN (ISRCTN14337451) on the 16th August 2022.

Background At least 5 years of adjuvant endocrine therapy substantially reduces risks of recurrence and mortality in oestrogen-receptor positive early breast cancer. However, adherence to endocrine therapy is sub-optimal; poor adherence is associated with higher risks of recurrence and death from breast cancer, worse cancer-specific health-related quality-of-life, and increased healthcare costs. The SWEET randomised control trial aims to evaluate effectiveness and cost-effectiveness of the HT&Me intervention in reducing poor adherence to adjuvant endocrine therapy and improve cancer-specific health-related quality-of-life in women with oestrogen-receptor positive early breast cancer. Methods This is a UK based, pragmatic, open label randomised control trial. Participants (stages 1–3 oestrogen-receptor positive breast cancer, completed surgery, within 14 weeks of first endocrine therapy prescription; n  = 1460) complete a baseline questionnaire, and are randomised to the HT&Me intervention plus usual care, or usual care alone. The HT&Me intervention is evidence-based, theory-informed and patient-centred. It consists of viewing an animation, two consultations with a SWEET study practitioner (a health care professional trained in delivering the intervention) approximately 3 months apart, access to the interactive HT&Me web-app for the 18 months, and regular monthly nudges. All participants complete follow-up questionnaires at 6, 12, and 18 months. A multi-method process evaluation will be conducted involving quantitative analysis exploring mechanisms of action of the intervention, and qualitative interviews with a sample of participants and health care professionals involved in the trial. Primary endpoints are adjuvant endocrine therapy adherence (combined self-report (Medication Adherence Report Scale) and Proportion of Days Covered calculated from prescription encashment records) and cancer-specific health-related quality-of-life (Functional Assessment of Cancer Therapy Scale- General). Secondary endpoints are adjuvant endocrine therapy-specific health-related quality-of-life and within-trial cost-utility analysis which will evaluate cost-effectiveness. Discussion The SWEET trial seeks to address a significant issue affecting the growing population of breast cancer survivors: poor adherence to adjuvant endocrine therapy. Challenges addressed and resolved within the protocol include the following: capacity at sites to deliver the intervention; variations in breast cancer services nationally; and measuring adherence. This trial has potential to improve quality of life and adherence to endocrine therapy; reducing numbers of recurrences and breast cancer deaths, benefiting women, their families and the health service. Trial registration ISRCTN Number: ISRCTN24852890 registered on 02.08.2023.

IntroductionPatients with node-positive breast cancer having primary surgery currently undergo axillary node clearance (ANC) to reduce the risk of breast cancer recurrence. Evidence that this highly morbid procedure improves survival is lacking, but approximately 30% of patients will develop lifelong complications which significantly impact their quality of life.Targeted axillary dissection (TAD) may be a safe, less morbid alternative to ANC and will be evaluated in the upcoming Targeted Axillary Dissection versus axillary node clearance in patients with POsitive axillary Lymph nodes in Early breast cancer (TADPOLE) randomised controlled trial.TAD is not currently routine practice in patients having primary surgery, so it is vital that the procedure is performed in an agreed upon, standardised way within the trial and procedure fidelity monitored to ensure the results are generalisable and will be accepted by the surgical community. Robust surgical quality assurance (SQA) is essential. Here we describe the first phase of the TADPOLE SQA, a consensus process with the breast surgical community to agree upon how (1) surgery should be performed and standardised; (2) procedure fidelity will be monitored and (3) requirements for surgeon credentialling within the trial.Methods and analysisThe consensus process will have three phases:Generation of a long list of possible components of TAD from a scoping review and expert opinion. Identified items will be categorised and formatted into Delphi consensus questionnaire items.At least two rounds of an online Delphi survey in which at least 100 breast cancer surgeons will rate the importance of mandating/prohibiting, standardising and/or monitoring each component.A consensus meeting with surgeons to discuss, agree upon and ratify the approach to SQA within TADPOLE.Ethics and disseminationEthical approval has been obtained from the University of Bristol Faculty of Health Sciences Ethics Committee. Educational materials including videos and webinars will be developed and shared with surgeons participating in TADPOLE. Results will be presented at national/international meetings and published in peer-reviewed journals.

BackgroundPrimary endocrine therapy (PET) is a treatment option for elderly patients with ER-positive breast cancer enabling frail patients to avoid surgery. As a long-term treatment option, it has been shown to be inferior to surgery in controlling local disease. Decision-making in these patients is crucial in avoiding treatment failure. We examined the influence of decision-making on outcomes of PET failure as a secondary analysis as part of a large observational study.MethodsConsecutive patients treated with PET between 2005 and 2015 for operable breast cancers were included in a retrospective observational study in 3 breast centres in the North-East. Treatment decision processes were examined by case note review and outcomes of treatment success or failure recorded.Results488 patients were included with mean follow-up of 31 months. Overall 63 (12%) experienced treatment failure. 227 (46.6%) were given a choice between surgery and PET at diagnosis. Logistic regression identified older age [OR 0.94 (0.91–0.96) p < 0.001] and reduced mobility [OR 0.6 (0.37–0.97) p 0.036] to be less likely offered surgery. Those offered surgery were more likely to experience treatment failure with PET [SHR 1.78 (1.05–3.02) p 0.033].ConclusionsDespite a low failure rate in our series (literature failure rates vary between 12 and 85%), these results suggest that those actively offered a choice between surgery and PET are at greater risk of failure when choosing PET.

BackgroundElderly patients are more likely to have oestrogen receptor positive cancers that can be treated without surgery with primary endocrine therapy (PET). Few studies have sought to identify predictors of failure of PET and so the aim of this study was to evaluate treatment failures in elderly breast cancer patients treated with PET and to determine predictors of failure.MethodsA retrospective observational study was performed on consecutive patients with ER-positive early stage breast cancer treated with PET between 2005 and 2015 in the three breast units in the North East of England. The primary outcome measure was treatment failure and secondary outcome measure was disease progression.Results488 patients were included with mean follow-up 31 months (SD 23). Overall, 206 patients were still alive with their disease controlled at the end of follow-up, 219 had died with their disease controlled and 63 (12%) experienced treatment failure. Younger age [SHR 0.96 (95% CI 0.94–0.99) p 0.013], larger tumours [SHR 1.03 (1.01–1.06) p 0.015], grade 3 cancers [SHR 3.58 (1.93–6.63) p < 0.001] and axillary lymph node metastases [SHR 1.93 (1.06–3.52) p 0.030] were all independent predictors of treatment failure. Disease progression was reported in 86 (17.6%) of patients.ConclusionsThis is the largest retrospective series evaluating PET treatment failure. Clear predictors of failure have been identified, which can be used to facilitate treatment decision making. These results support previous analyses, further validating our results.

Background Immediate breast reconstruction (IBR) is routinely offered to improve quality-of-life for women requiring mastectomy, but there are concerns that more complex surgery may delay adjuvant oncological treatments and compromise long-term outcomes. High-quality evidence is lacking. The iBRA-2 study aimed to investigate the impact of IBR on time to adjuvant therapy. Methods Consecutive women undergoing mastectomy ± IBR for breast cancer July–December, 2016 were included. Patient demographics, operative, oncological and complication data were collected. Time from last definitive cancer surgery to first adjuvant treatment for patients undergoing mastectomy ± IBR were compared and risk factors associated with delays explored. Results A total of 2540 patients were recruited from 76 centres; 1008 (39.7%) underwent IBR (implant-only [ n  = 675, 26.6%]; pedicled flaps [ n  = 105,4.1%] and free-flaps [ n  = 228, 8.9%]). Complications requiring re-admission or re-operation were significantly more common in patients undergoing IBR than those receiving mastectomy. Adjuvant chemotherapy or radiotherapy was required by 1235 (48.6%) patients. No clinically significant differences were seen in time to adjuvant therapy between patient groups but major complications irrespective of surgery received were significantly associated with treatment delays. Conclusions IBR does not result in clinically significant delays to adjuvant therapy, but post-operative complications are associated with treatment delays. Strategies to minimise complications, including careful patient selection, are required to improve outcomes for patients.

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.

PurposeThe B-MaP-C study investigated changes to breast cancer care that were necessitated by the COVID-19 pandemic. Here we present a follow-up analysis of those patients commenced on bridging endocrine therapy (BrET), whilst they were awaiting surgery due to reprioritisation of resources.MethodsThis multicentre, multinational cohort study recruited 6045 patients from the UK, Spain and Portugal during the peak pandemic period (Feb–July 2020). Patients on BrET were followed up to investigate the duration of, and response to, BrET. This included changes in tumour size to reflect downstaging potential, and changes in cellular proliferation (Ki67), as a marker of prognosis.Results1094 patients were prescribed BrET, over a median period of 53 days (IQR 32–81 days). The majority of patients (95.6%) had strong ER expression (Allred score 7–8/8). Very few patients required expedited surgery, due to lack of response (1.2%) or due to lack of tolerance/compliance (0.8%). There were small reductions in median tumour size after 3 months’ treatment duration; median of 4 mm [IQR − 20, 4]. In a small subset of patients (n = 47), a drop in cellular proliferation (Ki67) occurred in 26 patients (55%), from high (Ki67 ≥ 10%) to low (< 10%), with at least one month’s duration of BrET.DiscussionThis study describes real-world usage of pre-operative endocrine therapy as necessitated by the pandemic. BrET was found to be tolerable and safe. The data support short-term (≤ 3 months) usage of pre-operative endocrine therapy. Longer-term use should be investigated in future trials.

Background The LOw RISk DCIS (LORIS) study was set up to compare conventional surgical treatment with active monitoring in women with ductal carcinoma in situ (DCIS). Recruitment to trials with a surveillance arm is known to be challenging, so strategies to maximise patient recruitment, aimed at both patients and recruiting centres, were implemented. Methods Women aged ≥ 46 years with a histologically confirmed diagnosis of non-high-grade DCIS were eligible for 1:1 randomisation to either surgery or active monitoring. Prior to randomisation, all eligible women were invited to complete: (1) the Clinical Trials Questionnaire (CTQ) examining reasons for or against participation, and (2) interviews exploring in depth opinions about the study information sheets and film. Women agreeing to randomisation completed validated questionnaires assessing health status, physical and mental health, and anxiety levels. Hospital site staff were invited to communication workshops and refresher site initiation visits to support recruitment. Their perspectives on LORIS recruitment were collected via surveys and interviews. Results Eighty percent (181/227) of eligible women agreed to be randomised. Over 40% of participants had high anxiety levels at baseline. On the CTQ, the most frequent most important reasons for accepting randomisation were altruism and belief that the trial offered the best treatment, whilst worries about randomisation and the influences of others were the most frequent most important reasons for declining. Most women found the study information provided clear and useful. Communication workshops for site staff improved knowledge and confidence but only about half said they themselves would join LORIS if eligible. The most common recruitment barriers identified by staff were low numbers of eligible patients and patient preference. Conclusions Recruitment to LORIS was challenging despite strategies aimed at both patients and site staff. Ensuring that recruiting staff support the study could improve recruitment in similar future trials. Trial registration ISRCTN27544579, prospectively registered on 22 May 2014

Background and Aims: Breast cancer is the second most common cause of cancer deaths in women. It is a tumour which has been extensively studied at a molecular level and, compared to other solid tissue tumours, our understanding of its biology is extensive. There are however some patients who are considered to have good prognostic feature of their tumours who go on to die from their disease. Transcription factors are the end point of many cell signalling pathways. They form the link between exogenous hormones and growth factors and DNA transcription. For the purpose of this study 3 different transcription factors have been selected for investigation. STAT3 is activated by various growth factors and cytokines including EGF. It is classified as an oncoprotein as its activation can mediate tumorgenisis in nude mice. STAT3 has been shown to confer resistance to apoptosis in breast cancer cells and it is associated with poor outcome in high risk breast cancers. SP1 is a transcription factor which is essential in the expression and the action of estrogen receptors (ER). It is known to be over expressed in other solid tissue tumours but there has been little work into its role in breast cancer. NFkB is activated in many cell survival settings. It is involved in the transcription of anti-apoptotic genes and also plays a role in cell proliferation, angiogenisis and cell adhesion. It is associated in breast cancers with an over expression of the oncogene Bcl-2. It has not been show to be a marker of prognosis but does appear to identify breast cancers with a poor response to chemotherapy. The aim of this study is to investigate the role of these transcription factors in the behaviour of breast cancers and the outcome of the disease. It will also investigate the affect of EGF and estogen stimulation on STAT3 activation in breast cancer cell lines. Methods: This study consists of 2 elements. Firstly an assessment of transcription factor expression in breast cancer samples and secondly a cell model experiment to investigate the stimulation of STAT3 activation. A cohort of 213 patients who presented to the Queen Elizabeth Hospital with invasive breast cancer in 1999 was selected. Tumour samples from these patients were retrieved and using immunohistochemistry were tested for the expression of STAT3, SP1 and NFkB. These results were then correlated with pathological features of the tumours, tumour receptor status (ER, PR HER2 and EGFR) and outcome of the disease. Two cell lines, MCF7 and SKBr3, were cultured in depleted medium. These cells were then stimulated with estrogen and EGF alone and in combination. Flow-cytometry was then used to quantify the levels of phosphorylated STAT3 in the 2 cell lines over a 3 day time course. The level of phosphorylation was then compared to the control lines to asses the effect of stimulation. Results: 209 breast cancers were successfully analysed for the expression of STAT3, 27% of these cancers expressed nuclear STAT3. The results demonstrated a significant correlation of STAT3 expression with cancers of a high grade (p=<0.001), increasing tumour size (p=0.004), vessel space invasion (p=0.034) and lymph node metastases (p=0.015). STAT3 expression was shown to be significantly correlated to high Nottingham prognostic index (NPI) scores. With regards to receptor status it was show that STAT3 expression was significantly associated with ER negative and PR negative cancers (p=0.003), whereas there was no relationship with HER2 status. The results did show that there was a significant relationship between STAT3 expression and EGFR positive cancers (p=0.007). When disease outcome was investigated it was shown that there was a trend towards improved survival in the STAT3 negative group and a significant relationship between STAT3 expression and disease recurrence at 5 years (p=0.04). SP1 expression was determined in 208 of the cancer samples with 33% of the tumours having strong nuclear staining. There was no significant relationship between SP1 expression and any of the pathological features mentioned. SP1 expression was related to ER positive tumours (p=0.015). Though there was no relationship with 5 year survival it appears that SP1 expression does reduce the risk of late (>2yr) disease recurrence (p=0.005). NFkB was over expressed in 15% of the 208 cancers samples. Again a significant correlation was shown with high grade tumours (p=0.001) and large tumours (p=0.014). NFkB expression was also shown to be more prevalent in ER negative cancers (p=0.006) and EGFR positive tumours (p=0.007). There was no significant relationship between NFkB expression and disease outcome. The cell model results showed that in the EGFR positive ER negative cell line (SKBr3), EGF stimulation resulted in a biphasic response of STAT3 phosphorylation, whereas estrogen had no effect on phosphorylation. In the ER positive MCF7 cells, which express low levels of EGFR, again EGF stimulation resulted in a biphasic response curve. Estrogen stimulation does cause an increase in activation but when estrogen is added to EGF stimulation there is an inhibition of STAT3 phosphorylation. Conclusions: This study has demonstrated that STAT3 and SP1 expression is important in disease outcome in breast cancer patients. Though there are differences in levels of expression, NFkB does not appear to have a role in breast cancer outcome. The cell model has show that EGF stimulation of EGFR positive cell lines results in increased STAT3 activation and also that this effect is inhibited by the addition of estrogen stimulation. These results raise important questions which are discussed in the study and suggest areas for further investigation.