The 2022 Assisi Think Tank Meeting: White paper on optimising radiation therapy for breast cancer.

The present white paper, referring to the 4th Assisi Think Tank Meeting on breast cancer, reviews state-of-the-art data, on-going studies and research proposals. <70% agreement in an online questionnaire identified the following clinical challenges: 1: Nodal RT in patients who have a) 1-2 positive sentinel nodes without ALND (axillary lymph node dissection); b) cN1 disease transformed into ypN0 by primary systemic therapy and c) 1-3 positive nodes after mastectomy and ALND. 2. The optimal combination of RT and immunotherapy (IT), patient selection, IT-RT timing, and RT optimal dose, fractionation and target volume. Most experts agreed that RT- IT combination does not enhance toxicity. 3: Re-irradiation for local relapse converged on the use of partial breast irradiation after second breast conserving surgery. Hyperthermia aroused support but is not widely available. Further studies are required to finetune best practice, especially given the increasing use of re-irradiation.

The NeST (Neoadjuvant systemic therapy in breast cancer) study: National Practice Questionnaire of United Kingdom multi-disciplinary decision making.

BACKGROUND: Neoadjuvant systemic therapy (NST) is increasingly used in the treatment of breast cancer, yet it is clear that there is significant geographical variation in its use in the UK. This study aimed to examine stated practice across UK breast units, in terms of indications for use, radiological monitoring, pathological reporting of treatment response, and post-treatment surgical management. METHODS: Multidisciplinary teams (MDTs) from all UK breast units were invited to participate in the NeST study. A detailed questionnaire assessing current stated practice was distributed to all participating units in December 2017 and data collated securely usingREDCap. Descriptive statistics were calculated for each questionnaire item. RESULTS: Thirty-nine MDTs from a diverse range of hospitals responded. All MDTs routinely offered neoadjuvant chemotherapy (NACT) to a median of 10% (range 5-60%) of patients. Neoadjuvant endocrine therapy (NET) was offered to a median of 4% (range 0-25%) of patients by 66% of MDTs. The principal indication given for use of neoadjuvant therapy was for surgical downstaging. There was no consensus on methods of radiological monitoring of response, and a wide variety of pathological reporting systems were used to assess tumour response. Twenty-five percent of centres reported resecting the original tumour footprint, irrespective of clinical/radiological response. Radiologically negative axillae at diagnosis routinely had post-NACT or post-NET sentinel lymph node biopsy (SLNB) in 73.0 and 84% of centres respectively, whereas 16% performed SLNB pre-NACT. Positive axillae at diagnosis would receive axillary node clearance at 60% of centres, regardless of response to NACT. DISCUSSION: There is wide variation in the stated use of neoadjuvant systemic therapy across the UK, with general low usage of NET. Surgical downstaging remains the most common indication of the use of NAC, although not all centres leverage the benefits of NAC for de-escalating surgery to the breast and/or axilla. There is a need for agreed multidisciplinary guidance for optimising selection and management of patients for NST. These findings will be corroborated in phase II of the NeST study which is a national collaborative prospective audit of NST utilisation and clinical outcomes.

The Financial Impact on Reimbursement of Moderately Hypofractionated Postoperative Radiation Therapy for Breast Cancer: An International Consortium Report.

AIMS: Moderately hypofractionated breast irradiation has been evaluated in several prospective studies, resulting in wide acceptance of shorter treatment protocols for postoperative breast irradiation. Reimbursement for radiation therapy varies between private and public systems and between countries, impacting variably financial considerations in the use of hypofractionation. The aim of this study was to evaluate the financial impact of moderately hypofractionated breast irradiation by reimbursement system in different countries. MATERIALS AND METHODS: The study was designed by an international group of radiation oncologists. A web-questionnaire was distributed to representatives from each country. The participants were asked to involve the financial consultant at their institution. RESULTS: Data from 13 countries from all populated continents were collected (Europe: Denmark, France, Italy, the Netherlands, Spain, UK; North America: Canada, USA; South America: Brazil; Africa: South Africa; Oceania: Australia; Asia: Israel, Taiwan). Clinicians and/or departments in most of the countries surveyed (77%) receive remuneration based on the number of fractions delivered to the patient. The financial loss per patient estimated resulting from applying moderately hypofractionated breast irradiation instead of conventional fractionation ranged from 5-10% to 30-40%, depending on the healthcare provider. CONCLUSION: Although a generalised adoption of moderately hypofractionated breast irradiation would allow for a considerable reduction in social and economic burden, the financial loss for the healthcare providers induced by fee-for-service remuneration may be a factor in the slow uptake of these regimens. Therefore, fee-for-service reimbursement may not be preferable for radiation oncology. We propose that an alternative system of remuneration, such as bundled payments based on stage and diagnosis, may provide more value for all stakeholders.

Radiotherapy Trial Set-up in the UK: Identifying Inefficiencies and Potential Solutions.

AIMS: Radiotherapy clinical trials are integral to the development of new treatments to improve the outcomes of patients with cancer. A collaborative study by the National Cancer Research Institute Clinical and Translational Radiotherapy Research Working Group and the National Institute for Health Research was carried out to understand better if and why inefficiencies occur in the set-up of radiotherapy trials in the UK. MATERIALS AND METHODS: Two online surveys collected information on the time taken for UK radiotherapy trials to reach key milestones during set-up and the research support currently being provided to radiotherapy centres to enable efficient clinical trial set-up. Semi-structured interviews with project managers and chief investigators identified better ways of working to improve trial set-up in the future. RESULTS: The timelines for the set-up of 39 UK radiotherapy trials were captured in an online survey showing that the median time from grant approval to trial opening was 600 days (range 169-1172). There were 38 responses from radiotherapy centres to a survey asking about the current support provided for radiotherapy research. Most of these centres have more than one type of staff member dedicated to supporting radiotherapy research. The most frequent barrier to radiotherapy trial set-up identified was lack of physicists' time and lack of time for clinical oncologists to carry out research activities. Four main themes around trial set-up were identified from semi-structured interviews: the importance of communication and building relationships, the previous experience of the chief investigator and clinical trials units, a lack of resources and having the time and personnel required to produce trial documentation and to process trial approval requests. CONCLUSIONS: This unique, collaborative project has provided up to date information about the current landscape of trial set-up and research support in the UK and identified several avenues on which to focus future efforts in order to support the excellent radiotherapy trial work carried out across the UK.

Breast Cancer Demographics, Types and Management Pathways: Can Western Algorithms be Optimally used in Eastern Countries?

Over the past decade, breast cancer has overtaken cervical cancer to become the most common cancer among women in India, as in most Western nations. In addition to the high incidence, the morbidity and mortality associated with this malignancy are disproportionately higher in India. Although some efforts are being made to increase awareness about this disease, a large majority of Indian patients present with advanced disease. Here, important institutional data and treatment outcomes are reviewed and compared with data from the West. Additionally, we highlight recent efforts in setting up collaborative multicentre trials in breast cancer in India and suggest some ways forward to improve outcomes.

Axillary Surgery Following Neoadjuvant Chemotherapy - Multidisciplinary Guidance From the Association of Breast Surgery, Faculty of Clinical Oncology of the Royal College of Radiologists, UK Breast Cancer Group, National Coordinating Committee for Breast Pathology and British Society of Breast Radiology.

AIMS: These multidisciplinary guidelines aim to provide clinically helpful, evidence-based recommendations on the surgical management of the axilla in patients who have received neo-adjuvant chemotherapy for early breast cancer. MATERIALS & METHODS: Following a review of published evidence, a writing group representing all disciplines quorate within a breast cancer multidisciplinary meeting prepared the guidelines. KEY RECOMMENDATIONS: In patients presenting with clinically node negative axillae, sentinel node biopsy (SNB) may be performed prior to or on completion of neo-adjuvant chemotherapy (NACT). In patients presenting with clinically node positive axillae, SNB may be safely considered following completion of NACT. Four nodes should be removed with dual mapping. If evidence of complete pathological response of previous metastases is seen, axillary radiotherapy may be offered. If residual cancer (isolated tumour cells, micro- or macrometastes) is seen within the SNB, offer axillary node dissection.

The Assisi Think Tank Meeting Survey of post-mastectomy radiation therapy in ductal carcinoma in situ: Suggestions for routine practice.

BACKGROUND: Risk factors for local recurrence after mastectomy in ductal carcinoma in situ (DCIS) emerged as a grey area during the second "Assisi Think Tank Meeting" (ATTM) on Breast Cancer. AIM: To review practice patterns of post-mastectomy radiation therapy (PMRT) in DCIS, identify risk factors for recurrence and select suitable candidates for PMRT. METHODS: A questionnaire concerning DCIS management, focusing on PMRT, was distributed online via SurveyMonkey. RESULTS: 142 responses were received from 15 countries. The majority worked in academic institutions, had 5-20 years work-experience and irradiated <5 DCIS patients/year. PMRT was more given if: surgical margins <1 mm, high-grade, multicentricity, young age, tumour size >5 cm, skin- or nipple- sparing mastectomy. Moderate hypofractionation was the most common schedule, except after immediate breast reconstruction (57% conventional fractionation). CONCLUSIONS: The present survey highlighted risk factors for PMRT administration, which should be further evaluated.

The NeST (neoadjuvant systemic therapy in breast cancer) study - Protocol for a prospective multi-centre cohort study to assess the current utilization and short-term outcomes of neoadjuvant systemic therapies in breast cancer.

INTRODUCTION: Neoadjuvant systemic therapy (NST) has several potential advantages in the treatment of breast cancer. However, there is currently considerable variation in NST use across the UK. The NeST study is a national, prospective, multicentre cohort study that will investigate current patterns of care with respect to NST in the UK. METHODS AND ANALYSIS: Phase 1 - a national practice questionnaire (NPQ) to survey current practice.Phase 2 - a multi-centre prospective cohort study of breast cancer patients, undergoing NST.Women undergoing NST as their MDT recommended primary breast cancer treatment between December 2017 and May 2018 will be included. The breast surgery and oncological professional associations and the trainee research collaborative networks will encourage participation by all breast cancer centres.Patient demographics, radiological, oncological, surgical and pathological data will be collected, including complications and the need for further intervention/treatment. Data will be collated to establish current practice in the UK, regarding NST usage and variability of access and provision of these therapies. Prospective data on 600 patients from ~50 centres are anticipated.Trial registration: ISRCTN11160072. ETHICS AND DISSEMINATION: Research ethics approval is not required for this study, as per the online Health Research Authority decision tool. The information obtained will provide valuable insights to help patients make informed decisions about their treatment. These data should establish current practice in the UK concerning NST, inform future service delivery as well as identifying further research questions.This protocol will be disseminated through the Mammary Fold Academic Research Collaborative (MFAC), the Reconstructive Surgery Trials Network and the Association of Breast Surgery. Participating units will have access to their own data and collective results will be presented at relevant conferences and published in appropriate peer-reviewed journals, as well as being made accessible to relevant patient groups.

Implications of altered maternal cytokine concentrations on infant outcomes in children with prenatal alcohol exposure.

Excessive alcohol consumption has been shown to increase serum plasma levels of numerous immune cytokines. Maternal immune activation and elevated cytokines have been implicated in certain neurological disorders (e.g., autism and schizophrenia) in the offspring. We investigated the hypothesis that elevated cytokines during pregnancy are a risk factor in women who gave birth to a child with Fetal Alcohol Spectrum Disorder (FASD) or a child with neurobehavioral impairment, regardless of prenatal alcohol exposure. Moderate to heavy alcohol-exposed (AE) (N = 149) and low or no alcohol-exposed (LNA) (N = 92) women were recruited into the study during mid pregnancy (mean of 19.8 ± 5.8 weeks' gestation) in two regions of Ukraine: Khmelnytsky and Rivne. Maternal blood samples were obtained at enrollment into the study at early to mid-pregnancy and during a third-trimester follow-up visit and analyzed for plasma cytokines. Children were examined at 6 and/or 12 months of age and were classified as having FASD if their mothers reported alcohol use and if they had at least one standardized score (Bayley Scales of Infant Development II Mental Development Index [MDI], or Psychomotor Development Index [PDI]) below 85 with the presence or absence of physical features of FASD. In multivariate analyses of maternal cytokine levels in relation to infant MDI and PDI scores in the entire sample, increases in the ratio of TNF-α/IL-10 and IL-6/IL-10 were negatively associated with PDI scores at 6 months (p = 0.020 and p = 0.036, respectively) and 12 months (p = 0.043 and p = 0.029, respectively), and with MDI scores at 12 months (p = 0.013 and p = 0.050, respectively). A reduction in the odds ratio of having an FASD child was observed with increasing levels of IL-1ß, IL-2, IL-4, IL-6, and IL-10 in early to mid-pregnancy and IL-1ß and IL-10 during late pregnancy. However, women that failed to increase IL-10 levels in the third trimester in order to maintain the balance of pro- and anti-inflammatory cytokines had an elevated risk of having an FASD child, specifically a significant increase in the odds ratio of FASD with every one-unit log increase in late pregnancy TNF-α/IL-10 levels (aOR: 1.654, CI: 1.096-2.495, p = 0.017). These data support the concept that disruptions in the balance between pro- and anti-inflammatory cytokines may contribute to neurobehavioral impairment and alter the risk of FASD.

A Dosimetric Comparison of Breast Radiotherapy Techniques to Treat Locoregional Lymph Nodes Including the Internal Mammary Chain.

AIMS: Radiotherapy target volumes in early breast cancer treatment increasingly include the internal mammary chain (IMC). In order to maximise survival benefits of IMC radiotherapy, doses to the heart and lung should be minimised. This dosimetry study compared the ability of three-dimensional conformal radiotherapy, arc therapy and proton beam therapy (PBT) techniques with and without breath-hold to achieve target volume constraints while minimising dose to organs at risk (OARs). MATERIALS AND METHODS: In 14 patients' datasets, seven IMC radiotherapy techniques were compared: wide tangent (WT) three-dimensional conformal radiotherapy, volumetric-modulated arc therapy (VMAT) and PBT, each in voluntary deep inspiratory breath-hold (vDIBH) and free breathing (FB), and tomotherapy in FB only. Target volume coverage and OAR doses were measured for each technique. These were compared using a one-way ANOVA with all pairwise comparisons tested using Bonferroni's multiple comparisons test, with adjusted P-values ≤ 0.05 indicating statistical significance. RESULTS: One hundred per cent of WT(vDIBH), 43% of WT(FB), 100% of VMAT(vDIBH), 86% of VMAT(FB), 100% of tomotherapy FB and 100% of PBT plans in vDIBH and FB passed all mandatory constraints. However, coverage of the IMC with 90% of the prescribed dose was significantly better than all other techniques using VMAT(vDIBH), PBT(vDIBH) and PBT(FB) (mean IMC coverage ± 1 standard deviation = 96.0% ± 4.3, 99.8% ± 0.3 and 99.0% ± 0.2, respectively). The mean heart dose was significantly reduced in vDIBH compared with FB for both the WT (P < 0.0001) and VMAT (P < 0.0001) techniques. There was no advantage in target volume coverage or OAR doses for PBT(vDIBH) compared with PBT(FB). CONCLUSIONS: Simple WT radiotherapy delivered in vDIBH achieves satisfactory coverage of the IMC while meeting heart and lung dose constraints. However, where higher isodose coverage is required, VMAT(vDIBH) is the optimal photon technique. The lowest OAR doses are achieved by PBT, in which the use of vDIBH does not improve dose statistics.

Can Interrogation of Tumour Characteristics Lead us to Safely Omit Adjuvant Radiotherapy in Patients with Early Breast Cancer?

Adjuvant radiotherapy after breast-conserving surgery has been an important component of the standard of care for early breast cancer. Improvements in breast cancer care have resulted in a substantial reduction in local relapse rates over recent decades. Although the proportional benefits of adjuvant radiotherapy are similar for different prognostic risk groups of patients, the absolute benefits depend on the risk of relapse and therefore vary considerably between prognostic groups. Radiotherapy is not without risk and for some patients at very low risk of relapse the risks of radiotherapy may outweigh the benefit, leading to potential overtreatment. Randomised controlled trial (RCT) evidence shows that omission of radiotherapy in low risk early breast cancer does not reduce overall survival or increase breast cancer mortality and local recurrences are salvageable. Despite this there has not been a change in practice regarding omission of radiotherapy. The reasons for this may include challenges in patient selection. Recent advances in immunohistochemistry and genomic profiling may improve risk stratification and the development of biomarkers to directed therapies. Several RCTs have quantified the benefit of radiotherapy in reducing local relapse. Where a treatment benefit is known but is considered to be so small not to be clinically relevant then alternatives to RCTs may be considered to answer the question of need. This is because we can assess risk against a fixed 'absolute' boundary rather than needing a randomised comparator. The prospective cohort study is an alternative to the RCT design to answer the question of need for radiotherapy. The feasibility of recruitment into biomarker-directed de-escalation studies will become apparent as more studies open. The challenge is to determine if we are able to accurately risk stratify patients and avoid unnecessary toxicity, thereby tailoring the need for adjuvant breast radiotherapy on an individual patient basis.

Preoperative breast radiation therapy: Indications and perspectives.

Preoperative breast radiation therapy (RT) is not a new concept, but older studies failed to change practice. More recently, there has been interest in revisiting preoperative RT using modern techniques. This current perspective discusses the indications, summarises the published literature and then highlights current clinical trials, with particular attention to combining with novel drugs and optimising associated translational research.

Treatment of the axilla in patients with primary breast cancer and low burden axillary disease: Limitations of the evidence from randomised controlled trials.

Invasive breast cancer is the second most common cancer worldwide. It is known to metastasise to the regional axillary lymph nodes but there has been debate over what is the best way to stage and treat the axilla in patients presenting with primary breast cancer. Multiple trials over the last two decades have led to a change in practice from routine axillary lymph node dissection to sentinel lymph node biopsy in patients who are clinically lymph node negative preoperatively. This has resulted in new questions regarding subsequent treatment of some patients. This review will critically appraise the evidence on axillary treatment in patients with low burden axillary disease and highlight limitations of relevant randomised controlled trials.

Adipokines in Healthy Skeletal Muscle and Metabolic Disease.

Adipose tissue not only functions as a reserve to store energy but has become of major interest as an endocrine organ, releasing signalling molecules termed adipokines which impact on other tissues, such as skeletal muscle. Adipocytes, within skeletal muscle and adipose tissue, secrete adipokines to finely maintain the balance between feed intake and energy expenditure. This book chapter focuses on the three adipokines, adiponectin, leptin and IL-6, which have potent effects on skeletal muscle during rest and exercise. Similarly, adiponectin, leptin and IL-6 enhance glucose uptake and increase fatty acid oxidation in skeletal muscle. Fatty acid oxidation is increased through activation of AMPK (adenosine monophosphate-activated protein kinase signalling) causing phosphorylation and inhibition of ACC (acetyl-coenzyme A carboxylase), decreasing availability of malonyl CoA. Leptin and adiponectin also control feed intake via AMPK signalling in the hypothalamus. Adipokines function to maintain energy homeostasis, however, when feed intake exceeds energy expenditure adipokines can become dysregulated causing lipotoxicity in skeletal muscle and metabolic disease can prevail. Cross-talk between adipocytes and skeletal muscle via correct control by adipokines is important in controlling energy homeostasis during rest and exercise and can help prevent metabolic disease.