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Introduction: Decision making in surgical oncology of the breast has increased its complexity over the last twenty years. This Delphi survey investigates the opinion of an expert panel about the decision making process in surgical procedures on the breast for oncological purposes. Methods: Twenty-seven experts were invited to partake into a Delphi Survey. At the first round they have been asked to provide a list of features involved in the decision making process (patient's characteristics; disease characteristics; surgical techniques, outcomes) and comment on it. Using text-mining techniques we extracted a list of mono-bi-trigrams potentially representative of decision drivers. A technique of “natural language processing” called Word2vec was used to validate changes to texts using synonyms and plesionyms. Word2Vec was also used to test the semantic relevance of n-grams within a corpus of knowledge made up of books edited by panel members. The final list of variables extracted was submitted to the judgement of the panel for final validation at the second round of the Delphi using closed ended questions. Results: 52 features out of 59 have been approved by the panel. The overall consensus was 87.1% Conclusions: Text mining and natural language processing allowed the extraction of a number of decision drivers and outcomes as part of the decision making process in surgical oncology on the breast. This result was obtained transforming narrative texts into structured data. The high level of consensus among experts provided validation to this process. © 2022 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology

Background: Dose-dense sequential chemotherapy with anthracyclines and taxanes achieved an 18% reduction of recurrence risk in early breast cancer (BC). The optimal chemotherapy schedule and interval between cycles remain under investigation. Methods: Overall, 990 patients were randomised to receive either three cycles of epirubicin (E, 110 mg/m2) every 2 weeks followed by 3 cycles of paclitaxel (T, 200 mg/m2) every 2 weeks followed by three cycles of intensified CMF (Control Arm A, E-T-CMF) that was previously used in BC or three cycles of epirubicin followed by three cycles of CMF followed by nine consecutive weekly cycles of docetaxel (wD) 35 mg/m2 (Arm B, E-CMF-wD) or nine consecutive weekly cycles of paclitaxel (wT) 80 mg/m2 (Arm C, E-CMF-wT). Trastuzumab was administered for HER2-positive disease. Results: At a median follow-up of 13.3 years, 330 disease-free survival (DFS) events (33.3%) were reported. DFS and overall survival (OS) did not differ between patients in the combined B and C arms versus arm A either in the entire cohort (HR = 0.90, P = 0.38 and HR = 0.85, P = 0.20) or among trastuzumab-treated patients (HR = 0.69, P = 0.13 and HR = 0.67, P = 0.13). Thirty-four patients (3.4%) developed secondary neoplasms. Conclusions: Overall, no significant differences in survival were found amongst the studied regimens after a long-term observational period. Trial registration: Australian New Zealand Clinical Trials Registry ACTRN12610000151033. © 2022, The Author(s), under exclusive licence to Springer Nature Limited.

The Breast Surgery theoretical and practical knowledge curriculum comprehensively describes the knowledge and skills expected of a fully trained surgeon practicing in the European Union and European Economic Area (EEA). It forms part of a range of factors that contribute to the delivery of high quality cancer care. It has been developed by a panel of experts from across Europe and has been validated by professional breast surgery societies in Europe. The curriculum maps closely to the syllabus of the Union of European Medical Specialists (UEMS) Breast Surgery Exam, the UK FRCS (breast specialist interest) curriculum and other professional standards across Europe and globally (USA Society of Surgical Oncology, SSO). It is envisioned that this will serve as the basis for breast surgery training, examination and accreditation across Europe to harmonise and raise standards as breast surgery develops as a separate discipline from its parent specialties (general surgery, gynaecology, surgical oncology and plastic surgery).\ud \ud \ud \ud The curriculum is not static but will be revised and updated by the curriculum development group of the European Breast Surgical Oncology Certification group (BRESO) every 2 years.

Background: Tumor-infiltrating lymphocytes (TILs) and their subsets contribute to breast cancer prognosis. We investigated the prognostic impact of CD3+, CD8+ and FOXP3+ TILs in patients with early intermediate/high-risk breast cancer treated with adjuvant anthracycline-based chemotherapy within two randomized trials conducted by our Group. Methods: We examined 1011 patients (median follow-up 130.9 months) and their tumors for total, stromal (s) and intratumoral (i) CD3, CD8 and FOXP3 lymphocyte density (counts/mm2) on tissue-microarray cores by immunohistochemistry. Morphological sTIL density on whole H&E-stained sections was also evaluated. Results: The majority of TILs were CD3+. Total CD3 and CD8, sCD3 and sCD8, iCD3 and iCD8, sFOXP3 and iFOXP3 were strongly correlated (Spearman’s rho values > 0.6). High individual lymphocytic subsets and sTIL density were strongly associated with high tumor grade, higher proliferation and HER2-positive and triple-negative tumors (all p values < 0.001). Higher sTIL density (10% increments), high density of almost each individual marker and all-high profiles conferred favorable prognosis. However, when adjusted for sTIL density, stromal and intratumoral lymphocytic subsets lost their prognostic significance, while higher sTIL density conferred up to 15% lower risk for relapse. Independently of sTIL density, higher total CD3+ and CD8+ TILs conferred 35% and 28% lower risk for relapse, respectively. Conclusions: Stromal and intratumoral CD3+, CD8+ and FOXP3+ TIL density do not seem to add prognostic information over the morphologically assessed sTIL density, which is worth introducing in routine histology reports. © 2020, Springer-Verlag GmbH Germany, part of Springer Nature.

Multigene assays (MGAs) guide treatment in early-stage breast cancer (ESBC) enabling selective and effective use of adjuvant chemotherapy (CT). Support for all MGAs had previously been derived from retrospectively-analyzed, prospective studies. Only 2 ESBC MGAs, the 70-gene signature (MammaPrint®) and the 21-gene Recurrence Score (RS) assay (Oncotype DX®), are now supported by entirely prospective randomized phase 3 trials. These studies varied in their primary objectives, design, and eligibility. The MINDACT study provided the first level 1 evidence for the 70-gene signature, identifying a prognostic capability irrespective of lymph node (LN) or hormone receptor (HR) status. However, the study did not support predictive value for the assay regarding adjuvant CT utility. The second prospective study, WSG-PlanB, confirmed the prognostic value of the 21-gene RS assay in HR-positive tumors with RS ≤ 11. A 5-year disease free survival (DFS) of 94% was identified in this group when treated with endocrine therapy (ET) alone regardless of N0 or N1 nodal status. The final new prospective study, TAILORx, confirmed the prognostic value of the 21-gene assay in N0 HR-positive disease, demonstrating a lack of CT benefit in patients with midrange RS. The information from these phase 3 studies confirms that MGAs are not interchangeable and that each provides different information for differing patient populations. Prognosis-only is supported for the 70-gene signature while both prognosis and the predictive value of CT are provided by the 21-gene assay. This review assesses and contrasts these phase 3 studies in the context of target populations and clinical utility. © 2019 The Authors

Ductal cancer in situ (DCIS) is mainly a screen-detected disease and although the risk for breast cancer is age-dependent, most screening programs do not include women over the age of 75 years. Older women are usually excluded from clinical trials and treatment practices are largely based on observational studies or extrapolation of trial results from younger patients, leading to either over- or under-treatment of this population. We systematically reviewed available electronic databases for DCIS treatment patterns and outcomes in older patients 15 years. Inclusion criteria allowed for randomised controlled trials, cohort studies, case-control and cross-sectional studies, as well as meta-analyses, systematic reviews and position papers. Results showed that, although elderly are not necessarily frail, they are generally treated as such by physicians, aiming to de-escalate therapeutic interventions. After adjusting for frailty, age seems to be a significant factor for less surgery; however, older women with DCIS are more probable to receive surgery than their counterparts with early invasive cancer. DCIS biology and subtypes are independent risk factors for local recurrence or progression to invasive carcinoma, if DCIS is under-treated. The end-benefit of surgery, radio- and endocrine-therapy depend on additional parameters, such as life expectancy, co-morbidities and competing risks of death. Screen-detected DCIS in older women is a challenging clinical problem, mainly due to the lack of high-level data. Therapeutic strategies should be tailored to life expectancy and performance status, DCIS features and patient preference, aiming at combining optimal oncological outcomes with maintenance of quality of life. © 2020 Elsevier Inc.

Background: EUSOMA undertook the commitment of defining the requirements for a specialist breast centre, which has become the reference document for the implementation of breast centres. Summary: The EUSOMA requirements for a specialist breast centre give clear indications regarding the requisite caseload, dedicated team composition (core and non-core team), organisation, availability of services and equipment throughout the patient pathway, quality control, and application of a multidisciplinary approach. The minimum number of cases is 150 newly diagnosed breast cancer cases per year. Based on the EUSOMA requirements, a voluntary and accredited certification scheme has been developed. In Europe, other voluntary certification schemes are available, such as those developed by the German Cancer Society and German Society for Breast Disease, the National Cancer Peer Review Programme in the UK, and the "label de qualité" established by the Swiss Anticancer League and the Swiss Senology Society. The European Commission Initiative on Breast Cancer (ECIBC) has overseen the development of a European Quality Assurance Scheme. Key Messages: Nearly 20 years after the initial publication of the EUSOMA requirements, ensuring that all breast cancer patients in Europe are treated only in certified breast centres should be considered a high priority and eventually achieved through collaborative efforts. © 2019 © 2019 S. Karger AG, Basel.

Background The optimal ways of using aromatase inhibitors or tamoxifen as endocrine treatment for early breast cancer remains uncertain.Methods We undertook meta-analyses of individual data on 31 920 postmenopausal women with oestrogen-receptor-positive early breast cancer in the randomised trials of 5 years of aromatase inhibitor versus 5 years of tamoxifen; of 5 years of aromatase inhibitor versus 2-3 years of tamoxifen then aromatase inhibitor to year 5; and of 2-3 years of tamoxifen then aromatase inhibitor to year 5 versus 5 years of tamoxifen. Primary outcomes were any recurrence of breast cancer, breast cancer mortality, death without recurrence, and all-cause mortality. Intention-to-treat log-rank analyses, stratified by age, nodal status, and trial, yielded aromatase inhibitor versus tamoxifen first-event rate ratios (RRs).Findings In the comparison of 5 years of aromatase inhibitor versus 5 years of tamoxifen, recurrence RRs favoured aromatase inhibitors significantly during years 0-1 (RR 0.64, 95% CI 0.52-0.78) and 2-4 (RR 0.80, 0.68-0.93), and non-significantly thereafter. 10-year breast cancer mortality was lower with aromatase inhibitors than tamoxifen (12.1% vs 14.2%; RR 0.85, 0.75-0.96; 2p=0.009). In the comparison of 5 years of aromatase inhibitor versus 2-3 years of tamoxifen then aromatase inhibitor to year 5, recurrence RRs favoured aromatase inhibitors significantly during years 0-1 (RR 0.74, 0.62-0.89) but not while both groups received aromatase inhibitors during years 2-4, or thereafter; overall in these trials, there were fewer recurrences with 5 years of aromatase inhibitors than with tamoxifen then aromatase inhibitors (RR 0.90, 0.81-0.99; 2p=0.045), though the breast cancer mortality reduction was not significant (RR 0.89, 0.78-1.03; 2p=0.11). In the comparison of 2-3 years of tamoxifen then aromatase inhibitor to year 5 versus 5 years of tamoxifen, recurrence RRs favoured aromatase inhibitors significantly during years 2-4 (RR 0.56, 0.46-0.67) but not subsequently, and 10-year breast cancer mortality was lower with switching to aromatase inhibitors than with remaining on tamoxifen (8.7% vs 10.1%; 2p=0.015). Aggregating all three types of comparison, recurrence RRs favoured aromatase inhibitors during periods when treatments differed (RR 0.70, 0.64-0.77), but not significantly thereafter (RR 0.93, 0.86-1.01; 2p=0.08). Breast cancer mortality was reduced both while treatments differed (RR 0.79, 0.67-0.92), and subsequently (RR 0.89, 0.81-0.99), and for all periods combined (RR 0.86, 0.80-0.94; 2p=0.0005). All-cause mortality was also reduced (RR 0.88, 0.82-0.94; 2p=0.0003). RRs differed little by age, body-mass index, stage, grade, progesterone receptor status, or HER2 status. There were fewer endometrial cancers with aromatase inhibitors than tamoxifen (10-year incidence 0.4% vs 1.2%; RR 0.33, 0.21-0.51) but more bone fractures (5-year risk 8.2% vs 5.5%; RR 1.42, 1.28-1.57); non-breast-cancer mortality was similar.Interpretation Aromatase inhibitors reduce recurrence rates by about 30% (proportionately) compared with tamoxifen while treatments diff er, but not thereafter. 5 years of an aromatase inhibitor reduces 10-year breast cancer mortality rates by about 15% compared with 5 years of tamoxifen, hence by about 40% (proportionately) compared with no endocrine treatment. Copyright (C) Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Open Access article distributed under the terms of CC BY.

Aim: Due to increasing life expectancy, patients with breast cancer remain at risk of dying due to breast cancer over a long time. This study aims to assess the impact of age on breast cancer mortality and other cause mortality 10 years after diagnosis. Methods: Postmenopausal patients with hormone-receptor positive breast cancer were included in the Tamoxifen and Exemestane Adjuvant Multinational (TEAM) trial between 2001 and 2006. Age at diagnosis was categorised as

Several studies support an important role of angiogenesis in breast cancer growth and metastasis. The main objectives of the study were to investigate the immunohistochemical expression of vascular endothelial growth factor (VEGF) family ligands (VEGF-A and VEGF-C) and receptors (VEGFR1, VEGFR2 and VEGFR3) in breast cancer and their associations with clinicopathological parameters, cancer subtypes/subgroups and patient outcome. Formalin-fixed paraffin-embedded tumor tissue samples were collected from early-stage breast cancer patients treated with anthracycline-based chemotherapy within a randomized trial. Immunohistochemistry was performed on serial 2.5 μm thick tissue sections from tissue microarray blocks. High VEGF-A, VEGF-C, VEGFR1, VEGFR2 and VEGFR3 protein expression was observed in 11.8% (N = 87), 80.8% (N = 585), 28.1% (N = 202), 64.6% (N = 359) and 71.8% (N = 517) of the cases, respectively. Significant associations were observed among all proteins (all p-values

Background The administration of endocrine therapy for 5 years substantially reduces recurrence rates during and after treatment in women with early-stage, estrogen-receptor (ER)–positive breast cancer. Extending such therapy beyond 5 years offers further protection but has additional side effects. Obtaining data on the absolute risk of subsequent distant recurrence if therapy stops at 5 years could help determine whether to extend treatment. Methods In this meta-analysis of the results of 88 trials involving 62,923 women with ER-positive breast cancer who were disease-free after 5 years of scheduled endocrine therapy, we used Kaplan–Meier and Cox regression analyses, stratified according to trial and treatment, to assess the associations of tumor diameter and nodal status (TN), tumor grade, and other factors with patients’ outcomes during the period from 5 to 20 years. Results Breast-cancer recurrences occurred at a steady rate throughout the study period from 5 to 20 years. The risk of distant recurrence was strongly correlated with the original TN status. Among the patients with stage T1 disease, the risk of distant recurrence was 13% with no nodal involvement (T1N0), 20% with one to three nodes involved (T1N1–3), and 34% with four to nine nodes involved (T1N4–9); among those with stage T2 disease, the risks were 19% with T2N0, 26% with T2N1–3, and 41% with T2N4–9. The risk of death from breast cancer was similarly dependent on TN status, but the risk of contralateral breast cancer was not. Given the TN status, the factors of tumor grade (available in 43,590 patients) and Ki-67 status (available in 7692 patients), which are strongly correlated with each other, were of only moderate independent predictive value for distant recurrence, but the status regarding the progesterone receptor (in 54,115 patients) and human epidermal growth factor receptor type 2 (HER2) (in 15,418 patients in trials with no use of trastuzumab) was not predictive. During the study period from 5 to 20 years, the absolute risk of distant recurrence among patients with T1N0 breast cancer was 10% for low-grade disease, 13% for moderate-grade disease, and 17% for high-grade disease; the corresponding risks of any recurrence or a contralateral breast cancer were 17%, 22%, and 26%, respectively. Conclusions After 5 years of adjuvant endocrine therapy, breast-cancer recurrences continued to occur steadily throughout the study period from 5 to 20 years. The risk of distant recurrence was strongly correlated with the original TN status, with risks ranging from 10 to 41%, depending on TN status and tumor grade. (Funded by Cancer Research UK and others.)

BACKGROUND: Neoadjuvant chemotherapy (NACT) for early breast cancer can make breast-conserving surgery more feasible and might be more likely to eradicate micrometastatic disease than might the same chemotherapy given after surgery. We investigated the long-term benefits and risks of NACT and the influence of tumour characteristics on outcome with a collaborative meta-analysis of individual patient data from relevant randomised trials. METHODS: We obtained information about prerandomisation tumour characteristics, clinical tumour response, surgery, recurrence, and mortality for 4756 women in ten randomised trials in early breast cancer that began before 2005 and compared NACT with the same chemotherapy given postoperatively. Primary outcomes were tumour response, extent of local therapy, local and distant recurrence, breast cancer death, and overall mortality. Analyses by intention-to-treat used standard regression (for response and frequency of breast-conserving therapy) and log-rank methods (for recurrence and mortality). FINDINGS: Patients entered the trials from 1983 to 2002 and median follow-up was 9 years (IQR 5-14), with the last follow-up in 2013. Most chemotherapy was anthracycline based (3838 [81%] of 4756 women). More than two thirds (1349 [69%] of 1947) of women allocated NACT had a complete or partial clinical response. Patients allocated NACT had an increased frequency of breast-conserving therapy (1504 [65%] of 2320 treated with NACT vs 1135 [49%] of 2318 treated with adjuvant chemotherapy). NACT was associated with more frequent local recurrence than was adjuvant chemotherapy: the 15 year local recurrence was 21·4% for NACT versus 15·9% for adjuvant chemotherapy (5·5% increase [95% CI 2·4-8·6]; rate ratio 1·37 [95% CI 1·17-1·61]; p=0·0001). No significant difference between NACT and adjuvant chemotherapy was noted for distant recurrence (15 year risk 38·2% for NACT vs 38·0% for adjuvant chemotherapy; rate ratio 1·02 [95% CI 0·92-1·14]; p=0·66), breast cancer mortality (34·4% vs 33·7%; 1·06 [0·95-1·18]; p=0·31), or death from any cause (40·9% vs 41·2%; 1·04 [0·94-1·15]; p=0·45). INTERPRETATION: Tumours downsized by NACT might have higher local recurrence after breast-conserving therapy than might tumours of the same dimensions in women who have not received NACT. Strategies to mitigate the increased local recurrence after breast-conserving therapy in tumours downsized by NACT should be considered-eg, careful tumour localisation, detailed pathological assessment, and appropriate radiotherapy. FUNDING: Cancer Research UK, British Heart Foundation, UK Medical Research Council, and UK Department of Health. ispartof: LANCET ONCOLOGY vol:19 issue:1 pages:27-39 ispartof: location:England status: published

It is well recognized that the incidence of breast cancer increases significantly with age. Despite this, older people remain under-represented in many clinical trials and their management relies on extrapolation of data from younger patients. Providing an aggressive intervention can be challenging, particularly in less fit older patients where a conservative approach is commonly perceived to be more appropriate. The optimal management of this population is unknown and treatment decision should be personalized. This review article will discuss several controversial issues in managing older adults with early breast cancer in a multidisciplinary setting, including the role of surgical treatment of the axilla in clinically node negative disease, radiotherapy after breast conservation surgery in low-risk tumours, personalizing adjuvant systemic therapy, and geriatric assessments in breast cancer treatment decisions. © 2017 Elsevier Ltd

Background After 5 years of median follow-up, the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial reported no difference in disease-free survival between exemestane monotherapy and a sequential scheme of tamoxifen followed by exemestane in postmenopausal patients with early-stage, hormone receptor-positive breast cancer. As recurrence risk in hormone receptor-positive breast cancer remains linear beyond 5 years after diagnosis, we analysed long-term follow-up outcomes of this trial. Methods The TEAM trial, a multicentre, open-label, randomised, controlled, phase 3 trial, included postmenopausal patients with early-stage hormone receptor-positive breast cancer from nine countries. Patients were randomly allocated (1:1) by a computer-generated random permuted block method (block sizes 4–8) to either 5 years of oral exemestane monotherapy (25 mg once a day) or a sequential scheme of oral tamoxifen (20 mg once a day) followed by exemestane for a total duration of 5 years. After the publication of the IES trial, the protocol was amended (Dec 13, 2004). Patients assigned to tamoxifen were switched after 2·5–3·0 years to exemestane therapy for a total duration of 5·0 years of treatment. Randomisation was done centrally in each country. Long-term follow-up data for disease recurrence and survival was collected in six participating countries and analysed by intention to treat. The primary endpoint was disease-free survival at 10 years of follow-up. The trial is registered with ClinicalTrials.gov, numbers NCT00279448 and NCT00032136; with Netherlands Trial Register, number NTR 267; and the Ethics Commission Trial, number 27/2001. Findings 6120 patients of the original 9776 patients in the TEAM trial were included in the current intention-to-treat analysis. Median follow-up was 9·8 years (IQR 8·0–10·3). During follow-up, 921 (30%) of 3075 patients in the exemestane group and 929 (31%) of 3045 patients in the sequential group had a disease-free survival event. Disease-free survival at 10 years was 67% (95% CI 65–69) for the exemestane group and 67% (65–69) for the sequential group (hazard ratio 0·96, 0·88–1·05; p=0·39). Interpretation The long-term findings of the TEAM trial confirm that both exemestane alone and sequential treatment with tamoxifen followed by exemestane are reasonable options as adjuvant endocrine therapy in postmenopausal patients with hormone receptor-positive early breast cancer. These results suggest that the opportunity to individualise adjuvant endocrine strategy accordingly, based on patient preferences, comorbidities, and tolerability might be possible. Funding Pfizer, Dutch Cancer Foundation. © 2017 Elsevier Ltd

BACKGROUND: Prevention of bone metastases is a major issue for breast cancer patients, as it would improve quality of life in a population where long survival is anticipated. PATIENTS AND METHODS: Early breast cancer patients, who had been treated with anthracycline-based chemotherapy within two randomized trials, were included in the study. We evaluated, by quantitative reverse transcription–polymerase chain reaction, 819 formalin-fixed paraffin-embedded tumor tissue samples for mRNA expression of RANK, OPG, and RANKL, as well as their ratios, for potential prognostic significance for the development of bone metastases and also for disease-free survival (DFS) and overall survival. RESULTS: Median age was 52.7 years, whereas 54.2% of the patients were postmenopausal and 78.3% estrogen receptor/progesterone receptor positive. After a median follow-up of 119.9 months, 226 patients (27.6%) had died and 291 patients (35.5%) had disease progression. Low mRNA expression of RANKL was associated with postmenopausal status and greater number of positive lymph nodes (P = .002 and P