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Background: Idiopathic granulomatous mastitis (IGM) is a rare, benign inflammatory breast condition often mistaken for inflammatory breast cancer and, therefore, requires a biopsy for accurate diagnosis. Although not cancerous, IGM can cause emotional distress because of severe pain and ensuing breast deformity. Differentiating IGM from other breast inflammations caused by infections is essential. IGM mostly affects premenopausal women and is potentially associated with recent pregnancies and breastfeeding. The risk factors, including smoking and contraceptive use, have inconsistent associations. Steroid responses suggest an autoimmune component, though specific markers are lacking., Methods: We performed a narrative review on potential risk factors, diagnostics, and therapy of IGM., Results: Diagnostics and clinical management of IGM are challenging. The treatment options include NSAIDs, steroids, surgery, antibiotics, immunosuppressants, prolactin suppressants, and observation, each with varying effectiveness and side effects., Conclusions: Current IGM treatment evidence is limited, based on case reports and small series. There is no consensus on the optimal management strategy for this disease. The GRAMAREG study by the EUBREAST Study Group aims to collect comprehensive data on IGM to improve diagnostic and treatment guidelines. By enrolling patients with confirmed IGM, the study seeks to develop evidence-based recommendations, enhancing patient care and understanding of this condition.

Background: Randomized trials have shown that axillary clearance (AC) can safely be omitted in patients with sentinel lymph node-positive breast cancer. At the same time, de-escalation of chemotherapy in postmenopausal patients with ER+HER2- breast cancer may depend on detailed axillary nodal stage. The aim of this pre-specified secondary analysis of the SENOMAC trial was to investigate whether the choice of axillary staging affected the proportion of patients receiving adjuvant chemotherapy, and recurrence-free survival (RFS)., Methods: Proportion receiving adjuvant chemotherapy was calculated according to AC or sentinel lymph node biopsy (SLNB) only, menopausal status, and region of inclusion, for 2168 patients with clinically node-negative ER+HER2- breast cancer and 1-2 sentinel lymph node macrometastases included in the SENOMAC trial., Findings: In premenopausal patients, 514 out of 615 patients (83.6%) received adjuvant chemotherapy with no significant difference between randomization arms. In postmenopausal patients, the proportion receiving chemotherapy varied considerably by region and country (36.0-82.4%). In Denmark, where 194 out of 539 postmenopausal patients (36.0%) received adjuvant chemotherapy, rates differed significantly between the AC and the SLNB only arm (41.3% vs 31.4%, p = 0.019). After a median follow-up of 44.88 months for Danish postmenopausal patients, no significant difference was seen in 5-year RFS, which was 91% (85.6%-96.6%) for the SLNB only and 90.9% (86.3%-95.6%) for the AC arm (p = 0.42)., Interpretation: When omitting axillary clearance, and thus reducing the risk of long-term arm morbidity, potential under-treatment of postmenopausal patients with ER+HER2- breast cancer may require the development of new predictive and imaging tools., Funding: Swedish Research Council, Swedish Cancer Society, Nordic Cancer Union, Swedish Breast Cancer Association., Competing Interests: Dr. RO Bagge declares research grants from BMS, Endomagnetics Ltd, Skyline Dx and NeraCare GmbH as well as participation in advisory board for Amgen, BD/BARD, Bristol-Myers Squibb (BMS), Cansr.com, Merck Sharp & Dohme (MSD), Novartis, Roche and Sanofi Genzyme and stock or stock options in SATMEG Ventures AB. Thorsten Kuehn has payment or honoraria for presentations from MSD, Novartis, Lilly, Exact Sciences, Merit Medical, Sirius Medical and EndoMag and support for attending meetings from MSD, Lilly. All other authors declare no competing interests., (© 2024 The Author(s).)

Importance: In patients with clinically node-negative (cN0) breast cancer and 1 or 2 sentinel lymph node (SLN) macrometastases, omitting completion axillary lymph node dissection (CALND) is standard. High nodal burden (≥4 axillary nodal metastases) is an indication for intensified treatment in luminal breast cancer; hence, abstaining from CALND may result in undertreatment., Objective: To develop a prediction model for high nodal burden in luminal ERBB2-negative breast cancer (all histologic types and lobular breast cancer separately) without CALND., Design, Setting, and Participants: The prospective Sentinel Node Biopsy in Breast Cancer: Omission of Axillary Clearance After Macrometastases (SENOMAC) trial randomized patients 1:1 to CALND or its omission from January 2015 to December 2021 among adult patients with cN0 T1-T3 breast cancer and 1 or 2 SLN macrometastases across 5 European countries. The cohort was randomly split into training (80%) and test (20%) sets, with equal proportions of high nodal burden. Prediction models were developed by multivariable logistic regression in the complete luminal ERBB2-negative cohort and a lobular breast cancer subgroup. Nomograms were constructed. The present diagnostic/prognostic study presents the results of a prespecified secondary analysis of the SENOMAC trial. Herein, only patients with luminal ERBB2-negative tumors assigned to CALND were selected. Data analysis for this article took place from June 2023 to April 2024., Exposure: Predictors of high nodal burden., Main Outcomes and Measures: High nodal burden was defined as ≥4 axillary nodal metastases. The luminal prediction model was evaluated regarding discrimination and calibration., Results: Of 1010 patients (median [range] age, 61 [34-90] years; 1006 [99.6%] female and 4 [0.4%] male), 138 (13.7%) had a high nodal burden and 212 (21.0%) had lobular breast cancer. The model in the training set (n = 804) included number of SLN macrometastases, presence of SLN micrometastases, SLN ratio, presence of SLN extracapsular extension, and tumor size (not included in lobular subgroup). Upon validation in the test set (n = 201), the area under the receiver operating characteristic curve (AUC) was 0.74 (95% CI, 0.62-0.85) and the calibration was satisfactory. At a sensitivity threshold of ≥80%, all but 5 low-risk patients were correctly classified corresponding to a negative predictive value of 94%. The prediction model for the lobular subgroup reached an AUC of 0.74 (95% CI, 0.66-0.83)., Conclusions and Relevance: The predictive models and nomograms may facilitate systemic treatment decisions without exposing patients to the risk of arm morbidity due to CALND. External validation is needed., Trial Registration: ClinicalTrials.gov Identifier: NCT02240472.

Background: In luminal breast cancer, adjuvant CDK4/6 inhibitors (eg, abemaciclib) improve invasive disease-free survival. In patients with T1-2, grade 1-2 tumours, and one or two sentinel lymph node metastases, completion axillary lymph node dissection (cALND) is the only prognostic tool available that can reveal four or more nodal metastases (pN2-3), which is the only indication for adjuvant abemaciclib in this setting. However, this technique can lead to substantial arm morbidity in patients. We aimed to pragmatically describe the potential benefit and harm of this strategy on the individual patient level in patients from the ongoing SENOMAC trial., Methods: In the randomised, phase 3, SENOMAC trial, patients aged 18 years or older, of any performance status, with clinically node-negative T1-T3 breast cancer and one or two sentinel node macrometastases from 67 sites in five European countries (Denmark, Germany, Greece, Italy, and Sweden) were randomly assigned (1:1), via permutated block randomisation (random block size of 2 and 4) stratified by country, to either cALND or its omission (ie, they had a sentinel lymph node biopsy only). The primary outcome is overall survival, which is yet to be reported. In this post-hoc analysis, patients from the SENOMAC per-protocol population, with luminal oestrogen-receptor positive, HER2-negative, T1-2, histological grade 1-2 breast cancer, with tumour size of 5 cm or smaller were selected to match the characteristics of cohort 1 of the monarchE trial who would only have an indication for adjuvant abemaciclib if found to have 4 or more nodal metastases. The primary study objective was to determine the number of patients who developed patient-reported severe or very severe impairment of physical arm function after cALND (as measured by the Lymphedema Functioning, Disability, and Health [Lymph-ICF] Questionnaire) 1 year after surgery to avoid one invasive disease-free survival event at 5 years with 2 years of adjuvant abemaciclib, using invasive disease-free survival event data from cohort 1 of the monarchE trial. The SENOMAC trial is registered with ClincialTrials.gov, NCT02240472, and is closed to accrual and ongoing., Findings: Between Jan 31, 2015, and Dec 31, 2021, 2766 patients were enrolled in SENOMAC and randomly assigned to cALND (n=1384) or sentinel node biopsy only (n=1382), of whom 2540 were included in the per-protocol population. 1705 (67%) of 2540 patients met this post-hoc study's eligibility criteria, of whom 802 (47%) had a cALND and 903 (53%) had a sentinel lymph node biopsy only. Median age at randomisation was 62 years (IQR 52-71), 1699 (>99%) of 1705 patients were female, and six (<1%) were male. Among 1342 patients who responded to questionnaires, after a median follow-up of 45·2 months (IQR 25·6-59·8; data cutoff Nov 17, 2023), patient-reported severe or very severe impairment of physical arm function was reported in 84 (13%) of 634 patients who had cALND versus 30 (4%) of 708 who had sentinel lymph node biopsy only (χ 2 test p<0·0001). To avoid one invasive disease-free survival event at 5 years with adjuvant abemaciclib, cALND would need to be performed in 104 patients, and would result in nine patients having severe or very severe impairment of physical arm function 1 year after surgery., Interpretation: As a method to potentially identify an indication for abemaciclib, and subsequently avoid invasive disease-free survival events at 5 years with 2 years of adjuvant abemaciclib, cALND carries a substantial risk of severe or very severe arm morbidity and so cALND should be discouraged for this purpose., Funding: Swedish Research Council, the Swedish Cancer Society, the Nordic Cancer Union, and the Swedish Breast Cancer Association., Competing Interests: Declaration of interests JdB declares honoraria for educational event lectures for AstraZeneca, Novartis, and Pfizer. ODG declares honoraria for lectures and presentations from MSD, AstraZeneca, Eli Lilly, Becton, Dickinson and Company, and Bayer and the participation on a data safety monitoring or advisory board for MSD. MS is chairwoman for the Research Committee at the Swedish Cancer Society. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Introduction: Neoadjuvant chemotherapy (NAC) has a profound impact on surgical management of breast cancer. For this reason, the Italian Association of Breast Surgeons (ANISC) promoted the third national Consensus Conference on this subject, open to multidisciplinary specialists., Materials and Methods: The Consensus Conference was held on-line in November 2022, and after an introductory session with five core-team experts, participants were asked to vote on eleven controversial issues, while results were collected in real-time with a polling system., Results: A total of 164 dedicated specialists from 74 Breast Centers participated. Consensus was reached for only three of the eleven issues, including: 1) the indication to assess the response with Magnetic Resonance Imaging (79 %); 2) the need to re-assess the biological factors of the residual tumor if present (96 %); 3) the possibility of omitting a formal axillary node dissection for cN1 patients if a pathologic Complete Response (pCR) was confirmed with analysis of one or more sentinel lymph nodes (82 %). The majority voted in favor of mapping both the breast and nodal lesions pre-NAC (59 %), and against the omission of sentinel lymph node biopsy in cN0 patients in the case of pathologic or clinical Complete Response (69 %). In cases of cT3/cN1+ tumors with pCR, only 8 % of participants considered appropriate the omission of Post-Mastectomy Radiation Therapy., Conclusion: There is still a wide variability in surgical approaches after NAC in the "real world". As NAC is increasingly used, multidisciplinary teams should be attuned to conforming their procedures to the rapid advances in this field., Competing Interests: Declaration of competing interest None., (© 2024 Elsevier Ltd, BASO ∼ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Importance: Data on oncological outcomes after omission of axillary lymph node dissection (ALND) in patients with breast cancer that downstages from node positive to negative with neoadjuvant chemotherapy are sparse. Additionally, the best axillary surgical staging technique in this scenario is unknown., Objective: To investigate oncological outcomes after sentinel lymph node biopsy (SLNB) with dual-tracer mapping or targeted axillary dissection (TAD), which combines SLNB with localization and retrieval of the clipped lymph node., Design, Setting, and Participants: In this multicenter retrospective cohort study that was conducted at 25 centers in 11 countries, 1144 patients with consecutive stage II to III biopsy-proven node-positive breast cancer were included between April 2013 and December 2020. The cumulative incidence rates of axillary, locoregional, and any invasive (locoregional or distant) recurrence were determined by competing risk analysis., Exposure: Omission of ALND after SLNB or TAD., Main Outcomes and Measures: The primary end points were the 3-year and 5-year rates of any axillary recurrence. Secondary end points included locoregional recurrence, any invasive (locoregional and distant) recurrence, and the number of lymph nodes removed., Results: A total of 1144 patients (median [IQR] age, 50 [41-59] years; 78 [6.8%] Asian, 105 [9.2%] Black, 102 [8.9%] Hispanic, and 816 [71.0%] White individuals; 666 SLNB [58.2%] and 478 TAD [41.8%]) were included. A total of 1060 patients (93%) had N1 disease, 619 (54%) had ERBB2 (formerly HER2)-positive illness, and 758 (66%) had a breast pathologic complete response. TAD patients were more likely to receive nodal radiation therapy (85% vs 78%; P = .01). The clipped node was successfully retrieved in 97% of TAD cases and 86% of SLNB cases (without localization). The mean (SD) number of sentinel lymph nodes retrieved was 3 (2) vs 4 (2) (P < .001), and the mean (SD) number of total lymph nodes removed was 3.95 (1.97) vs 4.44 (2.04) (P < .001) in the TAD and SLNB groups, respectively. The 5-year rates of any axillary, locoregional, and any invasive recurrence in the entire cohort were 1.0% (95% CI, 0.49%-2.0%), 2.7% (95% CI, 1.6%-4.1%), and 10% (95% CI, 8.3%-13%), respectively. The 3-year cumulative incidence of axillary recurrence did not differ between TAD and SLNB (0.5% vs 0.8%; P = .55)., Conclusions and Relevance: The results of this cohort study showed that axillary recurrence was rare in this setting and was not significantly lower after TAD vs SLNB. These results support omission of ALND in this population.

Purpose: In Italy, Lombardy was the first region to reimburse multigene assays (MGAs) for patients otherwise candidates for chemotherapy. This is a real-world experience of MGAs usage in six referral cancer centers in Lombardy., Methods: Among MGAs, Oncotype DX (RS) was used in 97% of cases. Consecutive patients tested with Oncotype DX from July 2020 to July 2022 were selected. The distribution of clinicopathologic features by RS groups (low RS: 0-25, high RS: 26-100) was assessed using chi-square and compared with those of the TAILORx and RxPONDER trials., Results: Out of 1,098 patients identified, 73% had low RS. Grade and Ki67 were associated with RS (p < 0.001). In patients with both G3 and Ki67 > 30%, 39% had low RS, while in patients with both G1 and Ki67 < 20%, 7% had high RS. The proportion of low RS in node-positive patients was similar to that in RxPONDER (82% vs 83%), while node-negative patients with low RS were significantly less than in TAILORx (66% vs 86%, p < 0.001). The distribution of Grade was different from registration trials, with more G3 and fewer G1 (38% and 3%) than in TAILORx (18% and 27%) and RxPONDER (10% and 24%) (p < 0.001). Patients ≤ 50 years were overrepresented in this series (41%) than in TAILORx and RxPONDER (31% and 24%, respectively) (p < 0.001) and, among them, 42% were node positive., Conclusions: In this real-world series, Oncotype DX was the test almost exclusively used. Despite reimbursement being linked to pre-test chemotherapy recommendation, almost 3/4 patients resulted in the low-RS group. The significant proportion of node-positive patients ≤ 50 years tested indicates that oncologists considered Oncotype DX informative also in this population., (© 2024. The Author(s).)

Background: Trials evaluating the omission of completion axillary-lymph-node dissection in patients with clinically node-negative breast cancer and sentinel-lymph-node metastases have been compromised by limited statistical power, uncertain nodal radiotherapy target volumes, and a scarcity of data on relevant clinical subgroups., Methods: We conducted a noninferiority trial in which patients with clinically node-negative primary T1 to T3 breast cancer (tumor size, T1, ≤20 mm; T2, 21 to 50 mm; and T3, >50 mm in the largest dimension) with one or two sentinel-node macrometastases (metastasis size, >2 mm in the largest dimension) were randomly assigned in a 1:1 ratio to completion axillary-lymph-node dissection or its omission (sentinel-node biopsy only). Adjuvant treatment and radiation therapy were used in accordance with national guidelines. The primary end point was overall survival. We report here the per-protocol and modified intention-to-treat analyses of the prespecified secondary end point of recurrence-free survival. To show noninferiority of sentinel-node biopsy only, the upper boundary of the confidence interval for the hazard ratio for recurrence or death had to be below 1.44., Results: Between January 2015 and December 2021, a total of 2766 patients were enrolled across five countries. The per-protocol population included 2540 patients, of whom 1335 were assigned to undergo sentinel-node biopsy only and 1205 to undergo completion axillary-lymph-node dissection (dissection group). Radiation therapy including nodal target volumes was administered to 1192 of 1326 patients (89.9%) in the sentinel-node biopsy-only group and to 1058 of 1197 (88.4%) in the dissection group. The median follow-up was 46.8 months (range, 1.5 to 94.5). Overall, 191 patients had recurrence or died. The estimated 5-year recurrence-free survival was 89.7% (95% confidence interval [CI], 87.5 to 91.9) in the sentinel-node biopsy-only group and 88.7% (95% CI, 86.3 to 91.1) in the dissection group, with a country-adjusted hazard ratio for recurrence or death of 0.89 (95% CI, 0.66 to 1.19), which was significantly (P<0.001) below the prespecified noninferiority margin., Conclusions: The omission of completion axillary-lymph-node dissection was noninferior to the more extensive surgery in patients with clinically node-negative breast cancer who had sentinel-node macrometastases, most of whom received nodal radiation therapy. (Funded by the Swedish Research Council and others; SENOMAC ClinicalTrials.gov number, NCT02240472.)., (Copyright © 2024 Massachusetts Medical Society.)

This narrative work highlights a selection of published work from 2023 with potential implications for breast cancer practice. We feature publications that have provided new knowledge immediately relevant to patient care or for future research. We also highlight guidelines that have reported evidence-based or consensus recommendations to support practice and evaluation in breast cancer diagnosis and treatment. The scope of selected highlights represents various domains and disciplines in cancer control, from prevention to treatment of early and advanced breast cancer., Competing Interests: Declaration of competing interest N. Houssami receives funding via a NBCF Chair in Breast Cancer Prevention grant (EC-21-001) and a NHMRC Investigator (Leader) grant (1194410); MJ Cardoso and O Gentilini receive institutional funding as Leading Investigator and Principal Investigator of the Project: 101057389 — CINDERELLA — HORIZON-HLTH-2021-DISEASE-04. Maria-Joao Cardoso honoraria: AstraZeneca, Eli Lilly, MSD, Roche, Novartis. Oreste Gentilini honoraria: MSD, Astra-Zeneca, BD, Bayer, Eli-Lilly. Elżbieta Senkus honoraria: AstraZeneca, Cancérodigest, Curio Science, Egis, Eli Lilly, Exact Sciences, Gilead, high5md, MSD, Novartis, Pfizer, Pierre Fabre, Roche; travel support: AstraZeneca, Egis, Gilead, Novartis, Pfizer, Roche; contracted research: Amgen, AstraZeneca, Daiichi Sankyo, Eli Lilly, Novartis, OBI Pharma, Pfizer, Roche, Samsung; grants: Pfizer (Stowarzyszenie Różowy Motyl); medical writing: Astellas, AstraZeneca, Eli Lilly; royalties: Springer; leadership or fiduciary role: Stowarzyszenie Różowy Motyl; stock: AstraZeneca, Eli Lilly, Pfizer. Philip Poortmans no conflicts no disclose., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Currently, various techniques are available to mark and selectively remove initially suspicious axillary lymph nodes (target lymph nodes, TLNs) in breast cancer patients receiving neoadjuvant chemotherapy (NACT). To date, limited data are available on whether the use of magnetic seeds (MS) is suitable for localizing TLNs. This study aimed to investigate the feasibility of MS in patients undergoing target lymph node biopsy (TLNB) or targeted axillary dissection (TAD) after NACT., Methods: Prospective data from the ongoing multicentric AXSANA study were extracted from selected patients in whom the TLN had been marked with an MS before NACT and who were enrolled from June 2020 to June 2023. The endpoints of the analysis were the detection rate, the rate of lost markers, and the potential impairment on magnetic resonance imaging (MRI) assessment., Results: In 187 patients from 27 study sites in seven countries, MS were placed into the TLN before NACT. In 151 of these, post-NACT surgery had been completed at the time of analysis. In 146 patients (96.0%), a TLN could successfully be detected. In three patients, the seed was removed but no lymphoid tissue was detected on histopathology. The rate of lost markers was 1.2% (2 out of 164 MS). In 15 out of 151 patients (9.9%), MRI assessment was reported to be compromised by MS placement., Conclusion: MS show excellent applicability for TLNB/TAD when inserted before NACT with a high DR and a low rate of lost markers. Axillary MS can impair MRI assessment of the breast., Trial Registration Number: NCT04373655 (date of registration May 4, 2020)., (© 2023. The Author(s).)

The present review intends to discuss the controversies and strengths in clinically node-positive patients with axillary nodal status ypN i+ / mi after neoadjuvant chemotherapy. Over the past 20 years, a de-escalation approach toward axillary surgery has been observed in patients with breast cancer. The worldwide use of sentinel node biopsy in the upfront setting and after primary systemic therapy substantially reduced surgical complications or late sequelae and eventually improving quality of life of patients. However, the role of axillary dissection is still unclear in patients with low residual disease post-chemotherapy, namely those with micrometastases in the sentinel node, and its prognostic role is still not very clear. The aim of the present narrative review is to report the available evidence on this topic, discussing the pros and cons of performing axillary lymph node dissection in the infrequent finding of micrometastases in the sentinel node after neoadjuvant chemotherapy. We will also describe the ongoing prospective studies which are expected to shed light and guide future decisions., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Importance: Sentinel lymph node biopsy (SLNB) is the standard of care for axillary node staging of patients with early breast cancer (BC), but its necessity can be questioned since surgery for examination of axillary nodes is not performed with curative intent., Objective: To determine whether the omission of axillary surgery is noninferior to SLNB in patients with small BC and a negative result on preoperative axillary lymph node ultrasonography., Design, Setting, and Participants: The SOUND (Sentinel Node vs Observation After Axillary Ultra-Sound) trial was a prospective noninferiority phase 3 randomized clinical trial conducted in Italy, Switzerland, Spain, and Chile. A total of 1463 women of any age with BC up to 2 cm and a negative preoperative axillary ultrasonography result were enrolled and randomized between February 6, 2012, and June 30, 2017. Of those, 1405 were included in the intention-to-treat analysis. Data were analyzed from October 10, 2022, to January 13, 2023., Intervention: Eligible patients were randomized on a 1:1 ratio to receive SLNB (SLNB group) or no axillary surgery (no axillary surgery group)., Main Outcomes and Measures: The primary end point of the study was distant disease-free survival (DDFS) at 5 years, analyzed as intention to treat. Secondary end points were the cumulative incidence of distant recurrences, the cumulative incidence of axillary recurrences, DFS, overall survival (OS), and the adjuvant treatment recommendations., Results: Among 1405 women (median [IQR] age, 60 [52-68] years) included in the intention-to-treat analysis, 708 were randomized to the SLNB group, and 697 were randomized to the no axillary surgery group. Overall, the median (IQR) tumor size was 1.1 (0.8-1.5) cm, and 1234 patients (87.8%) had estrogen receptor-positive ERBB2 (formerly HER2 or HER2/neu), nonoverexpressing BC. In the SLNB group, 97 patients (13.7%) had positive axillary nodes. The median (IQR) follow-up for disease assessment was 5.7 (5.0-6.8) years in the SLNB group and 5.7 (5.0-6.6) years in the no axillary surgery group. Five-year distant DDFS was 97.7% in the SLNB group and 98.0% in the no axillary surgery group (log-rank P = .67; hazard ratio, 0.84; 90% CI, 0.45-1.54; noninferiority P = .02). A total of 12 (1.7%) locoregional relapses, 13 (1.8%) distant metastases, and 21 (3.0%) deaths were observed in the SLNB group, and 11 (1.6%) locoregional relapses, 14 (2.0%) distant metastases, and 18 (2.6%) deaths were observed in the no axillary surgery group., Conclusions and Relevance: In this randomized clinical trial, omission of axillary surgery was noninferior to SLNB in patients with small BC and a negative result on ultrasonography of the axillary lymph nodes. These results suggest that patients with these features can be safely spared any axillary surgery whenever the lack of pathological information does not affect the postoperative treatment plan., Trial Registration: ClinicalTrials.gov Identifier: NCT02167490.

Background: Breast cancer therapy improved significantly, allowing for different surgical approaches for the same disease stage, therefore offering patients different aesthetic outcomes with similar locoregional control. The purpose of the CINDERELLA trial is to evaluate an artificial-intelligence (AI) cloud-based platform (CINDERELLA platform) vs the standard approach for patient education prior to therapy., Methods: A prospective randomized international multicentre trial comparing two methods for patient education prior to therapy. After institutional ethics approval and a written informed consent, patients planned for locoregional treatment will be randomized to the intervention (CINDERELLA platform) or controls. The patients in the intervention arm will use the newly designed web-application (CINDERELLA platform, CINDERELLA APProach) to access the information related to surgery and/or radiotherapy. Using an AI system, the platform will provide the patient with a picture of her own aesthetic outcome resulting from the surgical procedure she chooses, and an objective evaluation of this aesthetic outcome (e.g., good/fair). The control group will have access to the standard approach. The primary objectives of the trial will be i) to examine the differences between the treatment arms with regards to patients' pre-treatment expectations and the final aesthetic outcomes and ii) in the experimental arm only, the agreement of the pre-treatment AI-evaluation (output) and patient's post-therapy self-evaluation., Discussion: The project aims to develop an easy-to-use cost-effective AI-powered tool that improves shared decision-making processes. We assume that the CINDERELLA APProach will lead to higher satisfaction, better psychosocial status, and wellbeing of breast cancer patients, and reduce the need for additional surgeries to improve aesthetic outcome., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Kaidar-Person et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Clinical axillary lymph node management in early breast cancer has evolved from being merely an aspect of surgical management and now includes the entire multidisciplinary team. The second edition of the "Lucerne Toolbox", a multidisciplinary consortium of European cancer societies and patient representatives, addresses the challenges of clinical axillary lymph node management, from diagnosis to local therapy of the axilla. Five working packages were developed, following the patients' journey and addressing specific clinical scenarios. Panellists voted on 72 statements, reaching consensus (agreement of 75% or more) in 52.8%, majority (51%-74% agreement) in 43.1%, and no decision in 4.2%. Based on the votes, targeted imaging and standardized pathology of lymph nodes should be a prerequisite to planning local and systemic therapy, axillary lymph node dissection can be replaced by sentinel lymph node biopsy ( ± targeted approaches) in a majority of scenarios; and positive patient outcomes should be driven by both low recurrence risks and low rates of lymphoedema., Competing Interests: Ana Bosch: Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Lilly, Roche, Novartis; Support for attending meetings and/or travel from Roche; Participation on a Data Safety Monitoring Board or Advisory; Giuseppe Curigliano: Consulting fees from BMS, Roche, Pfizer, Novartis, Lilly, Astra Zeneca, Daichii Sankyo, Merck, Seagen, Ellipsis, Gilead; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Lilly, Pfizer, Relay; Support for attending meetings and/or travel from Daichii Sankyo; Jana De Boniface: Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Astra Zeneca; Carsten Denkert: Grants from Myriad, Roche, BMBF, European Commission, GBG Foundation; consulting fees from MSD Oncology, Daiichi Sankyo, Molecular Health, AstraZeneca, Roche, Lilly; Peter Dubsky: Honoraria for presentations and Advisory from Roche and Astra Zeneca to Hirslanden Klinik St. Anna; Michael Knauer: Grants or contracts Agendia BV; Consulting fees from Myriad, Exact Sciences; Thorsten Kühn: Consulting fees from Merit Medical, Endomag, Hologic, Sirius Medical; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from GILEAD, MSD, Pfizer, Exact Sciences; Support for attending meetings and/or travel from Gilead, MSD; Sibylle Loibl: Grants or contracts from Abbvie, AZ, BMS/Celgene, DAichi Synkyo, Gilead, Molecular Health, Novartis, Pfizer, Roche; Royalties or licenses for Ki 67 Analyser, VM SCOPE; Consulting fees from AZ, Amgen, Abbvie, BMS, Celgene, Daichi Sankyo Eirgenix, Gilead, Lilly, Merck, MSD, Novartis, Olema, Pfizer, Pierre Fabre, Relay Therapeutics, Incyte, Roche, Sanofi, Seagen; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AZ, Gilead, Roche, Seagen, MSD, Pierre Fabre, MEDSCAPE; Patents planned, issued or pending EP14153692.0; EP21152186.9; EP15702464.7; EP15702464.7; Participation on a Data; Safety Monitoring Board or Advisory Board from Daichi Sankyo; Receipt of equipment, materials, drugs, medical writing, gifts or other services Daichiy Sankyo, Gilead, Novartis, AstraZeneca, Roche, Seagen; Icro Meattini: Consulting fees from Novartis, Pfizer, Eli Lilly, Seagen, Gilead; Katja Pinker: Consulting fees from Genentech, Inc., Merantix Healthcare, AURA Health Technologies GmbH; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: European Society of Breast Imaging (active), Bayer (active), Siemens Healthineers (ended), DKD 2019 (ended), Olea Medical (ended), Roche (ended); Trine Tramm: Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Pfizer, Roche; Support for attending meetings and/or travel from Roche and Novartis; Jong Han Yu: Consulting fees from Gencurix; Walter Paul Weber: Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from MSD; all other others have no conflicts of interest to declare., (© 2023 The Author(s).)

Adjuvant chemotherapy recommendations for ER+/HER2- early-stage breast cancers (eBC) involve integrating prognostic and predictive information which rely on physician judgment; this can lead to discordant recommendations. In this study we aim to evaluate whether Oncotype DX improves confidence and agreement among oncologists in adjuvant chemotherapy recommendations. We randomly select 30 patients with ER+/HER2- eBC and recurrence score (RS) available from an institutional database. We ask 16 breast oncologists with varying years of clinical practice in Italy and the US to provide recommendation for the addition of chemotherapy to endocrine therapy and their degree of confidence in the recommendation twice; first, based on clinicopathologic features only (pre-RS), and then with RS result (post-RS). Pre-RS, the average rate of chemotherapy recommendation is 50.8% and is higher among junior (62% vs 44%; p < 0.001), but similar by country. Oncologists are uncertain in 39% of cases and recommendations are discordant in 27% of cases (interobserver agreement K 0.47). Post-RS, 30% of physicians change recommendation, uncertainty in recommendation decreases to 5.6%, and discordance decreases to 7% (interobserver agreement K 0.85). Interpretation of clinicopathologic features alone to recommend adjuvant chemotherapy results in 1 out of 4 discordant recommendations and relatively high physician uncertainty. Oncotype DX results decrease discordancy to 1 out of 15, and reduce physician uncertainty. Genomic assay results reduce subjectivity in adjuvant chemotherapy recommendations for ER +/HER2- eBC., (© 2023. The Author(s).)

The past two decades have seen an unprecedented trend towards de-escalation of surgical therapy in the setting of early BC, the most prominent examples being the reduction of re-excision rates for close surgical margins after breast-conserving surgery and replacing axillary lymph node dissection by less radical procedures such as sentinel lymph node biopsy (SLNB). Numerous studies confirmed that reducing the extent of surgery in the upfront surgery setting does not impact locoregional recurrences and overall outcome. In the setting of primary systemic treatment, there is an increased use of less invasive staging strategies reaching from SLNB and targeted lymph node biopsy (TLNB) to targeted axillary dissection (TAD). Omission of any axillary surgery in the presence of pathological complete response in the breast is currently being investigated in clinical trials. On the other hand, concerns have been raised that surgical de-escalation might induce an escalation of other treatment modalities such as radiation therapy. Since most trials on surgical de-escalation did not include standardized protocols for adjuvant radiotherapy, it remains unclear, whether the effect of surgical de-escalation was valid in itself or if radiotherapy compensated for the decreased surgical extent. Uncertainties in scientific evidence may therefore lead to escalation of radiotherapy in some settings of surgical de-escalation. Further, the increasing rate of mastectomies including contralateral procedures in patients without genetic risk is alarming. Future studies of locoregional treatment strategies need to include an interdisciplinary approach to integrate de-escalation approaches combining surgery and radiotherapy in a way that promotes optimal quality of life and shared decision-making., Competing Interests: Declaration of competing interest Maggie Banys-Paluchowski received honoraria for lectures and participation in advisory boards from: Roche, Novartis, Pfizer, pfm, Eli Lilly, Onkowissen, Seagen, AstraZeneca, Eisai, AstraZeneca, Amgen, Samsung, Canon, MSD, GSK, Daiichi Sankyo, Gilead, Sirius Pintuition, Pierre Fabre, ExactSciences, and study support from: EndoMag, Mammotome, MeritMedical, Gilead, Sirius Pintuition, Hologic. Thorsten Kühn received honoraria from: Merit Medical, Endomagnetics, Hologic, Sirius Medical, Pfizer, MSD, Astra Zeneca, Daiichi Sankyo, Exact Sciences and study support from: Mammotome, Merit Medical, Sirius Medical, Endomagnetics, Hologic. David Krug has received honoraria from Merck Sharp & Dohme and Pfizer as well as research funding from Merck KGaA. Nina Ditsch received honoraria from: AstraZeneca, BLÄK, Daiichi-Sankyo, if-Kongress München, Leopoldina Schweinfurt, Lilly, Lukon, Molekular Health, MSD, onkowissen, Pfizer, RG Ärztefortbildungen, Roche, Seagen, UKA, BZKF Förderung, SerMA pilot Universität Augsburg. Other authors declare no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: In the last 2 decades, the optimal management of the axilla in breast cancer patients receiving neoadjuvant chemotherapy (NACT) has been one of the most frequently discussed topics. Little is known about the attitudes of surgeons/radiologists towards new developments such as targeted axillary dissection. Therefore, the NOGGO conducted a survey to evaluate the current approach to axillary management., Methods: A standardized digital questionnaire was sent out to > 200 departments in Germany between 7/2021 and 5/2022. The survey was supported by EUBREAST., Results: In total, 116 physicians completed the survey. In cN0 patients scheduled to receive NACT, 89% of respondents recommended sentinel lymph node biopsy (SLNB) after NACT. In case of ypN1mi(sn), 44% advised no further therapy, while 31% proposed ALND and 25% axillary irradiation. 64% of respondents recommended a minimally invasive axillary biopsy to cN + patients. TAD was used at the departments of 82% of respondents and was offered to all cN + patients converting to ycN0 by 57% and only to selected patients, usually based on the number of suspicious nodes at time of presentation, by 43%. The most common marking technique was a clip/coil. 67% estimated that the detection rate of their marker was very good or good., Conclusion: This survey shows a heterogenous approach towards axillary management in the neoadjuvant setting in Germany. Most respondents follow current guidelines. Since only two-thirds of respondents experienced the detection rate of the marker used at their department as (very) good, future studies should focus on the comparative evaluation of different marking techniques., (© 2022. The Author(s).)

Background: Surgical excision of a non-palpable breast lesion requires a localization step. Among available techniques, wire-guided localization (WGL) is most commonly used. Other techniques (radioactive, magnetic, radar or radiofrequency-based, and intraoperative ultrasound) have been developed in the last two decades with the aim of improving outcomes and logistics., Methods: We performed a systematic review on localization techniques for non-palpable breast cancer., Results: For most techniques, oncological outcomes such as lesion identification and clear margin rate seem either comparable with or better than for WGL, but evidence is limited to small cohort studies for some of the devices. Intraoperative ultrasound is associated with significantly higher negative margin rates in meta-analyses of randomized clinical trials (RCTs). Radioactive techniques were studied in several RCTs and are non-inferior to WGL. Smaller studies show higher patient preference towards wire-free localization, but little is known about surgeons' and radiologists' attitudes towards these techniques., Conclusions: Large studies with an additional focus on patient, surgeon, and radiologist preference are necessary. This review aims to present the rationale for the MELODY (NCT05559411) study and to enable standardization of outcome measures for future studies.

Competing Interests: Thorsten Kühn, Jean-Marc Classe, and Isabel T. Rubio: no conflict of interest; Oreste D. Gentilini: consultation fees and honoraria: MSD, Astra-Zeneca, BD, Bayer; Marjolein Smidt: grant from Servier Pharma and Nutricia Danone.

Background: There is no consensus on axillary management after neoadjuvant therapy (NAT) in patients with clinically node-positive (cN+) breast cancer. To investigate current clinical practice, an international survey was conducted among breast surgeons and radiation oncologists. The aim of the first part of the survey was to provide a snapshot of international discrepancies regarding axillary surgery in this context., Methods: The European Breast Cancer Research Association of Surgical Trialists (EUBREAST) developed a web-based survey containing 39 questions describing clinical scenarios in the setting of axillary management in patients with cN1 disease converting to ycN0 after NAT. The survey was then distributed to breast surgeons and radiation oncologists via 14 breast cancer societies between April and October 2021., Results: Responses from 349 physicians in 45 countries were recorded. The most common post-NAT axillary surgery in patients with cN1 disease converting to ycN0 was targeted axillary dissection (54.2 per cent), followed by sentinel lymph node biopsy (SLNB) alone (20.9 per cent), level 1-2 axillary lymph node dissection (ALND) (18.4 per cent), level 1-3 ALND (4 per cent), and targeted lymph node biopsy (2.5 per cent). For SLNB alone, dual tracers were most commonly used (62.3 per cent). Management varied widely in patients with ambiguous axillary status before initiation of treatment or a residual metastatic burden in the axilla after NAT. In patients with ycN+ tumours, ALND was the preferred surgical approach for 66.8 per cent of respondents., Conclusion: These results highlight the wide heterogeneity in surgical approaches to the axilla after NAT. To standardize the guidelines, further data from clinical research are urgently needed, which underlines the importance of the ongoing AXSANA (EUBREAST-3) study., (© The Author(s) 2022. Published by Oxford University Press on behalf of BJS Society Ltd. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Aim: Demand for nipple- and skin- sparing mastectomy (NSM/SSM) with immediate breast reconstruction (BR) has increased at the same time as indications for post-mastectomy radiation therapy (PMRT) have broadened. The aim of the Oncoplastic Breast Consortium initiative was to address relevant questions arising with this clinically challenging scenario., Methods: A large global panel of oncologic, oncoplastic and reconstructive breast surgeons, patient advocates and radiation oncologists developed recommendations for clinical practice in an iterative process based on the principles of Delphi methodology., Results: The panel agreed that surgical technique for NSM/SSM should not be formally modified when PMRT is planned with preference for autologous over implant-based BR due to lower risk of long-term complications and support for immediate and delayed-immediate reconstructive approaches. Nevertheless, it was strongly believed that PMRT is not an absolute contraindication for implant-based or other types of BR, but no specific recommendations regarding implant positioning, use of mesh or timing were made due to absence of high-quality evidence. The panel endorsed use of patient-reported outcomes in clinical practice. It was acknowledged that the shape and size of reconstructed breasts can hinder radiotherapy planning and attention to details of PMRT techniques is important in determining aesthetic outcomes after immediate BR., Conclusions: The panel endorsed the need for prospective, ideally randomised phase III studies and for surgical and radiation oncology teams to work together for determination of optimal sequencing and techniques for PMRT for each patient in the context of BR., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Preliminary clinical evidence suggests a detrimental effect of pathogenic variants of BRCA1 and 2 genes on fertility outcome. This meta-analysis evaluates whether women carrying BRCA mutations (BRCAm) have decreased ovarian reserve, in terms of Anti-Muellerian Hormone (AMH), compared to women without BRCAm (wild-type)., Material and Methods: Systematic searches of PubMed, Medline, Scopus, Embase, Science Direct and the Cochrane Library from inception until July 2020 were conducted. All studies comparing AMH level in fertile age women, with and without BRCA pathogenic variants were considered. Sub-analyses were performed according to age, presence of breast cancer, and type of mutation., Results: Among 64 studies, 10 series were included. For the entire cohort, a trend of reduced AMH level were found between BRCAm carriers and women without pathogenic variants. BRCAm carriers aged 41-years or younger had lower AMH levels compared to 41-years or younger wild type women (OR: 0.73 [95%CI-1.12;-0.35]; p = 0.0002). This finding was confirmed for BRCA1m carriers (OR: 1 [95%CI-1.96;-0.05]; p = 0.004) whereas no difference was observed between BRCA2m carriers and wild type women. The same analysis on breast cancer patients with and without BRCAm achieved the same results., Conclusion: Young BRCA1m carriers seem to have lower AMH level compared with wild type women and therefore a potential decreased ovarian reserve., Competing Interests: Declaration of competing interest The authors have nothing to declare. They have no conflict of interest., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Breast conserving surgery (BCS) plus radiation therapy (RT) or mastectomy have shown comparable oncological outcomes in early-stage breast cancer and are considered standard of care treatments. Postmastectomy radiation therapy (PMRT) targeted to both the chest wall and regional lymph nodes is recommended in high-risk patients. Oncoplastic breast conserving surgery (OBCS) represents a significant recent improvement in breast surgery. Nevertheless, it represents a challenge for radiation oncologists as it triggers different decision-making strategies related to treatment volume definition and target delineation. Hence, the choice of the best combination and timing when offering RT to breast cancer patients who underwent or are planned to undergo reconstruction procedures should be carefully evaluated and based on individual considerations. We present an Italian expert Delphi Consensus statements and critical review, led by a core group of all the professional profiles involved in the management of breast cancer patients undergoing reconstructive procedures and RT. The report was structured as to consider the main recommendations on breast reconstruction and RT and analyse the current open issues deserving investigation and consensus. We used a three key-phases and a Delphi process. The final expert panel of 40 colleagues selected key topics as identified by the core group of the project. A final consensus on 26 key statements on RT and breast reconstruction after three rounds of the Delphi voting process and harmonisation was reached. An accompanying critical review of available literature was summarized. A clear communication and cooperation between surgeon and radiation oncologist is of paramount relevance both in the setting of breast reconstruction following mastectomy when PMRT is planned and when extensive glandular rearrangements as OBCS is performed. A shared-decision making, relying on outcome-based and patient-centred considerations, is essential, while waiting for higher level-of-evidence data., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Axillary surgery in breast cancer (BC) is no longer a therapeutic procedure but has become a purely staging procedure. The progressive improvement in imaging techniques has paved the way to the hypothesis that prognostic information on nodal status deriving from surgery could be obtained with an accurate diagnostic exam. Positron emission tomography/magnetic resonance imaging (PET/MRI) is a relatively new imaging tool and its role in breast cancer patients is still under investigation. We reviewed the available literature on PET/MRI in BC patients. This overview showed that PET/MRI yields a high diagnostic performance for the primary tumor and distant lesions of liver, brain and bone. In particular, the results of PET/MRI in staging the axilla are promising. This provided the rationale for two prospective comparative trials between axillary surgery and PET/MRI that could lead to a further de-escalation of surgical treatment of BC. • SNB vs. PET/MRI 1 trial compares PET/MRI and axillary surgery in staging the axilla of BC patients undergoing primary systemic therapy (PST). • SNB vs. PET/MRI 2 trial compares PET/MRI and sentinel node biopsy (SNB) in staging the axilla of early BC patients who are candidates for upfront surgery. Finally, these ongoing studies will help clarify the role of PET/MRI in BC and establish whether it represents a useful diagnostic tool that could guide, or ideally replace, axillary surgery in the future.

Background: use of fibrin sealants following pelvic, paraaortic, and inguinal lymphadenectomy may reduce lymphatic morbidity. The aim of this meta-analysis is to evaluate if this finding applies to the axillary lymphadenectomy., Methods: randomized trials evaluating the efficacy of fibrin sealants in reducing axillary lymphatic complications were included. Lymphocele, drainage output, surgical-site complications, and hospital stay were considered as outcomes., Results: twenty-three randomized studies, including patients undergoing axillary lymphadenectomy for breast cancer, melanoma, and Hodgkin's disease, were included. Fibrin sealants did not affect axillary lymphocele incidence nor the surgical site complications. Drainage output, days with drainage, and hospital stay were reduced when fibrin sealants were applied ( p < 0.0001, p < 0.005, p = 0.008)., Conclusion: fibrin sealants after axillary dissection reduce the total axillary drainage output, the duration of drainage, and the hospital stay. No effects on the incidence of postoperative lymphocele and surgical site complications rate are found.

Background: DNA aberrant hypermethylation is the major cause of transcriptional silencing of the breast cancer gene 1 (BRCA1) gene in sporadic breast cancer patients. The aim of the present meta-analysis was to analyze all available studies reporting clinical characteristics of BRCA1 gene hypermethylated breast cancer in women, and to pool the results to provide a unique clinical profile of this cancer population., Methods: On September 2020, a systematic literature search was performed. Data were retrieved from PubMed, MEDLINE, and Scopus by searching the terms: "BRCA*" AND "methyl*" AND "breast". All studies evaluating the association between BRCA1 methylation status and breast cancer patients' clinicopathological features were considered for inclusion., Results: 465 studies were retrieved. Thirty (6.4%) studies including 3985 patients met all selection criteria. The pooled analysis data revealed a significant correlation between BRCA1 gene hypermethylation and advanced breast cancer disease stage (OR = 0.75: 95% CI: 0.58-0.97; p = 0.03, fixed effects model), lymph nodes involvement (OR = 1.22: 95% CI: 1.01-1.48; p = 0.04, fixed effects model), and pre-menopausal status (OR = 1.34: 95% CI: 1.08-1.66; p = 0.008, fixed effects model). No association could be found between BRCA1 hypermethylation and tumor histology (OR = 0.78: 95% CI: 0.59-1.03; p = 0.08, fixed effects model), tumor grading (OR = 0.78: 95% CI :0.46-1.32; p = 0.36, fixed effects model), and breast cancer molecular classification (OR = 1.59: 95% CI: 0.68-3.72; p = 0.29, random effects model)., Conclusions: hypermethylation of the BRCA1 gene significantly correlates with advanced breast cancer disease, lymph nodes involvement, and pre-menopausal cancer onset.

Aim: We report molecular subtype impact on 1325 early breast cancer (BCa) patients treated with whole breast hypofractionated (WBH) adjuvant forward-planned intensity modulated radiotherapy (F-IMRT) without boost., Methods and Materials: From 02/2009-05/2017 1325 patients with pTis-pT3, pNx-N1aM0 BCa who underwent breast conservation surgery were treated with WBHF-IMRT in our institute, to a total dose of 40 Gy/15 fractions, without boost. Median age: 62 (interquartile range-IQR-:51.14-70.53) years., Histology: 8% in situ carcinoma (ISC), 92% invasive tumors. Molecular subtypes (invasive tumors): 49.9% Luminal A, 33.1% Luminal B Her2 negative (-), 6.2% Luminal B Her2 positive (+), 3.6% Hormone Receptor (HR)- Her2+, 7.1% Triple negative (TNBC), and 0.2% HR+. Chemotherapy (CT) was prescribed in 28% of patients, hormonal therapy in 80.3%, monoclonal antibodies (MAb) in 86.8% of Luminal B Her2+ and 97.7% of HR- Her2+ patients., Results: Median follow up was 72.43 (IQR: 44.63-104.13) months. The 5-year Kaplan-Meier estimates of local relapse-free survival (LRFS) was 97.8%, regional-(RRFS) 98.6%, loco-regional- (LRRFS) 96.9%, distant- (DRFS) 96.6%, disease-free survival (DFS) 94.8% and overall survival (OS) 95.5%. Considering molecular subtypes, 5-year LRFS was: 99.8% for Luminal A, 96.7% for Luminal B Her2-, 94.1% for Luminal B Her2+, 87.9% for HR- Her2+, 95.1% for TNBC and 99.1% for in situ carcinoma., Conclusion: While the overall estimated probability of LR within 5 years after WBHF-IMRT without boost is good (2.2%), molecular subtypes have a strong impact, despite MAb therapy in Her2+ patients, and CT for TNBC patients, and could be used as a parameter in deciding the boost prescription., Competing Interests: Declaration of competing interest Dr. Andrei Fodor reports speaker honoraria from Accuray (AERO Academy) and Janssen (Janssen Academy); personal fees for Advisory Board from Sandoz Italia, and reimbursement for travel and accommodations for congresses from Ipsen, AB Medica, Astellas, unrelated to this work. Prof. Dr. Nadia Gisella Di Muzio reports speaker honoraria from Accuray (AERO Academy) and travel and accommodation for a congress from Ipsen, unrelated to this work. Dr. Giampaolo Bianchini reports Consultancy/Advisory role for Roche, Pfizer, AstraZeneca, Lilly, Novartis, Amgen, MSD, Chugai, Sanofi, Daiichi Sankyo, EISAI, Exact Sciences, Neopharm, unrelated to this work. All the other authors have nothing to disclose. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

In 2020, the American Society of Clinical Oncology (ASCO) annual meeting was held as a virtual conference. Overall, 461 abstracts focused on breast cancer management. As European Breast Cancer Association of Surgical Trialists (EUBREAST) we summarize and comment the results of these abstracts dealing with axillary management in breast cancer patients and offer an interpretation on how these findings may be incorporated into clinical practice and further research., Competing Interests: The authors declare no conflict of interest related to this paper, (© 2020 The Author(s).)

The evolution of axillary surgery in breast cancer has led from complete axillary dissection (AD) to sentinel node biopsy (SNB). It has not stopped yet but continues with a progressive de-escalation of surgical procedures aiming at axillary conservation. In parallel, the meaning of axillary surgery has changed as well. Over time, the dual role of both a therapeutic and a staging procedure has decreased leaving room to other modalities to treat and stage breast cancer. Although, the gold standard for axillary staging in early breast cancer remains SNB, the idea that axillary surgery could be even omitted has been proposed. The concept of abandoning axillary surgery is revolutionary but not new. Historical literature provides interesting data on patients who did not receive any axillary treatment at all with no impact on their survival. Starting from this, several ongoing trials are working to demonstrate that in selected breast cancer cohorts the information deriving from axillary surgery is superfluous and "axillary observation" alone is as effective as SNB. Whilst surgery has been de-escalated to less invasive procedures, systemic treatment, radiotherapy, multigene assays and advanced imaging modalities have gained ground in the management of breast cancer. New research is expected to help select the subgroups of patients for whom axillary surgery is not necessary anymore. This is a qualitative review reporting the most relevant literature data from historical trials on the omission of axillary surgery to the most recent and ongoing ones.

Background: Corona Virus Disease 19 (COVID-19) had a worldwide negative impact on healthcare systems, which were not used to coping with such pandemic. Adaptation strategies prioritizing COVID-19 patients included triage of patients and reduction or re-allocation of other services. The aim of our survey was to provide a real time international snapshot of modifications of breast cancer management during the COVID-19 pandemic., Methods: A survey was developed by a multidisciplinary group on behalf of European Breast Cancer Research Association of Surgical Trialists and distributed via breast cancer societies. One reply per breast unit was requested., Results: In ten days, 377 breast centres from 41 countries completed the questionnaire. RT-PCR testing for SARS-CoV-2 prior to treatment was reported by 44.8% of the institutions. The estimated time interval between diagnosis and treatment initiation increased for about 20% of institutions. Indications for primary systemic therapy were modified in 56% (211/377), with upfront surgery increasing from 39.8% to 50.7% (p < 0.002) and from 33.7% to 42.2% (p < 0.016) in T1cN0 triple-negative and ER-negative/HER2-positive cases, respectively. Sixty-seven percent considered that chemotherapy increases risks for developing COVID-19 complications. Fifty-one percent of the responders reported modifications in chemotherapy protocols. Gene-expression profile used to evaluate the need for adjuvant chemotherapy increased in 18.8%. In luminal-A tumours, a large majority (68%) recommended endocrine treatment to postpone surgery. Postoperative radiation therapy was postponed in 20% of the cases., Conclusions: Breast cancer management was considerably modified during the COVID-19 pandemic. Our data provide a base to investigate whether these changes impact oncologic outcomes., Competing Interests: Declaration of competing interest The authors declare no conflict of interest related to the publication., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Northern Italy has been one of the European regions reporting the highest number of COVID-19 cases and deaths. The pandemic spread has challenged the National Health System, requiring reallocation of most of the available health care resources to treat COVID-19-positive patients, generating a competition with other health care needs, including cancer. Patients with cancer are at higher risk of developing critical illness after COVID-19 infection. Thus, mitigation strategies should be adopted to reduce the likelihood of infection in all patients with cancer. At the same time, suboptimal care and treatments may result in worse cancer-related outcome. In this article, we attempt to estimate the individual risk-benefit balance to define personalized strategies for optimal breast cancer management, avoiding as much as possible a general untailored approach. We discuss and report the strategies our Breast Unit adopted from the beginning of the COVID-19 outbreak to ensure the continuum of the best possible cancer care for our patients while mitigating the risk of infection, despite limited health care resources. IMPLICATIONS FOR PRACTICE: Managing patients with breast cancer during the COVID-19 outbreak is challenging. The present work highlights the need to estimate the individual patient risk of infection, which depends on both epidemiological considerations and individual clinical characteristics. The management of patients with breast cancer should be adapted and personalized according to the balance between COVID-19-related risk and the expected benefit of treatments. This work also provides useful suggestions on the modality of patient triage, the conduct of clinical trials, the management of an oncologic team, and the approach to patients' and health workers' psychological distress., (© 2020 The Authors. The Oncologist published by Wiley Periodicals LLC on behalf of AlphaMed Press.)

Breast cancer (BC) metastasis accounts for the majority of deaths from BC. The rate of metastasis to uncommon sites is on the rise due to the more effective therapy prolonging survival and to the early detection on imaging. The evaluation of patient-reported symptoms is essential in detecting a recurrence as early as possible, which may impact survival. Hence, the knowledge of even the rare sites of BC metastasis is of paramount importance for the clinical interpretation of new symptoms in BC survivors. The term "unusual metastasis" defines a systemic failure with a frequency of ≤1% at each site and according to this unusual metastasis involve the central nervous system, secretory/endocrine organs and glands, internal organs and structures, and gynecological organs. The literature search was performed using the electronic database PubMed up to December 2018, with the following key words: {[rare(Title/Abstract)] OR [ unusual (Title/Abstract)] OR [ unconventional (Title/Abstract)]} AND {[ metastases (Title/Abstract)] OR [ metastasis (Title/Abstract)]} AND {[ breast (Title/Abstract)]} AND {[ cancer (Title/Abstract)] OR [ tumor (Title/Abstract)] OR [ tumour (Title/Abstract)] OR [neoplasm(Title/Abstract)]}. The search was limited to papers in English language. Of the 3,086 papers found, 757 were excluded as reporting animal models, 378 were not in English language, 1 was a duplicate of the same research, 1,414 did not report on BC metastases, 108 were previous review reviews on BC or tumour to tumour metastases; 428 papers were included in this review. Despite the improvements in BC management, most deaths from cancer result from metastases that are resistant to conventional therapies. In general, it is uncommon to find isolated rare metastases, the vast majority of these develops together with metastases in other sites, thus highlighting a worsening systemic disease. However, the early detection of even rare metastases represents the only chance to control the disease and prolong survival while waiting for the development of more effective systemic therapies., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tcr.2019.07.24). The focused issue “Rare Tumors of the Breast” was commissioned by the editorial office without any funding or sponsorship. The authors have no other conflicts of interest to declare., (2019 Translational Cancer Research. All rights reserved.)

Background: The management of axilla after Primary Systemic Therapy (PST) for breast cancer is a highly debated field. Despite the proven axillary downstaging occurring after PST, there is still some degree of reluctance in applying sentinel node biopsy (SNB) in the neoadjuvant setting., Patients and Methods: We performed a retrospective analysis on 181 PST patients with axillary positive nodes at presentation treated between 2005 and 2017 at San Raffaele Hospital in Milan. The aim was to observe the application time trend of SNB, to determine the imaging staging power and the axillary downstaging according to molecular subtypes., Results: Median follow-up after surgery was 32.5(IQR: 12-59) months. After PST, 119 (65.7%) patients had no clinically palpable nodes, 72 (39.7%) converted to N0 on final imaging and 34 (18.8%) underwent SNB with an increasing application trend. Axillary-US showed the highest accuracy (69.3%) in re-staging axilla after PST. Staging power of preoperative testing varied with tumour biology: Positive Predictive Value was higher in Luminal A (80% for clinical examination and 100% for axillary-US) and Luminal B (72% and 70.5%) tumours, whilst Negative Predictive Value was higher in HER2 positive (100% and 93.3%), and triple negative (71.4% and 93.3%) tumours. Ninety five (52.5%) patients experienced axillary downstaging after PST, by molecular subtype 15% (3/20) in Luminal A, 46.4% (45/97) in Luminal B, 90.9% (20/22) in HER2+ and 70.3% (26/37) in triple negative breast tumours., Conclusion: SNB application after PST for breast cancer in node positive patients at presentation is increasing. Pre-operative axillary imaging and tumour biology help identify patients who might be candidates for SNB as a single staging procedure., (Copyright © 2019 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Local treatment of the axilla in clinically node-negative (cN0) early breast cancer patients with routine sentinel lymph node biopsy (SLNB) is debated for various reasons: i) pN staging information may not be necessary for the postoperative treatment decision regarding adjuvant systemic therapy in the great majority of patients; ii) the SLNB-positive rate is declining below 20% in specialized breast centers; iii) albeit being a minimally invasive procedure, SLNB causes a significant reduction in quality of life in 23% of patients; and iv) previous randomized trials from the pre-SLNB era did not show a disadvantage for patients without axillary surgery with regard to overall survival. These data support the hypothesis that avoiding axillary treatment in patients with clinically and sonographically unsuspicious lymph nodes seems to be a safe option, although omitting axillary surgery may increase the risk of locoregional recurrence. Currently, the information regarding node-positive status is essential to guide postoperative treatment such as systemic or radiation therapies in a non-negligible minority of patients. Three ongoing prospective European trials (SOUND, INSEMA, BOOG 2013-08) with axillary observation alone versus SLNB in cN0 patients and primary breast-conserving surgery have the objective to evaluate oncologic safety when omitting SLNB.

Axillary surgery has undergone considerable changes in recent years, especially in relation to patients who undergo neoadjuvant chemotherapy (NACT). Due to constantly decreasing rates of recurrence and death from breast cancer, modern surgical strategies aim at de-escalating the extent of local treatment and avoiding unnecessary procedures. This relates especially to lymph node surgery which is associated with considerable morbidity. In patients who initially present with clinically node-negative disease, sentinel lymph node biopsy (SLNB) is increasingly performed after NACT. The determination of the post-NACT nodal status does not only spare patients from additional surgery but also allows the assessment of pathologic complete response which is increasingly becoming an important tool for treatment planning. Since more than 70% of these patients have a ypN0 status after NACT, future trials will aim to identify patients who might be spared any axillary surgery after NACT. In patients who initially present with positive lymph nodes, the success rates of SLNB in terms of detection and accuracy are less favorable compared to those in patients who undergo primary surgery. The clinical significance of this is unclear. To reduce unnecessary axillary dissection in patients with cN1ycN0 status, prospective outcome data after SLNB without further lymph node removal are urgently needed. Improvements in surgical technique by localizing positive nodes at the time of diagnosis and removing them in a targeted surgical procedure (targeted axillary dissection) are under evaluation. Risk assessment and patient selection (including gene expression profiles) might be other ways of safely omitting axillary dissection.

Introduction: Sentinel Lymph Node Biopsy (SLNB) is regarded as the standard procedure for nodal staging in patients with early breast cancer. In the last decade several randomized trials have been evaluating its role and indications., Materials and Methods: This article reviews recent and ongoing randomized trials on SLNB., Results: Four randomized controlled trials have recently shown evidence that SLNB either alone or followed by radiation therapy is effective for the management in patients with low axillary tumor burden in early breast cancer. Nine randomized controlled trials on SLNB are ongoing: four assessing its role in case of positive sentinel node, three evaluating whether SLNB itself can be omitted when the preoperative nodal imaging is negative, two are studying SLNB in the neoadjuvant setting., Discussion and Conclusion: SLNB either alone or with axillary radiotherapy has been shown to be non-inferior to complete axillary dissection in terms of local recurrence, disease-free survival and overall survival in early breast cancer with minimally metastatic axilla. So far, results from ongoing trials are going to confirm the appropriate treatment in patients with limited axillary nodal involvement, the role and the timing of SLNB within the neoadjuvant setting and to define whether surgery can be avoided in the axilla in early stage breast cancer patients with negative preoperative imaging., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

During the recent years an increase of mastectomy rates in early breast cancer patients has been observed. Nevertheless, several large population-based studies reported a possible improved outcome after breast conserving therapy compared to radical surgery, after all the adjustments. We hereby summarize our opinion on this topic suggesting that these robust and consistent data might challenge the statement that breast conserving therapy is merely not inferior to radical surgery., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The 1st International Consensus Conference for Breast Cancer in Young Women (BCY1) took place in November 2012, in Dublin, Ireland organized by the European School of Oncology (ESO). Consensus recommendations for management of breast cancer in young women were developed and areas of research priorities were identified. This manuscript summarizes these international consensus recommendations, which are also endorsed by the European Society of Breast Specialists (EUSOMA)., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Metformin has been associated with antitumour activity in breast cancer (BC) but its mechanism remains unclear. We determined whether metformin induced a modulation of apoptosis by terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) overall and by insulin resistance status in a presurgical trial., Methods: Apoptosis was analysed in core biopsies and in surgical samples from 100 non-diabetic BC patients participating in a randomised trial of metformin vs placebo given for 4 weeks before surgery., Results: Eighty-seven subjects (45 on metformin and 42 on placebo) were assessable for TUNEL measurement at both time points. TUNEL levels at surgery were higher than that at baseline core biopsy (P<0.0001), although no difference between arms was noted (metformin arm: median difference surgery-biopsy levels +4%, interquartile range (IQR): 2-12; placebo arm: +2%, IQR: 0-8, P=0.2). Ki67 labelling index and TUNEL levels were directly correlated both at baseline and surgery (Spearman's r=0.51, P<0.0001). In the 59 women without insulin resistance (HOMA index<2.8) ,there was a higher level of TUNEL at surgery on metformin vs placebo (median difference on metformin +4%, IQR: 2-14 vs +2%, IQR: 0-7 on placebo), whereas an opposite trend was found in the 28 women with insulin resistance (median difference on metformin +2%, IQR: 0-6, vs +5%, IQR: 0-15 on placebo, P-interaction=0.1)., Conclusion: Overall, we found no significant modulation of apoptosis by metformin, although there was a trend to a different effect according to insulin resistance status, with a pattern resembling Ki67 changes. Apoptosis was significantly higher in the surgical specimens compared with baseline biopsy and was directly correlated with Ki67. Our findings provide additional evidence for a dual effect of metformin on BC growth according to insulin resistance status.

Background: Approximately 10% of patients with breast cancer who are treated with breast-conserving surgery (BCS) develop an ipsilateral-breast tumor recurrence (IBTR). The optimal local therapy for women with BRCA-associated breast carcinoma remains controversial. We report the outcome of BCS in BRCA mutation carriers followed at a single institution., Methods: A total of 54 women with BRCA1/2-associated breast cancer treated with BCS and whole breast radiotherapy were matched for age, tumor size, and time of surgery with 162 patients with sporadic breast cancer who had the same treatment between February 1994 and October 2007. Primary end points were cumulative incidence of IBTR and contralateral breast cancer (CBC). Median follow-up was 4 years for both groups., Results: Median age was 36 and 37 years for mutation carriers and controls, respectively; mean tumor size was 1.8 cm in carriers and 1.9 cm in controls. Ten-year cumulative incidence of IBTR was 27% for mutation carriers and 4% for sporadic controls (hazard ratio 3.9; 95% confidence interval 1.1-13.8; P = 0.03). Ten-year cumulative incidence of CBC was 25% for mutation carriers and 1% for sporadic controls (P = 0.03)., Conclusions: Our data suggest that IBTR risk after BCS in BRCA1/2 mutation carriers is increased compared with patients who have sporadic breast cancer. Likewise, the risk of CBC seems to be increased in this group. These risks and the likelihood of developing new primary tumors should be discussed with carriers interested in breast conservation as well as when choosing risk-reducing strategies.

Introduction: Sentinel lymph node biopsy is an accepted standard of care for staging the axilla in patients with early-stage breast cancer. Little attention has been placed to the presence of intramammary sentinel lymph nodes (intraMSLNs) on preoperative lymphoscintigraphy., Methods: Between December 2001 and September 2006, in 9632 breast cancer patients with clinically uninvolved axillary nodes, lymphoscintigraphy was performed at the European Institute of Oncology (EIO). An axillary SLN (axSLN) was identified in 99.4% of cases. An intraMSLN was identified in association with the axillary sentinel lymph node in 22 patients (0.2%). In 15 cases both the axSLN and the intraMSLN were excised., Results: The intraMSLN was positive in six patients (micrometastatic in three cases). The axSLNs were negative in all 15 cases. Two patients with positive intraMSLNs and one patient with a negative intraMSLN underwent axillary dissection; all three cases had negative axillary nodes. At a median follow-up of 24 months, no locoregional or systemic recurrences were observed., Conclusions: Positive intraMSLNs can improve disease staging but do not necessarily portend axillary lymph node metastasis. When intraMSLNs and axSLNs are present, we advocate biopsy of both sites and that management of the axilla should rely on axSLN status. In cases with intraMSLNs as the only draining site on lymphoscintigraphy, decisions on axillary management should be made on individualized basis.

In the sentinel lymph node era, axillary lymph node dissection (ALND) for uninvolved axillary lymph nodes should be considered unnecessary and inappropriate. Between January 2000 and August 2005, 3487 out of 10,031 invasive breast cancer patients consecutively operated at the European Institute of Oncology were considered not suitable for sentinel lymph node biopsy (SNB) and were directly submitted to ALND ('direct ALND'). In 2875 cases (82%) a variable grade of axillary involvement was shown, while in 612 patients (18%) no evidence of metastatic spreading was documented in the axilla. In particular, the presence of suspicious nodes at pre-operative clinical evaluation of the axilla (191 patients), neoadjuvant treatment (188 patients), large tumour >2 cm (88 patients), multifocality of disease (76 patients), previous excisional biopsy (49 patients), were considered the most frequent contraindications to SNB and led to an 'unnecessary ALND'. According to the wider extension of the indications for SNB over the time, the number of 'unnecessary ALNDs' progressively decreased from 26% (in 2000) to 9% of the 'direct ALNDs' (in 2005). As the clinical indications to SNB are progressively extending to encompass most breast cancer patients with non-metastatic disease who were previously excluded, great effort should be made to avoid 'unnecessary ALNDs'.

Background: Previous mastectomy is unanimously considered to represent an absolute technical contraindication to sentinel lymph node biopsy (SLNB)., Methods: Four patients who underwent total mastectomy and plastic reconstruction with prosthesis, developed, during the follow up, a unique invasive limited local subdermic recurrence amenable to surgical excision, with clinically negative axillary nodes. In all patients preoperative lymphoscintigraphy with subdermal injection of (99m)Tc-labeled colloidal particles correctly showed an axillary sentinel lymph node (SLN)., Results: Metastases in SLN were detected in two patients, and a complete axillary dissection followed. The remaining two patients had a negative SLN and no axillary clearance was performed., Conclusions: In selected cases, the subdermal injection of radioisotope permits the identification of an axillary SLN, even in mastectomized patients. Despite SLNB in mastectomized patients being technically feasible, only a larger population and longer patient follow up could confirm its true predictive value. However, there are no anatomical or physiological reasons to exclude "a priori" this diagnostic opportunity., ((c) 2007 Wiley-Liss, Inc.)