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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.)

Introduction: Clipping and selective removal of initially suspicious axillary lymph nodes in breast cancer patients who have been sonographically down-staged by primary systemic therapy improves the accuracy of surgical staging and provides the opportunity for more conservative axillary surgery. This study evaluated whether preoperative ultrasound-guided wire localization of the clipped node is useful for routine clinical practice., Material and Methods: This prospective, single-center feasibility trial included patients with invasive breast cancer (cT1-3N1-3M0) treated by primary systemic therapy. They underwent ultrasound-guided core needle biopsy and clip placement into the most suspicious axillary lymph node prior to chemotherapy. After primary systemic therapy the clipped lymph node was localized by a wire. All patients underwent target lymph node biopsy, completion axillary lymph node dissection and, if yiN0, axillary sentinel lymph node biopsy. The primary study endpoint was the identification rate of the target lymph node., Results: All patients (n = 30) underwent successful clip insertion into the lymph node. After chemotherapy, the clipped target lymph node was visible by ultrasound in 83.3% (25/30). Wire localization was possible in 24 cases (80%), and the clipped node identification rate was 70.8% (17/24 cases). In 9/30 patients (30%) clipped node removal was not confirmed by intraoperative radiography., Conclusion: Ultrasound-guided wire localization of the target lymph node is not suitable for clinical practice because of limitations regarding clip visibility and selective surgical preparation of the target lymph node. Further prospective evaluation of alternative techniques is needed., (Copyright © 2018 The Author(s). Published by Elsevier Ltd.. 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 after publication of ACOSOG Z0011 data in 2010. Currently, prospective randomized surgical trials investigating the omission of SLNB in upfront breast-conserving surgery (BCS) and in the neoadjuvant setting, respectively. Several prospective randomized trials (SOUND, INSEMA, BOOG 2013–08, and NAUTILUS) with axillary observation alone versus SLNB in cN0 patients and primary BCS have primary objectives to evaluate oncologic safety when omitting SLNB. The Italian SOUND trial was the earliest to open in 2012 and has completed accrual in 2017. First oncologic outcome data are expected soon for SOUND and at the end of 2024 for INSEMA. Improvements in systemic treatments for breast cancer have increased the rates of pathologic complete response (pCR) in patients receiving neoadjuvant systemic therapy (NAST), offering the opportunity to de-escalate surgery in patients who have a pCR. Two prospective single-arm trials (EUBREAST-01, ASICS) include only patients with the highest likelihood of having a pCR after NAST (triple-negative or HER2-positive breast cancer) and type of surgery will be defined according to the response to NAST rather than on the classical T and N status. The ongoing trials will hopefully help us to understand whether we might take the best therapeutic decisions without the pathologic evaluation of nodal status. • Discussion of background for de-escalation strategies in axillary surgery. • Available current guidelines in early-stage invasive breast cancer. • Overview of randomized clinical trials with upfront breast-conserving surgery. • Overview of ongoing single-arm trials in the neoadjuvant setting. [ABSTRACT FROM AUTHOR]

Although the majority of breast cancer patients are clinically node-negative (cN0) at diagnosis, 15-20% will have a metastatic sentinel lymph node (SLN, pN1(sn)). While a less radical approach regarding axillary surgery in cN0 patients with a positive SLN biopsy is advocated, the limitations of 5 published trials on axillary management in pN1(sn) are discussed intensely in the literature and support the performance of ongoing validation and extension trials, especially considering the lack of data in the setting of mastectomy. As locoregional radiotherapy has a significant effect on both recurrence and survival, a standardization of locoregional radiotherapy in the situation of SLN biopsy alone in pN1(sn) patients has to be defined in the future, and de-escalation trials should embrace a truly multidisciplinary approach. This is also of utmost importance considering the fact that high-volume nodal disease requires an intensified adjuvant chemotherapy strategy to which patients omitting axillary dissection cannot be stratified. Finally, there is mounting evidence that the therapeutic role of extensive axillary surgery in low-volume nodal disease is negligible, and multidisciplinary and translational efforts must be undertaken to individualize treatment in order to gain a reasonable balance between necessary staging information and unnecessary treatment-related morbidity. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The impact of treatment for the primary tumor on distant metastases and survival in primary metastatic breast cancer patients is controversial. Previous retrospective studies and meta-analyses suggested a survival benefit for the removal of the primary tumor. Early follow-up data from 2 prospectively randomized trials presented at San Antonio Breast Cancer Symposium 2013 could not confirm this. Only a very small subgroup of patients with solitary bone metastases seemed to profit from surgery, while patients with multiple visceral metastases showed a worse prognosis with initial surgery. There are no studies available with the primary aim to investigate the impact of axillary lymph node surgery or locoregional radiotherapy on the survival of stage IV breast cancer patients. Based on current data, locoregional treatment in primary metastatic breast cancer should not be recommended in patients with asymptomatic primary tumor as a matter of routine. More solid conclusion of the impact of primary tumor treatment in stage IV breast cancer patients on their prognosis will be reached with the completion of the ongoing prospectively randomized trials. Until these studies are completed, locoregional therapy, which can provoke additional morbidity in a metastatic setting with limited live expectancy, is exclusively indicated for palliative reasons. © 2014 S. Karger GmbH, Freiburg [ABSTRACT FROM AUTHOR]

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. 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. 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 (χ2 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. 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. Swedish Research Council, the Swedish Cancer Society, the Nordic Cancer Union, and the Swedish Breast Cancer Association. [ABSTRACT FROM AUTHOR]

Simple Summary: Currently, the optimal axillary surgical approach for breast cancer patients with initial node-positive disease and conversion to clinically node-negative status after primary systemic therapy is unclear. The aim of our study was to evaluate the clinical impact of removing the initially most suspicious, labeled axillary lymph node in addition to the sentinel lymph node. Metastatic target lymph nodes were found in five out of 63 patients (7.9%), while the sentinel lymph node was either tumor-free or not detected. The removal of the target lymph node influenced the adjuvant systemic therapy in only one case (1.6%). However, complete axillary dissection was indicated in all five cases. Furthermore, with fewer than three sentinel lymph nodes removed, the target lymph node reduced the false-negative rate to less than 10%. We therefore conclude that although the target lymph node has a minor impact on adjuvant systemic therapy, it is relevant for surgical axillary management. Purpose: To assess the impact of the removal of the target lymph node (TLN) on therapy after the completion of primary systemic therapy (PST) in initially node-positive breast cancer patients. Methods: Pooled data analysis of participants of the prospective CLIP- and TATTOO-study at the University of Rostock was performed. Results: A total of 75 patients were included; 63 of them (84.0%) converted to clinically node-negative after PST. Both TLN and sentinel lymph node (SLN) were identified in 41 patients (51.2%). In five out of 63 patients (7.9%), the TLN was metastatic after PST and the SLN was either tumor-free or not detected. Axillary lymph node dissection (ALND) was conducted in all five patients. In one patient, systemic therapy recommendation was influenced by the TLN; adjuvant radiotherapy was influenced by the TLN in zero patients. For patients with fewer than three removed SLNs, the FNR was 28.6% for the SLN biopsy alone and 7.1% for targeted axillary dissection (TAD). Conclusions: Removal of the TLN in addition to the SLN after PST has only minimal impact on the type of adjuvant systemic therapy and radiotherapy. However, the extent of axillary surgery was relevantly affected and FNR was improved by TAD. [ABSTRACT FROM AUTHOR]

Simple Summary: Improvements in systemic treatments for breast cancer have increased the rates of pathologic complete response (pCR) in patients receiving preoperative systemic therapy (PST), offering the opportunity to de-escalate, and perhaps eliminate, surgery in patients who have a pCR. We propose a clinical trial in which only patients with the highest likelihood of having a pCR after PST will be included and type of surgery will be defined according to the response to PST rather than on the classical T (for tumor size in the breast) and N (for axillary lymph node involvement) status at presentation. In the planned trial, axillary surgery will be eliminated completely (no axillary sentinel lymph node biopsy) for initially clinical node-negative patients with radiologic complete remission and a breast pCR as determined in the lumpectomy specimen. Currently, axillary surgery for breast cancer is considered only as staging procedure, since the risk of developing metastasis depends on the biological behavior of the primary. The postsurgical therapy should be considered on the basis of biologic tumor characteristics rather than nodal involvement. Improvements in systemic treatments for breast cancer have increased the rates of pathologic complete response (pCR) in patients receiving neoadjuvant systemic therapy (NAST), offering the opportunity to de-escalate surgery in patients who have a pCR. European Breast Cancer Research Association of Surgical Trialists (EUBREAST)-01 is a clinical trial in which only patients with the highest likelihood of having a pCR after NAST (triple-negative or HER2-positive breast cancer) will be included and type of surgery will be defined according to the response to NAST rather than on the classical T (for tumor size in the breast) and N (for axillary lymph node involvement) status. In the discussed trial, axillary surgery will be eliminated completely (no axillary sentinel lymph node biopsy) for initially clinical node-negative (cN0) patients with radiologic complete remission and a breast pCR in the lumpectomy specimen. The trial design is a multicenter single-arm study with a limited number of patients (n = 267), which might give practice-changing results in a short period of time, sparing the time and the costs of a randomized comparison. [ABSTRACT FROM AUTHOR]

• Detailed evaluation of received radiotherapy in the randomized SENOMAC trial. • Inclusion of level I in the target more common after sentinel node biopsy only. • Significant dose in axillary level I regardless of inclusion in target volume. • No dose difference to axillary target volumes between randomization groups. • Inclusion of axillary level I raised dose to the humeral head. Recommendations for regional radiotherapy (RT) of sentinel lymph node (SLN)-positive breast cancer are debated. We here report a RT quality assessment of the SENOMAC trial. The SENOMAC trial randomized clinically node-negative breast cancer patients with 1–2 SLN macrometastases to completion axillary lymph node dissection (cALND) or SLN biopsy only between 2015–2021. Adjuvant RT followed national guidelines. RT plans for patients included in Sweden and Denmark until June 2019 were collected (N = 1176) and compared to case report forms (CRF). Dose to level I (N = 270) and the humeral head (N = 321) was analyzed in detail. CRF-data and RT plans agreed in 99.3 % (breast/chest wall) and in 96.6 % of patients (regional RT). Congruence for whether level I was an intended RT target was lower (78 %). In accordance with Danish national guidelines, level I was more often an intended target in the SLN biopsy only arm (N = 334/611, 55 %,) than in the cALND arm (N = 174/565, 31 %,). When an intended target, level I received prescribed dose to 100 % (IQR 98–100 %) of the volume. However, even when not an intended target, full dose was delivered to > 80 % of level I (IQR 75–90 %). The intentional inclusion of level I in the target volume more than doubled the dose received by ≥ 50 % of the humeral head. Congruence between CRF data and RT plans was excellent. Level I received a high dose coverage even when not intentionally included in the target. Including level I in target significantly increased dose to the humeral head. [ABSTRACT FROM AUTHOR]