Residual Axillary Metastases in Node-Positive Breast Cancer Patients After Neoadjuvant Treatment: A Register-Based Study.

BACKGROUND: Lymph node (LN) metastasis after neoadjuvant chemotherapy (NACT) generally warrants axillary lymph node dissection, which opposes guidelines of upfront surgery in many cases. We investigated the risk of having additional metastases in the axilla when the LNs removed by targeted axillary dissection (TAD) harbored metastases after NACT. We aimed to identify subgroups suitable for de-escalated axillary treatment. METHODS: This register-based study used data from the Danish Breast Cancer Cooperative Group database. Data were analyzed with logistic regression models. The primary outcome was the metastatic burden in non-TAD LNs in patients with positive TAD LNs after NACT. RESULTS: Among 383 patients, < 66.6% positive TAD LNs (adjusted odds ratio [OR] 0.34, 95% confidence interval [CI] 0.17-0.62), only isolated tumor cells (ITCs) [OR 0.11, 95% CI < 0.01-0.82], and breast pathological complete response (pCR) [OR 0.07, 95% CI < 0.01-0.56] were associated with a low risk of having more than three positive non-TAD LNs. In 315 patients with fewer than three positive non-TAD LNs, the proportion of positive TAD LNs (OR 0.45, 95% CI 0.27-0.76 for 33.3-66.6% vs. > 66.6%), size of the TAD LN metastasis (OR 0.14, 95% CI 0.04-0.54 for ITC vs. macrometastasis), tumor size at diagnosis (OR 0.30, 95% CI 0.15-0.64 for 20-49 mm vs. ≥ 50 mm) and breast pCR (OR 0.38, 95% CI 0.15-0.96) were associated with residual LN metastases in the axilla. CONCLUSIONS: Breast pCR or ITC only in TAD LNs can, with reasonable certainty, preclude more than three positive non-TAD LNs. Additionally, patients with only ITCs in the TAD LN had a low risk of having any non-TAD LN metastases after NACT. De-escalated axillary treatment may be considered in both subgroups.

Omitting Axillary Dissection in Breast Cancer with Sentinel-Node Metastases.

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.).

Surgical treatment of breast cancer.

Surgical treatment of breast cancer has changed towards less invasive procedures as summarised in this review. Breast conserving surgery (BCS) and radiotherapy (RT) are now recommended as standard of care. Several flexible marking methods for removal of non-palpable tumours have gradually replaced wire-guided localisation. Neoadjuvant systemic treatment increases tumour shrinkage and BCS and may lead to omission of axillary clearance (AC). The prognostic significance of AC in patients with metastases to 1-2 sentinel nodes at primary surgery is questioned. Results from the SENOMAC trial are expected to change guidelines from AC to axillary RT.

Breast reconstruction after mastectomy.

Patients requesting breast reconstruction after mastectomy is an increasing group at plastic- and breast surgery departments in Denmark. This review summarises the present surgical techniques for reconstruction with/without postoperative chemotherapy and/or radiation therapy. These surgical techniques are continuously updated. The most determining factor when selecting a reconstructive technique, is postoperative radiation therapy. Each patient is unique, and an individual assessment is made when planning surgery. The concept of a "babysitter implant" is currently being investigated in Denmark and might be an option for selected patients.

Indocyanine green angiography in oncoplastic breast surgery, a prospective study.

INTRODUCTION: The use of Indocyanine green angiography (ICG-A) in oncoplastic breast-conserving surgery (OBCS) has not yet been investigated. This prospective trial applied ICG-A in volume displacement and replacement OBCS to localize perforators and determine tissue supplied by the perforator. Furthermore, to investigate and correlate the intraoperative ICG-A to postoperative surgical site infection, skin necrosis, epidermolysis, and timely onset of adjuvant therapy. METHODS: ICG-A was performed at three pre-set timepoints during surgery; after lumpectomy, upon dissection of possible perforators, and after wound closure. All patients were followed with clinical evaluations before surgery, 4 weeks, 4-6 months, and 12 months postoperatively. RESULTS: Eleven patients were included: seven volume displacement and four volume replacement OBCS. ICG-A located the tissue supplied by the perforator and demonstrated sufficient perfusion in all cases. The ICG-A corresponded to the surgeons' clinical assessment. One patient developed a postoperative infection and seroma and was treated conservatively. No patients had postoperative necrosis, loss of reconstruction, or lymphedema of the arm. Edema of the breast occurred in four patients (36.4%). Scar assessments were significantly worse at 4-weeks and 4-6 months. The quality of life improved significantly during follow-up. Adjuvant treatment was administered timely in all cases. CONCLUSION: ICG-A was feasible for OBCS in assessing intraoperative perfusion. Perfusion was sufficient in all patients and corresponded to the surgeon's clinical evaluation. No patients developed postoperative necrosis. Though edema of the breast occurred in 36.4%, a larger sample size is needed to investigate a possible correlation with ICG-A. Further studies, which includes patients requiring extensive tissue replacement challenging the borders of perfusion, are needed.

Comparing Methods for Targeted Axillary Dissection in Breast Cancer Patients: A Nationwide, Retrospective Study.

BACKGROUND: Several techniques exist for performing targeted axillary dissection (TAD) after neoadjuvant chemotherapy with the removal of the sentinel node and a marked metastatic lymph node (LN). Two-step methods include coil-marking of the metastatic LN at diagnosis and re-marking with an intraoperatively identifiable marker before surgery. Because nondetection of the marked lymph node (MLN) warrants axillary clearance and many patients achieve axillary pathological complete response (ax-pCR), the success of TAD is crucial. We compare various two-step TAD methods in a Danish national cohort. METHODS: We included patients who received two-step TAD between January 1, 2016 and August 31, 2021. Patients were identified from the Danish Breast Cancer Group database and cross-checked with locally accessible lists. Data were extracted from the patient's medical files. RESULTS: We included 543 patients. In 79.4%, preoperative, ultrasound-guided re-marking was possible. Nonidentification of the coil-marked LN was more likely in patients with ax-pCR. The second markers used were hook-wire, iodine seeds, or ink marking on the axillary skin. Of patients with successful secondary marking, the MLN identification rate (IR) was 91%, and the sentinel node (SN) IR was 95%. Marking with iodine seeds was significantly more successful than ink marking with an odds ratio of 5.34 (95% confidence interval 1.62-17.60). The success rate of the complete TAD with the removal of MLN and SN was 82.3%. CONCLUSIONS: With two-step TAD, nonidentification of the coiled LN before surgery is frequent, especially in patients with ax-pCR. Despite successful remarking, the IR of the MLN at surgery is inferior to one-step TAD.

Targeted Axillary Dissection with 125I Seed Placement Before Neoadjuvant Chemotherapy in a Danish Multicenter Cohort.

BACKGROUND: Targeted axillary dissection (TAD), with marking of the metastatic lymph node before neoadjuvant chemotherapy (NACT), is increasingly used for breast cancer axillary staging. In the case of axillary pathological complete response (ax-pCR), axillary lymph node clearance can be omitted. Several marking methods exist, most using re-marking before surgery. Feasibility, learning curve, and identification rate (IR) vary. Marking with 125I seed before NACT makes re-marking at surgery redundant, possibly increasing feasibility and IR. Here, TAD with 125I seed placed before NACT is evaluated in a Danish multicenter cohort. METHODS: Patients staged with 125I TAD in Denmark between 1 January 2016 and 31 August 2021 were included. Patients were identified in radioactivity-emitting implant registries at the radiology departments and from the Danish Breast Cancer Group database. Data were extracted from patients' medical records. Information on patient/tumor characteristics, 125I seed activity, marking period, TAD success, number of sentinel nodes (SNs), the histopathological status of excised nodes, and whether the marked lymph node (MLN) was an SN were registered. RESULTS: 142 patients were included. The IR of the MLN was 99.3%, and the IR of the SLNB was 91.5%. TAD success was 91.5%. Minor challenges in marking or removal of the MLN were noted in three patients. In 72.3% of the patients, the MLN was a sentinel node. Overall, 40.8% had axillary pCR. CONCLUSION: TAD with 125I seed marking before NACT is feasible without re-marking at surgery and with only minor surgical challenges. The IR is high. Staging with TAD spares 41% of breast cancer patients an axillary dissection.

Current clinical practice in the management of phyllodes tumors of the breast: an international cross-sectional study among surgeons and oncologists.

PURPOSE: Phyllodes tumors of the breast are rare fibroepithelial lesions that are classified as benign, borderline or malignant. There is little consensus on best practice for the work-up, management, and follow-up of patients with phyllodes tumors of the breast, and evidence-based guidelines are lacking. METHODS: We conducted a cross-sectional survey of surgeons and oncologists with the aim to describe current clinical practice in the management of phyllodes tumors. The survey was constructed in REDCap and distributed between July 2021 and February 2022 through international collaborators in sixteen countries across four continents. RESULTS: A total of 419 responses were collected and analyzed. The majority of respondents were experienced and worked in a university hospital. Most agreed to recommend a tumor-free excision margin for benign tumors, increasing margins for borderline and malignant tumors. The multidisciplinary team meeting plays a major role in the treatment plan and follow-up. The vast majority did not consider axillary surgery. There were mixed opinions on adjuvant treatment, with a trend towards more liberal regiments in patients with locally advanced tumors. Most respondents preferred a five-year follow-up period for all phyllodes tumor types. CONCLUSIONS: This study shows considerable variation in clinical practice managing phyllodes tumors. This suggests the potential for overtreatment of many patients and the need for education and further research targeting appropriate surgical margins, follow-up time and a multidisciplinary approach. There is a need to develop guidelines that recognize the heterogeneity of phyllodes tumors.

Adjuvant treatment with trastuzumab of patients with HER2-positive, T1a-bN0M0 breast tumors: A systematic review and meta-analysis.

The benefit of adjuvant trastuzumab treatment in patients with HER2-positive breast tumors ≤ 10 mm without lymph node involvement (T1abN0) is insufficiently investigated. The aim of this systematic review and meta-analysis was to examine if adjuvant trastuzumab improves the prognosis in these patients. Databases were searched to identify interventional and observational studies evaluating the effect of trastuzumab on breast cancer specific survival (BCSS), disease free survival (DFS), distant recurrence free survival (DRFS), overall survival (OS) or recurrence free survival (RFS). Twelve studies examining the effect of trastuzumab and nine control studies without trastuzumab were identified (n = 6927). Median follow-up was 36-123 months. Significantly improved DFS (Hazard Ratio (HR) 0.14, p < 0.0001) and OS (HR 0.17, p = 0.011) were found for patients receiving trastuzumab and chemotherapy compared to no trastuzumab/chemotherapy based on four and two studies. The prognosis was good even for patients without trastuzumab treatment: 5-year DFS 88.3% and 5-year OS 95.9%.

Adjuvant chemotherapy in patients with ER-negative/HER2-negative, T1abN0 breast cancer: a nationwide study.

PURPOSE: The purpose of this study was to examine the effect of chemotherapy on invasive disease-free survival (iDFS) and overall survival (OS) in a nationwide cohort of patients with estrogen receptor (ER)-negative/human epidermal growth factor receptor 2 (HER2)-negative, T1abN0 breast cancer. METHODS: Patients with ER-negative/HER2-negative, T1abN0 breast cancer registered in the Danish Breast Cancer Group database between 2007 and 2016 were identified. The effect of adjuvant chemotherapy on iDFS and OS was analyzed with Cox proportional hazards analysis. RESULTS: In total, 296 patients were included in the statistical analyses. Of these, 235 (79.4%) received chemotherapy and 61 patients (20.6%) did not. Patients treated with chemotherapy were significantly younger, had a significantly higher proportion of grade 3 tumors, T1b tumors, and tumors of ductal subtype. With 7.7 years of median follow-up, treatment with chemotherapy was associated with a significant improvement in OS in the adjusted analysis, Hazard Ratio 0.35 (95% Confidence Interval (0.15-0.81), p = 0.02), chemotherapy vs. no chemotherapy. In the unadjusted analyses, patients with both T1a and T1b tumors had significantly improved OS with chemotherapy. At 5 years, OS was 100% vs. 94.4% and 93.8% vs. 81.3% for patients with T1a and T1b tumors, respectively, chemotherapy vs. no chemotherapy. With 4.9 years of median follow-up, iDFS was not significantly improved with chemotherapy. CONCLUSION: Patients with ER-negative/HER2-negative, T1abN0 breast cancer had significantly improved OS when treated with chemotherapy. This improvement was significant in patients with both T1a and T1b tumors, respectively. The effect was, however, limited in patients with T1a tumors.

Axillary surgery in oncologic breast surgery: a narrative review.

Background and Objective: With the improved survival for breast cancer there is now an increased focus on quality of life after treatment. Axillary surgery is known to be associated with significant risk of arm morbidity feared by the patients, and several studies have shown de-escalation is possible in different settings. In this review, an overview will be given on new techniques and procedures for de-escalation of axillary surgery in breast cancer patients and the subsequent implications for adjuvant systemic treatment. Methods: This study is a narrative review. PubMed was searched for relevant publications in English published between January 2018-June 2023. Only publications with major impact on clinical practice have been included with main emphasis on meta-analysis. In addition, Clinicaltrial.gov has been searched for on-going studies. Key Content and Findings: New tracer techniques are described as well as the on-going reduction in axillary lymph node dissection (ALND) at primary surgery even in node positive patients, and the axillary staging possibilities after down-staging of the axilla by neoadjuvant treatment. Finally axillary staging at local recurrence and in case of ductal carcinoma in situ is described. Conclusions: ALND is no longer routinely recommended in many node positive patients and further de-escalation is investigated. The lack of knowledge on precise axillary status will require cooperating studies between oncologists and breast surgeons in order to avoid escalation of systemic treatment due to the lack of applicability of trial eligibility criteria. Furthermore, investigations on the use of axillary imaging for staging are needed.

Benefit of adjuvant chemotherapy and trastuzumab in patients with HER2-positive, node-negative breast tumors ≤ 10 mm: a nationwide study.

PURPOSE: The purpose of this study was to evaluate the effect of chemotherapy and trastuzumab on invasive disease-free survival (iDFS) and overall survival (OS) in patients with human epidermal growth factor receptor 2 (HER2) positive, T1abN0 breast cancer. METHODS: In the Danish Breast Cancer Group database, patients with HER2-positive, T1abN0 tumors diagnosed between 2007 and 2016 were identified. Cox proportional hazards analysis was performed to analyze the association between adjuvant chemotherapy and trastuzumab and iDFS and OS. RESULTS: Of 605 patients included in the analyses, 465 patients received chemotherapy and trastuzumab and 140 patients did not. Chemotherapy and trastuzumab did not improve iDFS or OS significantly in adjusted analyses. 5-year iDFS was 92.3% vs. 89.9%, Hazard ratio (HR) 1.01 (p = 0.98), and 5-year OS was 97.4% vs. 94.3%, HR 0.60 (p = 0.15), chemotherapy and trastuzumab vs. no chemotherapy/trastuzumab. In unadjusted analyses, significant treatment benefit on OS was found in patients with T1b tumors. The largest absolute treatment benefits were found in patients with T1b tumors and estrogen receptor (ER) negative tumors, respectively, whereas treatment effects in patients with T1a tumors and ER-positive tumors, respectively, were limited. CONCLUSION: Adjuvant chemotherapy and trastuzumab did not improve OS or iDFS significantly in patients with HER2-positive, T1abN0 breast cancers in adjusted analyses. In unadjusted analyses, significant OS benefit was found in patients with T1b tumors. The largest absolute benefit was observed in patients with T1b tumors and ER-negative tumors, respectively, whereas the effect was limited in patients with T1a tumors and ER-positive tumors, respectively.

Radiation Induced Atypical Vascular Lesion in the Breast.

BACKGROUND AND PURPOSE: Atypical vascular lesion (AVL) became a separate WHO diagnosis in November 2019. Due to a possible risk of developing angiosarcoma, extensive surgery with excision of AVL has been recommended but the benefit from this is questionable. We investigated whether the change in WHO classification has led to an increase in the number of patients diagnosed with AVL, thereby leading to an increase in extensive surgery. METHOD: The Danish National Pathology Databank was used to identify patients diagnosed with AVL between June 1, 2010 to June 31, 2020. The rate of AVL diagnosed before and after change in WHO classification was compared. RESULTS: In total, 13 cases of AVL were identified, 3 cases diagnosed before changes in WHO classification corresponding to 0.025 cases per month, compared to 8 cases, 1.143 cases per month, after the change in WHO classification. This corresponded to a 45-fold increase (95%CI: 10.88-265,31) (P < .0001) in AVL diagnosis. The mean patient age at diagnosis was 67 years. Patients received treatment varying from yearly follow up to extensive surgery. Non developed angiosarcoma in the follow-up period of 22 months. CONCLUSION: The changes in WHO classification of AVL has led to a considerable increase in the number of patients diagnosed with the lesion. No standardized treatment exists for this rare condition, but extensive surgery is often recommended to this frail population despite the lack of evidence for prognostic benefit from the procedure. Prospective follow-up studies are needed to determine the optimal treatment strategy.

[Advanced locoregional chest wall recurrence of breast cancer].

Locoregional recurrence of breast cancer continues to be a significant clinical issue involving extensive examination programmes, modified oncologic therapy and advanced surgery. The latter includes tumour resection followed by reconstruction of the thoracic wall. The type of reconstruction depends on tumour location, depth, aetiology and whether the resection involves the stabilising osseous structures as summarised in this review. The treatment strategy is planned at multidisciplinary team conferences with the presence of relevant specialists to ensure evidence-based treatment of consistent quality.

Patient-reported outcomes one year after positive sentinel lymph node biopsy with or without axillary lymph node dissection in the randomized SENOMAC trial.

INTRODUCTION: This report evaluates whether health related quality of life (HRQoL) and patient-reported arm morbidity one year after axillary surgery are affected by the omission of axillary lymph node dissection (ALND). METHODS: The ongoing international non-inferiority SENOMAC trial randomizes clinically node-negative breast cancer patients (T1-T3) with 1-2 sentinel lymph node (SLN) macrometastases to completion ALND or no further axillary surgery. For this analysis, the first 1181 patients enrolled in Sweden and Denmark between March 2015, and June 2019, were eligible. Data extraction from the trial database was on November 2020. This report covers the secondary outcomes of the SENOMAC trial: HRQoL and patient-reported arm morbidity. The EORTC QLQ-C30, EORTC QLQ-BR23 and Lymph-ICF questionnaires were completed in the early postoperative phase and at one-year follow-up. Adjusted one-year mean scores and mean differences between the groups are presented corrected for multiple testing. RESULTS: Overall, 976 questionnaires (501 in the SLN biopsy only group and 475 in the completion ALND group) were analysed, corresponding to a response rate of 82.6%. No significant group differences in overall HRQoL were identified. Participants receiving SLN biopsy only, reported significantly lower symptom scores on the EORTC subscales of pain, arm symptoms and breast symptoms. The Lymph-ICF domain scores of physical function, mental function and mobility activities were significantly in favour of the SLN biopsy only group. CONCLUSION: One year after surgery, arm morbidity is significantly worse affected by ALND than by SLN biopsy only. The results underline the importance of ongoing attempts to safely de-escalate axillary surgery. TRIAL REGISTRATION: The trial was registered at clinicaltrials.gov prior to initiation (https://clinicaltrials.gov/ct2/show/NCT02240472).

Prediction of Pathologic Complete Response in Breast Cancer Patients Comparing Magnetic Resonance Imaging with Ultrasound in Neoadjuvant Setting.

BACKGROUND: Some subgroups of breast cancer patients receiving neoadjuvant chemotherapy (NACT) show high rates of pathologic complete response (pCR) in the breast, proposing the possibility of omitting surgery. Prediction of pCR is dependent on accurate imaging methods. This study investigated whether magnetic resonance imaging (MRI) is better than ultrasound (US) in predicting pCR in breast cancer patients receiving NACT. METHODS: This institutional, retrospective study enrolled breast cancer patients receiving NACT who were examined by either MRI or combined US and mammography before surgery from 2016 to 2019. Imaging findings were compared with pathologic response evaluation of the tumor. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy for prediction of pCR were calculated and compared between MRI and US. RESULTS: Among 307 patients, 151 were examined by MRI and 156 by US. In the MRI group, 37 patients (24.5 %) had a pCR compared with 51 patients (32.7 %) in the US group. Radiologic complete response (rCR) was found in 35 patients (23.2 %) in the MRI group and 26 patients (16.7 %) in the US group. In the MRI and US groups, estimates were calculated respectively for sensitivity (87.7 % vs 91.4 %), specificity (56.8 % vs 33.3 %), PPV (86.2 % vs 73.8 %), NPV (60.0 % vs 65.4 %), and accuracy (80.1 % vs 72.4 %). CONCLUSIONS: In predicting pCR, MRI was more specific than US, but not sufficiently specific enough to be a valid predictor of pCR for omission of surgery. As an imaging method, MRI should be preferred when future studies investigating prediction of pCR in NACT patients are planned.