BACKGROUND:Despite the paucity of outcome data, axillary lymph node dissection (ALND) is increasingly being omitted in patients with positive sentinel lymph nodes after neoadjuvant chemotherapy, particularly in those with low-volume residual disease. We investigated oncological outcomes in patients with breast cancer and residual micrometastases in the sentinel lymph nodes treated with or without ALND. METHODS:OPBC-07/microNAC was a retrospective cohort study, using data obtained from the institutional databases of 84 cancer centres in 30 countries. Patients aged 18 years or older with clinical T1-4, N0-3 breast cancer at diagnosis treated with neoadjuvant chemotherapy followed by surgery between Jan 1, 2013, and May 31, 2023, who were found to have residual micrometastases (metastasis measuring >0·2 mm or >200 cells, not exceeding 2·0 mm in size) on frozen section or on final paraffin sections as determined by sentinel lymph node biopsy, targeted axillary dissection (sentinel lymph node biopsy with single or dual-tracer mapping plus image-guided localisation of the initially biopsy-proven and clipped node), or the marking axillary lymph nodes with radioactive iodine seeds (MARI) procedure were eligible for inclusion. The primary endpoint was the 5-year rate of any axillary recurrence (isolated or combined with local or distant recurrence) stratified by type of axillary surgery. Given the median follow-up, here we report 3-year rates and exploratory 5-year estimates. This study was registered with ClinicalTrials.gov, NCT06529302. FINDINGS:1585 female patients with ypN1mi disease were analysed, of whom 804 (50·7%) underwent ALND and 781 (49·3%) did not. Of 1585 women, 238 (15·0%) self-identified as Asian, 65 (4·1%) as Black, 200 (12·6%) as Hispanic, 968 (61·1%) as White, and 114 (7·2%) as unknown race and ethnicity. 925 (58·4%) of 1585 women had cT2 tumours, 1054 (66·5%) were node positive, and 1267 (79·9%) received nodal radiotherapy. The median follow-up was 3·1 years (IQR 1·8-5·2). The 3-year rate of any axillary recurrence (isolated or combined with local or distant recurrence) for the entire cohort was 2·0% (95% CI 1·3-2·9), with no statistical difference identified by extent of axillary surgery. However, patients with triple-negative disease who did not receive ALND had significantly higher rates of any axillary recurrence than women treated with ALND (8·7% [95% CI 4·4-15·0] vs 2·4% [95% CI 0·7-6·5], p=0·018). On multivariable analysis, triple-negative breast cancer (hazard ratio 3·83 [95% CI 1·72-8·52]) and omission of nodal radiotherapy (2·62 [1·19-5·73]) but not omission of ALND (0·86 [0·37-2·00]) were independently associated with an increased risk of any axillary recurrence. INTERPRETATION:Overall, these results do not support ALND for all patients with ypN1mi on sentinel lymph node biopsy treated with nodal radiotherapy; however, tumour biology should be taken into account when considering ALND omission. FUNDING:US National Institutes of Health, National Cancer Institute.

Importance:Randomized trials established the safety of omitting axillary lymph node dissection (ALND) among patients with clinically node-negative breast cancer and less than 3 positive sentinel lymph nodes (+SLNs) having upfront surgery and adjuvant radiation. Patients with palpable mobile level I/II axillary adenopathy (cN1) were not eligible for these studies. Presently, more than 80% of patients with HR+/HER2- cN1 disease undergo ALND either at upfront surgery or after neoadjuvant therapy, despite evidence that 50% to 60% will have only 1 or 2 positive nodes. Objective:To determine upfront sentinel lymph node biopsy (SLNB) feasibility and evaluate ALND rate among patients with HR+/HER2- cN1 breast cancer selected with axillary ultrasound (AUS). Design, Setting, and Participants:This nonrandomized clinical trial involved patients with cTx/cT1-2 cN1 HR+/HER2- breast cancer with 3 or fewer morphologically abnormal nodes on AUS at 4 centers. The trial began on April 20, 2021, and the database for this report was frozen on September 26, 2024. Interventions:Patients underwent upfront lumpectomy/mastectomy and SLNB, with single/dual-tracer mapping. ALND was indicated for 3 or more positive SLNs. Main Outcomes and Measures:The primary outcome was ALND rate. Secondary outcomes were frequency of palpable nodes being radioactive/blue and locoregional recurrence. Results:Among 78 enrolled patients, the median (IQR) age was 58 (49.0-66.5) years. Most tumors were cT1 (37 [47%]) or cT2 (40 [51%]), 56 patients (72%) had ductal histology, and 59 tumors (76%) were moderately differentiated. On AUS, 39 patients (50%) had 1 abnormal-appearing node, 33 (42%) had 2, and 6 (8%) had 3. Median (IQR) pathologic tumor size was 2.3 (1.6-3.3) cm, 50 patients (64%) had lymphovascular invasion, and 54 (69%) had extracapsular extension. SLNB was performed with dual tracer in 68 (87%), and 3 or more SLNs were retrieved in 75 (96%). The palpable diseased nodes were blue and/or radioactive in 107 of 161 instances (66.5%). Overall, 24 patients (31%) had 1 +SLN, 30 patients (38%) had 2 +SLNs, and 24 patients (31%) had 3 or more +SLNs. SLNB alone was performed in 59 patients (76%), while 19 (24%) had ALND; indicated ALND was deferred in 5 cases. Among those with 12 months or more follow-up (n = 68; median, 25 months), there have been no isolated axillary or locoregional recurrences. Conclusions and Relevance:This study found that SLNB is feasible among patients with cN1 HR+/HER2- disease and that resection of palpable nodes is necessary to minimize false-negative rates. This approach affords the opportunity to omit ALND and minimize morbidity among patients with cN1 cancer and limited nodal burden. Trial Registration:ClinicalTrials.gov Identifier: NCT04854005.

Objective: This study prospectively compared lymphedema rates with perometer, tape measure, and bioimpedance spectroscopy (L-Dex) in patients with breast cancer undergoing axillary lymph node dissection (ALND). Background: Perometer, tape measure, and L-Dex are all used for diagnosing lymphedema, although lymphedema rates may vary between these techniques. Methods: From November 2016 to March 2020, patients who underwent ALND had arm measurements performed preoperatively and biannually with perometer, tape measure, and L-Dex. A lymphedema diagnosis was made if arm volume increased by ≥10% by perometer or tape measure, or if L-Dex increased ≥6.5 units from baseline. We assessed concordance between the different measurement techniques using scatter plots, Pearson correlations, and Cohen’s Kappa statistic. Results: We included 281 patients who underwent ALND and had at least one follow-up (median, 2.3 years; >1100 follow-up measurements). Two-year lymphedema rates were 21.9% with perometer, 34.6% with tape measure, and 67.5% with L-Dex. Evaluating all timepoints, we found moderate correlation between perometer and tape measure (R=0.67, P <0.001), perometer and L-Dex (R=0.66, P <0.001) and tape measure and L-Dex (R=0.57, P <0.001). Diagnostic agreement was weak between perometer and L-Dex (k=0.29, P <0.001), and tape measure and L-Dex (k=0.28, P <0.001); and moderate between perometer and tape measure (k=0.51, P <0.001). Conclusion: In our prospective ALND cohort, perometer, tape measure, and L-Dex demonstrated moderate correlation between measurements, and weak-to-moderate diagnostic agreement. Lymphedema rates varied between measurement techniques, with the highest rates observed with L-Dex, raising concern for overdiagnosis.

Landmark trials have demonstrated that residual microscopic disease in the undissected axilla does not translate to a higher risk of nodal recurrence, which laid the groundwork for trials examining the omission of axillary surgery. The SOUND and INSEMA randomized trials demonstrated no difference in disease-free survival in patients with small, cN0 breast cancer treated with or without sentinel lymph node biopsy (SLNB). Postmenopausal patients with luminal breast cancer undergoing lumpectomy with a normal preoperative axillary ultrasound are ideally suited for omission of SLNB, as systemic therapy decisions are increasingly based on genomic assays rather than pathologic nodal status.

This nonrandomized clinical trial analyzes data for patients who underwent upfront surgery to determine the feasibility of upfront sentinel lymph node biopsy and evaluate the rate of axillary lymph node dissection. QuestionWhat is the feasibility of upfront sentinel lymph node biopsy (SLNB) and the rate of axillary lymph node dissection (ALND) among patients with HR+/HER2- cN1 breast cancer selected with axillary ultrasound?FindingsIn this nonrandomized clinical trial including 78 consecutive patients with cTx/cT1-2 cN1 HR+/HER2- breast cancer with palpable, biopsy-proven nodal metastases, SLNB was feasible among patients with cN1 HR+/HER2- disease, with 3 or more SLNs retrieved in 96% of cases, and nearly 70% of patients meeting criteria for SLNB alone and able to avoid ALND.MeaningThis approach affords the opportunity to omit ALND and minimize morbidity among cN1 patients with limited nodal disease burden. ImportanceRandomized trials established the safety of omitting axillary lymph node dissection (ALND) among patients with clinically node-negative breast cancer and less than 3 positive sentinel lymph nodes (+SLNs) having upfront surgery and adjuvant radiation. Patients with palpable mobile level I/II axillary adenopathy (cN1) were not eligible for these studies. Presently, more than 80% of patients with HR+/HER2- cN1 disease undergo ALND either at upfront surgery or after neoadjuvant therapy, despite evidence that 50% to 60% will have only 1 or 2 positive nodes.ObjectiveTo determine upfront sentinel lymph node biopsy (SLNB) feasibility and evaluate ALND rate among patients with HR+/HER2- cN1 breast cancer selected with axillary ultrasound (AUS).Design, Setting, and ParticipantsThis nonrandomized clinical trial involved patients with cTx/cT1-2 cN1 HR+/HER2- breast cancer with 3 or fewer morphologically abnormal nodes on AUS at 4 centers. The trial began on April 20, 2021, and the database for this report was frozen on September 26, 2024.InterventionsPatients underwent upfront lumpectomy/mastectomy and SLNB, with single/dual-tracer mapping. ALND was indicated for 3 or more positive SLNs.Main Outcomes and MeasuresThe primary outcome was ALND rate. Secondary outcomes were frequency of palpable nodes being radioactive/blue and locoregional recurrence.ResultsAmong 78 enrolled patients, the median (IQR) age was 58 (49.0-66.5) years. Most tumors were cT1 (37 [47%]) or cT2 (40 [51%]), 56 patients (72%) had ductal histology, and 59 tumors (76%) were moderately differentiated. On AUS, 39 patients (50%) had 1 abnormal-appearing node, 33 (42%) had 2, and 6 (8%) had 3. Median (IQR) pathologic tumor size was 2.3 (1.6-3.3) cm, 50 patients (64%) had lymphovascular invasion, and 54 (69%) had extracapsular extension. SLNB was performed with dual tracer in 68 (87%), and 3 or more SLNs were retrieved in 75 (96%). The palpable diseased nodes were blue and/or radioactive in 107 of 161 instances (66.5%). Overall, 24 patients (31%) had 1 +SLN, 30 patients (38%) had 2 +SLNs, and 24 patients (31%) had 3 or more +SLNs. SLNB alone was performed in 59 patients (76%), while 19 (24%) had ALND; indicated ALND was deferred in 5 cases. Among those with 12 months or more follow-up (n = 68; median, 25 months), there have been no isolated axillary or locoregional recurrences.Conclusions and RelevanceThis study found that SLNB is feasible among patients with cN1 HR+/HER2- disease and that resection of palpable nodes is necessary to minimize false-negative rates. This approach affords the opportunity to omit ALND and minimize morbidity among patients with cN1 cancer and limited nodal burden.Trial RegistrationClinicalTrials.gov Identifier: NCT04854005

Breast cancer-related lymphedema (BCRL) is a common and debilitating sequela of axillary lymph node dissection (ALND). Although machine learning (ML)-based prediction models have been proposed, few focus exclusively on patients undergoing ALND, and direct comparisons with traditional statistical models remain limited. This study aimed to develop accurate and clinically feasible prediction models for BCRL using supervised ML and multivariable logistic regression. Demographic and clinical data were prospectively collected from women undergoing unilateral ALND for breast cancer at Memorial Sloan Kettering Cancer Center between 2016 and 2024. Supervised ML and multivariable logistic regression models to predict BCRL were trained and internally validated. Model performance was evaluated using area under the receiver operator characteristic curve (AUC), accuracy, sensitivity, specificity, and Brier score. Shapley additive explanations were used for model interpretability. A total of 474 eligible patients were included. BCRL developed in 113 (23.8

OBJECTIVE:This study prospectively compared lymphedema rates with perometer, tape measure, and bioimpedance spectroscopy (L-Dex) in patients with breast cancer undergoing axillary lymph node dissection (ALND). BACKGROUND:Perometer, tape measure, and L-Dex are all used for diagnosing lymphedema, although lymphedema rates may vary between these techniques. METHODS:From November 2016 to March 2020, patients who underwent ALND had arm measurements performed preoperatively and biannually with perometer, tape measure, and L-Dex. A lymphedema diagnosis was made if arm volume increased by ≥10% by perometer or tape measure, or if L-Dex increased ≥6.5 units from baseline. We assessed concordance between the different measurement techniques using scatter plots, Pearson correlations, and Cohen's Kappa statistic. RESULTS:We included 281 patients who underwent ALND and had at least one follow-up (median, 2.3 years; >1100 follow-up measurements). Two-year lymphedema rates were 21.9% with perometer, 34.6% with tape measure, and 67.5% with L-Dex. Evaluating all timepoints, we found moderate correlation between perometer and tape measure (R=0.67, P<0.001), perometer and L-Dex (R=0.66, P<0.001) and tape measure and L-Dex (R=0.57, P<0.001). Diagnostic agreement was weak between perometer and L-Dex (k=0.29, P<0.001), and tape measure and L-Dex (k=0.28, P<0.001); and moderate between perometer and tape measure (k=0.51, P<0.001). CONCLUSION:In our prospective ALND cohort, perometer, tape measure, and L-Dex demonstrated moderate correlation between measurements, and weak-to-moderate diagnostic agreement. Lymphedema rates varied between measurement techniques, with the highest rates observed with L-Dex, raising concern for overdiagnosis.

Breast cancer patients treated with axillary lymph node dissection (ALND) have an approximate 20–30

Breast cancer-related lymphedema (BCRL) is characterized by skin changes, swelling, fibrosis, and recurrent skin infections. Clinical studies have suggested that lymphedema results in skin barrier defects; however, the underlying cellular mechanisms and the effects of bacterial contamination on skin barrier function remain unknown. In matched biopsies from patients with unilateral BCRL, we observed decreased expression of filaggrin and the tight junction protein zona occludens-1 (ZO-1) in skin affected by moderate lymphedema, or by subclinical lymphedema in which dermal backflow of lymph was identified by indocyanine green lymphography, relative to controls (areas without backflow and from the unaffected arm). In vitro stimulation of keratinocytes with lymph fluid obtained from patients undergoing lymphedema surgery led to the same changes, as well as increased expression of keratin 14, a marker of immature keratinocytes. Finally, using mouse models of lymphedema, we showed that like the clinical scenario, the expression of skin barrier proteins was decreased relative to normal skin and that colonization with S. epidermidis bacteria amplified this effect, as well as lymphedema severity. Taken together, our findings suggest that lymphatic fluid stasis contributes to skin barrier dysfunction in lymphedema.

Background. Cellulitis, resulting from impaired lymphatic function, is a debilitating complication of breast cancer-related lymphedema (BCRL) that contributes to lymphedema progression. However, the clinical presentation and microbiologic profile of BCRL-associated cellulitis remain poorly defined. This study investigated the prevalence, clinical features, and treatment outcomes of cellulitis in BCRL, aiming to identify risk factors for recurrence and inform evidence-based treatment strategies. Methods. A retrospective review was conducted of cellulitis episodes among 2920 patients with BCRL treated at a single institution between 2000 and 2024. Demographic, clinical, microbiologic, and treatment data were analyzed. Univariate and multivariable Cox proportional hazards models were used to evaluate risk factors associated with recurrent cellulitis. Results. A total of 418 cellulitis episodes were documented among 231 patients with BCRL, indicating a prevalence of 7.9% (231/2920) and a recurrence rate of 39.0% (90/231). Blood cultures were obtained in 255 (61.7%) episodes, of which 33 (12.9%) were positive. Streptococcus agalactiae was the most frequently isolated pathogen (8/33; 24.2%). Risk factors independently associated with recurrence included any radiotherapy (hazard ratio [HR] 2.15; 95% confidence interval [CI] 1.24-3.72; P < 0.01), axillary lymph node dissection (HR 1.96; 95% CI 1.05-3.68; P < 0.05), and shorter time from BCRL diagnosis to the initial cellulitis episode (HR 0.99; 95% CI 0.99-0.99; P < 0.01). Conclusions. Cellulitis is a significant complication of BCRL with a high recurrence rate. Radiotherapy, axillary lymph node dissection, and early cellulitis onset are associated with recurrence. These findings support proactive surveillance and risk-stratified prevention strategies to reduce infection burden and improve outcomes in this high-risk population.

OBJECTIVE:To empirically determine a normative, distribution-based threshold for diagnosing breast cancer-related lymphedema (BCRL) and compare its diagnostic accuracy with the conventional 10% interlimb volume difference criterion. SUMMARY BACKGROUND DATA:BCRL is a common and morbid sequela of breast cancer treatment; however, diagnostic thresholds remain inconsistent and inadequately validated. The widely used threshold of ≥10% interlimb volume difference may miss clinically relevant cases. METHODS:This prospective cohort study analyzed preoperative bilateral limb measurements in 858 female breast cancer patients undergoing axillary surgery to derive a normative, distribution-based interlimb volume difference threshold. A threshold corresponding to 2 standard deviations (SD) above the mean (7.5%) was identified. Diagnostic performance of this proposed threshold was then compared with the conventional 10% cutoff in a subgroup of 167 patients who underwent axillary lymph node dissection (ALND) with up to 36 months of postoperative follow-up. RESULTS:Among 858 patients (median [IQR] age, 48 [40-56] years; median BMI, 25.5 [22.3-30.0] kg/m²), preoperative interlimb volume differences were normally distributed (mean, 0.24%; SD, 3.74%), supporting a proposed diagnostic threshold of 7.5%. In the 167 patients who underwent ALND, 72 (43.1%) met the ≥7.5% threshold versus 53 (31.7%) meeting the 10% threshold, yielding 19 additional diagnoses (+11.4%; P<0.001). Of those meeting the 7.5% threshold, 94.4% (68/72) reported symptoms and/or used compression garments. CONCLUSIONS:A normative, distribution-based threshold of 7.5% interlimb volume difference improves the identification of clinically meaningful BCRL compared with the traditional 10% cutoff. Adopting this empirically validated threshold may enhance early detection, intervention, and patient outcomes.

Randomized trials established the safety of postmastectomy radiation/regional nodal irradiation (PMRT) as an alternative to axillary lymph node dissection (ALND) for cN0 patients undergoing upfront mastectomy with one or two positive sentinel lymph nodes (+SLNs). In January 2022, the authors adopted a policy omitting routine frozen section for cT1-3N0 patients undergoing upfront mastectomy, and this study sought to examine the impact of this policy on axillary treatment. Consecutive patients with cT1-3N0 breast cancer who underwent upfront mastectomy from January 2022 to July 2023 were identified. For patients with three or more +SLNs and those with one or two +SLNs not meeting institutional PMRT criteria, ALND was indicated. This study evaluated ALND/PMRT rates after adoption of this policy. In this study, 623 patients with cT1-3N0 breast cancer had upfront mastectomy with sentinel lymph node biopsy. Overall, 4.7

The use of neoadjuvant chemotherapy (NAC) in cT1N0 patients with triple-negative (TN) or HER2-positive (HER2+) breast cancer has been controversial. It is unclear whether NAC or upfront surgery minimizes axillary dissection (ALND) risk in the contemporary cT1N0 TN/HER2+ patient population. Consecutive cT1N0 TN/HER2+ patients who received NAC or underwent upfront surgery at our institution between 01/2020–12/2022 were examined. ALND was indicated for any positive sentinel nodes (+SLNs) after NAC, ≥ 3 positive SLNs after upfront surgery, or 1–2 positive SLNs after upfront mastectomy not requiring radiotherapy (RT). Clinicopathologic features, nodal burden, and ALND rates were compared between NAC versus upfront surgery cohorts. Among 506 patients, 43

BACKGROUND:Chronic inflammatory responses initiated by lymphatic injury play a key role in the pathophysiology of secondary lymphedema; however, it is unknown if these responses vary by race/ethnicity. We assessed whether baseline differences in inflammation, characterized by crown-like structures of the breast (CLS-B), contributed to lymphedema risk in a diverse cohort of patients treated with axillary lymph node dissection (ALND). METHODS:Between 11/2016-03/2020, patients undergoing ALND were enrolled in a prospective lymphedema screening study. Race/ethnicity were self-reported. BMI and volumetric arm measurements were performed at baseline and biannually. Breast tissue was assessed for CLS-B utilizing a CD-68 IHC stain in non-tumor tissue. Lymphedema incidence was assessed using competing-risk analysis and compared between patients with and without CLS-B. RESULTS:Of 281 patients included, 11% self-identified as Asian, 20% Black, 8% Hispanic, 58% White, and 3% unknown. Median BMI was 26.3kg/m2; median follow-up was 2.99 years. Overall, 54% had CLS-B; prevalence varied by BMI (36% [BMI < 25], 63% [BMI 25-30], 70% [BMI > 30], p < 0.001) and by race/ethnicity (68% Black/64% Hispanic vs. 59% Asian/46% White, p = 0.02). The 2-year lymphedema rate was higher among Black and Hispanic women (32% Black/27% Hispanic versus 15% Asian/17% White, p = .012), and among women with CLS-B (27% vs. 12% [no CLS-B], p = 0.03). On multivariable analysis, Black race (p = 0.009), neoadjuvant chemotherapy receipt (p = 0.024), and older age (p = 0.002) were independently associated with lymphedema development, while CLS-B was not (p = 0.3). CONCLUSION:The higher CLS-B prevalence observed in Black women suggests an increased propensity for inflammation, although its role in lymphedema development remains uncertain.