Omission of axillary lymph node dissection in breast cancer patients with micrometastasis or isolated tumor cells in sentinel lymph nodes: a 12-year experience in a tertiary breast unit.

INTRODUCTION: After the IBCSG 23-01 trial, our breast center no longer performed axillary lymph node dissection (ALND) after detection of isolated tumor cells (ITC) or micrometastasis in the sentinel lymph nodes (SLN). A recent study suggested that up to half of the patients with micrometastasis in the SLN could benefit from ALND in terms of disease-free survival (DFS) and overall survival (OS). METHODS: This retrospective, unicentric, study analyzed 261 consecutive cT1-3 cN0 breast cancer patients with ITC or micrometastasis in their SLN. Primary objective was comparison of ALND vs. SLN biopsy (SLNB) with regard to DFS and OS. Secondary objectives included analysis of factors associated with an increased rate of locoregional recurrence (LRR), distant metastasis (DM) and metachronous contralateral breast cancer (MCBC). RESULTS: DFS events occurred in 19 patients (7.3%) and 14 patients died (5.4%). Median follow-up time was 78 months. 251 patients (96.2%) had micrometastasis in their SLN. There was no difference in the OS or DFS of ALND vs. SLNB patients. History of previous contralateral breast cancer and WBI were associated with an increased and decreased rate of LRR, respectively. Larger tumor size was associated with an increased rate of DM. Non-ductal histological types were associated with an increased rate of MCBC. DISCUSSION: Avoiding ALND may be safe in pN1mi/pN0(i+) patients. Besides, we strongly encourage clinicians to develop their own follow-up protocols based on the best available evidence, to rapidly identify and treat breast cancer recurrence.

Total Tumor Load to assist in the decision for additional axillary surgery in the positive sentinel node breast cancer patients.

The Total Tumor Load (TTL) concept has been demonstrated to accurately predict the status of the non-sentinel lymph nodes (NSLN) in breast cancer patients. In 2019, our center implemented the TTL cut-off of 30,000 CK19 mRNA copies/µL as sole criterion for deciding on performing ALND. This retrospective, unicentric, study analyzed 87 cT1-3N0 breast cancer patients treated consecutively in a period of two years and aimed to evaluate the performance of this criterion. Secondary objectives included the comparison of the criterion versus our previous Clinical Decision Rule (CDR) versus ACOSOG Z0011 criteria for avoiding an ALND in proportion of patients spared an ALND and in proportion of patients left with a surgically untreated metastasized axilla. An interim analysis revealed new TTL cut-offs for deciding on performing an ALND. The 30,000 CK19 mRNA copies/µL criterion yielded an area under the ROC Curve (AUC) of 0.849, a false positive (FP) rate of 30.1% and a positive predictive value (PPV) of 38.9%. The 30,000 CK19 mRNA copies/µL criterion spared 58.6% of the patients an ALND versus 41.4% with CDR versus 73.6% with Z0011 and left 0.0% patients with a surgically untreated metastasized axilla versus 21.4% with CDR versus 42.9% with Z0011. The new TTL cut-off of 260,000 CK19 mRNA copies/µL for deciding on an ALND yielded an AUC of 0.753, a FP rate of 13.7% and a PPV of 47.4%. This new criterion spared 78.2% of the study sample an ALND and left 35.7% of metastasized axillae surgically untreated. This study emphasizes the need to find a new balance between locoregional control and the morbidity associated with Berg levels I + II axillary lymph node dissection.

Factores predictivos de alta carga residual ganglionar axilar post biopsia de ganglio centinela positiva / Predictive factors of high residual burden in axillary lymph node after positive sentinel node biopsy

El estado axilar es un factor pronóstico para los estadios tempranos de cáncer de mama. Existen factores que podrían predecir riesgo de mayor enfermedad axilar. El objetivo es determinar cuáles son los factores predictivos independientes de alta carga residual ganglionar axilar (4 o más GNC comprometidos) luego de la BGC positiva. Estudio analítico, observacional, cohorte retrospectiva de pacientes con tumores T1-2, axila clínicamente negativa, a las que se les realizó cirugía conservadora (CC) y BGC con resultado positivo (marco o micrometástasis) y se les realizó posterior linfadenectomía axilar (LA). Del total de 325 pacientes, 96 tuvieron resultado positivo para metástasis en el ganglio centinela (29,5%) y también se les realizó LA. Se dividió a la población seleccionada en dos grupos según el compromiso de los GNC: baja carga axilar 0-3 GNC positivos, y alta carga axilar 4 o más GNC positivos. Se observaron como factores que demostraron mayor riesgo para alta carga axilar ganglionar residual al grado histológico, ki-67 y la invasión extracapsular en el GC; pero solamente la invasión extracapsular en el GC demostró ser significativa en el análisis multivariado. Probablemente con un mayor número de pacientes otras variables pudieran haber resultado factores de riesgo independiente

Axillary status is a prognostic factor for early stages of breast cáncer. There are predictive factors that might indicate the risk of greater axilary disease. The aim is to determine which are the independent predictive factor sor a high residual axillary nodal burden (four or more non-sentinel lymph nodes involved) after a positive sentinel node biopsy. Retrospective cohort analytic observational study of patients with T1-2 tumors, negative axilla, who underwent breast conserving surgery and sentinel node biopsy with a positive result (macro ­ or micro-metastasis) and later underwent lymph node dissection. Out of the total 325 patients, 96 got a positive result for metástasis in the sentinel lymph node (29.5%) and also underwent lymph node dissection. The selected population was divided into two groups according to the involvement of NSLNs: low axillary burden: 0-3 NSLNs, and high axillary burden: 4 or more positive NSLNs. Among the factors found to have a higher risk of high residual axillary nodal burden were the histologic grade, Ki-67 and the extracapsular invasión of the SLN, but only the extracapsular invasión of the SLN was found to be significant in the multivariate analysis. It is likely that with a higher number of patients, other variables might have been independent risk factors

Sentinel node total tumour load as a predictive factor for non-sentinel node status in early breast cancer patients - The porttle study.

OSNA is a molecular assay for the detection of sentinel node metastasis. TTL emerged as a concept that seems to accurately predict the status of the NSN. Authors tried to confirm this motion. This is a retrospective and multicentric study that analyzed 2164 patients, 579 of whom had positive SN and completion AD. Logistic regression models were performed in order to identify a suitable cutoff to identify patients who benefit from AD. Univariate and multivariate regression analysis showed a relationship between TTL>30000 and the presence of NSN metastasis (OR 2.84, CI 1.99-4.08, p < 0.001). Logistic regression indicated that the cutoff of 30000 copies/µL better discriminates patients with NSN positivity and allows wide use of these criteria. This cutoff value may safely assist clinicians and patients to decide to proceed or not with an AD.

Determinants for non-sentinel node metastases in primary invasive breast cancer: a population-based cohort study of 602 consecutive patients with sentinel node metastases.

BACKGROUND: Sentinel node biopsy (SNB) is the standard procedure for axillary staging in patients with clinically lymph node negative invasive breast cancer. Completion axillary lymph node dissection (c-ALND) may not be necessary for all patients as a significant number of patients have no further metastases in non-sentinel nodes (non-SN) and c-ALND may not improve survival. The first aim of our study is to identify clinicopathological determinants associated with non-SN metastases. The second aim is to determine the impact of the number of sentinel node (SN) with macro-metastases and the type of SN metastases on metastatic involvement in non-SN. METHODS: This is a retrospective study of 602 patients with primary invasive breast cancer operated on with SNB and c-ALND in Lund and Malmö during 2008-2013. All these patients had micro- and/or macro-metastases in SNs. Information was retrieved from the national Information Network for Cancer Care (INCA). The risk of metastases to non-SNs were analyzed in relation to clinicopathological determinants such as age, screening mammography, tumour size, tumour type, histological grade, estrogen status, progesterone status, HER2 status, multifocality and lymphovascular invasion. Additionally, we compared the association between the number of the SN and the type of metastases in SN with the risk of metastases to non-SNs. Binary logistic regression was used, yielding odds ratios (OR) with 95% confidence intervals (CI). RESULTS: We found that 211 patients (35%) had metastases in non-SNs and 391 patients (65%) had no metastases in non-SNs. Lobular type (18%) of breast cancer (1.73; 1.0 1-2.97) and multifocal (31.3%) tumours (2.20; 1.41-3.44) had a high risk of non-SNs metastases. As compared to only micro-metastases, the presence of macro-metastases in SNs was associated with a high risk of metastases to non-SNs (4.91; 3.01-8.05). The number of SN with macro-metastases, regardless of the number of SNs removed by surgery, increases the risk of finding non-SNs with metastases. The total number of SN removed by surgery had no impact on diagnosis of metastases in non-SNs. No statistically significant associations were observed regarding other studied determinants. CONCLUSION: We conclude in the present study that lobular cancer and multifocal tumours were associated with a high risk of non-SN involvement. The presence of the macro-metastases in SNs and the number of SN with macro-metastases has a positive association with presence of metastases in non-SNs. The total number of SNs removed by surgery had no impact on finding metastases in non-SNs. These factors may be valuable considering whether or not to omit c-ALND.

The impact of low volume lymph node metastases and stage migration after pathologic ultrastaging of non-sentinel lymph nodes in early-stage cervical cancer: a study of 54 patients with 4.2 years of follow up.

OBJECTIVES: To assess the significance of pathologic ultrastaging (PU) of sentinel (SLN) and non-sentinel (nSLN) lymph nodes (LNs) and the influence on cancer staging in patients with International Federation of Gynecology and Obstetrics (FIGO) stage IA2-IB1 cervical cancer. MATERIAL AND METHODS: A retrospective study was conducted with 54 patients divided into two equal-sized groups. In test group (n1), at least one SLN/patient was detected with blue dye. All excised LNs in this group were subjected to PU (4 µm slices/150 µm intervals) with hematoxylin-eosin staining and immunohistochemistry (AE1-AE3 antibodies). In none of the control group (n2) was PU performed, but in 2 patients SLN concept was performed. Patients in both groups underwent radical hysterectomy and lymphadenectomy. The effect of PU was expressed in puTNM and compared with both standard pTNM and FIGO systems. The influence of PU on patients' disease-free survival (DFS) and overall survival (OS) was assessed using Kaplan-Meier curves. RESULTS: In total, 516 LNs were extracted (66 SLNs, 36% bilaterally). Micrometastases (MIC) or isolated tumor cells (ITC) were detected in 34 of the 482 LNs (7.1%), including 16 MICs and 9 ITC in non-SLNs. False negative rates were: 3.7%/side-specific, and 7.4%/both sides. The use of PU resulted in stage change in 2 cases (N and M status change), FIGO stage did not changed. No PU impact on DFS or OS was observed. CONCLUSIONS: The risk of TNM stage migration in early cervical cancer is low, is more likely in inattentively evaluated patients, and has indeterminate prognostic and predictive value. Selection of cases with cT ≤ 2 cm and cN0 is sufficient to avoid the risk of improper staging.

Application of artificial neural networks for predicting presence of non-sentinel lymph node metastases in breast cancer patients with positive sentinel lymph node biopsies.

INTRODUCTION: The aim of this study was to present a new predictive tool for non-sentinel lymph node (nSLN) metastases. MATERIAL AND METHODS: One thousand five hundred eighty-three patients with early-stage breast cancer were subjected to sentinel lymph node biopsy (SLNB) between 2004 and 2012. Metastatic SLNs were found in 348 patients - the retrospective group. Selective axillary lymph node dissection (ALND) was performed in 94% of cases. Involvement of the nSLNs was identified in 32.1% of patients following ALND. The correlation between nSLN involvement and selected epidemiological data, primary tumor features and details of the diagnostic and therapeutic management was examined in metastatic SLN group. Multivariate analysis was performed using an artificial neural network to create a new nomogram. The new test was validated using the overall study population consisting of the prospective group (365 patients - SLNB between 01-07.2013). RESULTS: Accuracy of the new test was calculated using area under the receiver operating characteristics curve (AUC). We obtained AUC coefficient equal to 0.87 (95% confidence interval: 0.81-0.92). Sensitivity amounted to 69%, specificity to 86%, accuracy - 80% (retrospective group) and 77%, 46%, 66% (validation group), respectively. The Memorial Sloan-Kettering Cancer Center (MSKCC) nomogram the calculated AUC value was 0.71, for Stanford - 0.68, for Tenon - 0.67. CONCLUSIONS: In the analyzed group only the MSKCC nomogram and the new model showed AUC values exceeding the expected level of 0.70. Our nomogram performs well in prospective validation on patient series. The overall assessment of clinical usefulness of this test will be possible after testing it on different patient populations.

Factors Influencing Non-sentinel Node Metastasis in Patients with Macrometastatic Sentinel Lymph Node Involvement and Validation of Three Commonly Used Nomograms.

OBJECTIVE: Omitting axillary lymph node dissection (ALND) in a subgroup of patients with sentinel lymph node (SLN) metastasis is becoming a widely accepted practice. Avoiding the well-known complications of ALND is the sole aim without compromising the curative intention of surgery. MATERIALS AND METHODS: The data were probed for breast cancer patients that were operated on between February 2014 and June 2016. SLN biopsies were performed in 507 patients and out of 157 patients who underwent ALND for a metastatic SLN, 151 were found eligible for the analyses as having macrometastatic (>2mm) SLN. MD Anderson, Memorial Sloan Kettering Cancer Center and Helsinki nomograms were also tested in our patient population. RESULTS: Pathologic tumor size greater than 2 cm, the ratio of metastatic SLN to dissected SLN, metastatic tumor greater than 1 cm and tumors that extended outside the SLN's capsule were found to be associated with non-sentinel node metastasis in both univariate and multivariate tests. MD Anderson nomogram performed well with an area under the curve (AUC) value of 0.72. CONCLUSION: Our results suggest that ALND should be considered in patients with macrometastatic SLN greater than 10 mm in size, have extracapsular extension, have metastatic SLNs at a rate of more than 50% and whose primary tumor is greater than 2 cm.

A prediction tool incorporating the biomarker S-100B for patient selection for completion lymph node dissection in stage III melanoma.

INTRODUCTION: Completion lymph node dissection (CLND) in sentinel node (SN)-positive melanoma patients is accompanied with morbidity, while about 80% yield no additional metastases in non-sentinel nodes (NSNs). A prediction tool for NSN involvement could be of assistance in patient selection for CLND. This study investigated which parameters predict NSN-positivity, and whether the biomarker S-100B improves the accuracy of a prediction model. METHODS: Recorded clinicopathologic factors were tested for their association with NSN-positivity in 110 SN-positive patients who underwent CLND. A prediction model was developed with multivariable logistic regression, incorporating all predictive factors. Five models were compared for their predictive power by calculating the Area Under the Curve (AUC). A weighted risk score, 'S-100B Non-Sentinel Node Risk Score' (SN-SNORS), was derived for the model with the highest AUC. Besides, a nomogram was developed as visual representation. RESULTS: NSN-positivity was present in 24 (21.8%) patients. Sex, ulceration, number of harvested SNs, number of positive SNs, and S-100B value were independently associated with NSN-positivity. The AUC for the model including all these factors was 0.78 (95%CI 0.69-0.88). SN-SNORS was the sum of scores for the five parameters. Scores of ≤9.5, 10-11.5, and ≥12 were associated with low (0%), intermediate (21.0%) and high (43.2%) risk of NSN involvement. CONCLUSIONS: A prediction tool based on five parameters, including the biomarker S-100B, showed accurate risk stratification for NSN-involvement in SN-positive melanoma patients. If validated in future studies, this tool could help to identify patients with low risk for NSN-involvement.

Factores predictivos histológicos e inmunohistoquimícos de metástasis en ganglio no centinela en pacientes con cáncer de mama y ganglio centinela positivo / Histological and histochemical predicting factors of increased risk of metastatic compromise of non sentinel nodes, in patients with positive sentinel node biopsy

Introducción La biopsia del ganglio centinela (bgc) permite estadificar la axila en pacientes con cáncer de mama (cm) y axila clínicamente negativa. Mediante este procedimiento, se evita la linfadenectomía axilar en una proporción de pacientes. Sin embargo, frente a la positividad del ganglio centinela, una vez completada la linfadenectomía, un subgrupo de pacientes no tienen enfermedad residual en el resto de los ganglios axilares, definidos como ganglios no centinela. Objetivo Analizar los factores de predicción histológicos e inmunohistoquímicos de compromiso en ganglios no centinelas (gnc) en aquellas pacientes con bgc positiva seguida de linfadenectomía axilar, operadas por el Servicio de Patología Mamaria del Hospital Fernández en el período que transcurre entre enero de 1998 y marzo de 2016. Material y método Se realizaron 712 bgc entre los meses de enero de 1998 y marzo de 2016, en el Servicio de Patología Mamaria del Hospital Fernández. Del total, 140 resultaron positivas. Se analizó retrospectivamente la vinculación entre diversas características y la existencia de enfermedad axilar en gnc en 119 casos. Resultados Cuando la bgc resultó positiva, se encontró enfermedad en gnc en el 53,8% de los casos. El análisis univariable demostró correlación estadísticamente significativa entre presencia de metástasis en gnc y la presencia de 2 o más gc positivos, el tamaño tumoral mayor a 2 cm, el compromiso por macrometástasis del gc, la presencia del receptor her2 en el tumor y el alto grado mitótico y el compromiso de la cápsula ganglionar. Conclusiones Los factores independientes de compromiso de gnc son los siguientes: el alto grado mitótico, la presencia del receptor her2, la existencia de 2 o más gc positivos, el compromiso de la cápsula ganglionar.

Introduction The sentinel node biopsy can stage breast cancer patients with negative axillary lymph node examination. Using this procedure it is possible to avoid axillary lymph node dissection in some patients. However, when sentinel node biopsy results positive, once achieved the axillary node dissection, some patients do not have residual disease in the non sentinel nodes. Objective To study histological and histochemical predicting factors of increased risk of metastatic compromise of non sentinel nodes, in patients with positive sentinel node biopsy and subsequent axillary lymph node dissection, treated in the Breast Disease Division of Hospital Fernandez between January 1998 and March 2016. Materials and method Between January 1998 and March 2016, 712 patients underwent to node sentinel biopsy in the Breast Disease Division of Hospital Fernández. This study assessed, in a retrospective way, the association between the histological and histochemical predicting factors and non sentinel node disease in 119 cases. Results When sentinel node biopsy was positive, there was non sentinel lymph node metastasis in 53,8% of cases. The following variables were found to be potentially associated with non-sentinel node metastases in the univariated analysis: number of positive sentinel lymph node, size of the tumor, size of the metastasis in the sentinel lymph node, presence of her2 receptor in the tumor, high mitotic rate and extracapsular perinodal spread. Conclusions Independent factors for involvement of non sentinel nodes are: the high mitotic rate, the presence of her2 receptor in the tumor, the number of positive sentinel lymph nodes and the extracapsular perinodal spread.

Elaboration of a nomogram to predict nonsentinel node status in breast cancer patients with positive sentinel node, intraoperatively assessed with one step nucleic amplification: Retrospective and validation phase.

BACKGROUND: Tumor-positive sentinel lymph node (SLN) biopsy results in a risk of non sentinel node metastases in micro- and macro-metastases ranging from 20 to 50%, respectively. Therefore, most patients underwent unnecessary axillary lymph node dissections. We have previously developed a mathematical model for predicting patient-specific risk of non sentinel node (NSN) metastases based on 2460 patients. The study reports the results of the validation phase where a total of 1945 patients were enrolled, aimed at identifying a tool that gives the possibility to the surgeon to choose intraoperatively whether to perform or not axillary lymph node dissection (ALND). METHODS: The following parameters were recorded: Clinical: hospital, age, medical record number; Bio pathological: Tumor (T) size stratified in quartiles, grading (G), histologic type, lymphatic/vascular invasion (LVI), ER-PR status, Ki 67, molecular classification (Luminal A, Luminal B, HER-2 Like, Triple negative); Sentinel and non-sentinel node related: Number of NSNs removed, number of positive NSNs, cytokeratin 19 (CK19) mRNA copy number of positive sentinel nodes stratified in quartiles. A total of 1945 patients were included in the database. All patient data were provided by the authors of this paper. RESULTS: The discrimination of the model quantified with the area under the receiver operating characteristics (ROC) curve (AUC), was 0.65 and 0.71 in the validation and retrospective phase, respectively. The calibration determines the distance between predicted outcome and actual outcome. The mean difference between predicted/observed was 2.3 and 6.3% in the retrospective and in the validation phase, respectively. The two values are quite similar and as a result we can conclude that the nomogram effectiveness was validated. Moreover, the ROC curve identified in the risk category of 31% of positive NSNs, the best compromise between false negative and positive rates i.e. when ALND is unnecessary (<31%) or recommended (>31%). CONCLUSIONS: The results of the study confirm that OSNA nomogram may help surgeons make an intraoperative decision on whether to perform ALND or not in case of positive sentinel nodes, and the patient to accept this decision based on a reliable estimation on the true percentage of NSN involvement. The use of this nomogram achieves two main gools: 1) the choice of the right treatment during the operation, 2) to avoid for the patient a second surgery procedure.

Predictive Factors for Non-Sentinel Lymph Node Metastasis in Patients With Clinically Node-Negative Ipsilateral Multiple Breast Cancer Treated With Total Mastectomy.

BACKGROUND: Recent clinical trials have shown that axillary lymph node dissection can be omitted even with positive sentinel nodes (SN) unless the patient undergoes total mastectomy without irradiation. The aim of our study was to identify predictive factors for non-SN metastasis among patients with solitary or multiple breast cancer treated with total mastectomy. PATIENTS AND METHODS: Clinically node-negative breast cancer patients with pathologically node-positive disease treated with total mastectomy and axillary dissection after SN biopsy were retrospectively analyzed. Significant pathologic predictive factors for positive non-SN metastasis were also examined. RESULTS: There were 47 multiple and 143 solitary breast cancer patients. Pathologic diagnosis demonstrated that smaller invasion size but larger tumor size, including adjacent noninvasive cancer, was observed in multiple breast cancer. The number of involved SNs and the rate of non-SN metastasis were similar between the multiple and solitary groups. Regarding predictive factors for non-SN metastasis, lymphatic invasion and SN macrometastasis were significant factors in the solitary group, and pathologic invasion size > 2 cm was the only significant factor in the multiple group. CONCLUSION: Larger pathologic invasion size was important for predicting non-SN metastasis in multiple breast cancer.

Factors Influencing Non-sentinel Node Involvement in Sentinel Node Positive Patients and Validation of MSKCC Nomogram in Indian Breast Cancer Population.

Current guidelines recommend completion axillary lymphnode dissection (ALND) when sentinel lymphnode (SLN) contains metastatic tumor deposit. In consequent ALND sentinel node is the only node involved by tumor in 40-70 % of cases. Recent studies demonstrate the oncologic safety of omitting completion ALND in low risk patients. Several nomograms (MSKCC, Stanford, MD Anderson score, Tenon score) had been developed in predicting the likelihood of additional nodes metastatic involvement. We evaluated accuracy of MSKCC nomogram and other clinicopathologic variables associated with additional lymph node metastasis in our patients. A total of 334 patients with primary breast cancer patients underwent SLN biopsy during the period Jan 2007 to June 2014. Clinicopathologic variables were prospectively collected. Completion ALND was done in 64 patients who had tumor deposit in SLN. The discriminatory accuracy of nomogram was analyzed using Area under Receiver operating characteristic curve (ROC). SLN was the only node involved with tumor in 69 % (44/64) of our patients. Additional lymph node metastasis was seen in 31 % (20/64). On univariate analysis, extracapsular infiltration in sentinel node and multiple sentinel nodes positivity were significantly associated (p < 0.05) with additional lymph node metastasis in the axilla. Area under ROC curve for nomogram was 0.58 suggesting poor performance of the nomogram in predicting NSLN involvement. Sentinel nodes are the only nodes to be involved by tumor in 70 % of the patients. Our findings indicate that multiple sentinel node positivity and extra-capsular invasion in sentinel node significantly predicted the likelihood of additional nodal metastasis. MSKCC nomogram did not reliably predict the involvement of additional nodal metastasis in our study population.

Cross-validation of three predictive tools for non-sentinel node metastases in breast cancer patients with micrometastases or isolated tumor cells in the sentinel node.

BACKGROUND: We cross-validated three existing models for the prediction of non-sentinel node metastases in patients with micrometastases or isolated tumor cells (ITC) in the sentinel node, developed in Danish and Finnish cohorts of breast cancer patients, to find the best model to identify patients who might benefit from further axillary treatment. MATERIAL AND METHOD: Based on 484 Finnish breast cancer patients with micrometastases or ITC in sentinel node a model has been developed for the prediction of non-sentinel node metastases. Likewise, two separate models have been developed in 1577 Danish patients with micrometastases and 304 Danish patients with ITC, respectively. The models were cross-validated in the opposite cohort. RESULTS: The Danish model for micrometatases was accurate when tested in the Finnish cohort, with a slight change in AUC from 0.64 to 0.63. The AUC of the Finnish model decreased from 0.68 to 0.58 when tested in the Danish cohort, and the AUC of the Danish model for ITC decreased from 0.73 to 0.52, when tested in the Finnish cohort. The Danish micrometastatic model identified 14-22% of the patients as high-risk patients with over 30% risk of non-sentinel node metastases while less than 1% was identified by the Finish model. In contrast, the Finish model predicted a much larger proportion of patients being in the low-risk group with less than 10% risk of non-sentinel node metastases. CONCLUSION: The Danish model for micrometastases worked well in predicting high risk of non-sentinel node metastases and was accurate under external validation.