Management strategy of early-stage breast cancer patients with a positive sentinel lymph node: With or without axillary lymph node dissection

Critical Reviews in Oncology/Hematology 79 (2011) 293–301

Management strategy of early-stage breast cancer patients with a positive sentinel lymph node: With or without axillary lymph node dissection Jia-Jian Chen a,b , Jiong Wu a,b,∗ a

Department of Breast Surgery, Cancer Hospital/Cancer Institute, Fudan University, China b Department of Oncology, Shanghai Medical College, Fudan University, China Accepted 25 June 2010

Contents 1. 2.

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Therapeutic benefit of axillary lymph node dissection: a century of controversy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Possible relationship between the nodes examined and local control . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Possible influence of axillary local control on overall survival . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Superiority of sentinel lymph node biopsy, a more accurate staging procedure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Surgical accuracy of SLNB with an acceptable false-negative rate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Pathologic accuracy of SLNB for detection of occult metastases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The definition and clinical significance of a positive sentinel lymph node: possible relationship with non-SLN metastasis . . . . . . . Predictive models for positive non-SLN: the clinical value and limitation of nomograms and scoring systems . . . . . . . . . . . . . . . . . . 5.1. Adoption of mathematical models for predicting the likelihood of non-SLN metastases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Limitations of nomograms and scoring systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Current recommendations and future directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflicts of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abstract Sentinel lymph node biopsy (SLNB) has been generally adopted as an alternative procedure to axillary lymph node dissection (ALND) for node staging. ALND remains the standard management of the axilla when a tumor-positive sentinel lymph node (SLN) is identified. However, further analysis has demonstrated that in 40–70% of cases with metastasis to the axillary lymph nodes, the SLN is the only positive node. Therefore, the traditional recommendation that ALND is always necessary for management of early-stage breast cancer patients with a positive SLN should be re-evaluated. Several nomograms and scoring systems have been developed to calculate the probability of non-SLN involvement on the basis of several clinicopathological variables. However, the actual value of such nomograms or scoring systems in daily clinical practice should be evaluated. This review focuses on the above topics and pushes forward the current heated debate on the management of early-stage breast cancer patients with a positive SLN. © 2010 Elsevier Ireland Ltd. All rights reserved. Keywords: Breast carcinoma; Sentinel lymph node; Node metastasis; Prognosis

1. Introduction ∗

Corresponding author at: Department of Breast Surgery, Cancer Hospital/Cancer Institute, Breast Cancer Institute, Fudan University, 399 Ling-Ling Road, Shanghai 200032, China. Fax: +86 21 64434556. E-mail address: [email protected] (J. Wu). 1040-8428/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.critrevonc.2010.06.008

Breast cancer is becoming the most common malignancy in females worldwide. Axillary lymph node status

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still remains the single most important prognostic factor and forms one of the main determinants of adjuvant systematic treatment in patients with breast cancer [1]. Axillary lymph node dissection (ALND) was a part of the standard approach to breast cancer surgery during the last century [2]. Due to the popularization of screening policies and improvements in diagnostic methods, the incidence of node-involved disease is decreasing [3–5]. Over the last 20 years, sentinel lymph node biopsy (SLNB), defined as removal of the lymph node that first receives the lymphatic flow from the area of the primary tumor [6], was introduced and widely adopted as an alternative procedure to ALND for node staging [7,8]. This procedure, which avoids unnecessary ALND in nodenegative cases, is believed to have the similar loco-regional recurrence and overall survival as the traditional axillary staging technique with an improved quality of life [9–13]. ALND remains the standard management of the axilla when a tumor-positive sentinel lymph node (SLN) is identified. However, further analysis has demonstrated that in 40–70% of cases with metastasis to the axillary lymph nodes, the SLN is the only positive node [14–16]. When the SLN is the only node involved in the axilla, removal of that node alone might accurately stage the disease while achieving regional nodal control. Moreover, the therapeutic value of ALND in the management of early-stage breast cancer is the subject of ongoing debate [17–19]. Therefore, the traditional recommendation [20] that ALND is always necessary for management of early-stage breast cancer patients with a positive SLN should be re-evaluated. Although definitive recommendations cannot be made without the results of several ongoing multicentric randomized clinical trials [21–23], several nomograms [24–26] and scoring systems have already been developed to calculate the probability of non-SLN involvement on the basis of several clinicopathological variables in recent years. The nomograms and scoring systems were applied to identify a subgroup of patients with positive SLNs who have acceptably low probabilities of non-SLN involvements, for whom further axillary surgery is unnecessary. Nevertheless, the decision of whether to perform ALND for a patient with a positive SLN cannot be based on the nomogram score alone without considering multiple individual factors (e.g., patient age, comorbidities, probable systemic adjuvant therapy) [27]. Therefore, the actual value of the nomograms or scoring systems in daily clinical practice should be evaluated. This review focuses on the above topics and pushes forward the current heated debate on the management of early-stage breast cancer patients with a positive SLN.

2. Therapeutic benefit of axillary lymph node dissection: a century of controversy The axilla was recognized as the most common site of metastatic spread of breast cancer in the early 18th century. Halsted proposed [28] the orderly progression of breast can-

cer from the primary tumor to the regional lymphatic system followed by systemic spread, and he advocated the importance of ALND. As lymphatic drainage generally follows an orderly sequence from level I (nodes inferior and lateral to the pectoralis minor muscle) to level II (nodes posterior to the pectoralis minor muscle) and, rarely, to level III (nodes medial to the pectoralis minor and below the clavicle), the National Institutes of Health Consensus Conference [29] recommended examination of the level I and level II axillary lymph nodes as the standard care for patients with invasive breast cancer. Minimizing regional recurrence, maximizing survival, and accurately staging the disease are the main goals of ALND in early-stage breast cancer patients. However, several aspects of this procedure are still under debate. 2.1. Possible relationship between the nodes examined and local control Discussions over many years concerning ALND have not yet resulted in a conclusion about the optimal extent of surgery. Anatomical studies indicate 35–40 nodes present in the axilla [30], which can hardly be completely removed in surgery. Therefore, a truly node-negative axilla cannot be confirmed in practice. However, a negative result is more likely to be truly negative if more nodes can be retrieved [31]. From part of the Danish Breast Cancer Cooperative Group (DBCG) data, Axelsson et al. demonstrated that removal of more than 10 nodes would be accompanied by a lower axillary recurrence rate. After removal of 10–14 nodes, most nodepositive patients were diagnosed [32]. To dissect at least 20 nodes instead of 10–14 might further increase the probability of node positivity by approximately 10%, regardless of tumor size [33]. Fisher et al. [34] indicated a regional recurrence of 0.3% when more than 10 nodes were removed, while the recurrence rates were 12 and 21% when limited nodes were removed and no nodes were harvested, respectively. A minimum of 10 nodes is usually recommended for retrieval and pathological evaluation when ALND is indicated [32]. 2.2. Possible influence of axillary local control on overall survival The standard ALND was established on the Halstedian concept of sequential spread of tumor cells from the primary to the draining lymphatic system and beyond. This was disputed by Fisher et al., who suggested that breast cancer is a systemic disease from its onset, and variations in effective local treatment, such as treatments aimed at removing nodal metastases were unlikely to affect survival substantially [17,35,36]. This view was substantiated by data from the National Surgical and Bowel Project (NSABP) 04 and its recent updates [17,37], which were considered the best evidence that ALND itself serves no survival benefit. However, substantial evidence [38,39] suggests that local control provided by ALND translates into improved survival and

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indicates that the NSABP 04 was not adequately powered to detect a survival advantage with ALND [40]. In a metaanalysis of six trials evaluating standard surgical treatment with or without ALND, an average overall survival benefit of 5.4% was found for ALND [19]. Reports based on data from 70,000 patients from the American Surveillance Epidemiology and End Results (SEER) database support the notion that removal of a large number of regional nodes is important for long-term survival, even when all the nodes are interpreted as pathologically negative [41,42]. Further information was provided by a recent meta-analysis [43], which summarized the information of 42,000 women in 78 randomized treatment comparisons and indicated that improved local control in early-stage breast cancer has little effect on mortality during the first few years, but that it has definite, although moderate, effects by 15 years. For every four local recurrences avoided, one death caused by breast cancer could be avoided. A different suggestion based on the theory that nodal negativity might indicate a protective mechanism [34], proposed by Camp et al. [44], was that removal of more than 20 uninvolved lymph nodes reduces the axillary recurrence rate but is associated with poor survival. However, this could not be confirmed in other studies. On the contrary, Vinh-Hung et al. [45] proposed that even when the number of involved nodes is already large, each additional involved node increases the relative mortality hazard by at least 1.3%. The survival benefit of ALND associated with the total number of nodes examined or the number of uninvolved nodes could be translated into the elevated accuracy of staging. In conclusion, ALND serves more as a staging than as a therapeutic procedure, supporting the further clinical application of SLNB, a more accurate axillary staging procedure.

3. Superiority of sentinel lymph node biopsy, a more accurate staging procedure In recent years, SLNB has emerged as an alternative to conventional ALND for evaluation of axillary lymph node status that can significantly lower the risk of operative morbidity, a finding supported by several randomized prospective clinical trials [10,12]. SLNB is a staging procedure rather than a therapeutic intervention, and its utility mainly depends on surgical and pathologic accuracy, with a low false-negative rate in both.

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performed with SLNB, recent studies have less frequently presented data regarding SLNB false-negativity. However, a meta-analysis including 11 studies indicated that the falsenegative rate could be controlled to less than 5% [46] and in some studies, the false-negative rate of SLNB could even be approximately 1% with expert-level experience [47]. Performance of SLNB by an experienced surgeon [48] using a combined detection technique [49] with retrieval of more (at best, four) SLNs for examination [50–52] might improve accuracy. 3.2. Pathologic accuracy of SLNB for detection of occult metastases Both the number of sections examined and the interval of the sections were determined to be correlated with the probability of detecting occult metastases [53]. However, nodes harvested by ALND can only be bivalved and assessed on each cut face using hematoxylin and eosin (H&E) staining due to the labor- and time-intensive procedure required. SLNB with a limited number of retrieved nodes allows for a more accurate histopathological evaluation, with serial sectioning and immunohistochemistry, and even for further intensive techniques. Recent years, several intraoperative molecular tests, such as the GeneSearchTM breast lymph node assay and one-step nucleic acid amplification (OSNA), have also been developed to detect metastases >0.2 mm in SLNs. However, there still exist several limitations for the extended application in clinical practice of these products. A review of the literature indicated that 7–33% of patients with nodenegative breast cancer determined by routine histopathology were found to have occult metastases when serial sectioning was employed [54]. In addition the application of immunohistochemistry (IHC) using antibodies to cytokeratin further increased the yield of micrometastases. The combination of serial sectioning and IHC provides an upstaging of nodal status that reaches 29% in retrospective series [55,56] and may be necessary to detect micrometastatic foci [57]. Therefore, patients with negative SLNs represent a more selective group of patients who are truly node-negative. Accordingly, Langer et al. suggested that the observed survival benefit of SLNB compared with ALND was mainly due to the improved accuracy of staging methods [58].

3.1. Surgical accuracy of SLNB with an acceptable false-negative rate

4. The definition and clinical significance of a positive sentinel lymph node: possible relationship with non-SLN metastasis

The American Society of Clinical Oncology (ASCO) guidelines [8] recommended that SLNB be performed by an experienced surgeon, and that the false-negative rate (FNR) be less than 5%, as false-negative results might understage the disease, leading to a clinically relevant loco-regional relapse and potential distant metastases. Because the false-negative rate of SLNB can be calculated only when ALND is routinely

The application of SLNB resulted in a reclassification of pathologic nodal staging. The 7th edition of American Joint Committee on Cancer (AJCC) staging manual [59], reflecting the new ability to detect increasingly small tumor deposits, included a definition for micrometastases detected by H&E staining or by IHC only (pN1mi): greater than 0.2 mm and/or more than 200 cells, but not larger than 2.0 mm in diam-

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eter. Cases in which at least one micrometastasis but no macrometastases are detected, regardless of the number of involved nodes, are classified as pN1mi. Isolated tumor cells (ITC), according to the staging manual, are defined as small clusters of cells ≤0.2 mm, or non-confluent, or nearly confluent clusters of cells ≤200 cells, usually detected only by IHC or molecular analysis. The clinical implication of such smaller tumor deposits is largely unknown, and much controversy still exists as to what size of metastatic foci should be considered positive [60]. However, the majority of studies classify ITCs as node-negative (pN0[i+]) in the expectation that such patients be treated in the same manner as nodenegative patients (pN0). Risk for further involvement of non-SLNs in SLN-positive cases is partially associated with the size of SLN metastases [61,62]. As much as 50% of cases with SLN macrometastases have further non-SLN metastases [63]. The weighted mean estimate for the incidence of non-SLN metastases after low-volume SLN involvement (micrometastasis or smaller) is around 20%, whereas this incidence is around 9% if the SLN involvement is detected by IHC alone. Another systematic review [64] reported a wide range of non-SLN involvement, from 0 to 27%, associated with ITC in SLNs, with an overall pooled risk for such involvement of 12.3%; 63.5% of these non-SLN metastases were macrometastases.

5. Predictive models for positive non-SLN: the clinical value and limitation of nomograms and scoring systems It would be helpful to determine factors associated with non-SLN negativity or positivity and therefore recognize the patients with a positive SLN who are at the lowest risk of non-SLN involvement. Multiple studies indicate that several parameters are predictive of non-SLN positivity in breast cancer, including tumor-related characteristics (tumor type, invasive tumor size, lymphovascular invasion, multifocality, estrogen receptor status), and node-related characteristics (detection method, size of metastatic foci, presence of extracapsular spread, number and proportion of positive SLNs). Because the SLN is the only positive node in around 40–70% of cases, the management of patients with a positive SLN has been reconsidered; there is great interest in the development of predictive tools to select patients believed to be overtreated with ALND. 5.1. Adoption of mathematical models for predicting the likelihood of non-SLN metastases Several studies have concentrated on finding a combination of predictive parameters to establish a mathematical model that can identify patients with a positive SLN for whom routine ALND could be safely avoided. The most well-known mathematical models include the Memorial Sloan-Kettering Cancer Center (MSKCC, NY, USA, 2003) nomogram [24],

the M.D. Anderson Cancer Center scoring system (TX, USA, 2003) [65], the Tenon scoring system (Paris, France) [26], the Cambridge scoring system (London, UK, 2008) [66], and the Stanford scoring system (CA, USA, 2008) [67]. The nomogram from MSKCC is the best-validated mathematical model and was created using the pathological size, type, nuclear grade, lymphovascular invasion (LVI), multifocality and estrogen receptor status of the primary tumor, as well as the method of detecting SLN metastases, the number of positive SLNs and the number of negative SLNs. The MSKCC nomogram was developed with a cohort of 702 patients and subsequently validated with another subset of 373 patients, and is available online (www.mskcc.org/mskcc/ applications/nomograms v2/BreastNonSLN.aspx) in the form of a simple calculator. A more comprehensive tool, the receiver operating characteristic (ROC) curve, was applied to measure the performance of the MSKCC nomogram and indicated an area under the curve (AUC) of 0.77. The AUC values ranged from 0.68 [66] to 0.78 [68] in the validation studies with a case volume of over 100 patients; thus the MSKCC nomogram is regarded as the most valuable current predictive tool for non-SLN metastases. The M.D. Anderson scoring system, based on a retrospective evaluation of clinicopathological data from 131 patients with a positive SLN who underwent ALND, introduced a β coefficient to four parameters that independently and significantly predict non-SLN metastases. The parameters are scored (tumor size > 2 mm = 1, number of SLNs examined ≥3 = −2, largest SLN metastases > 2 mm = 2, presence of LVI = 1, and a score of 0 for the relevant parameter when one of these factors is absent). The scores for all parameters are summed to produce a total score for each patient, ranging from −2 to 4. It was found [65] that none of the patients with a score of ≤0 had additional positive non-SLNs identified by ALND. A third model, the Tenon scoring system, was introduced in 2005 to predict the likelihood of non-SLN metastases in patients with a positive SLN. Its first use involved an analysis of clinicopathological data from 71 SLN-positive patients who underwent ALND. Three parameters are involved and scored as follows: (1) the ratio of positive SLNs to the total number of removed SLNs = 1 (2 points), ≥0.5 (1 point), <0.5 (0 points); (2) macrometastasis in the SLN, presence (2 points), absence (0 points); and (3) tumor size > 20 mm (3 points), > 10 mm (1.5 points), ≤10 mm (0 points). The total score of the Tenon model ranges from 0 to 7, and it was demonstrated that if the patient’s score was <3.5, the probability of additional non-SLN metastases was only 2.7%. The last two models, the Cambridge scoring system and the Stanford scoring system, were published in 2008. The Cambridge scoring system was estimated from a database of 118 SLN-positive patients with subsequent ALND, incorporating three factors: histological grade of the primary tumor, maximum size of the overall SLN metastatic deposit and the proportion of metastatic SLNs. The AUC with the Cambridge scoring system was 0.84, while the AUC was 0.68 when

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applying the MSKCC nomogram to the same data. A superior ability to predict the likelihood of metastatic non-SLNs in SLN-positive patients was indicated using the Cambridge system. The Stanford scoring system was developed from a database of 285 patients with positive SLNs who underwent ALND in conjunction with an online calculation method. It was the first proposed method to emphasize synergistic interactions among patient characteristics. Three approaches, i.e., recursive partitioning with receiver operating characteristic curves (RP-ROC), boosted classification and regression trees (CART), and multivariate logistic regression (MLR) informed by CART, were applied for analysis. Three parameters, i.e., tumor size, lymphovascular invasion and the size of SLN metastases, were found to be significant predictors. When Kohrt et al. [67] applied the Stanford scoring system and MSKCC nomogram to a database of 77 patients who underwent ALND for positive SLNs, the AUC values were 0.74 and 0.62, respectively. 5.2. Limitations of nomograms and scoring systems It would be helpful to be able to predict which patients with a positive SLN should avoid removal of additional non-SLNs. The predictive models appear to provide a useful quantitative estimation of non-SLN metastases for both clinicians and patients when discussing the indication for ALND with SLNpositive patients. However, no models identified a subset of SLN-positive patients without risk of additional non-SLN involvement. Several limitations hamper the further routine clinical application of these predictive models. The first limitation is the lack of a common set of measurements. A meta-analysis [69] of 11 related studies demonstrated that in the presence of any one of five characteristics (SLN metastasis size > 2 mm, presence of extranodal extension in the SLN, tumor size > 2 cm, > 1 positive SLN, or LVI present in the primary tumor), there was a 2-fold increase in the likelihood of finding additional non-SLN metastases. It was suggested that a subgroup of patients theoretically lacking all five of the histopathological characteristics would have a <10% chance of non-SLN metastases. However, none of the predictive models contain all five individual characteristics. All the predictive models were developed from databases of original patient cohorts and could be accurate for prediction of the likelihood of non-SLN metastases in such patients. However, the variation in clinical practice and patient characteristics among institutes may influence the accuracy of predictive models applied to different patient populations, as indicated by the wide range of ROC values in MSKCC nomogram validation studies. Hence, it is highly recommended that predictive models developed at outside institutions be validated with a large local dataset and applied with caution. Also, it has been suggested that the application of more than one predictive model for clinical use in the same patient might have potential benefit. However, the probability of non-SLN metastasis differs among different methods in the

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same patient because the predictive models provide different ranges of predicted probabilities. Application of multiple models may not provide additional clinical benefit but rather create confusion when compared to application of a single, well-validated predictive model. The second limitation of these models is their limited clinical practicality. The predictive model itself provides no actual treatment recommendations. Several authors choose to apply the inherent false-negative rate of SLNB (<5% or <10%) as the acceptable risk when deciding whether to omit ALND in patients with a positive SLN [70,71]. Poirier et al. [72] performed a survey among surgeons in Quebec to determine the predicted non-SLN positivity below which they would not dissect the axilla, indicating that approximately 40% of 82 surgeons accepted a probability of 5% or less, while 17% of the surgeons would never leave an SLN-positive patient without axillary dissection, regardless of the nomogram result. The proportion of patients with low predictive scores is less than 10% [72,73], though they are actually the only patients with predictive probability low enough to benefit from the models. Park et al. [74] observed that MSKCC scores for SLN-positive patients who did not have ALND were significantly lower than for patients who received ALND with a wide range of differences (1–89%). Therefore, the predictive models are not likely to deeply impact the management strategy for SLN-positive patients. The predictive models just serve as additional references for SLN-positive patients in whom, for various reasons, ALND is to be avoided [75], and for surgeons who believe it is safe to omit ALND for SLN-positive patients with low predictive scores. The third limitation of the predictive models is their accuracy. The performance of the predictive models varies with different patient populations and different institutions. However, even for the MSKCC nomogram, the best-validated predictive model, performance is not perfect. Several aspects might affect the accuracy of the nomogram and related models. (1) A large dataset of SLN-positive patients is necessary to establish the nomogram, especially for the subset of patients with low predictive scores, who may be the only ones who can potentially benefit from the models. Most other models did not contain enough patients for effective analysis of this narrowly defined subgroup. Only the MSKCC nomogram involved a cohort of 702 node-positive patients for retrospective evaluation; however, this dataset was also relatively small compared to the number of parameters applied in the nomogram. (2) The nodes retrieved during ALND after identification of a positive SLN were examined by routine pathology only, which risks underestimation of non-SLN metastasis [76,77]. It was recommended that, if possible, the non-SLNs harvested be evaluated by enhanced pathological analysis (e.g., serial sectioning and immunohistochemistry) when developing the models. (3) Several definite parameters were excluded from the univariate or multivariate analysis on the relatively small patient volume. For example, the Tenon and Cambridge models did not include LVI for analysis, while neither extranodal extension nor the size of SLN metasta-

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sis was evaluated in the MSKCC nomogram. (4) Continuous variables, especially the size of SLN metastases, were always treated as ranked variables when developing models. The predictive accuracy of models in cases of SLN micrometastasis is reportedly limited [73,78]. However, patients with SLN micrometastasis only exhibit a low rate of non-SLN involvement, and the models are most needed by these patients and their surgeons for consultation. Houvenaeghel et al. [70] introduced a specific nomogram to predict non-SLN involvement in cases of SLN micrometastasis, but its performance was unsatisfactory, with an AUC of 0.66.

6. Current recommendations and future directions It is widely agreed that SLNB can safely replace the routine application of ALND, and the adoption of SLNB has spared nearly two-thirds of clinically node-negative breast cancer patients from unnecessary ALND. However, the management strategy for the remaining third that have residual nodal involvement is still under debate. A recent retrospective study [79], the MIRROR (Micrometastases and Isolated Tumor Cells: Relevant and Robust or Rubbish?) study in which all hospitals from the Netherlands have participated, suggested that ITCs or micrometastases in regional lymph nodes were associated with a reduced 5-year rate of diseasefree survival among women with favorable early-stage breast cancer who did not receive adjuvant therapy. This study was published in the New England Journal of Medicine, and was regarded as the best evidence for the notion that patients with micrometastases should receive adjuvant systemic therapy such as chemotherapy and/or hormonal therapy. Then should these patients receive a completion level I and II ALND before they receive adjuvant systemic therapy? ALND is the traditional recommendation for these SLNpositive patients and proponents of performing ALND after a positive SLNB argue that the application of ALND might provide additional information to benefit patients by guiding decisions on adjuvant therapy. It is also argued that potential improvement in local-regional control of axilla might translate into overall survival benefit. However, approximately 50% of SLN-positive patients have no non-SLNs involved, so ALND might have no additional therapeutic or diagnostic benefit. In addition, patients with SLN metastases generally receive systemic adjuvant therapy regardless of the presence of any additional nodal metastases. Moreover, several authors have suggested that residual axillary metastases do not always develop local recurrence, even if left untreated [37,80]. A recent retrospective study aiming to examine for node-positive patients who underwent SLNB alone versus SLNB with completion ALND, might provide further information [81]. The author suggested that after a median follow up of 63 months, in 20,075 patients with macroscopic nodal metastases, there was a nonsignificant trend toward better outcomes for completion ALND versus SLNB alone; while in 2203 patients with microscopic nodal metastases, there were

no significant difference in axillary recurrence or survival for patients who underwent SLNB alone versus completion ALND. The additional completion ALND did not appear to improve outcome for patients with microscopic nodal metastases compared with SLNB alone [81]. Taking into account an SLN false-negative rate of 5–10% and an axillary recurrence rate of 0.3%, fewer than 6% of patients with microscopic residual disease will have clinical manifestation [82]. Therefore, there should be a subset of SLN-positive patients in whom ALND may be safely omitted. Several predictive models have been adopted to screen out such a subset of SLN-positive patients who are at a very low risk of non-SLN metastases. However, the published evidence is not strong enough to encourage routine clinical application of these models, even for the wellvalidated nomogram, the MSKCC nomogram. Nevertheless, the MSKCC nomogram out-performed [83] clinicians in predicting non-SLN metastases, and it could provide additional objective information for both surgeons and patients during consultation. For patients with limited risk of additional non-SLN metastases, the application of ALND is less likely to positively impact outcomes and might add to morbidity. Prospective randomized controlled trials will move us closer to a definite answer regarding the management of breast cancer patients with a positive SLN. The American College of Surgeons Oncology Group (ACOSOG) Z0011 trial [84] randomized SLN-positive patients to either complete ALND or no further treatment to evaluate the differences in local recurrence and overall survival between the two groups. The International Breast Cancer Study Group (IBCSG) 23-01 trial [22] similarly randomized patients when SLN was positive for micrometastasis only to determine the prognostic significance of SLN micrometastasis in breast cancer patients. However, these two trials were closed prematurely due to slow accrual. It is also proposed that radiotherapy of the axilla may be an acceptable alternative to ALND for selected patients with positive SLNs; this is being tested in the European Organization for Research and Treatment of Cancer (EORTC) 10981-22023 AMAROS (After Mapping of the Axilla: Radiotherapy or Surgery) trial [21]. Until the results of the pending clinical trials are obtained, surgeons should make an individualized risk–benefit assessment for ALND based on the likelihood of non-SLN metastases. Conflicts of interest The authors declare that they have no conflicts of interest. Reviewers Mann B., Professor, Royal Melbourne Hospital, Department of Surgery, Parkville, Victoria 3050, Australia. Thompson A.M., Professor, Ninewells Hospital, University of Dundee, Dept. Surgery & Molecular Oncology, Dundee, Scotland DD1 9SY, United Kingdom.

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Acknowledgments This review was supported in part by grants from the Research Foundation of Sci-Tech Committee of Shanghai City (No. 54119524), and the “Shu Guang” Project Foundation of Education Committee of Shanghai City (No. 05SG04).

[19]

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Biography Jiong Wu is Professor of Department of Breast Surgery, Cancer Hospital/Institute, Fudan University, Shanghai. He is currently the Secretary of Breast Cancer Prevention and Treatment Group, Disease Prevention and Control Center of Shanghai; the Committee member, Specialty Branch of Breast Cancer, Chinese Anticancer Association; the Executive committee member and secretary, Specialty Branch of Breast Cancer, Chinese Anticancer Association; and Committee member, Specialty Branch of Soft Tissue Tumor, Chinese Anticancer Association. Prof. Wu’s research focuses on the basic and clinical research of breast cancer.