IJC International Journal of Cancer

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1 IJC International Journal of Cancer Sentinel node biopsy performance after neoadjuvant chemotherapy in locally advanced breast cancer: A systematic review and meta-analysis Simone Mocellin, Elena Goldin, Alberto Marchet and Donato Nitti Surgery Branch, Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy The use of sentinel node biopsy (SNB) after neoadjuvant chemotherapy (NAC) in patients with locally advanced breast cancer is debated. Our aim was to quantitatively review the available evidence on the performance of SNB after NAC in patients with locally advanced breast cancer. We performed a systematic review (by searching the PubMed, Cochrane and Scopus databases) and random effects meta-analysis to investigate on the feasibility and accuracy of SNB in these patients. The two outcomes of interest were the sentinel node identification rate (SIR) and the false negative rate (FNR). Sensitivity analysis and meta-regression were used to investigate the potential sources of between-study heterogeneity. We retrieved 72 eligible studies enrolling 7,451 patients. Upon meta-analysis, summary SIR resulted 89.6% [95% confidence interval (CI): ; heterogeneity I 2 : 76.9%], which poorly compares with the 95% SIR observed in some recent series of early breast cancer. The summary FNR resulted 14.2% (CI: ; heterogeneity I 2 : 29.1%), which was significantly higher than the 8 10% reference value. Considering an average post-nac lymph node positivity rate of 50%, the downstaging due to false negative SNB would occur in 7/100 patients (with an excess error rate of 2 3/100 as compared to the early-stage setting). No plausible source of between-study heterogeneity was found. Based on the largest series of studies ever meta-analyzed, our findings highlight the limits of SNB performance in this population, where the impact of SNB on patient survival is still to be defined. Sentinel node biopsy (SNB) has revolutionized the surgical approach to axillary lymph nodes in patients with early breast cancer, 1 and current international guidelines recommend no completion lymph node dissection not only in case of lack of metastatic disease but also in selected cases of positive sentinel node. 2 While the use of SNB is well established in patients with early-stage breast cancer, no consensus exists on its role in patients with locally advanced disease. 3 9 In the latter setting, the standard management of axillary lymph nodes remains radical lymph node dissection in most centers: this is due to the scattered evidence on SNB performance as well as to the lack of knowledge on the survival effects of a SNB-guided axillary node surgery in these patients. It has been hypothesized that colonization of lymphatic vessels by malignant cells during disease progression might alter the Key words: breast cancer, sentinel node biopsy, neoadjuvant chemotherapy, meta-analysis Additional Supporting Information may be found in the online version of this article. Grant sponsor: Cariparo Foundation (Italy) DOI: /ijc History: Received 11 Apr 2015; Accepted 12 June 2015; Online 17 June 2015 Correspondence to: Simone Mocellin, Surgery Branch, Department of Surgery, Oncology and Gastroenterology, University of Padova, Via Giustiniani 2, Padova, Italy, Tel.: , Fax: , simone.mocellin@unipd.it lymphatic flow: this would undermine the reliability of lymphatic mapping and ultimately the ability to identify the SN. The relatively recent implementation of neoadjuvant chemotherapy (NAC) might make the interpretation of these issues even more complex. NAC although associated with survival outcomes comparable to those observed with adjuvant chemotherapy regimens increases the rate of conservative surgery of the primary tumor (downstaging effect) and represents an in vivo chemosensitivity test (which helps modulating subsequent drug regimens) However, NAC might impair the performance of SNB in two ways: first, it might contribute to the above mentioned alteration of lymphatic flow by inducing tissue fibrosis; second, NAC might eliminate tumor deposits in the SN but not in non-sns, which would ultimately lead to an increased rate of false negative cases. To provide readers with a comprehensive and quantitative overview of the existing evidence in this field, we performed a systematic review and meta-analysis of the available literature regarding the performance of SNB after NAC in patients with locally advanced breast cancer. Material and Methods Search strategy We performed a comprehensive search of the international literature to identify studies (either retrospective or prospective) that examined the ability of SNB to assess the axillary lymph node status in patients with locally advanced breast cancer after NAC. Locally advanced disease was defined by a Int. J. Cancer: 138, (2016) VC 2015 UICC

2 Mocellin et al. 473 What s new? The use of sentinel node biopsy (SNB) to determine whether a tumor has spread into the lymphatic system has revolutionized the surgical management of early breast cancer. But whether SNB also benefits patients with locally advanced breast cancer undergoing neoadjuvant chemotherapy remains unknown. Here, meta-analysis of existing evidence shows that SNB performs less well and is less accurate in the setting of locally advanced disease. Potential misdiagnosis with SNB in this setting could result in incomplete lymph node dissection and incorrect downstaging of disease. More information is needed, however, to fully assess SNB in locally advanced disease. primary tumor not amenable to conservative surgery (due to unfavorable tumor/breast size ratio, as per surgeon s judgment) and/or by clinically positive axillary lymph nodes. We systematically searched the PubMed, Cochrane and Scopus databases for full-text articles published until December 2014, using the following key words: breast, cancer (or carcinoma ), sentinel node biopsy, neoadjuvant (or pre-operative, induction ) and chemotherapy. No language restriction was applied. We searched for additional references by cross-checking bibliographies of retrieved full-text articles and by scrutinizing relevant review articles and meta-analyses. The systematic review was carried out using established methods 14 and following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. 15 Inclusion of studies, data extraction and quality assessment were carried out independently by two authors (SM and EG) using dedicated data extraction forms. Disagreements were resolved by consensus and/or arbitration involving a third author (AM). A two-stage process was used: we first screened titles and abstracts; then, for all references categorized as eligible or uncertain, the full text was retrieved and final inclusion decisions were made after reading the full paper. The two performance parameters we considered were the sentinel node identification rate (SIR, defined as the number of cases with successfully identified SN over the number of SNB procedures attempted) and the false negative rate (FNR, defined as the number of false negative cases over the number of cases with positive axilla at the SNB and/or the completion lymph node dissection). To define the latter, SNB must be followed by completion lymph node dissection, so to define the false negative cases (i.e., patients with negative SNB but with one or more metastatic lymph nodes at completion lymph node dissection). A case was classified as positive (metastatic axilla) when the pathological examination of the SN and/or of the lymph nodes harvested at completion lymph node dissection revealed metastatic disease. Studies enrolling fewer than ten patients were excluded. We also excluded studies with possible overlap with the selected series (duplicate studies). Each study quality was assessed using the QUADAS-2 tool, a well-established guideline for studies on diagnostic test accuracy. 16 This tool consists of the following four domains aimed at identifying the risk of bias (classified as high, low or unclear) that would undermine the reliability of the evidence: 1. Patient selection: to verify that the spectrum of patients enrolled is representative of the patient population that will receive the index test in practice (selection bias). 2. Index test (in the present case: SNB): to assess if the index test results were interpreted without knowledge of the results of the reference standard, and if a positivity threshold (if any) was prespecified (and thus if the conduct or interpretation of the index test have introduced bias). 3. Reference test (pathology evaluation of the lymph node dissection following SNB): to assess if the reference standard utilized is likely to correctly classify the target condition (i.e., axilla lymph node status) and if the reference standard results were interpreted without knowledge of the results of the index test (and thus, if the reference standard, its conduct or its interpretation have introduced bias). 4. Flow and timing: to verify if there was an appropriate interval between index test and reference standard (to make sure the target condition did not change between the two tests), if all patients received the same reference standard (differential verification bias) and if all patients were included in the analysis (partial verification bias, reporting bias). Summary estimates of performance parameters were calculated by random effects meta-analysis using the inverse variance method. Meta-analysis included also evaluation of between-study heterogeneity, sensitivity analysis and examination for bias. Heterogeneity (true variance of effect size across studies) was quantified by means of I 2 statistic [which indicates the percentage of the variability in effect estimates due to true heterogeneity rather than sampling error (within study variance)] and formally tested by means of the v 2 -based Cochran s Q-test (to assess whether observed variance exceeds expected variance). Potential sources of heterogeneity were searched by random effects meta-regression; to this aim, the following covariates were considered: publication year, study design features (prospective vs. retrospective; monocentric vs. multicentric), patient mean age, primary tumor stage at presentation, clinical lymph node status before and after NAC, SIR (for FNR), pathological axillary lymph node positivity rate.

3 474 SNB performance after NAC in breast cancer The extent to which the combined risk estimate might be affected by individual studies (leading study effect) was assessed by consecutively omitting every study from the meta-analysis (leave-one-out sensitivity analysis). Sensitivity analysis was also used to verify the impact of low-quality studies (if any) on summary estimates. Funnel plots were used to detect the so-called small study effect. Publication and selection biases in meta-analysis are more likely to affect small studies, which also tend to be of lower methodological quality: this may lead to small study effect, where the smaller studies in a meta-analysis show larger treatment effects. Funnel plot asymmetry was formally investigated with the Egger linear regression approach. The trim-and-fill method was adopted to adjust summary estimates for potentially missing (unpublished) studies. 17 We formally compared summary estimates of SIR and FNR obtained with the meta-analysis to reference values (90 95% and 8 10%, respectively) derived from the international experience with SNB in patients with early-stage breast cancer 1 4 : to this aim, we considered the summary estimate significantly different from the reference value if the 95% confidence interval (CI) of the former does not cross the latter. The difference between summary values obtained in two subgroups was formally tested by means of the Cochran Q-test. All analyses were performed using the Stata SE 11.2 software (Stata Corp LP, College Station, TX). Results Characteristics of included studies Literature search yielded 410 articles. Screening by title and abstract reading led to the identification of 112 potentially relevant articles whose full text was retrieved: ultimately, 72 studies published between 2000 and 2014 met the inclusion criteria and thus were included for both qualitative and quantitative analyses (Fig. 1). Overall, 7451 patients were enrolled, with a mean of 103 patients per study (range: ). The main characteristics of these studies are presented in Tables 1 and 2. With regard to study quality, no high risk of bias was detected in any of the included study. Figure 1. Flow chart of literature search. SNB performance SIR was investigated in 71 studies (n 5 7,368) and ranged between 58.8 and 100%: upon meta-analysis, the summary SIR resulted 89.6% (95% CI: ), which poorly compared with the 95% reference value. Between-study heterogeneity was high (I 2 : 76.9%) and statistically significant (Q-test p values: <0.001); a small study effect was suggested by both visual inspection of funnel plot (which is available as Supporting Information Fig. 1) and statistically significant Egger test (p values: <0.001). After adjustment for potentially missing studies (n 5 20), the summary SIR resulted 86.9% (95% CI: ). Sensitivity analysis, subgroup analysis and meta-regression did not identify any potential source of heterogeneity. In particular, among patients with clinically negative lymph nodes before NAC (studies, n 5 7), the summary SIR was 94.0% (95% CI: ), whereas among patients with positive nodes (studies, n 5 16), the summary SIR was 89.5% (95% CI: ), the difference being statistically nonsignificant. FNR was investigated in 65 studies (n 5 6,467) and ranged between 0 and 38.9%: upon meta-analysis, the summary FNR resulted 14.2% (95% CI: ), a rate significantly higher than the 8 10% reference value. Between-study heterogeneity was moderate (I 2 : 29.1%, Q- test p values: 0.017) and small study effect was suggested by both visual inspection of funnel plot (which is available as Supporting Information Fig. 2) and statistically significant Egger test (p values: 0.002). After adjustment for potential missing studies (n 5 19), the summary FNR resulted 16.1% (95% CI: ). Sensitivity analysis, subgroup analysis and meta-regression did not identify any potential source of heterogeneity. In particular, among patients with clinically negative lymph nodes before NAC (studies, n 5 5), the summary FNR was 23.5% (95% CI: ), whereas among patients with positive nodes (studies, n 5 15), the summary FNR was 15.2% (95% CI: ), the difference being statistically nonsignificant. Discussion In this systematic review we collected the highest number of studies (n 5 72) and patients (n 5 74,51) ever considered in the field of SNB performance after NAC in patients with locally advanced breast cancer.

4 Mocellin et al. 475 Table 1. Main features of included studies: design, patients and tumor characteristics Author (year) PMID Center Design Country Age 1 pre-nac pre-nac post-nac T stage N stage N stage Aguiar (2012) Single Retrospective Brasil 48.3 T2 T4 N0 N2 Aihara (2004) Single Prospective Japan 47 T2 T4 N0 N1 Al Mushawah (2010) Single Retrospective USA T1 T4 N0 N1 Alvarado (2012) Single Prospective USA 51.4 T1 T4 N1 N3 Mixed Balch (2003) Single Prospective USA 51 T2 T3 N0 N1 Mixed Beatty (2009) Single Retrospective Sweden T1 T3 N0 N1 Mixed Boileau (2015) Multiple Prospective Canada 50 T0 T3 N0 N1 Boughey (2013) Multiple Prospective USA 55 T0 T4 N1 N2 Mixed Brady (2002) Single Retrospective USA 42 T1 T3 Breslin (2000) Single Prospective USA 45 T1 T3 N0 N1 Mixed Brown (2010) Single Retrospective USA T1 T3 N1 N3 Canavese (2011) Single Prospective Italy 50.5 T2 T4 N1 N3 Mixed Cheung (2009) Single Prospective China 53 T1 T2 N0 Negative Chintamani (2011) Single Retrospective India 47.3 T1 T4 N1 N2 Mixed Classe (2009) Multiple Prospective France T0 T3 N0 N1 Cohen (2000) Single Retrospective USA 45 T1 T3 N0 N2 Mixed Fernandez (2001) Single Retrospective Spain 52 T1 T4 N0 N1 Gatek (2012) Single Prospective Czech 57 T2 T4 N0 N2 Gimbergues (2008) Single Prospective France 53 T1 T3 N0 N2 Haid (2001) Single Retrospective Austria 53.4 T1 T3 N0 N1 Han (2013) Single Retrospective Korea 46 T1 T4 N0 N3 Mixed Hidar (2009) Single Retrospective Tunisia 49 T4 N0 N2 Negative Hino (2008) Single Retrospective Japan 48 T2 T3 N0 N1 Mixed Hunt (2009) Single Retrospective USA 51.7 T1 T3 N0 Negative Jones (2005) Single Retrospective USA T2 T4 N0 N2 Julian (2001) Single Retrospective USA T1 T3 N0 N1 Negative Kang (2004) Single Prospective Korea 47.3 T1 T4 N1 Mixed Khan (2005) Single Prospective USA T1 T4 N1 Kinoshita (2007) Single Prospective Japan 50.2 T2 T4 N0 N2 Mixed Komenaka (2010) Single Retrospective USA 45 T2 T3 N0 N1 Koslow (2014) Single Retrospective USA 52 T1 T4 N0 N2 Mixed Kuehn (2013) Multiple Prospective Germany 50 T1 T4 N1 N2 Negative Lang (2004) Single Retrospective USA 51.5 T1 T3 N0 N1 Le Bouedec (2006) Single Prospective France 52 T1 T3 N0 N1 Lee (2007) Single Prospective Korea 48.2 T1 T4 N1 Mixed Lee (2015) Single Prospective Korea 45 T1 T3 N1 N3 Mixed Li (2014) Single Retrospective China 51 T1 T4 Mamounas (2005) Multiple Prospective USA T1 T3 N0 N1 Medina (2008) Single Retrospective Mexico 43 T1 T4 N0 N1 Negative Miller (2002) Single Retrospective USA T1 T4 N0 Negative Nason (2000) Single Prospective USA 50.5 T1 T4 N0 N1 Navarro (2013) Single Prospective Spain 50.6 T2 T3 N0 Negative Newman (2007) Single Retrospective USA 45 T1 T4 N1 Ozmen (2010) Single Retrospective Turkey 43 T1 T4 N1 N2 Negative

5 476 SNB performance after NAC in breast cancer Table 1. Main features of included studies: design, patients and tumor characteristics (Continued) Author (year) PMID Center Design Country Age 1 pre-nac pre-nac post-nac T stage N stage N stage Papa (2008) Single Prospective Israel 46 T2 T3 N0 Negative Park (2013) Single Retrospective Korea 48.4 T1 T3 N1 Mixed Pecha (2011) Multiple Retrospective Czech T1 T4 N0 N1 Peley (2006) Single Retrospective Hungary T1 T3 N0 N1 Negative Piato (2003) Single Retrospective Brasil 49 T1 T2 N0 Negative Pinero (2014) Multiple Prospective Spain 45 T1 T4 N0 N1 Mixed Rebollo (2013) Single Prospective Spain 49.4 T1 T3 N0 N1 Negative Reitsamer (2010) Single Retrospective Austria 47 T1 T3 N0 N1 Ruano (2014) Single Prospective Spain 48 T1 T3 N0 N2 Rubio (2010) Single Prospective Spain 50 T1 T3 N0 N1 Negative Schwartz (2010) Single Retrospective USA 50 T0 T4 N0 N2 Mixed Shen (2007) Single Prospective USA 49 T1 T4 N1 N3 Mixed Shigekawa (2012) Single Retrospective Japan 53 T1 T4 N0 N3 Mixed Shimazu (2004) Single Retrospective Japan 51.3 T2 T4 N0 N2 Mixed Stearns (2002) Single Retrospective USA 46 T3 T4 N0 N3 Mixed Stell (2011) Single Retrospective USA 49.5 T1 T3 N0 N2 Negative Tafra (2001) Multiple Prospective USA 48 T1 T4 Takahashi (2012) Single Prospective Japan 52 T1 T3 N0 N1 Mixed Takei (2013) Single Retrospective Japan 49.2 T1 T4 N1 N3 Mixed Tanaka (2006) Single Retrospective Japan 50 T1 T3 N0 N2 Mixed Tausch (2008) Multiple Retrospective Austria 50 T1 T4 N0 N1 Negative Tausch (2011) Multiple Prospective Austria 48.4 T1 T4 N0 N1 Thomas (2011) Single Prospective India 49.4 T2 T4 N1 Negative Vigario (2003) Single Prospective Brasil 49.2 T1 T2 N0 Yagata (2013) Single Prospective Japan 49 T0 T4 N1 Yamamoto (2007) Single Retrospective USA 55.5 T1 T4 N0N1 Yu (2007) Single Retrospective Taiwan 42.6 T1 T3 Zhang (2013) Single Retrospective China 57 T1 T3 N0 N1 Mixed 1 Mean/median. Abbreviations: PMID: PubMed ID number; NAC: neoadjuvant chemotherapy. Upon meta-analysis of the available evidence, we found that in this setting the SNB performance is not as good as that observed in the early setting. In fact, the weighted average identification rate (summary SIR= 89.6%) resulted worse than that recently reported in patients with early-stage disease (95%). This conclusion is strengthened by the high degree of between-study heterogeneity (I 2 : 76.9%) and by the even lower identification rate after adjustment for small study effect (adjusted summary SIR: 86.9%). Similarly, the SNB accuracy (which is practically represented by the FNR, as no false positive are expected) was not as high as it is in the early-stage setting (summary FNR % vs. reference value of 8 10%). This implies that among 100 patients with metastatic disease in the axilla (after NAC), 14 patients would be misdiagnosed by SNB (instead of 8 10, as expected on the basis of the experience in the early setting). This excess of misdiagnosis (4 6/100) would lead to no completion lymph node dissection and to an erroneous downstaging of the disease (with an overestimation of the NAC efficacy). Considering a real scenario (i.e., the entire population of interest), averagely 50 of 100 patients with locally advanced breast cancer will end up to have a positive axilla after NAC (based on the mean percentage of positive axillae across the studies included in this meta-analysis). Among these 50 patients with a positive axilla, seven would be misdiagnosed as having no lymph node metastatic disease (instead of four to five patients as expected in the early setting), which leads to an excess error equal to 2 3/100 in the overall population of patients with locally advanced disease. These results would

6 Mocellin et al. 477 Table 2. Main features of included studies: sentinel node biopsy technical features and results Author Year radiocolloid blue dye combo SNB attempted SNB positivity SIR FNR Aguiar W Aihara T Al Mushawah F Alvarado R Balch G Beatty D Boileau J Boughey J Brady E Breslin T Brown A Canavese G Cheung T Chintamani_ Classe J Cohen L Fernandez A Gatek J Gimbergeus P Haid A Han A Hidar S Hino M Hunt K Jones J Julian T Kang S Khan A Kinoshita T Komenaka I Koslow S Kuehn T Lang J Le Bouedec G Lee S Li H Li J Mamounas E Medina H Miller A Nason K Navarro J Newman E Ozmen V

7 478 SNB performance after NAC in breast cancer Table 2. Main features of included studies: sentinel node biopsy technical features and results (Continued) Author Year radiocolloid blue dye combo SNB attempted SNB positivity SIR FNR Papa M Park S Pecha V Peley G Piato J Pinero A Rebollo A Reitsamer R Ruano R Rubio I Schwartz G Shen J Shigekawa T Shimazu K Stearns V Stell V Tafra L Takahashi M Takei H Tanaka Y Tausch C Tausch C_BIS Thomas S Vigario A Yagata H Yamamoto M Yu J Zhang G Abbreviations: SNB: sentinel node biopsy; SIR: sentinel node identification rate; FNR: false negative rate. be even worse if we considered the summary FNR adjusted for small study effect (16.1%), which would lead to an excess error equal 3 4/100. On the other hand, the survival consequences of this diagnostic error rate associated to SNB implementation in this setting are far from clear: in fact, no evidence from randomized controlled trials is available for locally advanced disease, as opposed to early disease (where SNB-guided management of axillary surgery has been demonstrated to be as effective as radical lymph node dissection performed routinely). Therefore, the therapeutic role of SNB in locally advanced breast cancer will remain unclear until the impact of completion lymph node dissection on the survival of SNB positive patients will be elucidated. As regards the prognostic role of SNB in these patients, the sentinel node status should guide clinicians in the decision-making process leading (or not) to prescribe postoperative (adjuvant) chemotherapy to eliminate the minimal residual disease. However, no clear evidence exists that adjuvant therapy adds any survival advantage to NAC. This is a quite different situation as compared to the early setting, where the sentinel node status can make the difference between receiving or not adjuvant chemotherapy, a treatment with a well-established impact on patient survival. Therefore, also in this case the impact of the excess error rate linked to a suboptimal SNB performance is unclear. As for the already existing literature on this subject, other five meta-analyses have been so far published (between 2006 and 2014) in this field, including studies that in turn enrolled 449 2,471 patients. The summary SIR and FNR ranged between 89 and 94% and between 7 and 14%, respectively. Our analysis, which is based on a much larger series of studies (n 5 72) and patients (n 5 7,451), appears to tip the balance toward worse performance values (summary SIR

8 Mocellin et al. 479 Figure 2. Scheme of proposal for the management of axillary lymph nodes in patients with locally advanced breast cancer. and FNR: 89.6 and 14.2%, respectively). Unfortunately, neither sensitivity analysis nor meta-regression could identify potential sources of heterogeneity [which was higher for SIR (I 2 : 76.9%) than FNR (I 2 : 29.1%)] and thus we cannot even hypothesize the possibility of obtaining better results in selected patient/disease categories. In this regard, the remarkable variability of data reported in many articles represents a major obstacle for a thorough assessment of the impact of several clinical, pathological or surgical variables on SNB performance, as suggested by some studies Therefore, studies specifically aimed at elucidating this issue are eagerly needed, which take into consideration all potentially relevant data including the level of surgeon experience, a piece of information virtually never reported in the currently available literature. In the light of our findings and awaiting for new evidence in this field, we propose a simple flow chart for the axilla management of patients with locally advanced breast cancer eligible for NAC (Fig. 2), which envisions three different scenarios. When lymph nodes are clinically positive after NAC, radical lymph node dissection is deemed necessary to remove chemoresistant metastatic disease. In contrast, when lymph nodes are clinically negative after NAC, SNB appears a reasonable compromise between elective radical lymph node dissection performed routinely and no surgery at all. In fact, in about 50% of cases the SN is References negative and thus in these cases the morbidity, psychological stress and costs for the healthcare system linked to completion lymph node dissection can be avoided. The higher FNR of the procedure as compared to the early setting might be acceptable in the light of some considerations: first, as above mentioned, there is no evidence of improved survival associated with radical lymph node dissection in these patients; second, the pathological and molecular features of the primary tumor are gaining more and more importance in the decision-making process underlying adjuvant chemotherapy choices, which diminishes the overall clinical impact of a diagnostic error due to false-negative findings; third, it should be remembered the potential role of ultrasound both in guiding surgeons in the management of axillary lymph nodes after NAC (which appears to keep the FNR below the 10%), 30 and in the early detection of axillary disease recurrence during follow-up, which has recently led to the design of the SOUND trial in the early setting. 31 Finally, if the sentinel node is positive, two options appear reasonable: one is to submit the patient to adjuvant chemotherapy and ultrasound-based follow-up: this approach appears to be justified considering the experience in the early-stage setting, where the sentinel node status provides the prognostic information needed to make therapeutic decisions and completion lymph node dissection has no therapeutic effect; moreover, some recent evidence appears to support this approach in the locally advanced setting as well. 32 On the other side, in the locally advanced stage the role of completion lymph node dissection has not been formally clarified; moreover, the presence of metastatic (though clinically occult) disease after NAC means that the minimal residual disease might be difficult to eradicate with adjuvant therapy as well: therefore, completion lymph node dissection might still represent a reasonable option in this patient subgroup, although radiotherapy is another option to be considered. In conclusion, we provided the most comprehensive overview of the existing literature on the performance of SNB in patients with locally advanced breast cancer undergoing NAC. Although many aspects need to be elucidated, the findings of our meta-analysis enable clinicians to make therapeutic decisions based on the best available evidence. Acknowledgement The work of Elena Goldin is supported by the Cariparo Foundation (Italy). 1. Berveiller P, Mir O, Veyrie N, et al. The sentinel-node concept: a dramatic improvement in breast-cancer surgery. Lancet Oncol 2010;11: Lyman GH, Temin S, Edge SB, et al. Sentinel lymph node biopsy for patients with early-stage breast cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol 2014;32: Fontein DB, van de Water W, Mieog JS, et al. Timing of the sentinel lymph node biopsy in breast cancer patients receiving neoadjuvant therapy recommendations for clinical guidance. Eur J Surg Oncol 2013;39: Mamounas EP. Timing of determining axillary lymph node status when neoadjuvant chemotherapy is used. Curr Oncol Rep 2014;16: Hoffmann J, Souchon R, Lebeau A, et al. German, Austrian and Swiss consensus conference on the diagnosis and local treatment of the axilla in breast cancer. Eur J Cancer 2013; 49:

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