Sentinel Lymph Node Biopsy After Chemotherapy

James W. Jakub & Judy C. Boughey

Published online: 9 March 2011# Springer Science+Business Media, LLC 2011

Abstract The timing of sentinel lymph node (SLN) biopsyin patients receiving neoadjuvant chemotherapy remains adebated topic, despite increasing literature supporting useof SLN biopsy after chemotherapy. This article outlines thearguments for SLN biopsy prior to initiation of systemictherapy versus after neoadjuvant chemotherapy and theliterature surrounding this debate. Additionally, specialpatient populations, including patients with inflammatorybreast cancer and those presenting with node-positivedisease, are discussed. SLN biopsy after completion ofchemotherapy is accurate for axillary staging of patientswith clinically node-negative axillas at presentation, exceptfor those with inflammatory breast cancer.

Keywords Breast cancer . Neoadjuvant chemotherapy .

Sentinel lymph node biopsy . Axillary lymph nodedissection . Inflammatory breast cancer

Introduction

Despite marked improvements in directing systemic ther-apy based on features of the primary tumor, the status of theaxillary nodal basin remains a critical component oftreatment decisions. Involvement of regional lymph nodeshas direct implications on systemic treatment recommenda-tions, radiation considerations, reconstructive options,

extent of operative intervention, as well as prognosisincluding local, regional, and distant recurrence. Addition-ally, nodal status is one of the most important prognosticindicators. Traditionally, the status of the axillary lymphnodes was determined up front with surgical removal andpathologic staging. This has followed a natural progressionfrom more radical to less aggressive surgical interventions,not only for treatment of the primary breast cancer but alsoin the surgical approach to the axilla. Axillary lymph nodedissection (ALND) has been replaced by sentinel lymphnode (SLN) surgery for staging of early breast cancer in theclinically node-negative patient [1–3]. Simultaneously therehas been a shift in the thought process of the sequencing ofbreast cancer therapies. As a result of better understandingof the metastatic process, systemic treatment is beingdelivered with increasing frequency in advance of surgicaltreatment. This neoadjuvant approach has raised a new setof questions.

It is well established that SLN biopsy is a reliable meansof staging patients with breast cancer. SLN surgery hasbeen shown to have less morbidity, including lymphedema,arm paresthesias, and decreased range of motion, thanALND [3–6]. The National Surgical Adjuvant Breast andBowel Project (NSABP) B-32 study randomized clinicallynode-negative women to an SLN biopsy alone or SLN withALND. Comparing the 3989 women with pathologicallynegative SLNs, there was no difference in overall survival,disease-free survival, or regional control between womenwith a negative SLN who had no further axillary surgery(n=2011) and those who underwent SLN and completionALND (n=1975) [7]. Thus, even though there is anaccepted false-negative rate associated with SLN surgery,the long-term oncologic outcomes remain equal to patientsundergoing an ALND. Some would even argue that a SLNbiopsy is actually a more accurate method of axillary

J. W. Jakub : J. C. Boughey (*)Department of Surgery, Mayo Clinic,200 First Street SW,Rochester, MN 55905, USAe-mail: boughey.judy@mayo.edu

J. W. Jakube-mail: jakub.james@mayo.edu

Curr Breast Cancer Rep (2011) 3:97–103DOI 10.1007/s12609-011-0040-x

staging than ALND. In this article, we attempt to summarizethe current state of axillary staging in those patients receivingneoadjuvant chemotherapy.

Clinically Node-Negative Patients

Neoadjuvant chemotherapy was first utilized in the settingof more advanced local regional disease. Many centers arenow favoring this approach with increasing frequency andconsider neoadjuvant therapy for any patient who willreceive chemotherapy. As a result, patients with smallerprimary tumors and clinically node-negative disease arebeing considered for chemotherapy prior to surgery withincreasing frequency. This has raised the issue of when tosurgically and pathologically stage the axilla. Regardless ofthe institutional preference, in the clinically node-negativepatient being considered for neoadjuvant chemotherapy, anaxillary ultrasound prior to treatment is advised. If any ofthe axillary lymph node(s) are radiographically suspicious,a fine-needle aspiration (FNA) or core needle biopsy of themost suspicious lymph node should be performed [8–10]. Ifpositive, this information is obtained in the least invasivemethod. If negative or if lymph nodes appear morpholog-ically normal on ultrasound, then SLN biopsy is stilladvised for axillary staging. One of the major debates inthis arena revolves around the appropriate timing of theSLN biopsy.

There are merits and pitfalls of both pre- and post-neoadjuvant chemotherapy SLN biopsy. Accepting thatboth sides have valid argument, we have outlined therationale and reviewed the literature for both approachesbelow. It is stressed that neoadjuvant therapy should onlybe initiated when the benefit of systemic therapy has beendetermined based on patient and tumor factors or docu-mented nodal positivity and will not be dependent on thesurgical staging of the axilla. If the information gained fromsurgical intervention and pathologic evaluation of the axillawould potentially alter systemic treatment recommenda-tions, then neoadjuvant therapy may not be appropriate.These decisions are becoming more complex and areideally made in the context of a multidisciplinary approach.

Whichever approach is chosen it must also be kept inmind that the accuracy of SLN biopsy is dependent on thepre-test probability of finding a positive lymph node. Evenif the false-negative rate stays static (which some argue itbecomes higher with increasing tumor size), the absolutenumber of patients falsely classified as node negative whenthey are actually node positive will be higher for cases withan increased incidence of nodal metastasis (ie, largertumors). Based on experience and published literature,one can reliably stage patients with T3 disease and aclinically negative axilla with SLN biopsy [11].

SLN Biopsy Prior to Neoadjuvant Chemotherapy

A number of surgeons/institutions advocate performingaxillary staging in the clinically node-negative patient in thetraditional sequence, specifically prior to initiation ofsystemic treatment. The main rationale for this approachis comfort with knowing the axillary stage prior tobeginning any therapy and the potential impact the axillarystatus may have on adjuvant treatment recommendations.There is an overwhelming amount of data to support SLNbiopsy being reliable in this context. The false-negative ratehas been shown in early studies to vary from 0% to 29%,averaging 7.3% overall [12], and there is no concern aboutthe potential for systemic therapy interfering with theaxillary staging. This allows for standard staging that weare accustomed to. Knowing the nodal status prior totreatment can guide therapeutic decisions. The downsideof this approach includes the requirement for twooperations—the initial SLN biopsy at the time ofdiagnosis and then the definitive breast surgery aftercompletion of chemotherapy. This approach can delaysystemic treatment, especially if the completion ALND isperformed at the time of SLN biopsy for node-positivecases. Surgeons vary in the timing of the ALND forpatients with positive SLNs, although the majorityperform this, along with the definitive breast surgery,after completion of chemotherapy. Importantly, SLNbiopsy prior to chemotherapy loses the ability to assessaxillary response to systemic therapy, which is known tocorrelate with survival [13, 14].

SLN biopsy prior to neoadjuvant chemotherapy subjectsmore patients to an ALND. So how does SLN biopsy pre-neoadjuvant chemotherapy result in more ALNDs than ifthe SLN biopsy was performed after systemic treatment? Itis understood that pathologic staging is more accurate thanclinical staging, and surgical staging with SLN biopsyidentifies disease in some patients with clinically negativeaxillas. This would be detected with an upfront SLNsurgery. One of the main goals of neoadjuvant therapy isa pathologic complete responses (pCR), defined as noresidual invasive disease in the breast or axilla. Therefore, aproportion of patients with node-positive disease will beconverted to node-negative status with neoadjuvant che-motherapy. Rates of pCR can be as high as 65% withtargeted therapy [15]. In NSABP B-18, the rate of nodalpositivity in the patients who underwent surgery first was58% compared to only 40% in those who receivedneoadjuvant chemotherapy [16]. Therefore, if the axillawas clinically negative before chemotherapy but diseasewas present, an upfront SLN biopsy would detect thisdisease and by today’s standards an ALND would beadvised after completion of chemotherapy, at the time ofdefinitive breast surgery. On the other hand, had a SLN

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biopsy been performed after chemotherapy, there is achance the axillary disease could be sterilized and ALNDavoided, resulting in fewer ALNDs performed overall.

The findings from the American College of SurgeonsOncology Group (ACOSOG) Z0011 study that a subset ofpatients with positive SLNs can be spared a completionALND is encouraging [17••, 18]. This trial included T1 andT2 tumors treated with breast-conserving therapy (BCT)and whole breast radiation and showed no difference inlocal recurrence or survival between patients treated withSLN alone or SLN and ALND for 1 to 2 positive SLNs.This trial excluded patients receiving neoadjuvant therapy;however, one could consider extrapolating to selectclinically node-negative patients who met study inclusioncriteria (T1 or T2 breast tumors and 1 or 2 positive SLNsplanned to receive whole breast radiation) prior to initiationof neoadjuvant chemotherapy. The implications of thisstudy are still being debated in the confines of day-to-dayclinical practice. Our institutional approach is upfrontaxillary ultrasound and FNA on all patients with invasivebreast cancer. If positive, ALND following neoadjuvanttherapy is advised. In the setting of a negative axillaryultrasound upfront, then SLN biopsy is performed follow-ing neoadjuvant systemic therapy. If the SLN is positiveafter neoadjuvant therapy, we have tended to be moreaggressive and favor directed axillary therapy (ALND and/or targeted regional nodal radiation) even for small volumedisease. If residual disease persists after the best systemictreatment has been given, we are less comfortable with nottreating the axillary basin.

Axillary Response Rate

pCR defined as no residual invasive disease in the breast orthe axilla is associated with improved long-term prognosiscompared to patients with residual disease after chemother-apy [13, 14, 19]. It should come as no surprise that patientswho respond to systemic treatment do better then those whodemonstrate resistance to our best therapy. The pCR ratevaries widely in the literature based on patient selection andtreatment utilized, with rates as high as 65% with the use oftrastuzumab combined with chemotherapy for Her2-positive breast cancer [15]. This field is evolving as weare gaining a better understanding of how to tailor specifictherapies to specific patient populations. In the future, wewill be more equipped to advise neoadjuvant treatment, andwhat specific type, versus surgical intervention up front.The ACOSOG Z1031 Cohort B is the first cooperativegroup trial to evaluate response and alter therapy based onan on-treatment biopsy, only after a few weeks intoneoadjuvant endocrine treatment. Measuring response inreal time and adjusting treatment accordingly, within a fewweeks if not a few days of initiation of therapy, is likely to

become standard in the future and is one of the yet unseenadvantages of a neoadjuvant approach.

Data consistently demonstrate that axillary response isone of the most powerful prognostic factors [13, 14, 20].Sakakibara et al. [21] evaluated 80 patients with FNA-positive axillary lymph nodes prior to initiation ofneoadjuvant chemotherapy. At completion of systemictherapy, the axillary lymph nodes underwent thoroughpathologic scrutiny, including 2-mm serial sections andimmunohistochemical (IHC) analysis. A pCR in the axillawas seen in 37.5%. Of those with metastatic diseaseremaining, 33 were macrometastasis, 9 were micrometa-stasis, and 8 only had isolated tumor cells (ITCs). Onlyestrogen receptor (ER) status and axillary lymph node pCR(which included residual ITCs) correlated with disease-freesurvival. Interestingly, pCR of the main tumor did notcorrelate with disease-free survival [21]. Beatty et al. [22]reported on 473 breast cancer patients receiving neo-adjuvant chemotherapy. A total of 309 were clinically nodepositive prior to treatment and 32% had a nodal pCR. Fromthis study, it is not entirely clear how many patients werestaged node positive upfront with a SLN biopsy. Becausethe SLN is, in many cases (up to 60%), the only positivelymph node, the axillary response cannot be determined inpatients who undergo a SLN biopsy prior to chemotherapyfollowed by ALND upon completion of systemic therapy.This is a limitation of many of the studies reporting on thisphenomenon.

One other limitation of post-treatment axillary surgicalstaging is that in a node-positive patient, the total number ofpositive lymph nodes cannot be known at the onset oftherapy without an ALND. However, the absolute numberof positive nodes at time of diagnosis is proving to haveless influence on treatment decisions and the post-treatmentnodal status may have more relevance. This is complicatedby the fact that most clinical trials, such as post-mastectomyradiation and timing of reconstruction, were conducted inan era prior to neoadjuvant chemotherapy. These nuancescreate routine unknowns in terms of evidence-basedtreatment recommendations.

SLN Biopsy After Neoadjuvant Chemotherapy

The advantages of SLN biopsy after neoadjuvant chemo-therapy, as noted above, include only one operation,knowing the axillary response after chemotherapy (whichmay be the most significant prognostic marker), and fewerpatients will require an ALND. So why is this approach notembraced by all? In terms of the patients with clinicallynode-negative disease prior to chemotherapy, one overrid-ing concern remains: is SLN biopsy accurate after systemictreatment? We must acknowledge that there is a false-negative rate associated with the use of SLN biopsy. By

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definition, patients with a false-negative SLN biopsy willhave residual disease in the axilla that is not removedbecause a completion ALND is not performed. In spite ofthis, patients undergoing surgical staging first with anegative SLN biopsy have a clinical axillary recurrencerate much lower than would be predicted based on studieswith back-up ALND and calculation of pathologic false-negative rates [7, 23]. Axillary recurrence even in thesetting of a positive SLN and no completion of ALND isuncommon [24–28]. In the setting of surgery aftercompletion of neoadjuvant chemotherapy, typically nofurther chemotherapy is given, and because this is a patientgroup with more aggressive disease (hence the use ofneoadjuvant chemotherapy), leaving behind disease thatwas unresponsive to chemotherapy and will not besurgically removed is unsettling. Therefore, until more databecome available, we still typically support axillarydirected therapy for the individual with a positive SLNfollowing neoadjuvant chemotherapy.

In patients receiving neoadjuvant chemotherapy, somesurgeons are concerned whether the chemotherapy hasaffected the axillary drainage and if it will impact theaccuracy of SLN biopsy. The fear is that fibrosis of thelymphatic channels or blockage of the lymphatics by tumorcells may interfere with drainage of the mapping agents[29]. Additionally, for the SLN biopsy to be accurate in thissetting, one could argue that all nodes must respond or notrespond with equal efficacy and/or the nodes need torespond in reverse order of their contamination. In otherwords, the SLN must be the first to be contaminated withmetastatic spread and the last to be sterilized for the SLNbiopsy to be reliable after chemotherapy, otherwise residualdisease could be present in nonsentinel nodes, whereas theSLN is negative and a false negative could result. Despitethese theoretic concerns, there is significant literatureshowing that the false-negative rate of SLN biopsy aftercompletion of neoadjuvant chemotherapy is similar to thatin the upfront setting. Multiple single institution studies aswell as analysis of multi-center trials and several meta-analyses have documented the accuracy of SLN surgeryafter completion of neoadjuvant chemotherapy, both interms of SLN identification rate and false-negative ratesbeing similar to those in patients undergoing SLN surgerywithout neoadjuvant chemotherapy [30–32]. In theseanalyses, the false-negative rate varies from 8% to 12%and the SLN identification rate is 90%.

There is a growing body of evidence confirming that not allnodal metastasis become clinically relevant. We know fromNSABP-04 that only about half of pathologic nodal diseasewill become clinically significant in breast cancer patients[33]. We also know the axillary recurrence rate in the SLNera is much lower then the false-negative rate based onpathologic staging in patients undergoing SLN biopsy

followed by routine ALND. This clinical parody also appearstrue for patients receiving neoadjuvant chemotherapy [34••].

Techniques for Accurate Identification of SLNsAfter Neoadjuvant Chemotherapy

In a recent report of 575 patients undergoing SLN biopsyafter neoadjuvant chemotherapy and 3171 patients under-going SLN without prior systemic therapy, the SLNidentification rate was shown to be higher with the use ofdual-agent mapping (combination of blue dye and radio-labeled colloid) than with use of a single-agent technique[34••]. SLN identification rates were slightly lower in theneoadjuvant chemotherapy group as compared with thesurgery-first group (97.4% vs 98.7%, respectively). SLNidentification rate improved with experience. The false-negative rate was not different between groups, being 4.1%(22/542) in the surgery-first group and 5.9% (5/84) in theneoadjuvant therapy group. False-negative events weremore likely with use of blue dye alone and when less thantwo SLNs were resected. After adjusting for clinical stage,there were no differences in local-regional recurrences,disease-free, or overall survival between the two groupsafter 47 months of follow-up.

Node-Positive Patients at Presentation

With the use of axillary ultrasound at the time of diagnosis,node positivity is increasingly being detected in the initialevaluation of patients presenting with breast cancer. OnceFNA or core needle biopsy of an axillary lymph node in apatient with breast cancer documents metastatic disease, thepatient is classified as node positive. Many of these patientsare then considered for neoadjuvant chemotherapy. Forthese patients, there is no debate about considering SLNprior to chemotherapy, as nodal positivity has beendocumented percutaneously without need for surgicalintervention. After completion of neoadjuvant chemother-apy, the recommendation for management of the axilla atthis time is an ALND. Omitting ALND in a patient withdocumented positive axillary disease prior to neoadjuvantchemotherapy is not currently advised. Evidence to datedoes not support relying on a post-chemotherapy negativeSLN biopsy alone in this setting. Previous smaller studieshave shown a false-negative rate of SLN biopsy varyingfrom 11% to 30% in these patients. The M.D. AndersonCancer Center evaluated 86 such patients and reported afalse-negative rate of 22% [35••]. A group in France had afalse-negative rate of 0% for their clinically node-negativecases; however, 8 of 27 cases with N1 and N2 disease hadfalse-negative sentinel node biopsies in this setting [36].Additionally, early results from the Investigation of Serial

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Studies to Predict Your Therapeutic Response with Imagingand Molecular Analysis (ISPY-1 TRIAL) have reported20% false-negative rate of SLN biopsies in patients thatwere known to be node positive at presentation. Given that100% of this patient population is node positive atdiagnosis, a high false-negative rate in this group is notacceptable and therefore ALND remains the standard ofcare in these women. ACOSOG currently has an open trial,Z1071 “A Phase II Study Evaluating the Role of SentinelLymph Node Surgery and Axillary Lymph Node DissectionFollowing Preoperative Chemotherapy in Women withNode Positive Breast Cancer T0-4, N1-2, M0 at initialdiagnosis”, which is a prospective trial specificallydesigned to answer this question (http://www.clinicaltrials.gov-NCT00881361). This trial is accruing well with over500 patients enrolled at the time of this writing out of aplanned accrual of 660, and we anticipate reporting theresults of this study by the end of 2011.

Inflammatory Breast Cancer

In patients with inflammatory breast cancer, ALND remainsthe standard recommendation for management of the axillaafter completion of neoadjuvant chemotherapy. This appliesto all cases that are documented node positive at presentationas well as those that are clinically node negative. Few studieshave evaluated SLN biopsy in this setting; however, one initialstudy of eight patients with inflammatory breast cancershowed a 25% failure rate of identification of a SLN and anadditional 25% false-negative rate [37]. More recently, astudy using patent blue dye only for lymphatic mapping of20 patients with clinically negative axillas after completionof neoadjuvant chemotherapy for inflammatory breast cancerreported a failed identification rate of 20% and a false-negative rate of 18% [38]. These studies are limited by smallpatient numbers. Obstruction of the lymphatics by tumoremboli is thought to interfere with the reliability of lymphaticmapping, and because dermal lymphatic infiltration is often apathologic feature associated with inflammatory breastcancer, unreliable mapping in this patient population shouldnot come as a surprise. Given the high incidence of residualnodal disease in these patients along with the low SLNidentification rate and high false negative rate, a completeALND remains the standard recommendation.

Axillary Lymph Node Count After Completionof Chemotherapy

Several studies have reported conflicting results on whether thenumber of axillary lymph nodes detected at ALND aftercompletion of chemotherapy is lower than in patients

undergoing surgery without neoadjuvant chemotherapy [39–41]. We recently reported a mean of 21.9 lymph nodesresected at ALND in patients after chemotherapy compared toa mean of 20.2 lymph nodes in the group undergoing surgeryfirst [42]. Factors that affect the number of lymph nodesreported include patient, surgeon, and pathologist factors. It isunlikely that lymph nodes disappear with chemotherapy,although fibrosis and decrease in size of lymph nodes canmake identification of these lymph nodes more challenging.

Conclusions

In the clinically node-negative patient, SLN biopsy isreliable following neoadjuvant chemotherapy and providesimportant prognostic information regarding response toneoadjuvant chemotherapy. It has the advantage of requir-ing only one operation and decreasing the overall numberof patients undergoing ALND. Use of dual-agent mappingand meticulous search for all SLNs is recommended todecrease the false-negative rate.

Until further information is available, in a patient docu-mented to be node positive prior to the initiation of neoadjuvantchemotherapy, an ALND is advised after the completion ofchemotherapy. For patients with inflammatory breast cancer,ALND is recommended after neoadjuvant chemotherapy.

Disclosure The authors report no potential conflicts of interestrelevant to this article.

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patients with documented node-positive breast cancer prior to theinitiation of neoadjuvant chemotherapy, followed by SLN andALND after completion of chemotherapy. It found a false-negativerate of 22%, which is why ALND remains the current standard ofcare for these patients. Lack of identification of histologic changesin the SLN may indicate false-negative SLNs.

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