Axillary Sentinel Lymph Node Biopsy After Neoadjuvant Chemotherapy for Carcinoma of the Breast

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1 Axillary Sentinel Lymph Node Biopsy After Neoadjuvant Chemotherapy for Carcinoma of the Breast Gordon F. Schwartz, MD, MBA 1 ; Jonathan E. Tannebaum, MD 1 ; Amelia M. Jernigan, MD 1 ; and Juan P. Palazzo, MD 1,2 BACKGROUND: The timing and accuracy of axillary sentinel lymph node biopsy (SLNB) in patients who are receiving neoadjuvant chemotherapy (NACT) for breast cancer are controversial. To examine the accuracy of SLNB after NACT, the authors performed SLNB after chemotherapy on all of patients who received NACT at their institution starting in January METHODS: Seventy-nine women who underwent NACT between 1997 and 2008 comprised this study and were divided as follows: 4 women had stage I disease, 60 women had stage II disease, and 15 women had stage III disease, including 10 women who had multicentric disease. Thirty-nine women (49.4%) had clinical evidence of axillary metastasis (N1-N2) at the time of diagnosis. The regimen, the duration of treatment, and the number of cycles of NACT depended on clinical response. The choice of breast conservation therapy or mastectomy was based on the patient s response to treatment and patient preference. All patients underwent SLNB after NACT. RESULTS: Seventythree patients underwent breast conservation therapy, and 6 patients underwent mastectomy. Sentinel lymph nodes were identified in 98.7% of patients (in 1 patient, SLNB failed to capture 1 proven axillary metastasis), and 29 patients underwent full axillary lymph node dissection. Fourteen patients (17.7%) had no residual carcinoma (invasive or ductal carcinoma in situ) in their breast, 5 patients (6.3%) had residual ductal carcinoma in situ (only), and 60 patients (75.9%) had residual invasive carcinoma. One false-negative SLNB was reported in the group of 23 patients who underwent full axillary dissection after a negative SLNB. No patient had a subsequent axillary recurrence. CONCLUSIONS: SLNB after NACT was feasible in virtually all patients and accurately selected patients who required complete level I and II axillary dissection. NACT frequently downstaged the axilla, converting patients with N1-N2 lymph node status to N0 status and also avoiding full axillary dissection in these patients. Cancer 2010;116: VC 2010 American Cancer Society. KEYWORDS: breast cancer, carcinoma of the breast, induction chemotherapy, neoadjuvant chemotherapy, preoperative chemotherapy, sentinel lymph node biopsy. Sentinel lymph node biopsy (SLNB) has become the international standard technique for the axillary staging of patients who have primary, operable (T1, T2, and selected T3), clinically lymph node-negative (N0) carcinoma of the breast. 1 An expert panel of the American Society of Clinical Oncology in 2005 stated that SLNB assessed axillary lymph node status with acceptable accuracy for a wide range of patients with early stage breast cancer. 2 If the SLNB is negative, then it can be presumed that the remainder of the axilla is disease-free, so that SLNB is equivalent to traditional level I and II axillary lymph node dissection (ALND) in accurately staging the axilla and minimizing axillary local recurrence. 3,4 Patients who have histologically negative SLNB alone, without further axillary surgery, have the same long-term outcomes with less morbidity and better functional outcomes than patients who undergo ALND. 5 The removal of negative lymph nodes provides no significant benefit. In addition to reduced morbidity, SLNB costs less, takes less time to perform, and is more likely to be performed on an outpatient basis than complete ALND. However, considerable variability has been reported in the false-negative rate and the failure to identify sentinel lymph nodes, emphasizing the importance of the learning curve for the SLNB procedure. 2 What constitutes appropriate training in the technique of SLNB has been addressed in numerous publications. 1,2,3,5 Corresponding author: Gordon F. Schwartz, MD, MBA, Breast Care Center, Kimmel Cancer Center, Department of Surgery, Thomas Jefferson University and Hospitals, 1015 Chestnut Street, Suite 510, Philadelphia, PA ; Fax: (215) ; gordon.schwartz@gmail.com 1 Breast Care Center, Kimmel Cancer Center, and Department of Surgery, Thomas Jefferson University and Hospitals, Philadelphia, Pennsylvania; 2 Department of Pathology, Anatomy and Cell Biology, Jefferson Medical College, Philadelphia, Pennsylvania DOI: /cncr.24887, Received: May 17, 2009; Revised: July 12, 2009; Accepted: July 14, 2009, Published online January 19, 2010 in Wiley InterScience ( Cancer March 1,

2 Neoadjuvant chemotherapy (NACT) represents the use of cytotoxic therapy as the first modality of treatment for a primary malignant tumor to downstage the primary tumor. 6 Regression of the primary tumor documents its in vivo sensitivity to chemotherapy; NACT also may permit the subsequent excision of the primary lesion with clear surgical margins, so that patients who have locally advanced breast cancer may become eligible for breast conservation therapy (BCT). 7 NACT also may clear the axilla of lymph node metastases in some patients. Significant residual lymph node metastasis after NACT has powerful prognostic value Whether NACT affects long-term survival remains contentious, but patients who achieve a complete pathologic responses apparently have better disease-free survival. 6 The optimal strategy for incorporating lymphatic mapping into NACT regimens has not been clearly defined. 11,12 Opinions differ considerably with respect to the timing of SLNB in patients who are receiving NACT, ie, before or after The American Society of Clinical Oncology expert panel concluded that there were insufficient data to recommend SLNB or to suggest the appropriate timing of SLNB for patients who are receiving preoperative systemic chemotherapy. 2 We and others contend that NACT extends the possibility of BCT without sacrificing accurate axillary staging. 27,28 Advocates of SLNB after NACT maintain that the technique is reliable and provides patients who have converted from lymph node-positive status to lymph node-negative status an alternative to complete ALND. Recommendations for SLNB before NACT generally are underpinned by the argument that post-treatment SLNB has a higher risk of failure to identify the true sentinel lymph node and an increased false-negative rate. However, we believe that SLNB after NACT is as accurate as SLNB before NACT; moreover, SLNB before NACT does not take advantage of the downstaging effect of NACT on axillary lymph nodes. Patients with positive pre-nact sentinel lymph nodes traditionally would be committed to completion ALND after NACT; therefore, at least traditionally, this approach commits the patient to 2 procedures irrespective of the final sentinel lymph node status. Confirming lymph node status before NACT, however, is of minimal value once the decision to use NACT has been made (usually on clinical grounds), whereas SLNB after NACT provides information regarding residual lymph node disease that has greater prognostic importance and may guide additional therapy. 17,20,26 The objective of the current study was to address 2 concerns regarding SLNB after NACT by reviewing 1 surgeon s experience with SLNB performed after NACT in 79 patients between January 1997, and September This study was reviewed and approved by the institutional review board. MATERIALS AND METHODS From January 1, 1997, through September 30, 2008, 79 patients who received NACT underwent SLNB after they completed NACT. All of these women were patients of the senior author (G.F.S.), a surgeon who specializes in diseases of the breast. The majority of patients presented with stage II breast cancer, tumors that measured >3.0 cm, or stage III breast cancer; tumor characteristics at diagnosis are summarized in Table 1. Axillary lymph node status was determined by clinical examination; patients had clinical N0-N2 axillae before chemotherapy. Axillary biopsy was not required to assess axillary status except in 2 patients who presented with T0N1-N2 findings. The decision to use NACT was based on findings in the breast except for these 2 patients. In our own practice, based on an internal review of our past data from complete axillary dissections (levels I, II, and III) performed during mastectomy, we have documented a 90% clinical accuracy rate (positive predictive value [PPV]) when we have called the axilla positive. However, 7 patients did have biopsy-proven axillary metastases before they received NACT, including the 2 patients who presented with T0N1-N2 cancers; 2 patients who presented after undergoing axillary biopsy or fine-needle aspiration performed elsewhere; and 3 patients who underwent axillary fine-needle aspiration to confirm the presence of metastatic disease before they would agree to NACT. The diagnosis of invasive carcinoma of the breast was confirmed by fine-needle aspiration, core biopsy, or excision of the breast lesion. The excisional biopsies had been performed elsewhere before we initially saw the patient. In these patients, NACT recommendations were made based on clinical records and pathology slides and on reports retrieved from other institutions and reviewed by us. All patients underwent initial metastatic evaluation to rule out stage IV disease. Next, patients were referred to a medical oncologist for the initiation of an NACT regimen. The NACT regimens used in this study are detailed in Table 1. Serial clinical examinations were performed by the senior author to assess response. Mammograms and occasional magnetic 1244 Cancer March 1, 2010

3 SLNB After Neoadjuvant Chemotherapy/Schwartz et al Table 1. Patient Characteristics, Treatment, and Microscopic Findings Characteristic No. of Patients Median age [range], y 50 [33-71] TNM stage of disease at presentation (all patients were M0) a T0N1 1 T0N2 1 T1N0 4 T1N1 4 T2N0 31 T2N1 20 T2N2 2 T3N0 4 T3N1 4 T3N2 2 T4N0 1 T4N1 2 T4N2 3 Chemotherapy regimen AC 27 CAF 9 AC1T 32 TA 6 CAFT 1 TC 4 Herceptin (in addition to chemotherapy) 11 Final pathologic diagnosis (after neoadjuvant chemotherapy) ID 34 DCIS 5 ID1DCIS 16 ID1tubular 1 IL 4 IL1LCIS 1 ID1IL 1 A indicates doxorubicin (Adriamycin); C, cyclophosphamide; F, 5- fluorouracil; T, paclitaxel (taxol); ID, invasive ductal carcinoma, not otherwise specified; DCIS, ductal carcinoma in situ; IDþtubular, invasive ductal carcinoma, tubular type; IL, invasive lobular carcinoma; LCIS, lobular carcinoma in situ. a All TNM staging is based on the American Joint Committee on Cancer Cancer Staging Manual, 6th edition, 2002 (see Green ). resonance imaging studies also were used selectively. Once a complete clinical remission had been achieved or the planned NACT regimen had been completed, definitive surgical treatment was recommended. Early in this study, the number of cycles used was variable, because we tried to achieve a plateau of response; however, since 2003, the maximum number of cycles has been 8 (with 2 exceptions). The median number of cycles was 6. At the completion of NACT, a surgical recommendation was made based on response to treatment, ie, BCT or mastectomy. In general, BCT was used when the residual tumor was small enough to be excised with a clear margin and with an acceptable cosmetic result. If the residual tumor was too large or the breast was too small, then mastectomy was recommended. SLNB was performed to assess axillary status in all patients, either at the start of the mastectomy or, in patients who underwent BCT, after there was histologic proof of the successful local excision of the residual carcinoma. Three milliliters of isosulfan blue dye (1%) were injected into the patient s breast with at least 1 ml injected intradermally and the rest injected into the parenchyma of the breast, peritumorally but outside the biopsy cavity. During a brief period when isosulfan blue was unavailable, 5 ml methylene blue dye were used instead. Either dye injection was followed by 4 to 7 minutes of massage. Clinical assessment by the senior author, location of the primary tumor, and the patient s body mass index determined variations in massage time. Early in the study, 5 patients also were mapped with technetium-99 radioisotope, but our success with blue dye alone (>98%) in identifying sentinel lymph nodes allowed the remaining patients to be mapped with blue dye alone. The skin incision was made in a skin fold in the lower one-third of the hair-bearing area of the ipsilateral axilla, starting behind the edge of the pectoralis major muscle and ending in front of the latissimus dorsi muscle. Efferent, blue-stained lymphatic channel(s) were identified and traced to sentinel lymph nodes, defined as any blue-stained lymph node package into which a blue lymphatic vessel drained. If a contiguous, nonstained lymph node was identified, then it also was excised. The senior surgeon personally prosected the specimen in the surgical pathology laboratory to retrieve the sentinel lymph node, and a dedicated technician prepared each frozen section (FS). Patients also had their specimens stained with hematoxylin and eosin (H&E) and cytokeratin after formalin fixation. Before 2003, because we were in the learning curve of SLNB after NACT, all patients underwent completion ALND. After we were satisfied with our accuracy in the identification of sentinel lymph nodes, only those patients who had positive sentinel lymph nodes underwent ALND. In all patients, the sentinel lymph nodes and the residual axillary specimens were processed separately. RESULTS Between 1997 and 2008, 79 women were enrolled in the current study. Patient characteristics are listed in Table 1. Cancer March 1,

4 The median age at presentation was 55 years (range, years). Fifty-three women (67.1%) presented with T2 tumors, 10 women (12.6%) presented with T3 tumors, and 6 women presented with T4 tumors (7.6%). The 4 patients with T1 tumors had more than 1 tumor in the breast, and their tumor classification was defined by the size of the largest tumor. Thirty-nine patients (49.4%) presented with palpable axillary lymph nodes that were considered clinically involved by tumor; 31 of those 39 patients had clinical N1 status, and 8 of those 39 patients had clinical N2 status. All patients received cyclic chemotherapy given every 2 or 3 weeks. From 3 to 17 cycles of NACT were administered. Chemotherapy details are listed in Table 1. After the completion of NACT in these 79 patients, the clinical response of 7 patients could not be determined because they had undergone an initial (unsuccessful) attempt at excising the primary tumor. Of the remaining 72 patients, 12 patients (16.7%) had a complete clinical response, which was defined as complete disappearance of the primary tumor on physical (and radiologic) examination. Fifty-two patients (72.9%) had a partial clinical response, which was defined as a decrease 30% in the greatest tumor dimension. Eight patients (11.4%) had a decrease <30% in their greatest tumor dimension. After NACT, the clinical lymph node status of 75 patients was documented. One patient had an equivocal lymph node status, 2 patients had no documentation of post-nact lymph node status in their chart, and 1 patient s lymph node status could not be assessed because of scar tissue from a previous axillary procedure. Of the remaining 75 patients who had clinical measurement of lymph node status after NACT, 62 patients (82.7%) had clinically negative lymph nodes, 10 patients (13.3%) had clinically involved lymph nodes that measured <1 cm in greatest dimension, and 3 patients (4%) had lymph nodes that measured >1 cm. Of the 39 patients who had clinically positive lymph nodes (N1-N2) at presentation, the lymph node status after NACT in 2 patients was equivocal. Of the remaining 37 patients who initially had positive lymph nodes, 26 patients (70.3%) converted to clinically negative lymph node status (N0), and 11 patients (29.7%) retained their clinically positive lymph node status after NACT. After chemotherapy, 12 of 79 patients (15.2%) were considered complete clinical responders, which we defined as having no clinical signs of disease in the breast or axilla. All 79 patients underwent SLNB using blue dye; in 76 patients, isosulfan blue dye was used, and 3 patients were mapped with methylene blue. After SLNB, 29 patients underwent level I and II axillary dissection, either because of a positive lymph node or during the learning curve period mentioned above. Twenty-three patients were in the learning curve of the study, so that each of them underwent level I and II dissection after SLNB, irrespective of their sentinel lymph node findings on FS. All patients underwent either local excision of the residual carcinoma or mastectomy with microscopic examination of tissue according to the College of American Pathologists protocol. 29 Six patients underwent mastectomy because BCT was untenable, including 3 women who had multicentric carcinoma and 3 women in whom the residual tumor was too large in relation to the size of the breast to use BCT with a satisfactory cosmetic result. These patients underwent SLNB as the first step in mastectomy through a separate, small axillary incision and had intraoperative examination (FS) of sentinel lymph nodes. We previously documented our favorable experience with FS examination of sentinel lymph nodes. 30 Fourteen patients (17.7%) had a complete pathologic response to NACT with no evidence of invasive or in situ carcinoma in the specimen at the time of definitive surgical treatment, 5 patients (6.3%) had residual ductal carcinoma in situ only with no residual invasive carcinoma, and 60 patients (75.9%) had residual invasive carcinoma. There was a discrepancy in theses rates when comparisons were made between clinical and pathologic responses. Two patients who had partial clinical responses actually did have microscopic complete responses. In those patients, the residual palpable disease at the site was tissue reaction or scar formation after chemotherapy. The final pathology for the remaining patients is noted in Table 1. Sentinel lymph nodes were identified in 78 of 79 patients, an identification rate of 98.7%. H&E staining of formalin-fixed tissue was performed on all sentinel lymph nodes. In the 78 successful SLNBs, a median of 3 sentinel lymph nodes (range, 1-9 sentinel lymph nodes) were identified. Twenty-three SLNBs yielded at least 1 sentinel lymph node that was positive for metastasis. Fifty-five SLNBs were negative for metastatic disease. A false-negative SLNB was defined as an SLNB that was negative for metastases but had axillary lymph node involvement documented either by further ALND or by axillary recurrence of disease. There was 1 false-negative (early) in this series in which 1 sentinel lymph node was identified as negative for metastatic disease on H&E, 1246 Cancer March 1, 2010

5 SLNB After Neoadjuvant Chemotherapy/Schwartz et al staining; however, on further ALND, 23 additional lymph nodes were removed, including 2 that were positive for metastatic disease (1 micrometastasis and 1 macrometastasis). Thus, among the patients who underwent completion dissection although they had negative sentinel lymph nodes, SLNB failed to capture 1 of 12 patients with proven axillary metastasis, yielding a negative predictive value (NPV) of 92.3% for the group that underwent completion axillary dissection, defining false-negative in this context as negative sentinel lymph nodes but positive nonsentinel lymph nodes on completion dissection. For the entire series of patients, specificity and PPV, by default, were 100%, because sentinel lymph node involvement, by definition, is lymph node involvement regardless of the status of the remaining axilla. If the same NPV were to be valid for the entire group that was valid for the patients who underwent full axillary dissection during the learning phase, then a truly negative SLNB would have occurred in 51 of 55 patients who had negative sentinel lymph nodes. Intraoperative FS was performed in 69 patients, and the results were recorded to measure the accuracy of FS after NACT. On FS analysis, there were 52 negative SLNBs and 15 positive SLNBs. Of 52 FS-negative patients, 49 patients were confirmed as negative on microscopic examination of formalin-fixed tissue, so the PPV for an FS that was called negative was 93%. No patient had a false-positive FS. The sentinel lymph node was the only positive lymph node in 6 of 18 patients with proven metastasis who underwent completion ALND. All patients have been followed by the senior author. At a median followup of 62 months, no patient has experienced an axillary lymph node recurrence. DISCUSSION Although the sentinel lymph node may accurately reflect axillary status before chemotherapy, there is only modest evidence supporting the accuracy of SLNB after chemotherapy. In general, SLNB without accompanying level I and II dissection has not been performed on patients with clinical evidence of axillary lymph node disease (Nþ) at diagnosis, even when the axillary status has been downstaged by treatment. Some authors regard the downstaging of clinically positive axillary lymph nodes to clinically lymph node-negative disease by NACT as a contraindication to SLNB, invoking possible alteration of intramammary lymphatic drainage, potentially multiple obscured and undetected sources of lymphatic drainage for larger tumors, and possible nonuniform cytotoxic response of axillary metastases. 12,15,21,31,32 Critics of post-nact SLNB also have suggested that SLNB can no longer accurately assess axillary status. They allege that, although NACT may eradicate micrometastases, it only reduces the size of nonsentinel lymph node macrometastases. This implies that, although SLNB correctly can identify axillary lymph node status in most patients after NACT, some patients may be under staged because of nonuniform responses within sentinel lymph nodes and nonsentinel axillary lymph nodes. 33 Supporting this position are several studies that demonstrated an unacceptably high false-negative rate when SLNB followed NACT (with false-negative defined as a negative sentinel lymph node but positive lymph nodes elsewhere in the axilla documented at completion dissection). 3,11,34 However, these allegations of treatment-related alterations in lymphatic architecture, function, and reliability have not been confirmed. 35 Statistical analysis is complicated by the small sample sizes in published series. The recommendation for NACT usually is made based on clinical, patient, and tumor characteristics, not on the proven microscopic status of the axillary lymph nodes. Consequently, SLNB results contribute only minimally when the procedure is performed before NACT. 9,26 Therefore, patients who have microscopically positive sentinel lymph nodes pretreatment that respond completely to NACT would undergo needless completion ALND. The majority of patients do achieve significant regression of both the primary tumor and axillary metastases, and clinical evidence of axillary lymph node involvement often is changed (ie, downstaged, ) by NACT. Therefore, we believed that it was reasonable and appropriate to examine the role of SLNB in patients, almost regardless of axillary status after NACT, but certainly in those patients who had clinically negative lymph nodes (N0) after NACT. The addition of ultrasound to the assessment of the axilla has been suggested but has not yet received universal acceptance. 6,36 If ultrasound were used with fine-needle aspiration biopsy of suspicious lymph nodes to document the persistence of axillary metastasis after NACT, then patients either could undergo traditional ALND without the preliminary step of SLNB (if they had positive lymph nodes), or they still could undergo SLNB to assess the response of proven lymph node disease to NACT. 37 Two crucial issues have been addressed in this study, namely, whether sentinel lymph nodes can be identified Cancer March 1,

6 Table 2. Simple Trials Reference Year No. of Patients Method SLN Detected: No. (%) Sensitivity False-Negative Results: No. (%) NPV, % Accuracy, % Gimbergues TC (93.8) 86 8 (14.3) Lee TC-99BD 170 (77.6) 94 7 (5.6) Shen TC-99BD 64 (92.8) (25) Kinoshita TC-99BD 72 (93.5) 89 3 (11.1) Jones TC-99BD 29 (81) 89 2 (11) Mamounas TC-99BD 363 (84.8) (10.7) Tanaka BD 63 (90) 95 1 (5) Kang TC-99BD 39 (72.2) 89 3 (11.1) Patel TC-99BD 40 (95) 89 0 (0) Shimazu TC-99þBD 44 (94) 88 4 (12.1) Piato TC (97.6) 83 3 (17) Reitsamer TC-99þBD 26 (86.7) 93 1 (7) Julian TC-99BD 31 (91.2) (0) SLN indicates sentinel lymph node; NPV, negative predictive value; TC-99, technetium-99m (radioisotope); BD, blue dye;, with or without. reliably after neoadjuvant chemotherapy and whether sentinel lymph nodes that are identified after NACT reliably predict axillary lymph node status. With respect to the first issue, we have achieved a detection rate of 98.7%. In 78 of 79 patients, blue dye identified at least 1 sentinel lymph node. Currently, achieving a detection rate 90% is suggested before surgeons who are learning the procedure perform SLNB without concurrent ALND. 2,5 Table 2 summarizes other investigators results with SLNB after induction chemotherapy. Other investigators also reported detection rates of % after induction chemotherapy, 23,38,39 as shown in Table 2. These data and ours suggest that a detection rate 90% is attainable. Sentinel lymph node identification is considered a function of surgeon experience. 5,21 In the current study, all sentinel lymph node biopsies were performed by 1 experienced surgeon. This differs from other studies in which the experiences of multiple surgeons using multiple techniques over a protracted period were combined. Breslin et al documented surgeon experience as an important factor in sentinel lymph node identification and reported improvements from 65% to 94% in their own identification rates over time. 40 In our review of articles that detailed authors experience with SLNB before and after NACT, in general, the authors who were been most critical of post-nact SLNB had smaller series of patients, and the articles were dated earlier than those advocating post-nact SLNB. Whether the same observations and conclusions would be warranted after a longer period of time and experience with a greater number of patients is speculative. Our own observations and conclusions clearly were justified more after we had performed 58 more surgeries. 27 We have demonstrated clearly that sentinel lymph node detection is feasible in patients after induction chemotherapy. A review of the literature revealed the ability of other investigators to achieve detection rates >90%. Therefore, we also conclude that NACT per se does not affect the identification of sentinel lymph nodes. Although the various techniques used for SLNB usually are considered comparable, isosulfan blue dye was the only method used in this series except for the few patients who were treated when it was not available and methylene blue was substituted and the initial 5 patients for whom we used both dye and radiocolloid. Other investigators have used various combinations of blue dye and technetium-99 in intradermal, peritumoral, and subareolar injections. 4,31,41,42 In all likelihood, surgeon experience and comfort with a particular technique is more important than the technique itself with regard to sentinel lymph node identification. Because the 98.7% detection rate achieved in the current series was accomplished using blue dye only after the first 5 patients, we cannot comment on the validity of other techniques in patients who are receiving neoadjuvant chemotherapy. However, we would expect the accuracy to be the same in the same experienced hands, irrespective of the technique chosen. The second issue we addressed was the accuracy of SLNB. The technique is useful only if the histopathology of the identified sentinel lymph node accurately reflects axillary lymph node status. The most significant failing of SLNB is the false-negative finding in which the sentinel lymph node is negative but metastases are present in other 1248 Cancer March 1, 2010

7 SLNB After Neoadjuvant Chemotherapy/Schwartz et al axillary lymph nodes. SLNB false-negative rates after chemotherapy ranged from 0% to 25%, as summarized in Table 2. We encountered 1 such false-negative result in a patient aged 45 years who presented initially with a T2N2 lesion. After 5 cycles of combined chemotherapy with doxorubicin and cyclophosphamide (AC), the primary tumor appeared to regress completely, although axillary lymph nodes remained palpable. After consultation with the medical oncology team, the patient received 3 additional cycles of paclitaxel in an attempt to achieve axillary remission as well. After this treatment, the axilla became clinically negative. SLNB identified 1 sentinel lymph node in the axilla. Although the sentinel lymph node was negative for any macroscopic or microscopic evidence of metastatic disease, completion axillary dissection revealed that 2 of 23 lymph nodes harbored metastatic invasive ductal carcinoma. This failure may be attributable to the disparity in response between the primary lesion and the axillary lymph nodes. The chemotherapeutic regimen was altered, because the axilla was refractory to cyclic AC therapy. If the same NPV were to be valid for the entire group that was valid for the patients who underwent full axillary dissection during the learning phase, then a truly negative SLNB would have occurred in 51 of the 55 sentinel lymph node-negative patients, as noted above. (If we had gone directly to axillary dissection without the attempt at SLNB in this 1 patient noted above, then our NPV for 78 patients would have been 100%.) For the entire series of patients, the PPV, by default, was 100%, because sentinel lymph node involvement, by definition, is lymph node involvement regardless of the status of the remaining axilla. Stearns et al reported 3 false-negative results, all in patients who received paclitaxel. 43 Whether this implies a relation between the drug used and the failure to detect axillary disease accurately is speculative but unlikely. The published proceedings of a 2001 consensus conference devoted to SLNB proposed that surgeons should conduct concomitant ALND until they achieve a falsenegative rate <5%. 5 Other experts have proposed similar cutoffs in the ongoing debate concerning SLNB learning curves and accreditation. Cox et al suggest that surgeons perform 20 sentinel lymph node biopsies with 1 falsenegative results before they discontinue using confirmatory axillary dissection. 13 In reviewing the literature that addresses SLNB and NACT, small sample size and its effect on outcome calculations are apparent. The 13 trials summarized in Table 2 averaged 98 patients (range, patients). In our own study, the small sample size was even more important, because the false-negative rate was calculated based on the number of patients who had residual disease in the axilla after chemotherapy. In our experience, this was a single patient who received a different course of treatment than the others in our group. Our own results also challenge the proposition that NACT should be considered a contraindication to SLNB, because at least 1 sentinel lymph node was identified in all 79 patients. The involved sentinel lymph node was the only lymph node that contained metastatic disease in 6 of 18 patients (33.3%) who had biopsy-proven axillary involvement. Other series reported this observation in 17% to 46% of patients. 13,42 Currently, the importance of this observation is uncertain. Although this may simply reflect the more careful processing to which the sentinel lymph node is subjected, it validates the assumption that the sentinel lymph node accurately predicts the status of the entire axilla. This finding also refutes the suggestion that the sentinel lymph node may be downstaged preferentially by chemotherapy, yielding a high false-negative rate. Further studies may elucidate the precise role of SLNB after induction chemotherapy, but the current results suggest that initial reports demonstrating an unacceptable false-negative rate should not dissuade surgeons from attempting SLNB under these circumstances. Experienced practitioners may detect the sentinel lymph node(s) regardless of preoperative chemotherapy. Moreover, low false-negative rates are attainable in this setting. Induction chemotherapy should not relegate clinically N0 patients after NACT to the morbidity of ALND. Encouraged by these results, we have abandoned automatic complete (levels I and II) ALND in patients who are receiving induction chemotherapy whose axillae are considered clinically negative after their chemotherapy, irrespective of their lymph node status before embarking on NACT. We perform SLNB on each of these patients after NACT, using the results from the biopsy to influence our decision for completion dissection. With a median follow-up of slightly more than 5 years, we have not encountered an axillary recurrence, although we recognize the relatively short-term period of follow-up observation. However, we believe that this observation (ie, the absence of axillary recurrence) is a reasonable surrogate for a truly negative SLNB, notwithstanding the unavoidable irradiation to the low axilla as part of the radiation fields when the whole breast is radiated, which can affect residual lymph node tissue at level I and often at level II as well. Cancer March 1,

8 In summary, we have demonstrated not only that the SLNB after neoadjuvant chemotherapy is not only a reasonable treatment option with a high likelihood of success but also that the accuracy of this procedure is likewise high enough to make SLNB after NACT the appropriate choice when the axilla has been downstaged to N0 status. In our experience, this is valid regardless of the findings at initial presentation. CONFLICT OF INTEREST DISCLOSURES The authors made no disclosures. REFERENCES 1. James TA, Edge SB. Sentinel lymph node in breast cancer. Curr Opin Obstet Gynecol. 2006;18: Lyman GH, Giuliano AE, Somerfield MR, et al. American Society of Clinical Oncology guideline recommendations for sentinel lymph node biopsy in early stage breast cancer. J Clin Oncol. 2005;23: Noguchi M. Current controversies concerning sentinel lymph node biopsy for breast cancer. Breast Cancer Res Treat. 2004;84: Naik AM, Fey J, Gemignani M, et al. 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