Sentinel Lymph Node Biopsy Is Accurate After Neoadjuvant Chemotherapy for Breast Cancer By Tara M. Breslin, Lisa Cohen, Aysegul Sahin, Jason B. Fleming, Henry M. Kuerer, Lisa A. Newman, Ebrahim S. Delpassand, Rosalyn House, Frederick C. Ames, Barry W. Feig, Merrick I. Ross, S. Eva Singletary, Aman U. Buzdar, Gabriel N. Hortobagyi, and Kelly K. Hunt Purpose: Sentinel lymph node (SLN) biopsy has proved to be an accurate method for detecting nodal micrometastases in previously untreated patients with early-stage breast cancer. We investigated the accuracy of this technique for patients with more advanced breast cancer after neoadjuvant chemotherapy. Patients and Methods: Patients with stage II or III breast cancer who had undergone doxorubicin-based neoadjuvant chemotherapy before breast surgery were eligible. Intraoperative lymphatic mapping was performed with peritumoral injections of blue dye alone or in combination with technetium-labeled sulfur colloid. All patients were offered axillary lymph node dissection. Negative sentinel and axillary nodes were subjected to additional processing with serial step sectioning and immunohistochemical staining with an anticytokeratin antibody to detect micrometastases. Results: Fifty-one patients underwent SLN biopsy after neoadjuvant chemotherapy from 1994 to 1999.

The SLN identification rate improved from 64.7% to 94.1%. Twenty-two (51.2%) of the 43 successfully mapped patients had positive SLNs, and in 10 of those 22 patients (45.5%), the SLN was the only positive node. Three patients had false-negative SLN biopsy; that is, the sentinel node was negative, but at least one nonsentinel node contained metastases. Additional processing revealed occult micrometastases in four patients (three in sentinel nodes and one in a nonsentinel node). Conclusion: SLN biopsy is accurate after neoadjuvant chemotherapy. The SLN identification improved with experience. False-negative findings occurred at a low rate throughout the series. This technique is a potential way to guide the axillary treatment of patients who are clinically node negative after neoadjuvant chemotherapy. J Clin Oncol 18:3480-3486. © 2000 by American Society of Clinical Oncology.

XILLARY LYMPH NODE dissection (ALND) is the standard of care for the nodal staging of patients with invasive breast cancer.1 Routine level I/II ALND provides prognostic information, may guide subsequent chemotherapy and radiotherapy treatment decisions in many patients with early-stage breast cancer, and achieves durable regional control in patients with axillary disease. Despite the utility of ALND, it can result in complications such as lymphedema and nerve injury. ALND may be unnecessary for patients without axillary disease and less critical for those patients who receive systemic treatment based on other prognostic indicators.2,3 Because indications for systemic cytotoxic chemotherapy have broadened to include all invasive tumors larger than 1 cm regardless of axillary

status, there is increasing interest in treating patients with stage II and III breast cancer with neoadjuvant chemotherapy.4 In early-stage breast cancer, when there is a lower likelihood of lymph node metastases, lymphatic mapping and sentinel lymph node (SLN) biopsy is an accurate predictor of the axillary nodal status.5-7 SLN biopsy seems feasible in a wide range of patients with clinically negative nodes, and it is currently being used for axillary staging and as a guide for subsequent therapy decisions in patients with early-stage disease.8 Previously, patients with larger tumors, previous excisional biopsies, or inner-quadrant lesions were thought to be poor candidates for lymphatic mapping and SLN biopsy.9,10 Experience with the technique has shown that all of these patient groups can successfully undergo SLN biopsy and that the main predictor of success with the procedure is the surgeon’s experience with the technique.5,11 The advantage of neoadjuvant chemotherapy is that it allows for an in vivo evaluation of response of the primary tumor to the chemotherapeutic agents. In this way, patients with tumors that do not respond can be offered alternate chemotherapy regimens, and patients with responding tumors may be candidates for less aggressive surgical therapies. Additionally, as a result of tumor downstaging many of the responding patients are able to undergo breastconserving treatments.12,13 Neoadjuvant chemotherapy has

A

From the Departments of Surgical Oncology, Pathology, Breast Medical Oncology, and Nuclear Medicine, University of Texas M.D. Anderson Cancer Center, Houston, TX. Submitted January 21, 2000; accepted June 6, 2000. Supported in part by a grant from BioGenex Corporation, San Ramon, CA. Address reprint requests to Kelly K. Hunt, MD, Department of Surgical Oncology, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Box-106, Houston, TX 77030; email khunt@ mail.mdanderson.org. © 2000 by American Society of Clinical Oncology. 0732-183X/00/1820-3480

3480

Journal of Clinical Oncology, Vol 18, No 20 (October 15), 2000: pp 3480-3486

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SLN BIOPSY ACCURATE AFTER CHEMOTHERAPY

also been shown to eradicate biopsy-proven axillary metastases as well as primary tumors in patients with large primary and locally advanced breast cancer.14 The axillae of these patients are often rendered clinically and pathologically negative by neoadjuvant chemotherapy. These patients, in theory, might not require an axillary lymph node dissection. In this study, we evaluated the feasibility and accuracy of SLN biopsy after neoadjuvant chemotherapy. Specifically, we sought to answer two questions: 1) Can the SLN reliably be identified after neoadjuvant chemotherapy? 2) Does the disease status of the SLN as determined by histologic examination accurately predict the axillary nodal status? PATIENTS AND METHODS Between 1994 and 1999, all patients who had lymphatic mapping and SLN biopsy as components of their treatment for breast cancer at the University of Texas M.D. Anderson Cancer Center were enrolled in a database. Surgical and pathologic data were gathered on all patients. Patients with T1N1M0 or T2-3N0-1M0 breast cancer were eligible for neoadjuvant chemotherapy, and for the current study, all patients who had lymphatic mapping and SLN biopsy after neoadjuvant chemotherapy were evaluated. Patients had clinical and radiographic assessment before treatment, including chest x-ray, liver function tests, liver imaging, bone scan, diagnostic mammography, and ultrasound of the breast and regional nodal basins. All biopsies performed at outside institutions were confirmed before initiation of treatment. Fine-needle aspiration (FNA) biopsy was performed for clinically or ultrasonographically suspicious axillary nodes. Patients were reviewed by a multidisciplinary team before chemotherapy and again after three to four cycles of therapy. Patients desiring breast-conserving treatment whose primary tumor response would permit breast-conserving treatment with acceptable cosmesis and negative surgical margins were offered this option. If these criteria could not be met, then modified radical mastectomy was recommended. To evaluate the feasibility of SLN biopsy in this particular population, patients with or without residual adenopathy after neoadjuvant therapy were included in this analysis. Intraoperative lymphatic mapping was performed with peritumoral injections of blue dye alone or in combination with technetium-labeled sulfur colloid. Only those lymph nodes with blue dye uptake and or radioactivity as detected with use of an intraoperative gamma probe were labeled as sentinel nodes. Abnormal appearing lymph nodes were sent to pathology as nonsentinel axillary lymph nodes or included as part of the axillary dissection specimen. Patients received four injections around the primary tumor or excisional biopsy site, and patients with nonpalpable tumors were injected under mammographic or ultrasound guidance. All patients were offered concomitant completion axillary lymph node dissection. In the first 31 successful mapping cases, negative SLNs and negative axillary nodes were subjected to serial step sectioning and immunohistochemical staining with an anticytokeratin antibody cocktail (BioGenex AE1/AE3, San Ramon, CA) to detect micrometastases. Two pathologists (A.S. and L.C.) reviewed these specimens. The remaining patients underwent SLN biopsy followed by axillary lymph node dissection with serial sectioning of the SLNs only. In this group, immunohistochemical analysis was used only to confirm malignancy in cells with a suspicious appearance. A false-negative finding was defined as a negative SLN in a patient

with disease detected in at least one non-SLN. The overall falsenegative rate was determined by the following formula: (no. of patients with false-negative SLN)/(no. of patients with any axillary metastases) ⫻ 100.

RESULTS

Patient and Tumor Characteristics There were 51 patients who received neoadjuvant therapy and underwent attempted SLN biopsy as part of their surgical treatment. The median age at the time of diagnosis was 45 years (range, 25 to 68 years). Biopsy was obtained through FNA of the breast and an axillary lymph node in six patients, core needle biopsy of the breast in 35 patients, excisional breast biopsy in five patients, and incisional breast biopsy in five patients. In the patients who were diagnosed using FNA of the breast, needle biopsy of the axilla proved the presence of invasive disease by confirming axillary lymph node metastases. Clinical stage at diagnosis was IIa in 25 patients, IIb in 12 patients, and IIIa in 14 patients. At the time of initial evaluation, the median tumor size in the 41 assessable patients was 5.0 cm (range, 1.0 to 13.0 cm). Ten patients had tumors that could not be evaluated at presentation because of previous excisional or incisional biopsy. Nineteen patients had palpable axillary lymph nodes at presentation. Sixteen patients with clinically palpable or sonographically abnormal lymph nodes were evaluated with FNA, and 14 of these patients were positive for malignant cells (Table 1). To determine which patients were the best candidates for the procedure, all patients (even those patients with residual axillary adenopathy after neoadjuvant chemotherapy) were included in this analysis. Neoadjuvant Therapy Thirty-five patients were treated with fluorouracil, cyclophosphamide, and doxorubicin (FAC), two patients with high-dose FAC, eight patients with paclitaxel followed by FAC, five patients with doxorubicin plus docetaxel, and one patient with tamoxifen. The majority of patients (n ⫽ 43) received four cycles of chemotherapy before surgery (six patients had three cycles, one patient had two cycles, and one patient had one cycle). In the 41 patients with measurable disease in the breast, the median clinical tumor size was reduced from 5.0 cm to 2.0 cm (all but one of the patients demonstrated a decrease in size of the primary tumor). Only six of the 19 patients with palpable disease had residual axillary adenopathy (palpable or sonographically detectable) after chemotherapy. After 3 to 4 weeks of postoperative recovery, all patients received an additional four cycles of adjuvant chemotherapy and radiotherapy to either the breast (for patients undergoing breast-conserving therapy) or the chest wall and regional lymph nodes, as indicated.

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3482 Table 1.

BRESLIN ET AL Patient and Tumor Characteristics Before Chemotherapy

Characteristic

Median age, years Median tumor size, cm Tumor location UOQ UIQ LOQ LIQ Central Diagnostic biopsy technique Core needle FNA primary ⫹ FNA LN Excisional Incisional Histology of primary tumor Infiltrating ductal Infiltrating lobular Mixed ductal and lobular Mucinous Medullary Palpable axillary nodes Positive axillary FNA

Table 2.

Surgical Treatment and Results of SLN Biopsies

No. of Patients

Patients No.

45 5.0 27 12 6 2 4

35 6 5 5 44 4 1 1 1 19 14

Abbreviations: LN, lymph node; UOQ, upper outer quadrant; UIQ, upper inner quadrant; LOQ, lower outer quadrant; LIQ, lower inner quadrant.

Surgical Treatment and Pathologic Results Forty-one patients underwent breast-conserving surgery, and 10 underwent modified radical mastectomy. Of the patients who had breast conservation surgery, 38 underwent completion axillary dissection, and three patients declined completion axillary dissection. Twenty-four patients underwent tumor localization with either mammography or ultrasound because of nonpalpable or indistinctly palpable tumors. Twenty-eight patients (54.9%) had histologically positive axillary nodes (Table 2). The median residual histopathologic tumor size was 1.6 cm (range, 0.0 to 6.0 cm) in 41 assessable patients. The remaining 10 patients were not assessable after chemotherapy because they had undergone complete or partial resection of the primary tumor as part of their initial diagnostic evaluation. Twelve of the 14 patients with positive FNA biopsies of the axillary lymph nodes before chemotherapy had persistently positive lymph nodes on final histologic examination (10 SLNs and two axillary nodes); seven of the patients (70%) with positive SLNs had additional positive nodes. The pathologic status of SLNs and non-SLNs is summarized in Table 3. Lymphatic Mapping Fifty-one patients underwent attempted lymphatic mapping and SLN biopsy. Blue dye alone was used for

Type of surgery Segmental mastectomy ⫹ SLNBx ⫹ ALND Segmental mastectomy ⫹ SLNBx Modified radical mastectomy ⫹ SLNBx Intraoperative mapping technique Dye alone Dye ⫹ radioactive colloid SLN identified* Positive SLN SLN-only positive node

%

38 3 10 23 28 43 22/43† 10/22†

84.3 51.2 45.5

Abbreviation: SLNBx, sentinel lymph node biopsy. *Median number of SLNs per patient ⫽ 2. †No. of patients/total no. of patients.

lymphatic mapping in the first 23 patients, and after 1997, a combination of blue dye and technetium-labeled sulfur colloid was used to identify SLNs. Overall, there were 43 successful (84.3%) and eight unsuccessful (15.7%) mapping cases. For purposes of discussion, the patients were grouped chronologically into three groups: group 1 (patient nos. 1 to 17), group 2 (patient nos. 18 to 34), and group 3 (patient nos. 35 to 51) (Fig 1). The SLN identification rates in each group were as follows: group 1, 64.7%; group 2, 94.1%; and group 3, 94.1%. In seven (87.5%) of the eight unsuccessful cases, blue dye alone was used for SLN localization, and six (75.0%) of these eight cases occurred in the earliest part of our experience (group 1). Six of the patients in which mapping was unsuccessful had nonpalpable tumors at the time of surgery, and the mapping agent was injected under ultrasound guidance. Another patient had a large resolving hematoma resulting from an excisional biopsy, and yet another proved to have a multifocal tumor that, on permanent histologic examination of the breast, had replaced most of the breast parenchyma. Three of the eight patients had

Table 3.

Pathologic Status of Sentinel Nodes and Axillary Nodes* No. of Axillary Nodes

Sentinel nodes Positive Negative Total

Positive

Negative

Total No.

22 3 25

NA 18 18

22 21 43

Abbreviations: NA, not applicable; TP, true positive; TN, true negative; FN, false negative; PPV, positive predictive value; NPV, negative predictive value. *Sensitivity: TP/(TP ⫹ FN) ⫽ 22/25 ⫽ 88%; Specificity: TN/(TN ⫹ FP) ⫽ 18/18 ⫽ 100%; PPV: TP/(TP ⫹ FP) ⫽ 22/22 ⫽ 100%; NPV: TN/(TN ⫹ FN) ⫽ 18/21 ⫽ 90%; Accuracy: (TP ⫹ TN)/no. of cases ⫽ (22 ⫹ 18)/43 ⫽ 93%.

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SLN BIOPSY ACCURATE AFTER CHEMOTHERAPY

Fig 1. SLN identification rate as a function of time. There was one false-negative event in each group.

four or more positive nodes on axillary dissection. Although three of the eight unsuccessful mapping cases had palpable adenopathy at the beginning of chemotherapy, none had palpable axillary nodes at the time of surgery (Table 4). In the 43 patients who underwent successful mapping procedures, there was a median of two SLNs removed per patient (range, one to five SLNs), and there were 22 patients (51.2%) with at least one positive SLN. In 10 patients (45.5%), the SLN was the only positive node. Three patients had false-negative findings (the SLN was negative, and there were positive non-SLNs). One false-negative event occurred in each of the three time periods, with an overall false-negative rate calculated at 12.0%. Two of the patients with a false-negative SLN biopsy presented with axillary adenopathy, and both of these patients continued to have abnormal lymph nodes after chemotherapy. Blue dye alone was used for two of the three cases with a false-negative SLN. Further pathologic evaluation of the false-negative cases revealed fibrosis and xanthomatous reaction consistent with therapy effect in an SLN from one case and atypical cells in an axillary lymph node that stained positive for keratin in another case. The presence of these atypical

Table 4. Patient No.

1 2 3 4 5 6 7 8

Histology

Invasive Invasive Invasive Invasive Invasive Invasive Invasive Invasive

ductal ductal ductal ductal ductal lobular ductal lobular

cells would suggest that these nodes were involved with metastatic tumor cells before chemotherapy. The third patient had no evidence of therapy effect in either the SLNs or non-SLNs (Table 5). In three cases, the SLNs were noted intraoperatively to be enlarged. One of these patients had two positive SLNs with metastatic foci of 0.1 cm and 0.4 cm each. There was no evidence of therapy effect or fibrosis in either of the other two patients. All negative SLNs and non-SLNs from the first 31 successful mapping procedures were re-evaluated using serial step sectioning and immunohistochemical staining for cytokeratin to detect occult micrometastatic disease. A total of 300 negative lymph nodes were re-examined for this study (45 negative SLNs and 255 negative non-SLNs). Four initially negative lymph nodes (three SLNs and one nonSLN) were converted from negative to positive status using serial sectioning and immunohistochemical analysis. In three of the four patients in whom occult lymph node metastases were detected, the metastatic foci were less than 0.5 mm in the sections studied. The fourth patient had a small cluster of metastatic cells. DISCUSSION

The results of this study indicate that lymphatic mapping and SLN biopsy are accurate techniques in breast cancer patients who are treated with neoadjuvant chemotherapy. In the current study of 51 patients who had SLN biopsy after neoadjuvant chemotherapy, the overall SLN identification rate was 84.3%. Although this identification rate is lower than that reported in current studies of early-stage breast cancer cases, it reflects the learning curve associated with the procedure.6,11,15,16 Our identification rate of 94.1% in the last 34 patients is similar to that reported in other current series describing SLN biopsy in early-stage breast cancer patients. Other reports of the use of SLN biopsy after neoadjuvant chemotherapy are available only in abstract form at this

Characteristics of Patients With Unsuccessful SLN Identification After Neoadjuvant Chemotherapy

Initial Tumor Size (cm)

2.0 2.5 4.0 5.0 5.0 6.0 2.0 3.0

Quadrant

Biopsy of Primary

Clinical Axillary Status Before Chemotherapy

Clinical Axillary Status After Chemotherapy

UOQ UIQ UIQ UIQ UOQ Central LOQ Central

Core Core Incisional Core Incisional Core Core Excisional

N0 N0 N0 N1 N0 N1 N2 N0

N0 N0 N0 N0 N0 N0 N0 N0

SLN Biopsy Technique

Dye Dye Dye Dye Dye Dye Dye Dye

alone alone alone alone alone alone ⫹ colloid alone

Abbreviations: UOQ, upper outer quadrant; UIQ, upper inner quadrant; LOQ, lower outer quadrant.

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No. of Positive Nodes/Total No. of Nodes

0/15 0/0 9/18 0/20 0/10 16/27 4/18 0/19

3484

BRESLIN ET AL Table 5.

Patient No.

1 2 3

Histology

Invasive ductal Invasive ductal Invasive ductal

Characteristics of Patients With False-Negative Sentinel Nodes Who Received Neoadjuvant Chemotherapy

Initial Tumor Size (cm)

10.0

Quadrant

Biopsy of Primary

Prechemotherapy Clinical Nodal Status

Prechemotherapy Axilla FNA

Postchemotherapy Clinical Nodal Status

Central

FNA

Negative

Not done

Negative

3.0

UOQ

Incisional

Positive

Positive

Positive

4.5

Lower central

Core needle

Positive

Positive

Positive

SLN Biopsy Technique

Pathology of SLN

No. of SLN

No. of Positive Nodes/Total No. of Nodes

Dye alone Dye alone Dye ⫹ colloid

Therapy effect Negative

3

1/23

3

2/19

Negative

2

3/25

Abbreviation: UOQ, upper outer quadrant.

time.17,18 Anderson et al17 reported their early experience with 69 cases of SLN biopsy for breast cancer. Their report included 14 patients who had undergone neoadjuvant chemotherapy, and three of those patients had false-negative SLN biopsy results (the false-negative rate for this subset was 25%). Based on this experience, they concluded that the use of SLN biopsy was contraindicated after neoadjuvant therapy. The current report of 51 cases, all treated with neoadjuvant chemotherapy, does not support their conclusion. Technical failures (ie, inability to locate the SLN) still occur, but they are infrequent and seem to reflect the learning curve demonstrated by other groups for early stage-breast cancer. Seven of the eight unsuccessful mapping cases occurred early in our experience when the surgeons and consulting services were becoming familiar with the technique. Those seven patients were also mapped with blue dye alone, and for patients with postchemotherapy changes in the primary tumor and lymphatics, the addition of technetium-labeled sulfur colloid for identifying the SLN(s) may be beneficial. Three of the unsuccessfully mapped patients had four or more positive lymph nodes at axillary dissection, and this may have contributed to lymphostasis and slower migration of the mapping agent. In the most recent unsuccessful case, the patient had a large postbiopsy hematoma that had not fully resolved at the time of surgery. As it developed, the organizing hematoma and resultant inflammation may have also caused distortion of breast parenchyma and alteration of lymphatic drainage patterns. The large biopsy cavity may have also hampered accurate identification of the lymphatic drainage if the mapping agent was inadvertently injected into the cavity and not the breast parenchyma. Winchester et al19 suggested that modification of the injection technique by using a higher number of injection sites might aid in identification of SLNs for patients with large tumors or previous excisional biopsies. The theory behind this recommendation is that the traditional four-quadrant injection technique may miss the area of breast parenchyma leading to the first

draining lymphatic channel.19 Other maneuvers in use to improve the likelihood of SLN identification include injecting the radioisotope the evening before surgery (to allow for the slower migration time seen in breast tissue), increasing the volume of radioisotope injection, varying the injection technique, and using preoperative lymphoscintigraphy to identify drainage outside of the axillary nodal basin.20-22 The false-negative rate of 12.0% reported here is also similar to that reported for initial series on lymphatic mapping.7,15 A uniform acceptable false-negative rate has yet to be established, but several groups have suggested that a rate between 2% and 5% may be a reasonable goal.23,24 The method used for determining the false-negative rate in this study depends on the total number of patients with any positive nodes. Because of this, the false-negative rate fluctuates based on the number of patients with positive nodes in the population studied. Two of the three falsenegative cases in our study had residual axillary adenopathy (palpable or sonographically abnormal) at the time of surgery. It is possible that ongoing clinically detectable nodal disease may result in occlusion of the lymphatic channels to the SLN(s) by tumor emboli and could lead to mislabeling of a non-SLN as a SLN. Neoadjuvant chemotherapy may cause disappearance or regression of metastatic disease in some nodes (SLNs) but not in other nodes. This situation might lead to identification of a pathologically negative SLN, while residual disease remains in other axillary nodes. If the two false-negative cases with persistent adenopathy are excluded from analysis on this basis, the false-negative rate drops to 4.3%, which is similar to currently reported series for early-stage breast cancer. Closer histopathologic evaluation of the SLN increased the yield of positive SLNs in this study. This finding is in agreement with studies by Turner et al25 and Giuliano et al15 who found that approximately 10% of patients were upstaged when the SLNs were examined with serial step sectioning and immunohistochemical analysis. All of the metastases detected by closer examination of the lymph nodes in this study were single cells or groups of cells less

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SLN BIOPSY ACCURATE AFTER CHEMOTHERAPY

than 0.5 mm in diameter, and only one patient had additional positive axillary nodes. Micrometastatic disease in stage I or II breast cancer has been shown to have a negative impact on survival.26 Upstaging with the use of immunohistochemical analysis and serial step sectioning for patients with early-stage breast cancer could lead to increased numbers of stage I patients being offered chemotherapy as a result of closer examination of the lymph nodes. Proponents of using SLN biopsy as an alternative to axillary dissection to stage the axillary lymph nodes cite the potential for minimizing surgical complications such as lymphedema and painful neuropathy.27 In addition, closer histopathologic evaluation of a few special nodes most likely to harbor metastases may increase diagnostic yield and alter subsequent therapy decisions. In patients treated with neoadjuvant chemotherapy, the decision to administer chemotherapy has already been made, so the nodal information may affect decisions to use radiotherapy or postoperative chemotherapy. The pathologic axillary nodal status of breast cancer patients after neoadjuvant chemotherapy has been shown to correlate with disease-free survival. Kuerer et al28 found that breast cancer patients with documented axillary metastases before treatment who had complete axillary response after neoadjuvant chemotherapy had a 5-year disease-free survival rate of 87% versus 51% for patients with residual nodal disease. They performed serial step sectioning and immunohistochemical analysis on the histologically negative lymph nodes and found four patients (10%) with occult nodal metastases. Because of the small number of patients in that study, no conclusions could be drawn regarding the clinical significance of these occult residual nodal metastases in their patients.28 Other studies have also shown improved survival for patients with clinically positive axillae who are pathologically free of disease after neoadjuvant

chemotherapy.29,30 SLN biopsy has been proposed as a diagnostic procedure to document nodal disease and better stratify patients before neoadjuvant therapy.24 The potential benefit of SLN biopsy for patients in whom the decision has already been made to administer chemotherapy is that SLN biopsy is a minimally invasive method of assessing axillary status. For patients with biopsy-proven axillary metastases, SLN biopsy can provide a measure of the response of the axillary metastases to chemotherapy, and some patients may be spared the morbidity of axillary lymph node dissection. Our series demonstrates the feasibility and accuracy of SLN biopsy in breast cancer patients after neoadjuvant chemotherapy. The majority of patients treated with neoadjuvant chemotherapy in this group demonstrated a significant response in the primary tumor. Many of these patients were then able to undergo breast-conserving surgical treatments. Similarly, patients with a clinically negative axilla underwent successful intraoperative mapping with a high degree of accuracy. Unlike patients with early-stage breast cancer and small foci of metastatic disease in the SLNs, the patients in whom prechemotherapy FNA revealed positive nodes were likely to have both positive SLNs and additional positive axillary nodes. These patients require additional therapy for the axilla, either completion ALND or axillary irradiation. Additional studies are needed to answer the ongoing debate regarding optimal treatment of the axilla for patients who are rendered clinically node negative after neoadjuvant treatment. This question is the basis of a current protocol at the M.D. Anderson Cancer Center, where SLN biopsy is used to stratify the axillary treatment of patients after neoadjuvant chemotherapy. After neoadjuvant chemotherapy, patients in this protocol with positive SLNs are randomized to axillary dissection or axillary irradiation.

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21. Klimberg VS, Rubio IT, Henry R, et al: Subareolar versus peritumoral injection for location of the sentinel lymph node. Ann Surg 229:800-865, 1999 22. Borgstein PJ, Meijer S, Pijpers R: Intradermal blue dye to identify sentinel lymph node in breast cancer. Lancet 349:1668-1669, 1997 23. Hunt KK, Ross MI: Lymphatic mapping for breast cancer: Surgical advance in evolution. Oncology 12:1297-1298, 1998 24. Cox CE, Pendas S, Cox JM, et al: Guidelines for sentinel node biopsy and lymphatic mapping of patients with breast cancer. Ann Surg 227:645-651; 651-653, 1998 25. Turner RR, Ollila DW, Krasne DL, et al: Histopathologic validation of the sentinel lymph node hypothesis for breast carcinoma. Ann Surg 226:271-278, 1997 26. International (Ludwig) Breast Cancer Study Group: Prognostic importance of occult ALN metastases from breast cancers. Lancet 335:1565-1568, 1990 27. Chu KU, Turner RR, Hansen NM, et al: Do all patients with sentinel node metastasis from breast carcinoma need complete axillary dissection? Ann Surg Oncol 229:536-541, 1999 28. Kuerer HM, Newman LA, Buzdar AU, et al: Residual metastatic axillary lymph nodes following neoadjuvant chemotherapy predict disease-free survival in patients with locally advanced breast cancer. Am J Surg 176:502-509, 1998 29. McCready DR, Hortobagyi GN, Kau SN: The prognostic significance of lymph node metastases after preoperative chemotherapy for locally advanced breast cancer. Arch Surg 124:21-25, 1989 30. Botti C, Vici P, Lopez M: Prognostic value of lymph node metastases after neoadjuvant chemotherapy for large-sized operable carcinoma of the breast. J Am Coll Surg 181:202-208, 1995

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