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10.1245/ASO.2006.05.017
Annals of Surgical Oncology 13:708-711 (2006)
© 2006 Society of Surgical Oncology
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Original Article

Survival Outcomes in Node-Negative Breast Cancer Patients Evaluated With Complete Axillary Node Dissection Versus Sentinel Lymph Node Biopsy

Charles Cox, MD1, Laura White, BS1, Nathon Allred1, Michael Meyers1, Daniel Dickson, BS1, Elisabeth Dupont, MD1, Alan Cantor, PhD2, Quan Ly, MD1, Sophie Dessureault, MD, PhD1, Jeff King, BS1, Santo Nicosia, MD3, Vesna Vrcel, MD3 and Nils Diaz, MD3

1 Department of Surgery, Comprehensive Breast Cancer Program, H. Lee Moffitt Cancer Center and Research Institute at the University of South Florida, 12902 Magnolia Drive, Tampa, Florida 33612
2 Department of Biostatistics, H. Lee Moffitt Cancer Center and Research Institute at the University of South Florida, Tampa, Florida 33612
3 Department of Pathology, Comprehensive Breast Cancer Program, H. Lee Moffitt Cancer Center and Research Institute at the University of South Florida, Tampa, Florida 33612

Correspondence: Address correspondence and reprint requests to: Charles Cox, MD; E-mail: coxce{at}moffitt.usf.edu.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Background: Sentinel lymph node (SLN) biopsy combined with microstaging-associated immunohistochemical staining for cytokeratin more accurately assigns patients to their corresponding diagnostic stage. The purpose of this study was to compare the survival outcomes of node-negative patients who received an SLN biopsy with historical control data of node-negative patients who received routine complete axillary lymph node dissection (CALND) in the pre-SLN biopsy era.

Methods: Under institutional review board approval, 2458 node-negative invasive breast cancer patients between the ages of 25 and 94 years (mean, 60 years) were treated at our institution from January 1986 to May 2004. Of these 2458 patients, 604 (25%) were evaluated with CALND, whereas 1854 (75%) were evaluated with SLN biopsy. All were treated according to the current stage-specific guidelines. Kaplan-Meier graphs of overall survival and disease-free survival were constructed for each group of patients, and the two groups were compared by using the log-rank test.

Results: Overall survival and disease-free survival for the CALND and SLN biopsy groups did not differ significantly (P = .98). The average number of lymph nodes extracted in the pre-SLN biopsy group was 18, whereas the average number of SLNs extracted in the post-SLN biopsy group was 3.

Conclusions: The survival rate among node-negative breast cancer patients who received an SLN biopsy alone has proven to have no significant difference (P = .98) from the survival rate among node-negative patients who received a CALND. SLN biopsy alone should replace CALND as the primary tool for axillary staging of breast cancer in node-negative patients.

Key Words: Sentinel lymph nodes • Complete axillary lymph node dissection • Breast cancer • Lymphatic mapping • Axillary staging


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Prognosis for breast cancer patients is largely dependent on the status of the axillary nodal basin. Studies have demonstrated improved sensitivity and accuracy associated with sentinel lymph node (SLN) biopsy when combined with immunohistochemical staining for cytokeratin (CK-IHC) to locate metastatic disease. The SLNs that are found to be histologically negative for metastatic disease are rarely associated with metastases to non-SLNs (false-negative assessment). In fact, the predictive value of SLN biopsy is ≥96%.1,2 Follow-up studies of SLN biopsy report that there have been no axillary recurrences in patients who had negative pathologic findings of the SLN(s),3,4 whereas others have reported an incidence of ≤.2% local axillary recurrence in long-term follow-up of SLN-negative patients.

SLN biopsy offers a thorough analysis of the axilla based on serial sectioning of the nodes and CK-IHC staining. As a result, most large series of SLN biopsy report a 10% upstaging of patients that is due to more careful assessment of nodes. Therefore, patients are more accurately assigned to their corresponding stage and can therefore be treated proportionately. However, a large series with a long-term follow-up on the effect that an SLN biopsy alone, as opposed to a routine complete axillary lymph node dissection (CALND), has on recurrence and survival has yet to be described in the published literature. The purpose of this study was to compare outcomes in node-negative invasive breast cancer patients who received an SLN biopsy with historical control data of node-negative patients who received a routine CALND in the pre-SLN biopsy era. Indeed, retrospective trials have variably demonstrated improvement in survival outcomes when micrometastatic disease is detected. Prospective trials (American College of Surgeons Oncology Group Z0010) evaluating the effects of micrometastatic disease have yet to be published. This study is the first to demonstrate long-term survival outcomes for node-negative breast cancer patients evaluated prospectively with SLN biopsy as the primary staging method when compared with historical controls with CALND in the pre-SLN era.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Under institutional review board approval, we reviewed our database for the records of 2458 node-negative invasive breast cancer patients between the ages of 25 and 94 years (mean, 60 years) who were treated at our institution from January 1986 to May 2004. This database is checked for accuracy against two other independently accrued, prospectively gathered databases, including the Moffitt Cancer Center Tumor Registry and the institutional National Comprehensive Cancer Network database. Of these 2458 patients, 604 (25%) were treated before April 1994, when SLN evaluation was first introduced, and therefore received a CALND as their primary mode of axillary staging, whereas 1854 (75%) were treated during the SLN biopsy era and therefore received an SLN biopsy as their primary mode of axillary staging. Under current staging guidelines, all invasive breast cancer patients receive a lumpectomy or mastectomy and an SLN biopsy by using a combination technique of both blue dye and radiocolloid.5 The SLNs are then serially sectioned at 2-mm intervals and tested with hematoxylin and eosin (H&E). If the nodes are negative, they are further analyzed with step sections by CK-IHC (CAM; Becton Dickinson, Franklin Lakes, NJ). Before the SLN biopsy was introduced, however, a routine CALND was conducted with either a lumpectomy or mastectomy, and the nodes were evaluated by using standard histological techniques. Each node was bivalved, and nodal sections were stained with H&E only.

All patients were evaluated and treated according to the current stage-specific guidelines. Kaplan-Meier graphs of overall survival (OS) and disease-free survival (DFS) were then obtained for each group. Statistical analyses were performed that compared the CALND node-negative group with the SLN biopsy node-negative group by using the log-rank test (Figs. 1Go and 2Go). A P value <.05 was considered statistically significant.


Figure 1
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  		FIG. 1. Overall survival comparison between patients who received a complete axillary lymph node dissection (CALND; n = 604) and those who received a sentinel lymph node biopsy (SLNbx) alone (n = 1854).

 

Figure 2
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  		FIG. 2. Disease-free survival comparison between patients who received a complete axillary lymph node dissection (CALND; n = 604) and patients who received a sentinel lymph node biopsy (SLNbx) alone (n = 1854).

 

   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
The comparison of OS and DFS for the CALND and SLN biopsy groups did not differ significantly: OS comparison, P = .98; DFS comparison, P = .48. However, there was a small separation between the curves on the DFS graph, and this may suggest a slightly increased DFS among the SLN biopsy group. The follow-up time for the CALND group is much longer than that for the SLN biopsy group, because they all received their treatment before April 1994. Had we the same follow-up time for the SLN biopsy group, one might speculate that the separation could have been larger.

Table 1Go notes the breakdown of staging among each group. Because we excluded all patients with inflammatory T3 and T4 disease and because our patient population consisted of only (node-negative) N0 patients, most cases were stage I disease. In the CALND group, the average number of lymph nodes extracted was 18, whereas the average number of SLNs extracted in the SLN biopsy group was 3. The median follow-up time for the CALND group was 7 years, and the median follow-up time for the SLN biopsy group was 2 years.


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  		TABLE 1. Breakdown of stages among both the CALND and SLN biopsy groups
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
It has been previously reported in detail that SLN biopsy greatly reduces the need for CALND in women with breast cancer.6 Veronesi et al.6 presented data that strongly agree with our conclusion in that there is a slightly greater survival rate in the SLN biopsy group, although it was not significant. The effect of this stage shifting based on IHC staining would require at least a 20% difference in 20% of the patients to achieve significance.

Huvos et al.7 stated that the prognosis of patients with micrometastases is comparable to that of node-negative patients. However, as noted in this article, there is a slight—yet not significant—separation of the two groups, as shown in Figs. 1Go and 2Go. This separation may be attributed to the fact that within the CALND cases are those that were negative with H&E analysis but perhaps harbored occult micrometastasis. If the patients with micrometastases were culled out of the CALND group, the two curves would presumably merge, and there would be no difference in the survival rates. SLN biopsy allows routine performance of serial sectioning and subsequent IHC staining. Both increase the chances of finding a positive axillary lymph node in breast cancer.8

As one might notice, there is a large numerical difference between our two comparative populations. This may be primarily due to changes in patient volume from the early years of our institution to the inception of SLN biopsy. Our institution was opened in 1986, and because SLN biopsy was first introduced in April 1994, this offered the researchers an 8-year time frame for accrual to the CALND group. April 2004 marked 10 years since the initiation of SLN biopsy and therefore offered the researchers a greater patient population for accrual. Furthermore, it is expected that many patients were and will continue to be referred to our institution to be evaluated with an SLN biopsy because it serves a very large demographical area.


   CONCLUSIONS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
The OS rate among node-negative breast cancer patients who received an SLN biopsy alone as their method of axillary staging has proven to have very little difference (P = .98) from the survival rate among node-negative patients who received a routine CALND. As has been previously reported, SLN biopsy improves staging accuracy,9 reduces the false-negative rate,10 and provides the prediction of non-SLN metastasis11,12 when accompanied by IHC staining of the SLNs. We conclude that SLN biopsy should replace CALND as the primary tool for axillary staging of breast cancer and should be universally applied as the standard of care for axillary staging of all breast cancer.

Received for publication June 9, 2005. Accepted for publication November 10, 2005.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 

  1. Canavese G, Gipponi M, Catturich A, et al. Sentinel lymph node mapping in early-stage breast cancer: technical issues and results with vital blue dye mapping and radioguided surgery. J Surg Oncol 2000; 74:61–8.[Medline]
  2. Veronesi U, Paganelli G, Viale G, et al. Sentinel lymph node biopsy and axillary dissection in breast cancer: results in a large series. J Natl Cancer Inst 1999; 91:368–73.[Abstract/Free Full Text]
  3. Shivers S, Cox C, Leight G, et al. Final results of the Department of Defense multicenter breast lymphatic mapping trial. Ann Surg Oncol 2002; 9:248–55.[Abstract/Free Full Text]
  4. Hansen NM, Grube BJ, Giuliano AE. The time has come to change the algorithm for the surgical management of early breast cancer. Arch Surg 2002; 137:1131–5.[Abstract/Free Full Text]
  5. Cox C, Pendas S, Cox JM, et al. Guidelines for sentinel lymph node biopsy and lymphatic mapping of patients with breast cancer. Ann Surg Oncol 1998; 227:645–53.
  6. Veronesi U, Paganelli G, Viale G, et al. A randomized comparison of sentinel-node biopsy with routine axillary dissection in breast cancer. N Engl J Med 2003; 349:546–53.[Abstract/Free Full Text]
  7. Huvos AG, Hutter RV, Berg JW. Significance of axillary macrometastases and micrometastases in mammary cancer. Ann Surg 1971; 173:44–6.[Medline]
  8. Jannink I, Fan M, Nagy S, et al. Serial sectioning of sentinel nodes in patients with breast cancer: a pilot study. Ann Surg Oncol 1998; 5:310–4.[Abstract]
  9. Giuliano AE, Dale PS, Turner RR, et al. Improved staging of breast cancer with sentinel lymphadenectomy. Ann Surg 1995; 3:394–401.
  10. Liberman L. Pathologic analysis of sentinel lymph nodes in breast carcinoma. Cancer 2000; 88:971–7.[CrossRef][Medline]
  11. Weiser MR, Montgomery L, Tan LK, et al. Lymphovascular invasion enhances the prediction of non-sentinel node metastases in breast cancer patients with positive sentinel nodes. Ann Surg 2001; 8:145–9.
  12. Turner RR, Chu KU, Qi K, et al. Pathologic features associated with nonsentinel lymph node metastases in patients with metastatic breast carcinoma in a sentinel lymph node. Cancer 2000; 89:574–81.[CrossRef][Medline]



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