As advances in systemic therapy improve our ability to individualize breast cancer treatment, and improve response rates and outcomes, it is important to reevaluate the most appropriate form of local-regional management. When chemotherapy is used in the neoadjuvant setting, response is determined surgically after the neoadjuvant chemotherapy. Response evaluation involves resection of any residual disease in the tumor bed in the breast, as well as staging of the ipsilateral axillary lymph nodes.

Increasingly, comprehensive imaging of the breast and the ipsilateral axilla is performed at initial presentation with breast cancer, including ipsilateral axillary ultrasound to evaluate the morphology of the axillary nodes sonographically. In cases where lymph nodes appear abnormal, percutaneous biopsy of ipsilateral nodes to evaluate for nodal involvement is performed at presentation. Thus, lower volume of nodal disease can be detected than when using physical examination alone. Surgical axillary staging after neoadjuvant chemotherapy is influenced by clinical nodal stage at presentation. In cases with clinically negative lymph nodes at presentation, staging of the regional lymph nodes with sentinel lymph node biopsy after neoadjuvant chemotherapy has been shown to have a similar false-negative rate to the use of sentinel lymph node surgery without any prior systemic therapy. Until recently, in cases documented to be node-positive at presentation, axillary lymph node dissection after completion of neoadjuvant chemotherapy was standard practice.

The ACOSOG Z1071 study was a prospective, single-arm phase II clinical trial designed to evaluate the false-negative rate of sentinel lymph node surgery in patients with biopsy-proven node-positive disease treated with neoadjuvant chemotherapy.

The primary endpoint of the study was the false-negative rate of sentinel lymph node surgery in patients with clinical N1 disease with two or more sentinel nodes resected. The study enrolled a total of 756 women across 136 institutions. The false-negative rate was 12.6%.

 The data also showed that when dual mapping agents were utilized, the false-negative rate was statistically lower at 10.8%. Additionally, when more than two sentinel nodes were resected, the false-negative rate fell to 9.1%. Other studies have also evaluated this question. The SN FNAC study conducted in Canada was a smaller study similar to Z1071 that showed a false-negative rate of 9.6% based on local site review of sentinel lymph node histology. When central review of the sentinel lymph nodes was utilized, the false-negative rate was 8.4%.

Additionally, the SENTINA study conducted in Germany evaluated this question in patients who were clinically node-positive without requiring histological or cytological confirmation of nodal involvement at presentation. The researchers evaluated the role of sentinel lymph node biopsy in those patients who had normalization of the appearance of the lymph nodes on ultrasound examination.

This study reported a false-negative rate of 14.2% when all patients were evaluated; however, when limiting the evaluation to those patients with two or more sentinel nodes resected, the false-negative rate was 9.6%.

 Additionally, this study, similar to Z1071, showed that the false-negative rate decreased as the number of sentinel nodes resected increased.

As we reevaluate the appropriate axillary surgery for staging in patients with node-positive breast cancer, it becomes important to consider the likelihood of nodal response and the potential advantages of utilizing sentinel lymph node surgery.

		Table. Results from recent clinical trials evaluating the false-negative rate of sentinel lymph node surgery after neoadjuvant chemotherapy for node-positive breast cancer.

		FNR indicates false-negative rate; SLN, sentinel lymph node.

With current chemotherapy, approximately 40% of patients who are node-positive at presentation will convert to node-negative, and this percentage is as high as 70% in those patients with HER2-positive disease. Thus, a significant number of patients will have negative lymph nodes and may not benefit from axillary lymph node dissection, which is associated with significant comorbidities. Therefore, finding a way to avoid subjecting all patients with node-positive breast cancer to complete axillary lymph node dissection for axillary staging could significantly decrease the morbidity of breast cancer surgery. Sentinel lymph node surgery provides an opportunity for us to evaluate the axilla and identify patients with residual nodal disease and potentially avoid axillary lymph node dissection in those patients where chemotherapy has cleared the disease from the ipsilateral axilla.

Careful patient selection to avoid use of sentinel node surgery in patients at high likelihood of residual nodal disease will further help decrease the number of false-negative events associated with the adoption of this nodal staging procedure in clinical practice. In patients for whom imaging and physical examination indicates a high likelihood of residual disease burden in the breast and/or axilla that has not responded to neoadjuvant chemotherapy, axillary lymph node dissection may be the preferred axillary staging. However, in those cases where physical examination and imaging along with axillary ultrasound indicate a high likelihood of nodal response, sentinel lymph node surgery may well be the preferred method of axillary staging.

When utilizing sentinel lymph node surgery for patients with node-positive breast cancer, accurate identification of the sentinel lymph nodes is recommended and use of dual agent tracer assists in minimizing failure to identify sentinel lymph nodes.

In cases where lymphatic mapping fails or only a single sentinel node can be identified, axillary lymph node dissection remains the recommendation. In cases with two or more sentinel nodes identified, sentinel lymph node surgery can be utilized for evaluation of residual disease in the axilla.

The findings of these studies indicate that sentinel node surgery after neoadjuvant chemotherapy for patients with node-positive breast cancer may be an option for staging the axilla to assess for the presence of residual disease.

			Boughey JC, Suman VJ, Mittendorf EA, et al. Sentinel lymph node surgery after neoadjuvant chemotherapy in patients with node-positive breast cancer: the ACOSOG Z1071 (Alliance) clinical trial. 

			Boileau JF, Poirier B, Basik M, et al. Sentinel node biopsy following neoadjuvant chemotherapy in biopsy proven node positive breast cancer: the SN FNAC study. 

			Kuehn T, Bauerfeind I, Fehm T, et al. Sentinel-lymph-node biopsy in patients with breast cancer before and after neoadjuvant chemotherapy (SENTINA): a prospective, multicentre cohort study. 

			Boughey JC, Suman VJ, Mittendorf EA, et al. Factors affecting sentinel lymph node identification rate after neoadjuvant chemotherapy for breast cancer patients enrolled in ACOSOG Z1071 (Alliance) [published online January 20, 2014]. 

Articles

As advances in systemic therapy improve our ability to individualize breast cancer treatment, and improve response rates and outcomes, it is important to reevaluate the most appropriate form of local-regional management.

Judy C. Boughey, MD, FACS

Articles

Minimizing Axillary Surgery for Patients With Node-Positive Breast Cancer