Earlier this year, the surgical community lost a renowned innovator, researcher, and surgical oncologist with the passing of Donald Morton, MD, FACS. Among Dr. Morton’s most significant contributions to surgical oncology was the development of sentinel lymph node (SLN) surgery for patients with melanoma that was subsequently extended to breast cancer and other solid tumors. SLN surgery allows for accurate nodal staging with lower morbidity than a complete lymphadenectomy. The procedure has been legitimized in prospective randomized breast cancer trials, and, for patients with clinically node-negative disease, SLN surgery is standard for axillary evaluation. For SLN-negative patients, axillary lymph node dissection (ALND) can be omitted without diminishing local-regional control, disease-free survival, or overall survival.1,2
While SLN surgery is used in the management of patients with clinically node-negative breast cancer, ALND remains standard practice for patients presenting with clinically node-positive disease. However, breast cancer oncologists are aware that neoadjuvant chemotherapy will clear axillary disease in 30 percent to 40 percent of these patients.3,4 Patients experiencing a nodal pathologic complete response (pCR) would not be expected to benefit from complete ALND; therefore, investigators questioned the potential role of SLN surgery. This question was formally addressed in an American College of Surgeons Oncology Group (ACOSOG) trial—ACOSOG Z1071.
ACOSOG Z1071 was a phase II study designed to determine the SLN surgery false-negative rate (FNR) in clinically node-positive breast cancer patients treated with neoadjuvant chemotherapy (see figure). The protocol encouraged using dual tracer technique and specified that at least two SLNs be resected. The primary aim was to determine the SLN surgery FNR in clinical N1 patients with at least two SLNs removed. The prescribed criterion for success was a FNR of 10 percent.
The trial enrolled 756 patients, including 649 with clinical N1 disease who completed chemotherapy and then underwent SLN surgery and ALND. The SLN identification rate was 92.9 percent. In the 525 patients in whom two or more SLNs were found, 215 (40.9 percent) had a nodal pCR. Metastases were identified in the ALND specimen in 39 patients with negative SLNs; therefore, the FNR was 12.6 percent.3
The Z1071 trial does provide data informing a way forward toward a surgical approach to the clinically node-positive axilla determined by response to therapy. Improvements in patient selection and approach are anticipated to help improve the performance of SLN surgery. With respect to patient selection, patients in the trial underwent axillary ultrasound (AUS) before and after chemotherapy. A secondary endpoint of the trial was to determine how the post-neoadjuvant chemotherapy AUS lymph node appearance affects the FNR and to determine how the AUS status correlates with residual pathologic disease. These critical data, which will determine if AUS has a role in selecting patients for SLN surgery, have not yet been reported.
It is also possible that molecular subtype may guide patient selection. Although the nodal pCR rates in clinically node-positive patients receiving neoadjuvant chemotherapy are 30 percent to 40 percent for all comers, the rates are highest in patients with hormone receptor-negative, high-grade tumors, and human epidermal growth factor receptor 2-positive tumors treated with neoadjuvant chemotherapy plus trastuzumab in whom axillary pCR rates of 74 percent have been reported.4,5 The Z1071 trial was not designed to address the impact of tumor biology on the SLN surgery FNR.
Surgical technique will also be critical. The Z1071 trial recommended use of dual tracers, which was done in 79.1 percent of patients. In these patients, the FNR was 10.8 percent versus 20.3 percent when a single agent was employed.3 To ensure that complete SLN surgery was performed, the trial required removal of at least two SLNs. The FNR was 31.5 percent when one SLN was removed, 21 percent when two were removed, and 9.1 percent when three or more were removed. Three or more SLNs were identified in 57.1 percent of patients.3 Although these data demonstrate that the FNR decreases with an increasing number of SLNs removed, most surgical oncologists recognize that some patients have only a single SLN present. Experienced surgeons must assess the quality of mapping and determine if SLN surgery is appropriate for a given patient.
Additional data from the Z1071 trial presented at the 2012 San Antonio Breast Cancer Symposium suggest that it is useful to place a clip in the biopsy-proven positive lymph node at diagnosis and to ensure that the clipped lymph node is removed during SLN surgery. In 96 patients with a clipped node documented to be in one of the SLNs, the FNR was 7.4 percent. Clearly, the Z1071 trial will offer much important data to help inform patient selection and surgical technique.
Continued improvements in systemic therapy will lead to increased pCR rates providing additional incentive to optimize local regional management. SLN surgery in clinically node-positive patients receiving neoadjuvant chemotherapy should not be abandoned based on the Z1071 results. The trial data should guide future efforts to personalize local regional management. To move forward in a thoughtful manner—that is what Dr. Morton would expect of us.
- Krag DN, Anderson SJ, Julian TB, et al. Sentinel-lymph-node resection compared with conventional axillary-lymph-node dissection in clinically node-negative patients with breast cancer: Overall survival findings from the NSABP B-32 randomised phase 3 trial. Lancet Oncol. 2010;11(10):927-933.
- Veronesi U, Viale G, Paganelli G, et al. Sentinel lymph node biopsy in breast cancer: Ten-year results of a randomized controlled study. Ann Surg. 2010;251(4):595-600.
- 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. JAMA. 2013;310(14):1455-1461.
- Hennessy BT, Hortobagyi GN, Rouzier R, et al. Outcome after pathologic complete eradication of cytologically proven breast cancer axillary node metastases following primary chemotherapy. J Clin Oncol. 2005;23(36):9304-9311.
- Dominici LS, Negron Gonzalez VM, Buzdar AU, et al. Cytologically proven axillary lymph node metastases are eradicated in patients receiving preoperative chemotherapy with concurrent trastuzumab for HER2-positive breast cancer. Cancer. 2010;116(12):2884-2889.