The decision for systemic therapy is increasingly based on the characteristics of the primary tumor, and in the genomic era we are getting so much information—both prognostic and predictive—that the role of axillary node staging for treatment selection will continue to decline.
—Hiram S. Cody III, MD
For the past 40 years the story of breast cancer surgery in general, and for the past 20 years the management of the axilla in particular, has been one of increasing conservatism. To give our readers insight into the current and future direction of axillary management, The ASCO Post spoke with Hiram S. Cody III, MD, principal investigator of Memorial Sloan Kettering Cancer Center’s Sentinel Lymph Node Biopsy Program. Dr. Cody presented a Meet the Professor session on this issue at the recent Society of Surgical Oncology (SSO) Annual Cancer Symposium in Phoenix.1
Have we reached consensus on the survival benefit of axillary dissection?
The survival advantage of axillary dissection, if any, is probably very small. This was first studied 30 years ago by the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-04 trial,2 in which women with clinically node-negative primary breast cancer had a mastectomy with or without axillary dissection. Despite axillary recurrence in about 20% of patients treated without axillary dissection (75% of these within 2 years), there was no survival advantage for either arm.
The dominant rationale for axillary dissection in subsequent trials by the NSABP and others was prognostication to guide systemic therapy; local control was regarded as a secondary goal, and any survival benefit was speculative. The historic 2005 Oxford Overview3 showed for the first time that local control and survival were related, but that a survival benefit was not apparent until the absolute rate of local recurrence had been reduced by at least 10%. It seems clear that the small single-digit differences in local recurrence observed between the various strategies of axillary management in contemporary practice will not affect survival.
Sentinel Lymph Node Biopsy
Is sentinel lymph node biopsy as good as axillary dissection?
Overwhelming data show that for node-negative breast cancer patients, sentinel lymph node biopsy is just as effective as axillary dissection in staging accuracy, local control, and survival, but with substantially less morbidity. It’s now clear that many sentinel lymph node–positive patients can also avoid axillary dissection, as evidenced by the ACOSOG Z0011 trial,4 in which patients with positive sentinel nodes were randomly assigned to axillary dissection vs no further axillary treatment.
At 6 years, there were no differences in local control or survival between arms (even though axillary dissection found additional axillary node metastases in 27% of patients, axillary local recurrence was < 1% in each arm). The Z0011 patients were cN0, had no more than two positive sentinel lymph nodes, and no extranodal extension. All had breast conservation with whole-breast radiotherapy, and no other axillary-specific treatment. Some of the success of Z0011 may be due to the inadvertent axillary radiation inherent in whole-breast radiotherapy.
What about patients outside the Z0011 selection criteria, especially those receiving neoadjuvant chemotherapy?
Going forward, we must ask whether sentinel lymph node–positive patients outside the Z0011 selection criteria can avoid axillary dissection as well. Lively debate still surrounds the integration of sentinel node biopsy with neoadjuvant chemotherapy and postoperative radiotherapy—a topic of particular current interest as more clinical trials transition to the neoadjuvant model.
We have a substantial literature showing that the success rate and accuracy of sentinel node biopsy are roughly comparable, whether done before or after systemic adjuvant therapy. For clinically node-negative patients, sentinel node biopsy after neoadjuvant chemotherapy seems safe, reasonable, and has the added advantage of sparing patients another trip to the OR.
What about patients with biopsy-proven axillary metastases prior to neoadjuvant chemotherapy?
Neoadjuvant chemotherapy downstages the axilla. Among patients with biopsy-proven axillary node metastases, contemporary treatment regimens yield axillary complete response rates of 40% or more. Could these patients avoid axillary lymph node dissection?
Just last year, two major prospective trials began to address this question. ACOSOG Z10715 is a prospective observational trial of patients with positive axillary nodes who had neoadjuvant chemotherapy followed by sentinel node biopsy and a “backup” axillary dissection. Sentinel lymph nodes were found in 90% of patients, and if two or more sentinel nodes were removed, the false-negative rate of sentinel node biopsy was 12.8%, slightly higher than the authors’ predefined threshold of 10%. The false-negative rate was significantly higher if only one sentinel lymph node was removed (30%) or when patients’ sentinel nodes were mapped with a single agent (dye or isotope) vs dual agent (dye plus isotope), 20% vs 10%. The take-home message is that for sentinel node biopsy done after chemotherapy, technique matters: one must map with dye plus isotope and remove at least two (and preferably more) sentinel nodes.
In the German trial SENTINA,6 patients were stratified by clinical axillary node status. If cN0, they had sentinel lymph node biopsy before chemotherapy; sentinel node–negative patients had no further axillary treatment, and sentinel node–positive patients received chemotherapy followed by repeat sentinel node biopsy and axillary dissection. If cN1-2, they received chemotherapy followed by sentinel node biopsy; those who became cN0 had sentinel node biopsy and axillary node dissection, and those who remained cN1-2 had axillary dissection.
For the cN0 patients with positive sentinel lymph nodes upfront, the performance of the repeat sentinel node biopsy postchemotherapy was poor, with only 60% success and a 50% false-negative rate. For the cN1-2 patients who converted to cN0 postchemotherapy, performance was better (and comparable to ACOSOG Z1071): 80% success and 14% false-negative rate. The take-home message from SENTINA is that sentinel node biopsy works best if done once, after chemotherapy.
One must acknowledge that although these two large prospective trials specifically address the performance characteristics of sentinel node biopsy following neoadjuvant therapy, they do not ask whether local therapy can be modified based on the response to neoadjuvant therapy.
So where do we go from here?
Two new randomized trials specifically address axillary management following neoadjuvant chemotherapy in patients with proven axillary node metastases. In both trials, patients receive neoadjuvant chemotherapy followed by sentinel lymph node biopsy.
If the sentinel nodes have converted to benign, NSABP B-51/Radiation Therapy Oncology Group (RTOG) 1304 randomly assigns patients to nodal radiotherapy vs no nodal radiotherapy (without further surgery). If the sentinel nodes remain positive, Alliance A11202 randomly assigns patients to axillary dissection vs no axillary dissection (with nodal raditoherapy for all patients). These two trials will give us a more definitive answer as to the longer-term safety of sentinel node biopsy after neoadjuvant chemotherapy and whether we can modify local therapy based on the response to neoadjuvant chemotherapy.
The decision for systemic therapy is increasingly based on the characteristics of the primary tumor, and in the genomic era we are getting so much information—both prognostic and predictive—that the role of axillary node staging for treatment selection will continue to decline. New trials are certain to compare the outcomes of sentinel node biopsy vs no axillary staging, and the axillary dissection of the future will be an operation done most often to salvage local recurrences rather than prevent them. ■
Disclosure: Dr. Cody reported no potential conflicts of interest.
1. Cody HS: Update on the axilla management in breast cancer—what is next? Meet the Professor session. SSO Annual Cancer Symposium. Presented March 15, 2014.
2. Fisher B, Redmond C, Fisher ER, et al: Ten-year results of a randomized clinical trial comparing radical mastectomy and total mastectomy with or without radiation. N Engl J Med 312:674-681, 1985.
3. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG): Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: An overview of the randomised trials. Lancet 366:2087-2106, 2005.
4. Giuliano AE, McCall L, Beitsch P, et al: Locoregional recurrence after sentinel lymph node dissection with and without axillary dissection in patients with sentinel lymph node metastases. The American College of Surgeons Oncology Group Z0011 randomized trial. Ann Surg 252:426-432, 2010.
5. 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 310:1455-1461, 2013.
6. 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. Lancet Oncol 14:609-618, 2013.