Sentinel lymph node biopsy (SLNB) has revolutionized the surgical management of the axilla for patients with early breast cancer. SLNB initially became standard regional therapy for women who were both clinically and pathologically node-negative. Subsequently, SLNB has been established as appropriate management in patients with very low axillary tumor burden, defined as isolated tumor cells or micrometastatic disease (< 2 mm); it provides accurate staging information with no detriment to regional control. More recently, the treatment of the axilla has evolved for women with macrometastatic axillary disease. Three randomized controlled trials have compared different regional treatment strategies for patients with > 2 mm of axillary tumor burden. Here we review the evolution of SLNB for the management of clinically node-negative breast cancer, and we address the current controversies and management issues.
Although axillary lymph node dissection (ALND) remained the standard of care for all breast cancer patients until the early 2000s, evidence that not all microscopic axillary disease requires surgical removal has been present for decades. The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-04 trial established survival equivalence between clinically node-negative breast cancer treated with either total mastectomy alone with delayed axillary dissection for nodal recurrence, or total mastectomy with immediate axillary clearance. In these patients, who received no systemic or radiation therapy (RT), the subsequent axillary failure rate in the total-mastectomy-alone group (19%) was only about half that predicted from the proportion of patients with axillary metastases who underwent an ALND (40%). Compared with the patients enrolled in this early trial, the breast cancer patients seen today not only have smaller cancers and lower nodal disease burden, but the majority of patients, even those with T1 tumors and pathologically negative nodes, are treated with adjuvant systemic therapy, which is now recognized to improve local control. Decisions regarding the type of systemic therapy are rarely made based on the extent of axillary nodal disease, raising the question of whether ALND is necessary for local control or contributes to survival in patients with sentinel node metastases treated in the modern multidisciplinary era.
Sentinel Lymph Node Biopsy for Pathologically Negative Lymph Nodes
It is well documented that in women with clinically node-negative early breast cancer, a negative sentinel lymph node biopsy (SLNB) provides accurate staging information without increasing the risk of regional recurrence or decreasing survival. Veronesi et al, between 1998 and 1999, randomized women with clinical T1N0 breast cancer and a negative sentinel lymph node (SLN) to SLNB alone or SLNB followed by ALND. A total of 341 women with node-negative disease were included in the analysis. Of the women randomized to ALND, 5% (8/174) were found to have a false-negative SLNB. Among all eligible patients, there was 1 axillary recurrence at 7 years follow-up, in a patient treated with SLNB alone. The annual rate of events associated with breast cancer, including local, regional, and distant recurrence, did not differ between the groups (11.5 per 1,000 events in the ALND arm, and 9.8 per 1,000 events in the SLNB arm). Five-year disease-free survival (DFS) and overall survival (OS) were also similar (DFS: 88.9% in the ALND group vs 92.2% in the SLNB group, log-rank P = .2; OS: 96.4% vs 98.4%, respectively). NSABP B-32, between 1999 and 2004, similarly randomized patients with clinically node-negative breast cancer and a negative SLN to SLNB alone or SLNB followed by ALND. Of these patients, 85% received systemic therapy and 82% received RT. There were no differences in local recurrence (P = .55), regional recurrence (P = .22), DFS (8-year estimates: 82% in the ALND group vs 82% in the SLNB group), or OS (8-year estimates: 92% in the ALND group vs 90% in the SLNB group). Importantly, both treatment arms experienced a < 1% rate of regional recurrence as first event in spite of a false-negative rate of 10% in patients who underwent ALND after SLNB.[4,5] A meta-analysis of 48 studies that included nearly 15,000 patients with SLN-negative breast cancer who did not have a subsequent ALND, with a median follow-up of 34 months, found an overall axillary recurrence rate of just 0.3%. This axillary recurrence rate is substantially lower than the accepted false-negative rate of approximately 7% for the procedure, demonstrating again that not all microscopic axillary disease becomes clinically apparent. Additionally, in two randomized studies that compared the identification of axillary nodal metastases with SLNB vs ALND alone,[8,9] no differences were observed, illustrating the point that while failure to identify the correct sentinel node or all of the sentinel nodes is associated with a false-negative rate of 5% to 10%, a similar false-negative rate occurs after ALND, which is due to the inability of the pathologist to perform a detailed examination of all the nodes in an ALND specimen.
The Axillary Lymphatic Mapping Against Nodal Axillary Clearance (ALMANAC) trial studied the morbidity and quality of life associated with SLNB compared with ALND. Women who underwent SLNB alone experienced significantly less lymphedema (relative risk [RR], 0.37) and less sensory loss (RR, 0.37) than women in the ALND group at 12 months. SLNB alone was associated with shorter time to resumption of normal daily activities (P < .001), as well as improved patient-recorded quality of life and arm functioning scores (P ≤ .003). SLNB data showing similar survival outcomes and extremely low regional recurrence rates in conjunction with decreased postoperative morbidity compared with ALND established this less-invasive surgical procedure as standard staging and regional surgery for patients with a negative SLN.
A consequence of the SLNB procedure is the ability to perform a more thorough evaluation of a smaller number of lymph nodes, resulting in an increased detection of micrometastases and isolated tumor cells (ITCs). Micrometastases are defined as a tumor deposit greater than 0.2 mm and/or more than 200 cells, but less than 2.0 mm, while ITCs are clusters of cells not greater than 0.2 mm or fewer than 200 cells. A prospective comparison of axillary metastasis detection between routine ALND specimen evaluation and SLNs evaluated by serial sectioning followed by both hematoxylin and eosin (H&E) staining and cytokeratin immunohistochemistry (IHC) revealed significantly higher axillary metastatic detection rates in the SLNB group (42% in the SLNB group vs 29% in the ALND group; P < .03). Significantly fewer patients in the ALND-alone group had micrometastatic disease, defined as ≤ 2 mm of tumor burden, compared with those who also underwent SLNB with a combination of detection techniques (3% vs 16%, respectively; P < .0005). The significance and surgical management of this low-volume SLN disease burden has since been studied.
Between 2001 and 2010, the International Breast Cancer Study Group (IBCSG) 23-01 trial recruited women from 27 institutions with a primary breast tumor ≤ 5 cm and only micrometastatic disease in an SLN; the women were randomized to SLNB alone or standard completion ALND. The trial closed early because of low accrual and lower-than-projected event rates (target accrual, 1,960; actual accrual, 934). SLN evaluation consisted of serial sectioning and either H&E staining or IHC. Patient and tumor characteristics included a median age of 54 years, 69% with T1 tumors, 90% with estrogen receptor (ER)-positive tumors, 91% treated with lumpectomy, and 96% receiving systemic therapy. Additional positive lymph nodes were identified in 13% of patients in the ALND arm. At a median follow-up of 5 years, the axillary recurrence rate was < 1% in both arms. Survival outcomes were similar in the ALND-alone and SLNB-alone groups (DFS: 84% vs 88%, respectively, log-rank P = .16; OS: 98% vs 98%, respectively, log-rank P = .73).
Similarly, between 2001 and 2008, a multicenter randomized controlled trial in Spain compared ALND vs SLNB alone in 233 clinically node-negative patients with tumor size < 3.5 cm and an SLN with micrometastatic disease. SLNs were evaluated with serial sectioning and both routine H&E staining and IHC. Ninety-two percent of the women were treated with lumpectomy and 93% received adjuvant systemic therapy. At a median follow-up of 5.2 years, there were only four cases of any disease recurrence; these included two axillary nodal recurrences in the SLNB group and one axillary soft-tissue recurrence in the ALND arm. The overall DFS was 98%; there was no difference between the surgical arms (log-rank P = .33). The above-mentioned trials, which resulted in similar regional recurrence and survival for patients treated with SLNB and those treated with ALND for micrometastatic disease, used both H&E staining and IHC to pathologically assess SLNs. The American College of Surgeons Oncology Group (ACOSOG) Z0010 trial was a prospective observational study that aimed to evaluate the prevalence and significance of IHC-detected occult micrometastases in SLNs and bone marrow in women with clinical T1/T2,N0 breast cancer. A total of 5,210 patients underwent breast-conserving surgery and SLNB, evaluated only by H&E staining. Of women with an identified SLN, 24% had H&E-detected positive axillary disease. From the remaining patients, 3,326 H&E-negative SLNs were sent to a central laboratory for IHC evaluation, and treating physicians were blinded to these results. Of the H&E-negative SLNs, 10.5% were found to contain IHC-detected occult metastases. At a median follow-up of 6.3 years, among women with H&E-negative SLNs, the presence of IHC evidence of occult metastasis had no significant association with recurrence or death: the 5-year DFS was 92% for the IHC-negative SLNs and 90% for the IHC-positive SLNs (P = .82). The NSABP B32 trial also examined the prognostic significance of IHC-only SLN metastases. When results were initially reported at 5 years of follow-up, small but statistically significant decreases in DFS and OS were seen in patients with micrometastatic disease (DFS with occult metastases detected, 86%, vs with occult metastases not detected, 89%, P = .02; OS, 95% vs 96%, respectively, P = .03). However, with 10 years of follow-up, although a 4% difference in DFS (P = .02) persisted, no statistically significant difference in OS was observed between the groups.
These data highlight the fact that micrometastatic disease is safely managed with SLNB alone, and that the additional identification of IHC micrometastatic disease does not impact recurrence or OS; IHC is therefore not warranted. Updated National Comprehensive Cancer Network (NCCN) guidelines support this statement and note that SLN involvement is defined by multilevel nodal sectioning with H&E staining alone, with routine IHC not recommended. A review of the National Cancer Database showed that over time, women with micrometastatic SLN metastases were increasingly managed with SLNB alone, with the proportion of such cases managed in this way increasing from 25% to 45% between 1998 and 2005 (P < .001). Interestingly, the presence of ITCs or micrometastatic disease in the SLN does not guarantee the absence of macrometastatic disease in non-SLNs. Two meta-analyses reported additional non-SLN disease in 12% to 20% of women with ITCs or micrometastases in the SLN, and frequently, the additional disease consisted of macrometastases.[18,19] Given that macrometastatic disease is knowingly and safely left behind in the axilla of patients with micrometastatic SLN disease, the arbitrary cut-off of 2 mm of tumor burden (below which it is considered safe to omit an ALND) was questioned.
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