Initial concerns regarding the use of SLNB after NAC focused on the theoretical lymphatic alterations secondary to treatment-related fibrosis and the possibility of non-uniform therapeutic response in the axilla. These factors would render the sentinel node an unreliable indictor of axillary nodal status and result in an unacceptably high false-negative rate (FNR) (6). The feasibility of SLNB, however, has been demonstrated in multiple early studies (7), and while certain small studies demonstrated FNRs up to 33% (8,9,10), larger studies have affirmed the accuracy of SLNB following NAC. Hunt et al. (6) performed a large, single-center retrospective analysis of 3,746 cT1-3N0 patients who underwent SLNB from 1994 to 2007. Using blue dye, Tc-labeled sulfur colloid, or a combination of the two, surgeons performed sentinel lymph node (SLN) surgery after NAC in 575 (15.3%) of patients. Successful identification of the SLN was slightly lower in the NAC group when compared to the surgery-first group (97.4% vs. 98.7%, respectively [p = 0.02]). There was no significant difference in the FNR between the two groups, with an FNR of 4.1% in the surgery-first group, and 5.9% FNR in the NAC group (p = 0.39). Prospective, multicenter data are also available from the GANEA trial (11), which enrolled 195 patients, the majority of whom had T2 or T3 disease, and included both cN0 and cN1 patients. After NAC, the detection rate among the cN0 patients was 94.6%, with the FNR just under 10% (9.4%). High identification rates coupled with low FNRs have also been borne out in large meta-analyses, with identification rates ranging from 90% to 94% and FNRs ranging from 7% to 12% among cN0 patients undergoing SLNB following NAC (12,13,14,15).

With the feasibility of SLNB after NAC established, the timing of SLNB has also been questioned. It has been argued that pre-NAC SLNB provides accurate axillary staging, separating node-negative patients who can avoid ALND and axillary radiation, from node-positive patients, who may benefit from adjuvant radiation therapy (RT). Negative SLNB prior to NAC has been shown to accurately predict a pathologically negative axilla after NAC (16), but performing SLNB prior to NAC has several drawbacks: patients are subjected to an additional surgical procedure, NAC would be delayed to allow for wound healing, and, perhaps most importantly, a positive pre-NAC SLNB obviates the possible avoidance of an ALND in the setting of a complete axillary response.

Studies consistently report lower rates of nodal positivity among cN0 patients undergoing axillary surgery following NAC when compared to upfront surgery, highlighting the ability of NAC to downstage microscopic axillary disease. The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-18 trial enrolled almost 1,100 cN0 patients to compare preoperative versus postoperative chemotherapy (doxorubicin and cyclophosphamide [AC]), finding 33% of patients were pathologically node positive after NAC compared to 48% of women undergoing upfront surgery (p < 0.001) (17). Similarly, NSABP B-27, which examined the addition of preoperative or postoperative docetaxel (T) to preoperative AC, found 40% nodal positivity in the group undergoing preoperative ACT versus 49% nodal positivity in the group undergoing preoperative AC and postoperative T (p < 0.001) (18). Hunt et al. also reported a significant decrease in nodal positivity rates after NAC versus upfront surgery in cN0 patients in their single-center experience, although the greatest benefit was seen in patients with T2 and T3 tumors (6% decrease in T1 tumors, 16% decrease in T2 tumors, 21% in T3 tumors) (Table 27-1) (6).

SENTinel NeoAdjuvant (SENTINA), a multicenter randomized clinical trial, included both cN0 and node-positive patients. Patients who were initially cN0 underwent SLNB (with radiocolloid alone, blue dye alone, or both) prior to NAC; those found to be pathologically node negative did not undergo any further axillary surgery (n = 662), while those with a positive SLNB underwent a repeat SLNB and ALND after NAC (n = 360). In stark contrast to results from a previous smaller study, which demonstrated a detection rate of 97% and an FNR of 4.5% (19), the repeat-SLNB arm after NAC had a disappointing overall SLN detection rate of 60.8% and an FNR of 51.6% (20), results too poor to support attempts at repeat SLNB among those with an upfront microscopically positive SLN. The latest edition of the National Comprehensive Cancer Network (NCCN) guidelines recommends that in cN0 patients, SLNB should preferably be performed after preoperative systemic therapy (21).

While these data speak to the technical feasibility and optimal timing of SLNB, the oncologic safety and possible sequelae of a false-negative SLNB must also be considered. It stands to reason that a false-negative SLNB following NAC may have differing oncologic repercussions compared to patients treated with upfront surgery, given that axillary disease left in situ following NAC is uniquely chemotherapy resistant. Existing studies, however, have failed to bear out this concern. Hunt et al. found a 1.2% regional recurrence rate at a median follow-up of 47 months in node-negative patients undergoing SLNB alone after NAC, as compared to a 0.9% recurrence rate in patients undergoing SLNB prior to NAC (6). Smaller studies following cN0 women treated with SLNB alone after NAC have also failed to note any axillary recurrences at a median follow-up of more than 4 years (22,23). These data support the use of SLNB alone following NAC in patients who are both clinically and pathologically node negative. The standard of care remains to proceed with a completion ALND for any positive SLN identified after NAC.

Use of NAC is now one strategy to minimize the likelihood of requiring an ALND among early-stage breast cancer patients. Axillary downstaging has been well documented in large studies, with rates ranging from 35% to 63% (24,25,26), although given variable nodal response to chemotherapy by receptor profile, the ability to downstage microscopic axillary disease expectedly differs by tumor subtype. Table 27-2 shows rates of nodal pCR among women with biopsy-proven nodal metastases broken down by tumor receptor profile. The highest rates of nodal pCR are seen in HER2+ tumors (65% to 97%), while the lowest rates are in HR+/HER2- cancers (21%), with triple negative pCR rates in between (47% to 49%) (24,27).

To minimize the risk of ALND in early-stage breast cancer patients, practitioners should understand how this differential response to NAC by disease subtype can affect surgical decision making. In a retrospective analysis of a Memorial Sloan Kettering Cancer Center cohort of cT1-2N0 patients, factors associated with the likelihood of undergoing ALND in patients who received upfront surgery (breast-conserving surgery [BCS] or mastectomy) or NAC were examined (30). As per American College of Surgeons Oncology Group (ACOSOG) Z0011 criteria, patients in the upfront BCS cohort underwent ALND if they had ≥3 positive SLNs.
In the upfront mastectomy group, patients underwent ALND for any axillary micro- or macrometastases, but not for isolated tumor cells (ITCs). In the post-NAC group, ALND was indicated for any evidence of nodal disease, including ITCs, and if ≥3 negative SLNs were not identified. Rates of ALND were found to be lower in estrogen receptor (ER)+/progesterone receptor (PR)+ HER2 patients undergoing upfront BCS versus those who underwent NAC (15% vs. 34% respectively, p < 0.001), given the low rate of nodal pCR experienced in patients with this tumor profile. However, when comparing management with upfront mastectomy to NAC, patients with triple-negative breast cancer (TNBC) or HER2+ disease, subtypes with a much greater likelihood of achieving a nodal pCR, ALND rates were significantly lower following NAC. This speaks against the use of NAC for early-stage ER+/PR+, HER2- tumors solely for microscopic nodal downstaging, while supporting its use in appropriate patients with TNBC and HER2+ tumors.