Ann Surg Oncol
https://doi.org/10.1245/s10434-021-11194-5
ORIGINAL ARTICLE – BREAST ONCOLOGY
Surgical Management of Axilla of Triple-Negative Breast Cancer
in the Z1071 Era: A Propensity Score-Matched Analysis
of the National Cancer Database
Samer A. Naffouje, MD1 , Vayda Barker, BS2, M. Catherine Lee, MD3, Susan J. Hoover, MD3, and
Christine Laronga, MD3
1
Department of Surgical Oncology, H. Lee Moffitt Cancer Center, Tampa, FL; 2University of South Florida College of
Medicine, Tampa, FL; 3Breast Oncology Program, H. Lee Moffitt Cancer Center, Tampa, FL
ABSTRACT
Background. The role of sentinel lymph node biopsy
(SLNB) in triple-negative breast cancer (TNBC) patients
who present with clinical N1 (cN1) disease and undergo
complete clinical response (cCR) to neoadjuvant systemic
therapy (NAST) remains unclear. We aimed to study the
outcomes of SLNB versus axillary lymph node dissection
(ALND) in this setting.
Patients and Methods. Patients with cN1 TNBC who
showed cCR to NAST were selected from the National
Cancer Database (NCDB), and propensity score matched
1:1 between SLNB and ALND in all-comers, ypN0, and
ypN1 subgroups. Overall survival (OS) was compared
using the Kaplan–Meier method. Cox regression was used
to identify predictors of OS.
Results. Of the 2953 patients selected. 1062 (36.0%)
underwent SLNB and 1891 (64.0%) underwent ALND.
There was a chronological increase in national SLNB uti-
lization (from 20% in 2012 to 46% in 2017). One thousand
three patients were propensity matched between SLNB and
ALND, and no OS difference was noted (81.73 ± 1.04 vs.
80.07 ± 0.70 months; p = 0.127). In the ypN0 subgroup,
Samer A. Naffouje and Vayda Barker have contributed equally to this
work.
Ó Society of Surgical Oncology 2021
First Received: 30 August 2021
Accepted: 24 November 2021
S. A. Naffouje, MD
e-mail: samer.naffouje@moffitt.org;
samernaffouje@hotmail.com
884 pairs were matched and no significant OS difference
was found (85.29 ± 0.84 vs. 82.60 ± 0.68 months; p =
0.638). In ypN? patients, 129 pairs were matched and
demonstrated a trend toward decreased OS with SLNB
(64.37 ± 3.12 vs. 72.45 ± 72.45; p = 0.085). Cox regres-
sion identified age, inner tumors, advanced T stage, partial/
no in-breast response, and nodal status as unfavorable
predictors of OS. Definitive axillary surgical procedure was
not a predictor in the final model.
Conclusion. SLNB and ALND appear to yield comparable
OS in cN1 TNBC patients who demonstrate cCR to NAST.
Caution should be exercised in ypN1 patients as worse OS
could be associated with SLNB.
Triple-negative breast cancer (TNBC) represents
15–20% of all breast cancers,1,2 and is more commonly
observed in premenopausal women under age 40 compared
with those aged 40 or older (12.2% vs. 5.7%; OR 1.53),3
with a disproportionate number being of African descent.4,5
TNBC is defined by the lack of expression of estrogen
receptors (ER), progesterone receptors (PR), and absence
or nonamplification of human epidermal growth factor
receptor 2 (HER2).5,6 TNBC is an aggressive phenotype
associated with increased frequency of distant metastasis,
higher recurrence rates, and a lower overall survival (OS)
when compared with other breast cancer subtypes.5,7,8
Despite this aggressive nature, TNBC is associated with
relatively high pathological complete response (pCR) rates
after neoadjuvant systemic therapy (NAST).6,9 pCR is an
excellent prognostic indicator as it is associated with a
significantly higher OS rate.10 The current pCR rate ranges
from 35 to 45% when NAST (adriamycin, cyclophos-
phamide, and paclitaxel) is used to treat TNBC.5,8

However, with the use of newer agents, such as platinum-
based neoadjuvant chemotherapy, the pCR rate for TNBC
patients approaches * 54%.9,11 These high pCR rates after
NAST have been found to be comparable in clinically node
negative and clinically node positive disease.12
Due to the relatively high pCR rates seen in TNBC
patients with confirmed node positive disease treated with
NAST, the need for axillary lymph node dissection
(ALND), a procedure associated with significant morbid-
ity,13 has been brought into question. If the axilla could be
accurately staged to assess for pCR using sentinel lymph
node biopsy (SLNB)—a less invasive, lower morbidity
procedure12 with a low false-negative rate, instead of
ALND—then we could mitigate the risk of lymphedema
without compromising outcome (OS). ACOSOG Z1071
targeted this question by evaluating the false-negative rate
(FNR) for SLNB following NAST in clinically node pos-
itive (without fixed or matted nodes) (cN1) breast cancer
patients. Although this trial concluded the overall FNR was
not less than the prespecified threshold of 10%, they found
certain factors significantly decreased the FNR, such as the
usage of dual tracers (FNR 10.8%) for sentinel lymph node
identification and retrieval of C 3 sentinel lymph nodes
(FNR 9.1%).14 These findings encouraged a shift away
from ALND in favor of SLNB in cN1 invasive breast
cancer patients treated with NAST, particularly those with
TNBC. However, the effects of using SLNB over ALND
on OS rate in TNBC cN1 patients have yet to be deter-
mined. Thus, we retrospectively analyzed the American
College of Surgeons Commission on Cancer National
Cancer Database (NCDB) to examine the trends and OS
rate of this practice.
PATIENTS AND METHODS
The NCDB for breast cancer (2012–2017) was utilized
for this analysis. Only female adult patients with a histo-
logic diagnosis of unilateral infiltrative ductal
adenocarcinoma were selected. Selection criteria for
receptor status included those with TNBC, defined as ER/
PR expression of \ 1%, and HER2 score of 0/1? on
immunohistochemistry (IHC) or score of 2? on IHC with
negative gene amplification on fluorescence in situ
hybridization (FISH) or chromogenic in situ hybridization
(CISH). With regards to clinical staging, only patients with
nonmetastatic, clinically node-positive (cN1) disease and
reported clinical T stage were included. Of note, all
patients had biopsy confirmation of their cN1 status.
Patients who were not reported to have a histologic con-
firmation of their nodal clinical staging were excluded.
S. A. Naffouje et al.
To address our clinical question, we only selected
patients who were reported to have received multiagent
NAST and demonstrated a clinical complete response
(cCR) to the neoadjuvant course of treatment as reported to
the NCDB. Patients missing data on clinical response to
NAST and those who had a partial or no clinical response
were excluded. Of note, for breast cancer, the NCDB
reports on the clinical response to NAST without elabo-
ration on whether this report is based on clinical or
radiographic response, or both. As of 2012, the intent of the
lymphadenectomy associated with the primary disease site
is reported by the NCDB as SLNB, SLNB and staged
ALND, and planned ALND. Therefore, only patients with
available data on the intended and definitive axillary sur-
gical procedure were included.
After applying the inclusion/exclusion criteria, the
population was divided into SLNB versus ALND groups
based on the reported definitive axillary procedure (SLNB
? staged ALND was included in the ALND cohort). We
used conditional logistic regression to compare categorical
variables, and mixed effect modeling to compare continu-
ous variables between the unmatched groups. A propensity
score was calculated based on a logistic regression model
that included all other demographic and clinical variables:
age, race/ethnicity, Charlson score, side, location in the
breast, grade, clinical T stage, type of mastectomy, in-
breast response, pathologic nodal status, adjuvant axillary
radiation, and adjuvant systemic therapy. Patients were
then matched between the two groups based on a 1:1 ratio
following the nearest neighbor method with a 0.1 caliper
width and a mandatory exact match for pathologic nodal
status. The Kaplan–Meier method was used to study OS,
and the log-rank test was used to compare OS outcomes.
Identical matching and inferential methodologies were
followed in the subsets of patients with ypN0 (pathologi-
cally confirmed node negative following NAST) and ypN?
(pathologically confirmed node positive following NAST)
to compare OS between SLNB and ALND in each subset.
Finally, Cox regression analysis was applied in the
unmatched cohort of all the patients and in those with
ypN? who had SLNB as a definitive axillary surgical
management to identify independent predictors of OS.
Statistical significance was set at \ 0.05 throughout the
study. IBM SPSS v25 (Armonk, NY) with R (3.3.3 ver-
sion) Essentials’ plug-in was used to perform data analysis.
RESULTS
The NCDB between 2012 and 2017 included 1,438,537
new cases of breast cancer in the USA. After applying our
selection criteria, 2953 adult females with nonmetastatic,
any cT, cN1 unilateral TNBC with cCR to NAST were
SLNB versus ALND after NAST in TNBC

FIG. 1. Flow diagram of

selection steps. ALND axillary NCDB Breast Cancer 2012-2017
lymph node dissection, NCDB N=1,438,537
National Cancer Database,
NAST neoadjuvant systemic Males N=12,557
therapy, SLNB sentinel lymph Bilateral cancer or unknown N=5,549
node biopsy
Females, age 18-90, with unilateral
breast cancer
N=1,420,431

Other pathologies N=264,597

Other/missing receptor status N=1,040,069

Triple-negative
invasive ductal adenocarcinoma
N=115,765 cT0 N=3,021
cN0 N=77,116
cN2 N=4,048
cN3 N=9,089
cM1 N=2,235
Clinical stage cT1-T4 cN1 cM0/Mx
N=20,256
No NAST N=8,669
Single agent or missing data of NAST N=464
Partial clinical response N=2,620
No clinical response N=632
Missing response reporting N=4,876
Multiagent NAST
with complete clinical response
N=2,995

Missing reporting on surgical management

of the axilla
N=42

Reported definitive surgical

management of the axilla
N=2,953

SLNB ALND
N=1,062 N=1,891

1:1 matching

SLNB ALND
N=1,003 N=1,003

included. All the selected patients had available data on the
intended and definitive axillary surgical management and
on the number of retrieved and positive nodes. Figure 1
shows a flow diagram of the inclusion/exclusion criteria
and the study design.
The mean age of the selected population was 50.98 ±
11.84 years (median 51 years), and 665 patients (22.5%)
were African-American. The majority of patients were
otherwise healthy (Charlson score 0; N = 2575, 87.2%),
and the cancers were distributed equally between the two
sides. The most common location in the breast was the
upper outer quadrant (N = 1337, 45.3%), and most patients
had cT2 disease (N = 1665, 56.4%). Of the 2953 patients,
1761 (59.6%) had a mastectomy for the surgical treatment
of the breast; 1019 (34.5%) demonstrated an in-breast
pathologic complete response (pCR), reported as ypT0/Tis
that correlated with their cCR. Most patients (N = 1691,
57.3%) had a partial pathologic response (pPR), as reported
 S. A. Naffouje et al.

by T downstaging on final pathology, whereas a minority
(N = 243, 8.2%) had no pathologic response (pNR) with no
T downstaging (i.e., ypT = cT).
Regarding the surgical management of the axilla, 1062
(36.0%) patients had SLNB, 375 (12.7%) had staged
SLNB-ALND, and 1516 (51.3%) had ALND. There was an
increase in the utilization of SLNB as a definitive axillary
procedure over the study period, from 20% in 2012 to 46%
in 2017. Figure 2 demonstrates the chronological trends of
the intended axillary surgical management in the selected
population. In the adjuvant setting, 1371 (46.4%) patients
received axillary radiation, whereas only 247 (8.4%) were
reported to receive additional adjuvant systemic therapy.
Table 1 presents the demographic and clinical character-
istics of the selected patient population.
After patient selection, the population was divided into
two groups based on the definitive surgical procedure of
the axilla: SLNB versus ALND. Baseline comparison of
clinical and demographic characteristics demonstrated that
SLNB patients were more likely to have earlier clinical T
stages, higher rates of in-breast response to NAST (pCR
rates were 42.5% vs. 30.0%; p \ 0.001), lower rates of
pathologically node-positive disease (12.7% vs. 21.0%; p\
0.001), and less likely to receive adjuvant systemic therapy
(6.9% vs. 9.2%; p = 0.028). Of note, the mean number of
examined nodes in the SLNB group was 3.1 (median, 3
nodes), compared with 10 nodes in the ALND group
(median, 10 nodes). After calculation of the propensity
score accounting for all the available clinical and demo-
graphic variables, 1003 pairs of patients were matched
between the groups. All the baseline differences resolved in

FIG. 2. a Trends of surgical

axillary management between
(a) 100
Intent of axillary
2012 and 2017 in patients with 90 surgical
cN1 TNBC infiltrative ductal management
carcinoma who demonstrated 80 40% ALND
44%
complete clinical response to 52% 50% Staged SLNB - ALND
neoadjuvant chemotherapy as 70 SLNB
67% 65%
reported in the selected NCDB
cohort. b Geographic trends of 60
Percent

the utilization of SLNB, SLNB- 14%

50 14%
ALND, and ALND during the
11%
study period. ALND axillary 40 14%
lymph node dissection, SLNB
sentinel lymph node biopsy, 30 10%
TNBC triple-negative breast 12%
42% 46%
cancer 20 39%
34%
26%
10 20%

0
2012 2013 2014 2015 2016 2017
Year of diagnosis

(b) West North Central

East North Central
ALND 53%
SLNB-ALND 7% ALND 53%
SLNB 40% SLNB-ALND 13%
SLNB 34% New England
Pacific ALND 60%
ALND 56% SLNB-ALND 14%
SLNB-ALND 10% SLNB 26%
SLNB 34%

Mid Atlantic
ALND 40%
SLNB-ALND 19%
SLNB 41%

Mountain
ALND 44%
SLNB-ALND 14%
South Atlantic
SLNB 42% ALND 52%
SLNB-ALND 14%
West South Central SLNB 34%
East South Central
ALND 58% ALND 49%
SLNB-ALND 11% SLNB-ALND 11%
SLNB 31% SLNB 40%
SLNB versus ALND after NAST in TNBC

TABLE 1 Demographic and Age in years Mean ± SD (median) 50.98 ± 11.84 (51)
perioperative characteristics of
the selected cohort (N = 2953) Race/ethnicity White 1871 (63.4%)
Black 665 (22.5%)
Hispanic 250 (8.5%)
Other 167 (5.7%)
Charlson score 0 2575 (87.2%)
1 315 (10.7%)
2 46 (1.6%)
3? 17 (0.6%)
Side Right 1409 (47.7%)
Left 1544 (52.3%)
Location in breast Central 78 (2.6%)
Upper inner 275 (9.3%)
Lower inner 136 (4.6%)
Upper outer 1371 (45.3%)
Lower outer 232 (7.9%)
Tail 22 (0.7%)
Overlapping 637 (21.6%)
Not specified 236 (8.0%)
Nottingham grade Low 51 (1.7%)
Intermediate 240 (8.1%)
High 2041 (69.1%)
Not reported 621 (21.0%)
Clinical T stage cT1 579 (19.6%)
cT2 1665 (56.4%)
cT3 471 (15.9%)
cT4 238 (8.1%)
Breast surgery Lumpectomy 1192 (40.4%)
Mastectomy 1761 (59.6%)
Axillary management SLNB 1062 (36.0%)
SLNB-ALND 375 (12.7%)
ALND 1516 (51.3%)
In-breast response pCR 1019 (34.5%)
pPR 1691 (57.3%)
pNR 243 (8.2%)
Whole breast radiation No 1899 (64.3%)
Yes 1054 (35.7%)
Chest wall radiation No 2144 (72.6%)
Yes 809 (27.4%)
Axillary radiation No 1582 (53.6%)
Yes 1371 (46.4%)
Adjuvant systemic therapy No 2706 (91.6%)
Yes 247 (8.4%)
ALND axillary lymph node dissection, pCR pathologic complete response, pNR pathologic no response,
pPR pathologic partial response, SD standard deviation, SLNB sentinel lymph node biopsy

the matched dataset with adequate balance in all the vari- survival analysis in the matched cohort of all patients,
ables. Table 2 presents the comparison between the patients with ypN0, and patients with ypN? comparing the
unmatched and matched SLNB versus ALND groups. outcomes of SLNB vs. ALND as a definitive surgical
Figure 3 demonstrates the results of the Kaplan Meier management of the axilla.
 S. A. Naffouje et al.

TABLE 2 Unmatched and matched datasets of SLNB versus ALND (N = 2953)

Unmatched dataset Matched dataset 1:1

SLNB ALND SD p-Value SLNB ALND SD p-Value

N 1062 1891 1003 1003

Age 50.76 ± 11.92 51.10 ± 11.87 0.044 0.477 50.88 ± 11.96 50.70 ± 11.29 0.023 0.726
Race/ethnicity 0.013 0.918 0.010 0.977
White 669 (63.0%) 1,202 (63.6%) 630 (62.8%) 625 (62.3%)
Black 243 (22.9%) 422 (22.3%) 230 (22.9%) 235 (23.4%)
Hispanic 87 (8.2%) 163 (8.6%) 84 (8.4%) 81 (8.1%)
Other 63 (5.9%) 104 (5.5%) 59 (5.9%) 62 (6.2%)
Charlson score 0.011 0.949 0.026 0.711
0 928 (87.4%) 1,647 (87.1%) 873 (87.0%) 890 (88.7%)
1 110 (10.4%) 205 (10.8%) 106 (10.6%) 93 (9.3%)
2 18 (1.7%) 28 (1.5%) 18 (1.8%0 15 (1.5%)
3? 6 (0.6%) 11 (0.6%) 6 (0.6%) 5 (0.5%)
Side 0.017 0.368 0.012 0.592
Right 495 (46.6%) 914 (48.3%) 478 (47.7%) 490 (48.9%)
Left 567 (53.4%) 977 (51.7%) 525 (52.3%) 513 (51.1%)
Location 0.049 0.418 0.014 1.000
Central 28 (2.6%) 50 (2.6%) 27 (2.7%) 26 (2.5%)
Upper inner 103 (9.7%) 172 (9.1%) 95 (9.5%) 97 (9.7%)
Lower inner 56 (5.3%) 80 (4.2%) 46 (4.6%) 47 (4.7%)
Upper outer 476 (44.8%) 861 (45.5%) 451 (45.0%) 454 (45.3%)
Lower outer 86 (8.1%) 146 (7.7%) 83 (8.3%) 83 (8.3%)
Tail 10 (0.9%) 12 (0.6%) 10 (1.0%) 11 (1.1%)
Overlapping 233 (21.9%) 404 (21.4%) 224 (22.3%) 216 (21.5%)
Not specified 70 (6.6%) 166 (8.8%) 67 (6.7%) 70 (7.0%)
Grade 0.045 0.108 0.006 0.994
Low 18 (1.7%) 33 (1.7%) 16 (1.6%) 15 (1.5%)
Intermediate 76 (7.2%) 164 (8.7%) 74 (7.4%) 73 (7.3%)
High 763 (71.8%) 1278 (67.6%) 718 (71.6%) 716 (7.4%)
Not reported 205 (19.3%) 416 (22.0%) 195 (19.4%) 199 (19.8%)
Clinical T stage 0.140 \ 0.001* 0.021 0.830
cT1 192 (18.1%) 387 (20.5%) 184 (18.3%) 181 (18.0%)
cT2 670 (63.1%) 995 (52.6%) 627 (62.5%) 631 (62.9%)
cT3 163 (15.3%) 308 (16.3%) 155 (15.5%) 161 (16.1%)
cT4 37 (3.5%) 201 (10.6%) 37 (3.7%) 30 (3.0%)
In-breast response 0.130 \ 0.001* 0.002 0.996
pCR 451 (42.5%) 568 (30.0%) 397 (39.6%) 397 (39.6%)
pPR 549 (51.7%) 1142 (60.4%) 544 (54.2%) 543 (54.1%)
pNR 62 (5.8%) 181 (9.6%) 62 (6.2%) 63 (6.3%)
Path node status 0.103 \ 0.001* 0.000 1.000
Negative 927 (87.3%) 1,494 (79.0%) 876 (87.3%) 876 (87.3%)
Positive 135 (12.7%) 397 (21.0%) 127 (12.7%) 127 (12.7%)
Breast surgery 571 621 0.201 \0.001* 512 485 0.027 0.228
Lumpectomy (53.8%) (32.8%) (51.0%) (48.4%)
Mastectomy 491 (46.2%) 1270 (67.2%) 491 (49.0%) 518 (51.6%)
Axillary radiation 472 (44.4%) 899 (47.5%) 0.030 0.105 451 (45.0%) 439 (43.8%) 0.012 0.590
Adjuvant systemic 73 (6.9%) 174 (9.2%) 0.040 0.028* 73 (7.3%) 78 (7.8%) 0.009 0.672

ALND axillary lymph node dissection, pCR pathologic complete response, pNR pathologic no response, pPR pathologic partial response, SD standard
difference, SLNB sentinel lymph node biopsy
*
Statistically significant
SLNB versus ALND after NAST in TNBC
Kaplan–Meier analysis was then applied to study and
compare overall survival (OS) in the matched dataset. After
a median follow up of 39.47 ± 17.82 months, no difference
was noted in OS between SLNB and ALND in the selected
population (mean OS, 81.73 ± 1.04 vs. 80.07 ± 0.70
months, median OS not reached in either group; p = 0.127).
In a subgroup analysis, we divided the population based on
the pathologic nodal status into ypN0 and ypN? subgroups
and repeated the propensity score matching methodology
for SLNB versus ALND. Supplementary Tables 1 and 2
summarize the comparative analysis of the subgroups in
the unmatched and matched datasets. In the cohort of ypN0
patients, we matched 884 patients with SLNB with their
peers who had ALND. Kaplan–Meier analysis continued to
show no difference in OS between SLNB and ALND
(mean OS 85.29 ± 0.84 vs. 82.60 ± 0.68 months, median
OS not reached in either group; p = 0.638). However, in the
cohort analysis of 129 matched pairs of patients with
ypN?, there was a trend toward worse OS with SLNB
compared with ALND (mean OS, 64.37 ± 3.12 vs. 72.45 ±
2.77 months; p = 0.085). Patients who had ALND as their
definitive axillary surgical management had a statistical
trend toward improved 5-year overall survival compared
with those who had SLNB (74% vs. 65%; p = 0.070).
Finally, we performed a Cox univariable and multi-
variable regression analysis to identify the significant OS
predictors in the selected patients. The final multivariable
model concluded that increasing age, medial tumors (upper
inner and lower inner), advanced T stage (T4 vs. T1),
partial or no in-breast pathologic response, and pathologic
nodal status were unfavorable predictors of OS. The
definitive surgical procedure of the axilla or the surgical
choice of lumpectomy versus mastectomy for the surgical
management of the breast were not significant predictors in
the univariate model. Table 3 shows the results of the Cox
regression analysis for the predictors of OS in the selected
patient population. Similarly, we applied a Cox regression
analysis in the subset of patients who had ypN? after
SLNB as a definitive procedure of the axilla (N = 135). A
similar profile of predictors was concluded, as upper inner
tumors, T4 tumors, and tumors that did not demonstrate in-
breast pCR had worse OS. Of important note, adjuvant
axillary radiation and adjuvant systemic therapy did not
have a significant predictive value on OS in this subset of
patients. Table 4 summarizes the result of the Cox
regression analysis in patients with ypN? after SLNB.
DISCUSSION
For the past few decades, axilla management in breast
cancer has been a topic of continuous debate. Historically,
ALND was used as a prognostic indicator and therapeutic
intervention in breast cancer.15,16 However, due to the
significant morbidity associated with ALND, such as
lymphedema in the upper extremity, shoulder rigidity,
paresthesia, and weakness in the arm and hand,16 the need
for ALND has been reevaluated following the discovery of
new treatments/therapies associated with lower morbidity,
such as SLNB. In 2010, the National Surgical Adjuvant
Breast and Bowel Project (NSABP) B32 found equivalent
OS and disease-free survival (DFS) rates for cN0 patients
treated with upfront surgery including either ALND or
SLNB, making it standard practice to perform SLNB in
place of ALND in cN0 patients.17 For patients with early
cN0 breast cancer who received breast-conserving surgery
with planned adjuvant whole-breast radiation, found to
have low-volume nodal disease (micrometastatic: up to two
macrometastatic lymph nodes) at upfront SLNB surgery,
omission of complete ALND (CALND) did not compro-
mise OS or DFS rates.18 For cN0 patients with NAST,
reliability of identifying a SLN and having a low FNR was
contentious for many years. For a subset of patients in the
NSABP B27 trial with cN0 disease treated with NAST,
SLNB was performed and was found to be accurate with a
low FNR.19 Knowing that a proportion of cN? patients
will be downstaged to yN0, ACOSOG Z1071 (Alliance)
aimed to assess the FNR after NAST in cN1 patients; they
found an acceptably low FNR when dual tracers and
retrieval of C 3 SLNs were used,14 indicating SLNB may
serve as an acceptable staging method over ALND in this
subset of patients. In this study, and other similar ones, all
patients had a planned CALND allowing for identification
of the FNR. As such, large-scale studies are yet to elucidate
the OS and DFS rates for ALND versus SLNB only in cN1
patients with a cCR to NAST. Despite this lack of clinical
outcomes data, clinicians have started using SLNB over
ALND in this subset of patients. We analyzed the NCDB to
uncover the trends and OS rates associated with this
national practice in TNBC cN1 patients with a cCR to
NAST.
Between 2012 and 2017, there was a notable increase in
the percentage of TNBC cN1 patients treated with SLNB
without complete ALND, indicating a growing acceptance
of SLNB in place of ALND in cN1 TNBC patients treated
with NAST. This finding is in concordance with other
studies that analyzed the usage of ALND and SLNB in
other breast cancer subtypes.20 We used propensity score
matching to minimize the effect of confounding variables
on the outcomes. The Kaplan–Meier analysis revealed no
significant OS difference between ALND and SLNB in the
selected population or in the matched ypN0 subgroup.
However, there was a trend towards worse OS in the ypN?
SLNB subgroup when compared with the ypN? ALND
subgroup. Considering literature and National Cancer
Comprehensive Cancer Network (NCCN) guidelines, these
 S. A. Naffouje et al.

(a) 1.0 (b) 1.0

0.9 0.9

0.8 0.8
Cumulative Overall Survival

Cumulative Overall Survival

0.7 0.7

0.6 0.6

0.5 0.5

0.4 0.4

0.3 0.3

0.2 0.2

0.1 SLNB 81.73 ± 1.04 months 0.1

p=0.127 ypN0 SLNB 85.29 ± 0.84 months
ALND 80.07 ± 0.70 months p=0.638
ypN0 ALND 82.60 ± 0.68 months
0.0 0.0
0 12 24 36 48 60 72 84 0 12 24 36 48 60 72 84
Months Months
SLNB SLNB
N entering 1,003 786 696 450 248 120 36 N entering 884 669 595 388 210 98 33
N withdrawing 49 77 222 180 124 79 32 N withdrawing 61 65 193 166 110 65 30
N exposed to risk 911 747 585 360 186 80 20 N exposed to risk 777 636 498 305 155 65 18
N of events 4 13 24 22 4 5 0 N of events 3 9 14 12 2 0 0
Cumulative survival 1.00 0.98 0.94 0.88 0.86 0.81 0.81 Cumulative survival 1.00 0.98 0.95 0.92 0.90 0.90 0.90
ALND ALND
N entering 1,003 782 673 478 316 182 78 N entering 884 688 593 420 283 171 66
N withdrawing 58 89 175 155 128 103 72 N withdrawing 74 82 162 132 109 104 62
N exposed to risk 907 737 585 400 252 130 42 N exposed to risk 697 647 512 354 228 119 35
N of events 5 20 20 7 6 1 0 N of events 6 13 11 5 3 1 0
Cumulative survival 0.99 0.97 0.93 0.92 0.90 0.89 0.89 Cumulative survival 0.99 0.97 0.95 0.94 0.92 0.92 0.92

(c) 1.0
0.9

0.8
Cumulative Overall Survival

0.7

0.6

0.5

0.4

0.3

0.2

0.1
ypN0+ SLNB 64.37 ± 3.12 months
p=0.085
ypN0+ ALND 72.45 ± 2.77 months
0.0
0 12 24 36 48 60 72 84
Months
SLNB
N entering 129 113 106 64 40 22 3
N withdrawing 4 13 31 14 16 14 2
N exposed to risk 127 106 90 57 32 15 2
N of events 2 4 11 10 2 5 0
Cumulative survival 0.98 0.92 0.83 0.69 0.65 0.43 0.43

ALND
N entering 129 100 85 53 42 20 9
N withdrawing 5 12 21 10 19 11 8
N exposed to risk 121 94 71 48 32 14 5
N of events 0 8 6 1 3 0 0
Cumulative survival 1.00 0.91 0.84 0.82 0.74 0.74 0.74
 SLNB versus ALND after NAST in TNBC

b FIG. 3. Kaplan–Meier overall survival analysis of SLNB versus SLNs.24 Of note, in both Cox regression analyses, inner
ALND. a In the matched datasets of all patients, b in the matched tumors were predictive of worse OS. This finding supports
dataset of ypN0 patients, and c in the matched dataset of ypN?
patients. ALND axillary lymph node dissection, SLNB sentinel lymph the idea that inner quadrant tumors have occult metastases
node biopsy to the internal mammary nodes, an area no longer routinely
surgically resected.25,26 However, debate remains over this
topic and more research is needed to determine the validity
and the mechanism of this finding.
results are notable. Currently, SLNB alone is acceptable in
Due to the retrospective nature of this analysis and the
cN1 patients with a ypN0 nodal status after NAST, as long
inherent limitations of the NCDB, we recognize several
as [ 2 SLNs are resected and dual tracers are used to
shortcomings of this study such as misreporting, data loss,
minimize FNR.21 However, the guidelines are less clear
and missing information. For example, we could not ana-
when considering cN1 patients with ypN? nodal status
lyze DFS rates due to the lack of recurrence data reported
after NAST. This situation poses a more complex challenge
in the NCDB. DFS rate is a critical outcome measure
for the treating oncologist given the paucity of high-level
needed to provide a more thorough comparison of ALND
data that address such a scenario. We believe that such
and SLNB in cN1 TNBC patients with a cCR to NAST. A
complex cases warrant a multidisciplinary discussion to
major shortcoming of this study was that the NCDB does
encompass all variables related to each case and to deter-
not report whether SLNB included the previously biopsy-
mine the soundest medical approach while respecting the
proven metastatic clinical lymph nodes (i.e., details related
patient’s comorbidities and preferences. Our results indi-
to targeted axillary dissection). Caudle and colleagues
cate that SLNB may be associated with worse OS rates
demonstrated that the clipped (previously biopsy-proven
compared with ALND in cN1 TNBC patients with a cCR
metastatic lymph node) was not the SLN in 23% of cases.27
to NAST who are ypN?. Even though the matched ypN?
Since the NCDB does not collect data on whether the SLN
subgroup was small and the OS difference between ALND
contained a clip, the FNR may be higher than reported. In
and SLNB was not significant, the trend towards worse OS
our opinion, this flaw would have a significant impact on
with SLNB is noteworthy. Due to the inherent limitations
the analysis, since a higher rate of patients reported to have
of the NCDB, the median follow-up time in our analysis
ypN0 on SLNB would be false-negatives and would
was * 3 years. With a longer follow-up time, it is likely
actually harbor residual disease that could potentially shift
the trend towards worse OS with SLNB would become
the survival curve. In addition, given how data is currently
significant, considering the peak risk of recurrence in
reported by the NCDB, it was not possible to determine the
TNBC is 3 years after surgery and half of primary TNBC
nodal yield or the number of positive nodes in SLNB
cases recur in distant locations by 5 years.2,22
versus ALND in patients who underwent both.
The Cox regression analysis revealed similar OS pre-
Another limitation revolves around the selection and
dictors in both the unmatched population and the ypN?
inclusion of patients with cCR as reported by the registry.
subgroup who underwent SLNB as definitive axillary sur-
This was derived from a site-specific factor that reports on
gical intervention. A noteworthy finding of the regression
‘‘response to neoadjuvant therapy’’ as stated by a clinician
analysis in the latter subgroup was the lack of significance
on clinical exam, not by final pathology report. The
of either adjuvant systemic therapy or axillary radiation on
selection bias associated with this variable is twofold; 4876
survival despite the concern of residual axillary disease.
patients were eliminated during selection for lack of clear
This finding could be explained by the small sample size
reporting on clinical response, in addition to the very low
and low number of events that could mask the difference in
negative predictive values of clinical exam, ultrasound, and
survival outcomes, especially with a median follow-up of
both in assessing axillary response following NAST, as
40.6 ± 19.6 months in that subgroup. Another explanation
demonstrated by the SENTINA28 and SN FNAC trials.29
could be the biology of the disease in this specific sub-
Moreover, the specific regimens used for systemic therapy
group, which already demonstrated its resistance by the
were not reported, making it impossible to compare treat-
lack of response to NAST in the nodal basin. The models
ment outcomes. Finally, we believe the reported utilization
also indicate that the in-breast pathologic response to
of axillary radiation in the adjuvant setting is somewhat
NAST is a strong predictor of long-term outcomes, which
low in this cohort, especially in the ypN? patient sub-
coincides with current literature showing pCR as an
groups. Adjuvant axillary radiation is currently being
excellent survival indicator.23 This was also depicted in the
investigated along with regional node irradiation (RNI) in
GANEA trial, although survival was not a primary out-
the study arm of the ALLIANCE A011202 trial
come, where residual in-breast tumor C 5 mm and
(NCT01901094) against the control arm of completion
lymphovascular invasion were significant predictors of
ALND and RNI (and radiation of undissected axilla) in
axillary involvement regardless of the number of retrieved
patients with ypN? on SLNB after NAST. Moreover, the
 S. A. Naffouje et al.

TABLE 3 Cox univariate and

Univariate analysis Multivariate analysis
multivariate regression analysis for
predictors of overall survival in the Hazard ratio [95% CI] p-Value Hazard ratio [95% CI] p-Value
unmatched dataset of all patients (N
= 2953) Age 1.019 [1.008–1.030] 0.001* 1.016 [1.005–1.027] 0.005*
Race/ethnicity
White Referent
Black 1.058 [0.777–1.442] 0.719
Hispanic 0.888 [0.530–1.487] 0.651
Other 0.622 [0.305–1.267] 0.191
Charlson score
0 Referent
1 1.123 [0.746–1.691] 0.579
2 1.724 [0.765–3.886] 0.189
3? 2.614 [0.836–8.177] 0.099
Side
Right Referent
Left 0.773 [0.596–1.004] 0.053
Location
Central 0.868 [0.317–2.376] 0.783 0.777 [0.284–2.130] 0.624
Upper inner 1.732 [1.113–2.696] 0.015* 1.893 [1.214–2.950] 0.005*
Lower inner 1.889 [1.353–2.638] 0.001* 1.895 [1.355–2.649] 0.002*
Upper outer Referent
Lower outer 1.376 [0.801–2.366] 0.248 1.510 [0.876–2.600] 0.138
Tail 2.592 [0.816–8.226] 0.106 3.561 [0.852–5.281] 0.115
Overlapping 1.889 [0.753–2.638] 0.299 1.895 [0.355–2.649] 0.246
Not specified 1.464 [0.599–3.349] 0.423 1.768 [0.532–2.761] 0.155
Grade
Low Referent
Intermediate 1.325 [0.512–3.433] 0.562
High 1.786 [0.823–1.918] 0.197
Not reported 0.757 [0.301–1.902] 0.554
Clinical T stage
cT1 Referent Referent
cT2 0.912 [0.632–1.316] 0.622 0.979 [0.677–1.415] 0.910
cT3 1.374 [0.895–2.110] 0.147 1.492 [0.960–2.317] 0.075
cT4 2.443 [1.563–3.820] \ 0.001* 1.970 [1.219–3.186] 0.006*
In-breast response
pCR Referent Referent
pPR 1.381 [1.188–1.552] \ 0.001* 1.643 [1.448–1.915] 0.014*
pNR 2.005 [1.762–2.381] \ 0.001* 1.989 [1.638–2.535] 0.001*
Path node status
Node negative Referent Referent
Node positive 3.380 [2.601–4.392] \ 0.001* 3.229 [2.477–4.211] \ 0.001*
Breast surgery
Lumpectomy Referent
Mastectomy 1.153 [0.879–1.512] 0.304
Axillary surgery
SLNB Referent
ALND 0.971 [0.736–1.281] 0.837
Axillary radiation 1.006 [0.775–1.306] 0.964
Adjuvant systemic 1.242 [0.800–1.927] 0.335
ALND axillary lymph node dissection, CI confidence interval, pCR pathologic complete response, pNR pathologic no
response, pPR pathologic partial response, SLNB sentinel lymph node biopsy *statistically significant
SLNB versus ALND after NAST in TNBC

TABLE 4 Cox univariate and Univariate analysis Multivariate analysis

multivariate regression analysis
for predictors of overall survival Hazard ratio [95% CI] p-Value Hazard ratio [95% CI] p-Value
in patients with ypN? after
SLNB as definitive surgical Age 1.023 [0.995–1.052] 0.103
axillary management (N = 135) Race/ethnicity
White Referent
Black 1.055 [0.466–2.390] 0.897
Hispanic 2.189 [0.857–5.594] 0.102
Other 1.811 [0.417–7.873] 0.428
Charlson score
0 Referent
1 2.198 [0.764–6.323] 0.144
2 N/A
3? N/A
Side
Right Referent
Left 1.166 [0.592–2.297] 0.657
Location
Central 1.413 [0.180–11.115] 0.742 1.816 [0.226–4.619] 0.575
Upper inner 4.837 [1.914–12.224] 0.001* 2.843 [1.063–7.603] 0.037*
Lower inner N/A N/A
Upper outer Referent 0.155 Referent
Lower outer 2.188 [0.743–6.447] 0.054 2.172 [0.726–6.496] 0.076
Tail 7.770 [0.966–9.475] 0.702 5.316 [0.896–7.101] 0.608
Overlapping 1.209 [0.458–3.196] 0.887 1.293 [0.483–3.461] 0.715
Not specified 1.161 [0.147–9.166] 1.480 [0.181–2.093] 0.565
Grade
Low N/A
Intermediate 1.234 [0.366–4.157] 0.978
High Referent
Not reported 2.040 [0.953–4.368] 0.066
Clinical T stage
cT1 Referent Referent
cT2 1.342 [0.773–1.601] 0.248 1.280 [0.822–1.672] 0.345
cT3 1.626 [0.882–2.387] 0.173 1.691 [0.990–2.300] 0.118
cT4 1.976 [1.517–2.952] 0.001* 1.986 [1.441–3.057] 0.002*
Breast surgery
Lumpectomy
Mastectomy
In-breast response
pCR Referent Referent
pPR 1.238 [1.111–1.511] 0.001* 1.233 [1.102–1.532] 0.002*
pNR 1.577 [1.192–1.733] \ 0.001* 1.642 [1.342–3.962] \ 0.001*
Axillary radiation 0.936 [0.472–1.857] 0.850
Adjuvant systemic 0.444 [0.106–1.859] 0.266
ALND axillary lymph node dissection, CI confidence interval, pCR pathologic complete response, pNR
pathologic no response, pPR pathologic partial response, SLNB sentinel lymph node biopsy
*
Statistically significant

NSABP B-51 (NCT01872975) is also studying the role of patients with ypN0 on SLNB after cN1 at presentation. The
adjuvant axillary radiation in a design comparing ‘‘com- results of these trials are anticipated to answer the
prehensive’’ with standard post-resection radiation in

questions on the outcomes of different adjuvant modalities,
and ro help determine the most appropriate management of
this subset of patients.
CONCLUSIONS
SLNB and ALND appear to yield comparable OS in
cN1 TNBC patients who demonstrate cCR to NAST.
Caution should be exercised in ypN1 patients as worse OS
could be associated with SLNB.
Supplementary Information The online version contains
supplementary material available at https://doi.org/10.1245/s10434-
021-11194-5.
AUTHORS’ CONTRIBUTIONS Study conception and design:
S.A.N. and C.L. Acquisition of data: S.A.N. Analysis and interpre-
tation of data: S.A.N. and C.L. Drafting of manuscript: S.A.N., V.B.,
and C.L. Critical revision: S.A.N., V.B., M.C.L., S.J.H., and C.L.
DISCLOSURE Samer A. Naffouje and Vayda Barker contributed
equally to this work, therefore they both merit to have their names
listed as first authors.
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