ORIGINAL ARTICLE
Sentinel Node Biopsy Alone or With Axillary Dissection in Breast
Cancer Patients After Primary Chemotherapy: Long-Term Results
of a Prospective Interventional Study
Gabriele Martelli, MD,*✉ Francesco Barretta, PhD,† Rosalba Miceli, PhD,†
Secondo Folli, MD,* Ilaria Maugeri, MD,* Chiara Listorti, MD,*
Gianfranco Scaperrotta, MD,‡ Paolo Baili, PhD,§ Giancarlo Pruneri, MD,∥
Giuseppe Capri, MD,¶ and Cristina Ferraris, MD*
Objective: To ascertain, in cN0/1 breast cancer patients given primary
chemotherapy followed by sentinel node biopsy (SNB), whether SNB
alone is adequate axillary treatment if the sentinel nodes (SNs) are
clear (pN0).
Summary Background Data: 2020 guidelines do not recommend SNB in
most cN1 patients with clear SNs after primary chemotherapy because
the high SNB false negative rate might lead to poorer outcomes.
Methods: We prospectively assigned SNB after primary chemotherapy to
353 consecutive cT2 cN0/1 patients, median age 47 years (range 22-76)
treated from 2007 to 2015. If the SNs were pN0, patients generally
received no further axillary treatment (SNB only); if the SNs were pN1,
completion axillary dissection (AD) (SNB + AD) was usually performed.
Primary outcomes were overall (OS) and disease-free (DFS) survival in
SNB only versus SNB + AD patients, assessed by Kaplan-Meier and
compared using log-rank test, with use of propensity scores to account
for bias due to nonrandom assignment to SNB versus SNB + AD.
Results: Median follow-up was 108 months, interquartile range 66 to 136.
OS and DFS did not differ significantly between the groups by propensity
score- weighted comparison: 10-year OS 89% [95% confidence interval
(CI): 81%- 99%] in SNB only patients versus 86% (95%CI: 78%–95%) in
From the *Breast Unit, Surgery, Fondazione IRCCS National Cancer
Institute and Foundation, Milan, Italy; †Unit of Clinical Epidemiology
and Trial Organization, Fondazione IRCCS National Cancer Institute
and Foundation, Milan, Italy; ‡Breast Unit, Imaging, Fondazione
IRCCS National Cancer Institute and Foundation, Milan, Italy; §Ana-
lytical Epidemiology and Health Impact Unit, Fondazione IRCCS
National Cancer Institute and Foundation, Milan, Italy; ∥Breast Unit,
Pathology, Fondazione IRCCS National Cancer Institute and Founda-
tion, Milan, Italy; and ¶Breast Unit, Medical Oncology, Fondazione
IRCCS National Cancer Institute and Foundation, Milan, Italy.
✉ Gabriele.martelli@istitutotumori.mi.it.
Author contributions: Gabriele Martelli MD: Study conception and design,
analysis and interpretation of data, writing of paper.
Francesco Barretta PhD: Statistical analysis.
Rosalba Miceli PhD: Statistical analysis and interpretation of data.
Secondo Folli MD: Analysis and interpretation of data.
Ilaria Maugeri MD: Acquisition of data.
Chiara Listorti MD: Acquisition of data.
Gianfranco Scaperrotta MD: Review of mammographic findings.
Paolo Baili PhD: Database maintenance.
Giancarlo Pruneri MD: Review of pathological slides.
Giuseppe Capri MD: Acquisition and interpretation of data.
Cristina Ferraris MD: Acquisition of data.
The authors report no conflicts of interest.
Supplemental digital content is available for this article. Direct URL citations
appear in the printed text and are provided in the HTML and PDF ver-
sions of this article on the journal’s website, www.annalsofsurgery.com.
Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.
ISSN: 0003-4932/22/27605-e544
DOI: 10.1097/SLA.0000000000004562
e544 | www.annalsofsurgery.com
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SNB + AD patients; 10-year DFS 79% (95%CI: 68%–92%) versus 69%
(95%CI: 58%–81%). No SNB-only patient developed axillary failure.
Conclusions: cT2 cN0/1 patients whose SNs are disease-free (pN0) after
primary chemotherapy can be offered SNB (with no further axillary
treatment if the SNs are negative), irrespective of axillary status
beforehand, without affecting OS or DFS.
Keywords: axillary dissection, breast cancer, disease-free survival, neo-
adjuvant chemotherapy, overall survival, sentinel node biopsy
(Ann Surg 2022;276:e544–e552)
P rimary chemotherapy was originally introduced for breast
cancer patients with large operable disease to reduce tumor
burden and render conservative surgery feasible.1,2 Studies on
primary chemotherapy3–5have shown that pathological complete
response (pCR) in the breast, axilla or both predicts good out-
come, with lower probability of recurrence and death. Up to 40%
of patients with a clinically involved axilla (cN1) achieve complete
pathological response (pN0) after primary chemotherapy6,7 sug-
gesting that – in patients who achieve cN0 – sentinel node biopsy
(SNB) may be indicated, and if the sentinel nodes (SNs) are neg-
ative, axillary dissection (AD) and its sequelae can be avoided.
Nevertheless, current guidelines8 do not unconditionally
recommend SNB when the axilla is clinically positive before
chemotherapy but cN0 after, because of the high false negative
rate (FNR) which might be responsible for poorer outcome.
However, a high FNR for SNB may have no clinical sig-
nificance. Randomized trials9–12 that compared AD to SNB or
observation in cN0 patients not given primary chemotherapy
reported that the rate of axillary failure in groups not receiving
AD was much lower than expected and that failure did not
adversely affect long-term outcomes.
We investigated the issue of SNB in patients receiving
primary chemotherapy by recruiting cT2 cN0/1 breast cancer
patients, scheduled for primary chemotherapy, to a prospective
interventional study (registered as NCT04436809): instead of
cN1 patients proceeding directly to AD and breast surgery after
chemotherapy, they were scheduled for SNB (as were cN0). In
both groups, if the SNs were disease-free no further axillary
treatment was given; if the SNs were involved, AD was per-
formed. Our study hypothesis was that SNB (plus no AD if the
SN is negative) is adequate treatment in patients who are cN0
after primary chemotherapy, irrespective of clinical axillary
status before chemotherapy.
The main study endpoints were overall survival (OS) and
disease-free survival (DFS) in the SNB only and SNB +AD
Annals of Surgery  Volume 276, Number 5, November 2022
Annals of Surgery  Volume 276, Number 5, November 2022
FIGURE 1. Study flow chart together with events according to sentinel node (SN) status and axillary treatment after primary
chemotherapy in 353 cT2 cN1/0 breast cancer patients.
groups. The secondary endpoint was rate of axillary failure in
the SNB only group. We also assessed the pathological response
to primary chemotherapy as a predictor of long-term outcome.
PATIENTS AND METHODS
Patients
We prospectively recruited 353 consecutive cT2 cN0/1
breast cancer patients, median age 47 years (range 22–76), who
underwent primary chemotherapy followed by surgery at the
National Cancer Institute of Milan between 2007 and 2015.
Patients with previous malignancy, synchronous breast cancer,
or distant metastasis at diagnosis were excluded, as were patients
who remained cN1 after primary chemotherapy. Post-
chemotherapy surgery consisted of breast surgery plus SNB, in
all cases. If the SN was pN0, patients generally received no
further axillary treatment; if the SN was pN1 patients generally
received completion AD; however, there were exceptions as
illustrated on the study flow chart (Fig. 1).
The study protocol was approved by the Ethical and
Scientific Committee of our Institute. All patients gave written
informed consent. Prechemotherapy work-up consisted of
physical examination (including palpation of the axilla), mam-
mography, breast and axillary ultrasound, and core biopsy of the
primary. If the axilla was positive by palpation/US, the patient
was considered cN1. Needle biopsy of the axilla was not
employed. All patients had invasive disease. In this prospective
study there were few missing data and surrogate molecular
subtyping was available for over 99% of cases (Table 1).
Treatments
Primary chemotherapy was adriamycin plus taxol for
4 cycles, followed by cyclophosphamide, methotrexate, 5-fluo-
rouracil plus trastuzumab [in human epidermal growth factor
receptor 2 (HER2)- positive patients only] for 4 additional
cycles. Response was assessed every three months by physical
examination, mammography and axillary/breast ultrasound.
Surgery was performed within 30 days of completing
chemotherapy.
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Primary Chemotherapy and the Axilla
Hormonal therapy (tamoxifen or aromatase inhibitor) for
5 years was prescribed to patients with ER + disease. Luteinizing
hormone-releasing hormone analogs were administered in asso-
ciation with hormonal therapy in premenopausal patients.
Patients with HER2 overexpression received trastuzumab for
12 months. These treatments started immediately after surgery.
Patients undergoing quadrantectomy received post-
operative whole breast radiotherapy to the residual breast with 2
opposing tangential fields, conventional fractionation (50 Gy in
25 fractions) plus a 10 Gy boost to the tumor bed. No attempt
was made to include axillary, supraclavicular, or internal
mammary nodes in the irradiation fields. Women scheduled for
mastectomy, who also had ≥4 pathological axillary nodes,
received regional/chest wall irradiation.
Biological Profile
On core biopsy, grade was assessed according to Elston
and Ellis.13 Hormone receptors were determined immunohis-
tochemically (IHC).14 Cancers were considered positive for
estrogen (ER) or progesterone (PgR) receptors if ≥10% of cancer
cell nuclei were immunostained. HER2 expression was deter-
mined by IHC. HER2 was positive when IHC score was 3+, or 2
+with, in addition, fluorescence in situ hybridization (FISH)
indicating gene amplification. HER2 was negative when IHC
was 0 or 1+(no FISH). HER2 was unknown for IHC 2+ and
FISH unavailable.15 Surrogate molecular subtype was assigned
according to Goldhirsch et al16 except that Ki67 was considered
positive when > 20% of cancer cell nuclei stained positive.17
Lymphatic Mapping
Radiolabeled (99mTc) colloid was injected peritumorally.
Lymphoscintigraphy was performed about 3 hours (range 1–
18 hours) before surgery to ascertain the presence of an axillary
hotspot. A gamma probe was used intraoperatively to identify
hotspots (SNs) and aid their surgical removal. All hot nodes
were removed and examined intraoperatively. SNs with micro-
metastases were considered positive (pN1) whereas SNs with
isolated tumor cells were considered negative (pN0).
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Martelli et al Annals of Surgery  Volume 276, Number 5, November 2022

TABLE 1. Clinical Characteristics of 353 Consecutive Breast Cancer Patients Before Primary Chemotherapy, Overall and According
to Axillary Treatment, Before and After Weighting
Observed Weighted*
Overall SNB SNB + AD Overall SNB SNB + AD
N = 353 N = 194 N = 159 SMD N = 142.48 N = 70.13 N = 72.35 SMD
Age (yrs) 0.120 0.052
Median (interquartile range) 47.00 47.50 47.00 48.00 47.00 48.00
(41.00.55.00) (41.25.57.00) (41.00.54.00) (40.13.54.00) (40.00.54.00) (41.00.56.97)
Tumor size (mm) 0.024
Median (interquartile range) 30.00 30.00 30.00 0.048 30.00 30.00 30.00
(25.00.36.00) (25.00.35.00) (25.00.38.00) (25.00.35.00) (25.00.35.00) (25.00.35.00)
Clinical lymph node status 0.694 0.674
cN0 nonpalpable 137 (38.8%) 103 (53.1%) 34 (21.4%) 50.6 (35.5%) 35.8 (51.1%) 14.8 (20.5%)
cNl palpable 216 (61.2%) 91 (46.9%) 125 (78.6%) 91.9 (64.5%) 34.3 (48.9%) 57.6 (79.5%)
Histology 0.287 0.041
Invasive ductal carcinoma 321 (90.9%) 177 (91.2%) 144 (90.6%) 132.5 (93.0%) 65.2 (93.0%) 67.3 (93.0%)
Invasive lobular carcinoma 26 (7.4%) 11 (5.7%) 15 (9.4%) 9.9 (6.9%) 4.9 (6.9%) 5.0 (7.0%)
Other invasive histotypes 6 (1.7%) 6 (3.1%) 0 (0.0%) 0.1 (0.0%) 0.1 (0.1%) 0.0 (0.0%)
Type of surgery 0.186 0.014
Mastectomy 140 (39.7%) 69 (35.6%) 71 (44.7%) 45.4 (31.9%) 22.1 (31.6%) 23.3 (32.2%)
Quadrantectomy 213 (60.3%) 125 (64.4%) 88 (55.3%) 97.0 (68.1%) 48.0 (68.4%) 49.1 (67.8%)
Nuclear grade 0.457 0.086
G1 2 (0.6%) 0 (0.0%) 2 (1.3%) 0.3 (0.2%) 0.0 (0.0%) 0.3 (0.4%)
G2 190 (53.8%) 87 (44.8%) 103 (64.8%) 75.8 (53.2%) 37.5 (53.4%) 38.3 (52.9%)
G3 161 (45.6%) 107 (55.2%) 54 (34.0%) 66.5 (46.6%) 32.7 (46.6%) 33.8 (46.7%)
Receptor status 0.491 0.308
ER positive, PGR positive 208 (58.9%) 103 (53.1%) 105 (66.0%) 83.0 (58.2%) 44.7 (63.8%) 38.3 (52.9%)
ER positive, PGR negative 43 (12.2%) 17 (8.8%) 26 (16.4%) 19.9 (14.0%) 6.4 (9.1%) 13.5 (18.7%)
ER negative, PGR positive 12 (3.4%) 8 (4.1%) 4 (2.5%) 5.1 (3.6%) 2.0 (2.9%) 3.1 (4.3%)
ER negative, PGR negative 90 (25.5%) 66 (34.0%) 24 (15.1%) 34.5 (24.2%) 17.0 (24.3) 17.5 (24.2%)
HER2 status 0.059 0.006
Negative 83.4 (58.5%) 109 (56.2%) 94 (59.1%) 83.4 (58.5%) 41.1 (58.7%) 42.2 (58.4%)
Positive 59.1 (41.5%) 85 (43.8%) 65 (40.9%) 59.1 (41.5%) 29.0 (41.3%) 30.1 (41.6%)
Ki67 (%) 0.134
Median (interquartile range) 25.00 30.00 18.00 0.566 25.00 26.51 22.91
(15.00.40.00) (18.00.50.00) (12.00.30.50) (15.00.40.00) (15.00.40.00) (15.00.40.00)
Ki67 0.520 0.124
≤20 155 (43.9%) 64 (33.0%) 91 (57.2%) 60.8 (42.6%) 27.9 (39.7%) 32.9 (45.5%)
> 20 193 (54.7%) 128 (66.0%) 65 (40.9%) 79.8 (56.0%) 41.4 (59.1%) 38.3 (53.0%)
Not available 5 (1.4%) 2 (1.0%) 3 (1.9%) 2.0 (1.4%) 0.8 (1.2%) 1.1 (1.6%)
Surrogate molecular subtype 0.521 0.038
Luminal A 83 (23.5%) 33 (17.0%) 50 (31.4%) 34.7 (24.4%) 17.6 (25.0%) 17.2 (23.7%)
Luminal B, HER2-negative, 69 (19.5%) 40 (20.6%) 29 (18.2%) 25.8 (18.1%) 12.3 (17.6%) 13.5 (18.7%)
Ki67 > 20
Luminal B, HER2-positive 111 (31.4%) 55 (28.4%) 56 (35.2%) 47.4 (33.3%) 23.2 (33.1%) 24.2 (33.5%)
HER2 positive 39 (11.0%) 30 (15.5%) 9 (5.7%) 11.7 (8.2%) 5.8 (8.2%) 5.9 (8.2%)
Triple negative 51 (14.4%) 36 (18.6%) 15 (9.4%) 22.8 (16.0%) 11.2 (16.0%) 11.6 (16.0%)
*Weighted values derived from application of the inverse probability treatment weighting.HER 2 indicates human epidermal growth factor receptor 2.

Statistical Methods
The primary study endpoints were DFS and OS, reckoned
from date of surgery. DFS was time to recurrence (local relapse,
contralateral breast cancer, distant metastases), other malignancy,
or death, whichever occurred first. OS was time to death for any
cause. Time was censored for living patients who were event-free at
most recent follow up. OS and DFS curves were estimated using the
Kaplan-Meier method and compared using the log-rank test. To
compare DFS and OS in the SNB only and SNB + AD groups, we
estimated propensity score as a balancing score to account for the
bias due to nonrandom assignment of treatment. Propensity score is
the probability of treatment assignment in an individual conditional
to measured baseline covariates.18We used the method of stabilized
weights applied to the inverse probability of treatment weighting to
arrive at propensity scores such that each individual’s weighting was
equal to the inverse of the probability of receiving the treat-
ment.19Propensity score was estimated using a multivariable logistic
model with binary response (SNB or SNB + AD) and the following
observed variables (covariates): age at surgery (continuous), surro-
gate molecular subtype (luminal A, luminal B HER2 negative Ki-
67 > 20, luminal B HER2 positive, HER2 positive, triple negative),
histology (invasive ductal carcinoma, invasive lobular carcinoma,
other invasive histotypes), grade (G3 vs G1-G2), preoperative
clinical lymph node status (cN1 vs cN0), type of surgery (quad-
rantectomy vs mastectomy) and pathological lymph node status
(pN1 vs pN0) determined on the SN in SNB only cases and on the
axilla in AD cases. Radiotherapy versus no radiotherapy was not
included in the propensity score because all quadrantectomy
patients received radiotherapy and few (12.9%) mastectomy
patients received radiotherapy, so type of surgery was a good proxy

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Annals of Surgery  Volume 276, Number 5, November 2022
for radiotherapy. Patient age was modeled as a continuous variable
using three-knot restricted cubic splines to obtain a flexible fit.20
To further investigate outcomes in relation to prognostic var-
iables, multivariable Cox models were used to estimate hazard ratios,
with 95% confidence intervals, for death and events contributing to
DFS, in relation to: axillary treatment, pathological lymph node
status, response to primary chemotherapy, histology, grade, and
surrogate molecular subtype – all categorized as stated above.
Median follow up was estimated by the reverse Kaplan-
Meier method using OS data.21 Differences in general and dis-
ease characteristics between the groups were assessed by the
standardized mean difference (SMD).22 SMDs ≥0.3 were con-
sidered to indicate an important between-group imbalance. The
statistical analyses employed SAS (Cary, NC) and R software23
Follow Up
Physical examination and breast/axillary ultrasound were
performed every 6 months for the first 5 years and yearly thereafter.
Mammography, chest X-ray and bone scan were performed yearly.
Disease status or cause of death was ascertained from clinical
records or by contacting the general practitioners of patients no
longer in follow up. No cases were lost to this ascertainment.
RESULTS
Median follow up was 108 months overall, interquartile
range (IQR) 66 to 136 months, 87 months (IQR 48–112 months)
in the SNB only group, and 139 months (IQR 107–151 months)
in the SNB + AD group.
Table 1 summarizes the clinical characteristics of the 353
patients before primary chemotherapy, overall and by treatment
group. The left side of the table shows the observed data, the
right side shows the weighted data. The groups differed most
markedly for the observed variables: clinical lymph node status,
grade, receptor status, Ki-67, and surrogate molecular subtype
(SMD > 0.3). After weighting, most covariates (included in the
logistic model to estimate the propensity score) were well-bal-
anced, with only receptor status remaining slightly unbalanced
(ER +, PgRþ 60% vs 49.7%; ER +, PgR– 10.6% vs 19.1% in the
SNB only and SNB + AD groups, respectively, SMD 0.286).
All 213 quadrantectomy patients received irradiation to
the ipsilateral breast. Of the 140 patients who received mastec-
tomy, 18 (12.9%) had ≥4 involved axillary nodes and received
regional/chest wall irradiation.
Supplementary Table 1, http://links.lww.com/SLA/C673
shows the pathological response of the breast to primary che-
motherapy: 55 (15.6%) patients, 26 in the SNB and 29 in the
SNB + AD group, had complete pathological response, 280
(79.3%) had partial response, and 18 (5%) had stable/progressive
disease. Complete pathological response of the breast occurred
in 15/39 (38.5%) HER2-positive, 18/51 (35.3%) triple negative,
TABLE 2. Pathological Response of the Breast to Primary Chemotherapy According to Surrogate Molecular Subtype
Luminal A Luminal B, HER2 Negative, Ki67 > 20
N = 83 N = 69
Response of primary to neoadjuvant chemotherapy
Complete response 3 (3.6%) 4 (5.8%)
Partial response 76 (91.6%) 58 (84.1%)
Stable disease 3 (3.6%) 6 (8.7%)
Progressive disease 1 (1.2%) 1 (1.4%)
HER 2 indicates human epidermal growth factor receptor 2.
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Primary Chemotherapy and the Axilla
15/111 (13.5%) luminal B HER2-positive, 4/69 (5.8%) luminal B
HER2-negative Ki67 > 20, and 3/83 (3.6%) luminal A cases.
Stable/progressive disease mainly occurred in patients with
luminal A or luminal B disease, the only exception being one
triple-negative patient who had stable disease; no HER2-positive
or triple-negative patients had disease progression (Table 2).
A median of two SNs (range 1 –8) was removed from the
entire cohort; in 117 (33%) patients one SN was removed.
Of the 137 patients who were cN0 before chemotherapy
(Fig. 1), the SNs were pathologically disease-free in 104 (76%)
and metastatic in 33 (24%). Of the 104 patients with a pN0 SN,
95 received no further axillary treatment and 9 received AD. Of
the 33 patients with a pN1 SN, 8 received no further axillary
treatment and 25 received AD.
Of the 216 patients who were cN1 (palpation/ultrasound)
before chemotherapy, the axilla was disease-free in 121 (56%) on
histological examination (SN negativity in those given SNB only was
considered to indicate a negative axilla): 81 of these received SNB
only, and 40 received SNB + AD (with no positive nodes found on
pathological examination). Of the 95 cN1 patients with a positive SN
after chemotherapy, 85 received AD and 10 received SNB only.
Of the 225 (104 cN0, 121 cN1) patients whose SNs were
pN0 after primary chemotherapy, 49 (9 + 40) had AD. The latter
patients received AD after consulting with physicians extraneous
to our study. In all 49 patients non-SNs were negative.
Of the 128 (33 + 95) patients whose SNs were pN1 after
primary chemotherapy, 18 (8 + 10) received no further axillary
treatment. Among these 18 patients, 8 had 1 micrometastatic SN with
a median of 1 negative SNs removed (range 1–4). In the remaining 10
patients, there was a median of 1 (range 1 -3) metastatic SNs (subtotal
or massive involvement) and 4 (median, range 2–
7) negative SNs. All 18 patients expressed a desire to
forego AD: we accepted patient wishes and opted for follow-up.
Among these 18 patients, 4 developed distant metastases, 2 of
whom died of disease, but none developed overt axillary disease.
In fact no patient in the present study developed overt axillary
disease after median followups of 87 months (SNB group) and
139 months (SNB + AD group).
Among the 110 patients (25 + 85) who received SNB +
AD, in 47 (43%) only the SNs were positive; in the remaining 63
(57%) non- SNs were also positive (median 1, range 1–27; IQR
0–3). Among the latter, in 11 there were micrometastases only, in
32 maximum involvement was subtotal and in 20 there was
massive involvement. In no case was there extracapsular inva-
sion or perinodal fat infiltration.
Overall 90 events occurred after a median disease-free
interval of 38 months (IQR 23–77 months): 21 in patients ini-
tially cN0 and 69 in patients initially cN1. Ten events were
another malignancy and 80 were breast cancer-related (contra-
lateral breast cancer, local relapse, distant metastases); 19/80
were in initially cN0 patients and 61/80 were in initially cN1
Luminal B, HER2 Positive HER2 Positive Triple Negative
N = 111 N = 39 N = 51
15 (13.5%) 15 (38.5%) 18 (35.3%)
90 (81.1%) 24 (61.5%) 32 (62.7%)
3 (2.7%) 0 (0.0%) 1 (2.0%)
3 (2.7%) 0 (0.0%) 0 (0.0%)
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Martelli et al Annals of Surgery  Volume 276, Number 5, November 2022

patients. Distant metastases occurred in 39 (30%) patients with a
pN1 SN and 21 (9%) with a pN0 SN. No HER2-positive patients
developed distant metastases, whereas 6/51 (11.7%) patients with
triple-negative disease developed distant metastases, 5 within
2 years of surgery.
Overall, 41 patients died of breast cancer, 16 with pN0
SNs and 25 with pN1 SNs. Table 3 shows Kaplan-Meier esti-
mates of 10year OS and DFS by treatment group, pathologic
response of the breast to primary chemotherapy, and disease
characteristics at pretreatment biopsy. OS and DFS did not
differ significantly between the groups by weighted comparison
(see also Fig. 2): 10-year OS was 89% [95% confidence interval
(CI): 81–99%] in the SNB only group versus 86% (95%CI: 78–
95%) in the SNB + AD group; corresponding figures for DFS
were 79% (95%CI: 68–92%) versus 69% (95%CI: 58–81%).
In the multivariable Cox models to estimate hazard ratios
for death and DFS events, interaction terms between axillary
treatment and SN pathological status were not significant (P =
0.830 for death; P = 0.786 for DFS events), and only the pN
status of SNs was significantly associated with both risk of death
and risk of a DFS event (Supplementary Table 2, http://links.
lww.com/SLA/C673).
In un-weighted comparisons, considering cases with pN0
and pN1 SNs separately, OS and DFS did not vary significantly
with axillary treatment (SNB vs SNB + AD) (Fig. 3), although
none of the patients with pN1 SN reached 10 years of follow up.
In the SNB only group, OS and DFS did not vary sig-
nificantly with pN0/1 status, however in the SNB + AD group,
OS (P= 0.048) and DFS (P < 0.002) were significantly worse in
pN1 than pN0 patients (Fig. 4).
Among patients who were initially cN1, those who remained
pN1 after primary chemotherapy had worse OS and DFS than cN1
patients who downstaged to pN0: 10-year OS 90.3% (95%CI:
84.3%–96.7%) for pN0, versus 74.8% (95%CI; 65.6%–85.3%) for
pN1, P= 0.004; 10-year DFS 76.3% (95% CI: 68.0%–85.6%) for
pN0 versus 52.6% (95% CI:42.7%–64.8%) for pN1, P < 0.001
(Supplementary Fig. 1, http://links.lww.com/SLA/C672).
Neither histology and nor grade was associated with sig-
nificant variations in OS or DFS (Supplementary Fig. 2, http://
links.lww.com/SLA/C672). As expected, OS and DFS (both P =
0.004) varied significantly with response to primary chemo-
therapy, with complete and partial responders doing better than
those with stable or progressive disease. (Supplementary Fig. 3,
http://links.lww.com/SLA/C672). OS and DFS also varied sig-
nificantly with surrogate molecular subtype (Supplementary Fig.
3, http://links.lww.com/SLA/C672), with HER2-positive patients
doing better than the others.
Finally, outcomes were not associated with the clinical
status of the axilla before chemotherapy (Supplementary http://
links.lww.com/SLA/C672). Thus, in pN0 patients 10-year OS
was 92.9% (95% CI: 87.5%–98.7%) for cN0, and 90.3% (95% CI:
84.3%–96.7%) for cN1 (P= 0.818); and in pN1 patients 10-year
OS was 83.9% (95% CI: 69.4%–100%) for cN0 and 74.8% (95%
CI: 65.6%–85.3%) for cN1 (P = 0.430). Findings were similar for
DFS: In pN0 patients 10-year DFS was 84.0% (95% CI: 75.4%–
93.6%) for cN0 and 76.3% (95% CI; 68.0%–85.6%) for cN1 (P=
0.257) whereas in pN1 patients 10-year DFS was 63.0% (95% CI:
46.0%–86.2%) for cN0 and 52.6% (95% CI:42.7%–64.8%) for
cN1 (P= 0.316).
DISCUSSION
The main study endpoints – OS and DFS – did not differ
significantly between the SNB only and SNB + AD groups by

TABLE 3. Kaplan-Meier Estimates of 10-Year OS and DFS According to Treatment Group and Disease Characteristics
10-yr OS (95% CI) P value 10-y DFS (95% CI) P value*
Treatment group† 0.388 0.283
SNB 89% (81%–99%) 79% (68%–92%)
SNB + AD 86% (78%–95%) 69% (58%–81%)
Pathological sentinel lymph node in SNB treatment group
ypN0 92% (88%–97%) 0.145 82% (76%–90%) 0.068
ypN1‡ — —
Pathological sentinel lymph node in SNB + AD treatment group
ypN0 90% (81%–99%) 0.145 75% (64%–86%) 0.068
ypN1 77% (68%–86%) 54% (45%–65%)
Response to primary chemotherapy 0.004 0.004
CR 91% (83%–99%) 69% (58%–82%)
PR 86% (81%–91%) 73% (66%–79%)
SD/PD 58% (37%–93%) 36% (18%–74%)
Histology 0.675 0.919
Invasive ductal carcinoma 86% (82%–91%) 70% (65%–77%)
Invasive lobular carcinoma 77% (59%–100%) 71% (54%–92%)
Other invasive histotypes 100% 63% (32%–100%)
Grade 0.103 0.585
G1-G2 88% (83%–94%) 69% (61%–77%)
G3 82% (75%–90%) 73% (65%–81%)
Surrogate molecular subtype 0.031 0.008
Luminal A 82% (72%–93%) 66% (55%–79%)
Luminal B, HER2-negative, Ki67 > 20 84% (75%–95%) 53% (39%–73%)
Luminal B, HER2-positive 89% (83%–96%) 78% (70%–87%)
HER2 positive 100% 85% (72%–100%)
Triple negative 78% (66%–92%) 67% (54%–83%)
*P-value from log-rank test.
†Weighted values derived from application of inverse probability treatment weighting.
‡No patients in pN1 subgroup had reached ten years of follow-up at most recent follow-up.CR indicates complete response; PR, partial response; SD, stable disease; PD,
progression disease.

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Annals of Surgery  Volume 276, Number 5, November 2022
FIGURE 2. Kaplan-Meier curves showing
propensity score-weighted overall survival
(panel A) and propensity score-weighted
disease-free survival (panel B) according to
surgical axillary treatment: SNB only versus
SNB plus axillary dissection (SNB + AD).
weighted comparison (Fig. 2). Similarly, in pN0 (SN-negative)
patients (Fig. 3) outcomes did not differ between SNB only and
SNB + AD groups. These findings are evidence that in cT2 cN0/
1 breast cancer patients who are cN0 after primary chemo-
therapy, SNB can be offered (with no further axillary treatment
given if the SNs are negative), irrespective of axillary status
beforehand, without affecting overall or DFS.
Equally important was the finding that no patient who
received no further axillary treatment after a negative SN devel-
oped axillary relapse over a median follow-up of 87 months.
These results are in full accord with those of the retro-
spective study of Galimberti et al24 which analyzed 396 cT1-4 cN0/
1/2 breast cancer patients who became or remained cN0 after
neoadjuvant treatment and underwent SNB, but received no fur-
ther axillary treatment if the SNs were negative: only 1 axillary
failure was reported after a median follow up of 61 months, and
survival endpoints in SNB only patients did not differ significantly
between those initially cN0 and those initially cN1.
A persistent concern about offering SNB to cN1 patients
who become pN0 after primary chemotherapy is that the SN
FNR may be “too high.” Mainly for this reason the 2017 Saint
Gallen consensus conference25 recommended that SNB be
reserved for post chemotherapy patients with > 2 negative SNs.
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Primary Chemotherapy and the Axilla
The 2020 NCCN guidelines are similarly cautious.8 In fact
numerous studies26–28 have investigated the accuracy of SNB
after primary chemotherapy in initially cN1 patients. In the
NSABP B-27,26 Sentina27 and Alliance28 studies, the FNR (on
AD) was above the 10% considered acceptable, and these studies
advised against SNB. By contrast, Newman et al29 reported an
FNR of 8.6%, Boileau et al6 reported an FNR of 8.4%, and
Canavese et al30 reported an FNR of 5.1%. All these studies
concluded that SNB was reliable after preoperative chemo-
therapy. However, irrespective of the FNR, and as noted pre-
viously, randomized trials on SNB11,12 reported much lower
axillary failure rates (around 1%) than expected from the FNR
in the AD arms, and these failures had no impact on survival.
Similarly, in the Z0011,31and 23–0132 trials on patients with
proven axillary involvement and no AD, axillary failure rates
were low and longterm outcomes that were no worse than those
in patients given AD.
It is noteworthy that none of the SNB only patients in our
study experienced axillary failure, and none of the 18 patients (8
initially cN0; 10 initially cN1) with a positive SN (pN1) who did
not receive AD had axillary failure, even though 4 of these
developed distant metastases. These findings support the idea
that SNB is sufficient axillary treatment, not only when the SN is
pN0 but also in some cases when it is pN1 (Fig. 3).
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Martelli et al Annals of Surgery  Volume 276, Number 5, November 2022

FIGURE 3. Kaplan-Meier curves for overall survival (panels A and C) and disease-free survival (panels B and D) according to
treatment: SNB only versus SNB plus axillary dissection (SNB + AD), in patients with pN0 sentinel nodes (panels A and B) and pN1
sentinel nodes (panels C and D).

Overall, our data suggest that the FNR of SNB has no
relevance in this setting. We were not concerned with the FNR
in this study, but presumably it was high in some of our SNB
only patients; nevertheless, it had no adverse effect on out-
comes. We note that 40 patients who started out cN1 and had a
negative SNB in fact received AD (against protocol). In these
40 patients, no involved axillary nodes were found on AD, so
the FNR was zero. This finding suggests that the FNR is not
always high in the neoadjuvant setting. But the number of
cases is small.
As expected, outcomes were good in the 55 patients
(15.6% of total, Supplementary Fig. 3, http://links.lww.com/
SLA/C672) who achieved breast pCR. Of these, 45 initially had
cN1 disease (2 luminal A, 1 luminal B, 11 luminal B HER2+, 13
HER2+ and 18 triple negative) with 36 downstaging to pN0 (2
luminal A, 1 luminal B, 6 luminal B HER2þ, 11 HER2þ and 16
triple negative). Sixteen of the 18 patients with triple negative,
and 11/13 patients with HER2+ disease, downstaged to pN0.
The remaining 10/55 were cN0 in the axilla (1 luminal A, 3
luminal B, 4 luminal B Her2+, 2 HER2+, no triple negative): 7
(2 luminal B, 3 luminal B HER2+ and 2 HER2+) turned out to
be pN0 at surgery. The 36 + 7 patients with pathological
complete remission to breast and axilla probably obtained no
benefit from the surgery and would be candidates for trials on
the omission of surgery.33
In 2 studies,3,34 up to 36% of patients with triple-negative
disease achieved pCR after primary chemotherapy, and up to 50%
of patients with HER2-positive ER-negative disease achieved pCR
using agents such as trastuzumab. Much lower pCR rates were
achieved in patients with ER-positive HER2-negative tumors.
We also found that the response of the axilla to primary
chemotherapy influenced outcomes. Specifically, of the 216
(61.2% of total) patients who were cN1 before primary chemo-
therapy, 121 (56%) were pN0 in the axilla after chemotherapy
against 95 who were pN1 (Fig. 1): 10-year DFS in the former
was 76.3%, compared to 52.6% (P < 0.001) in the latter (Sup-
plementary Fig. 1, http://links.lww.com/SLA/C672). The data of
Figure 4 provide further indication of the importance of the
response of the axilla to primary chemotherapy in predicting
outcomes: in general outcomes were worse in pN1 patients,
irrespective of whether or not AD was given.
A recent pooled analysis35 also found that DFS was worse
in initially cN1 patients who remained pN1, than in patients who
downstaged to pN0. Finally, we note that outcomes were not

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Annals of Surgery  Volume 276, Number 5, November 2022
FIGURE 4. Kaplan-Meier curves showing overall survival (panels A and C) and disease-free survival (panels B and D) according to
SN status (pN0/1) in patients given SNB only (panels A and B) or SNB plus axillary dissection (SNB + AD) (panels C and D).
associated with the clinical status of the axilla before chemo-
therapy (Supplementary Fig. 4 http://links.lww.com/SLA/C672).
Limitations are that the study was a nonrandomized
interventional trial that enrolled a relatively small number of
patients, and that the axilla was assessed “clinically” by pal-
pation and ultrasound, not needle biopsy. It is also important to
note that follow-up in the SNB + AD group was considerably
longer (139 months, IQR 107–151) than follow-up in the SNB
only group (87 months, IQR 48–112). The reason for this is that
at the beginning of the study many pN0 patients opted for AD
on the advice of external physicians. As time passed more pN0
patients opted for no further axillary treatment.
To conclude, our results indicate that patients whose SNs
are pN0 after primary chemotherapy can be safely proposed no
further axillary surgery, irrespective of axillary status before
chemotherapy. Our data also suggest that some patients who are
pN1 after primary chemotherapy do not benefit from AD
(Fig. 3), although further studies are required to confirm this.
Finally, since pathological complete remission in the breast and/
or axilla was associated with good long-term outcomes, whereas
disease progression during chemotherapy was associated with
poorer prognoses, we suggest that the response to primary
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Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.
Primary Chemotherapy and the Axilla
chemotherapy may be at least as important as surrogate
molecular subtype in predicting outcomes.
ACKNOWLEDGMENTS
The authors thank Simone Bonfarnuzzo and Ilaria Cavallo
for managing the study database, and Don Ward for help with the
English.
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