new england
journal of medicineThe

established in 1812

April 4, 2024

vol. 390

no. 13

Omitting Axillary Dissection in Breast Cancer
with Sentinel-Node Metastases
J. de Boniface, T. Filtenborg Tvedskov, L. Rydén, R. Szulkin, T. Reimer, T. Kühn, M. Kontos, O.D. Gentilini,
R. Olofsson Bagge, M. Sund, D. Lundstedt, M. Appelgren, J. Ahlgren, S. Norenstedt, F. Celebioglu, H. Sackey,
I. Scheel Andersen, U. Hoyer, P.F. Nyman, E. Vikhe Patil, E. Wieslander, H. Dahl Nissen, S. Alkner, Y. Andersson,
B.V. Offersen, L. Bergkvist, J. Frisell, and P. Christiansen, for the SENOMAC Trialists’ Group*​​a bs t r ac t
BACKGROUND

Trials evaluating the omission of completion axillary-lymph-node dissection inpatients with clinically node-negative breast cancer and sentinel-lymph-node metastases have been compromised by limited statistical power, uncertain nodal radiotherapy target volumes, and a scarcity of data on relevant clinical subgroups.
METHODS

We conducted a noninferiority trial in which patients with clinically node-negative
primary T1 to T3 breast cancer (tumor size, T1, ≤20 mm; T2, 21 to 50 mm; andT3, >50 mm in the largest dimension) with one or two sentinel-node macrometastases (metastasis size, >2 mm in the largest dimension) were randomly assigned
in a 1:1 ratio to completion axillary-lymph-node dissection or its omission (sentinel-node biopsy only). Adjuvant treatment and radiation therapy were used in accordance with national guidelines. The primary end point was overall survival. We
report here the per-protocol and modified intention-to-treat analyses of the prespecified secondary end point of recurrence-free survival. To show noninferiority
of sentinel-node biopsy only, the upper boundary of the confidence interval for thehazard ratio for recurrence or death had to be below 1.44.

The authors’ full names, academic degrees, and affiliations are listed in the
Appendix. Dr. de Boniface can be contacted at ­jana​.­de-boniface@​­ki​.­se or at
the Breast Center, Department of Surgery,
Capio St. Göran’s Hospital, Mariebergsgatan 2, 11219 Stockholm, Sweden.
*A list of the clinical collaborators in the
SENOMAC Trialists’ Group is provided
in the Supplementary Appendix, available
at NEJM.org.
N Engl J Med 2024;390:1163-75.
DOI: 10.1056/NEJMoa2313487
Copyright © 2024 Massachusetts Medical Society.

CME

RESULTS

Between January 2015 and December 2021, a total of 2766 patients were enrolled
across five countries. The per-protocol population included 2540 patients, of whom1335 were assigned to undergo sentinel-node biopsy only and 1205 to undergo
completion axillary-lymph-node dissection (dissection group). Radiation therapy including nodal target volumes was administered to 1192 of 1326 patients (89.9%) in
the sentinel-node biopsy–only group and to 1058 of 1197 (88.4%) in the dissectiongroup. The median follow-up was 46.8 months (range, 1.5 to 94.5). Overall, 191 patients had recurrence or died. The estimated 5-year recurrence-free survival was 89.7%(95% confidence interval [CI], 87.5 to 91.9) in the sentinel-node biopsy–only groupand 88.7% (95% CI, 86.3 to 91.1) in the dissection group, with a country-adjusted
hazard ratio for recurrence or death of 0.89 (95% CI, 0.66 to 1.19), which was significantly (P<0.001) below the prespecified noninferiority margin.
CONCLUSIONSThe omission of completion axillary-lymph-node dissection was noninferior to themore extensive surgery in patients with clinically node-negative breast cancer who
had sentinel-node macrometastases, most of whom received nodal radiation therapy.
(Funded by the Swedish Research Council and others; SENOMAC ClinicalTrials.gov
number, NCT02240472.)
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T h e n e w e ng l a n d j o u r na l o f m e dic i n e

I

A Quick Takeis available at
NEJM.org

1164

n 2010 and 2011, the American Collegeof Surgeons Oncology Group (ACOSOG)
Z0011 trial1,2 showed the safety of the omission of completion axillary-lymph-node dissection (the removal of additional axillary lymph
nodes after biopsy of sentinel lymph nodes hasrevealed metastases) among patients with clinically node-negative (cN0) breast cancer undergoing breast-conserving surgery and whole-breast
radiotherapy in whom sentinel-lymph-node biopsy
had revealed one or two metastases. Since then,the use of completion axillary-lymph-node dissection has been steadily decreasing. In somecountries, the adaptation of guidelines has beenslow, owing mainly to underrecruitment in the
ACOSOG Z0011 trial and the premature closureof that trial in combination with a large noninferiority margin, short follow-up, and uncertainties regarding irradiated nodal volumes and any
consequences for adjuvant therapies.3-5 In a later
article,6 the investigators reported that postoperative radiation therapy with the use of hightangents had been used in more than half thepatients and that protocol-prohibited nodal radiation therapy had been used in 19%. Detailed
treatment records were available for only 228 of
856 patients.6
In the European Organization for Research
and Treatment of Cancer (EORTC) 10981-22023
Comparison of Complete Axillary Lymph Node
Dissection with Axillary Radiation Therapy inTreating Women with Invasive Breast Cancer(AMAROS) trial, completion axillary-lymph-nodedissection was replaced with axillary radiation
therapy.7 Mastectomy was not an exclusion criterion, but only 248 such patients (17.4%) underwent randomization. Although neither of thesetrials reached statistical power for their respective
end points, no benefit of completion axillarylymph-node dissection was observed after 10 years
of follow-up.8,9 Signs of lymphedema, however,were twice as common after completion axillarylymph-node dissection than after axillary radiation therapy in the AMAROS trial.7,9
In 2015, we opened the SENOMAC trial forenrollment. The aim of this trial was to validate
results from previous trials in a sufficiently large
cohort focused only on patients with sentinelnode macrometastases and to extend eligibility
criteria to include important underrepresented
subgroups — namely, patients undergoing mastectomy, those with sentinel-node extracapsularn engl j med 390;13

extension or T3 tumors (tumor size, >50 mm in
the largest dimension), and men.

Me thods
Trial Design and Oversight

For this prospective, randomized, phase 3 trial,
we chose a noninferiority design because of the
known clinical advantages of sentinel-node biopsy regarding long-term complications to thearm (e.g., lymphedema). We aimed to show thatthe omission of completion axillary-lymph-nodedissection would not worsen overall survival (theprimary end point) by more than a small, clinically acceptable margin. The original trial protocol, which is available with the full text of thisarticle at NEJM.org, has been published previously.10 The authors vouch for the completenessand accuracy of the data and for the fidelity ofthe trial to the protocol.
The trial was conducted at 67 hospitals in
Sweden, Denmark, Germany, Greece, and Italy.
Ethics approval was obtained from the Swedish
Ethical Review Authority in 2014 and from relevant ethics review boards in the participating
countries. All the patients provided informed
written consent. The trial was conducted andmonitored according to Good Clinical Practiceguidelines. Clinical data were recorded in anelectronic case-report form, and data quality was
thoroughly reviewed and optimized to address
any outlying, missing, or incongruent values.
The manuscript was written by the authors, andno one who is not an author contributed to thewriting of the manuscript. The funders had nopart in the design, performance, analysis, orreporting of the trial.
Patient Selection

Female and male adult patients who had cN0
breast cancer with a tumor stage of T1, T2, orT3 (tumor size, T1, ≤20 mm; T2, 21 to 50 mm;
and T3, >50 mm in the largest dimension) and
one or two sentinel-node macrometastases (metastasis size, >2 mm in the largest dimension)
were eligible for inclusion. Preoperative ultrasonography of the axilla was mandatory. Patientswere ineligible if they had extraaxillary regional
or distant metastases, a history of invasive breast
cancer, breast cancer in both breasts if one of thebreasts met exclusion criteria, medical contraindications against radiation therapy or systemic
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Omit ting Axillary Dissection in Breast Cancer

treatment, or an inability to understand the trial
information. Additional micrometastases (metastasis size, ≤2 mm in the largest dimension) on
sentinel-node biopsy and extracapsular extension
were allowed. Patients who had suspicious but
nonpalpable axillary lymph nodes on ultrasonography were eligible even if metastasis was confirmed by fine-needle aspiration. After a protocol
amendment in 2016, primary systemic treatment
was allowed if the sentinel-node biopsy was performed before the start of treatment.
Treatment and Follow-up

After patients underwent sentinel-node biopsy,
they underwent randomization by means of acomputerized system either to completion axillarylymph-node dissection or to no further axillary
surgery (sentinel-node biopsy only). Dependingon the use of intraoperative frozen section,
which is sometimes used by hospitals to receive
preliminary results of sentinel-node biopsy during surgery, completion axillary-lymph-node dissection was performed either during the same
surgery (intraoperative randomization) or during
a second surgery (postoperative randomization).
Breast-conserving surgery and mastectomy were
eligible interventions. Negative surgical margins
were mandatory. Sites in Germany and Italy limited trial inclusion to patients undergoing mastectomy because the ACOSOG Z0011 criteria had
been implemented in national guidelines.
A sentinel node was defined as any lymph
node that had accumulated tracer material (bluedye or isotope) or was considered to be suspicious for cancer on intraoperative palpation.
Lymph nodes that did not fulfill these criteria
but that had been randomly removed during
surgery were not classified as sentinel nodes,
and metastases in such nonsentinel nodes did
not lead to exclusion. The recommendations of
the American Joint Committee on Cancer wereapplied for the assessment of histopathological
specimens.11
Adjuvant systemic treatment was recommended according to relevant national guidelines andcould consist of endocrine treatment or chemotherapy (or both), with or without targeted treatment. Whole-breast radiation therapy after breastconserving surgery was mandatory. Indications
for radiation-therapy boost to the tumor bed,radiation therapy to the chest wall after mastectomy, and radiation therapy to regional lymphn engl j med 390;13

nodes were in accordance with national guidelines. Quality control of radiation therapy was
performed by means of source-data verification(with data from the registered electronic casereport form compared with the actual plans forradiation therapy) for all the patients who underwent randomization in Sweden or Denmark until
May 31, 2019. Given that the protocol did not
stipulate any specific radiation-therapy target
volumes or doses, the occurrence of protocolprohibited radiation therapy was not assessed.
The concordance between data from the registered electronic case-report form regarding radiation therapy to the breast or chest wall andnodal target volumes (yes or no) and the actual
radiation therapy received according to radiationtherapy plans was evaluated. A detailed radiationtherapy review to evaluate the clinical significance of specific nodal target volumes and doses
is ongoing.
At enrollment, all the patients completed
questionnaires about health-related quality oflife and long-term complications to the arm (theEORTC Quality of Life Questionnaire [QLQ-C30],
the breast cancer–specific QLQ-BR23 questionnaire, the EuroQol Group 5-Dimension questionnaire, and the Lymphedema Functioning, Disability, and Health Questionnaire), and according
to the protocol, patients will receive these questionnaires again after 1, 3, 5, and 10 years. No
clinical measurements of lymphedema were conducted. Although 1-year questionnaire data froma Swedish–Danish subpopulation were publishedin 2022,12 the 3-year data for the entire trial
population are not yet available.
Follow-up is being assessed by means of annual mammography for 5 years and another mammography after 10 years. Annual clinical examinations were mandatory initially, but owing to
the interruption of some clinical services during
the coronavirus disease 2019 pandemic, the requirement for clinical visits was replaced with theoption of remote visits.
End Points

The primary end point was changed from breast
cancer–specific survival to overall survival in 2020
on the basis of a recommendation from the independent data and safety monitoring board. Prespecified secondary end points were recurrencefree survival, breast cancer–specific survival,
and patient-reported outcomes. The definition of
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T h e n e w e ng l a n d j o u r na l o f m e dic i n erecurrence-free survival follows the updated StanThe per-protocol population consisted of all
dardized Definitions for Efficacy End Points the patients who underwent axillary surgery ac(STEEP) criteria13 and includes invasive recur- cording to their randomized group assignment.
rence and death.
Patients who did not meet all the inclusion criteria or who met any of the exclusion criteria at
Power Computation
the time of randomization, even if the situation
Clinical noninferiority was defined as 5-year was discovered later, were excluded from the peroverall survival that was not worse by more than protocol analyses.
2.5 percentage points when completion axillarylymph-node dissection was omitted — that is, Statistical Analysis
94.0% in the dissection group and 91.5% in the The present analysis pertains to the prespecified
sentinel-node biopsy–only group. This margin secondary end point of recurrence-free survival.
was intentionally small — half the margin that Descriptive clinical data are summarized for thewas used in the ACOSOG Z0011 trial — in order two treatment groups. Categorical variables are
to increase clinical applicability and to be com- presented as frequencies and percentages, andparable with oncologic trials evaluating systemic continuous variables are presented as means withtherapies. Thus, we calculated that in order for standard deviations or as medians with ranges.
the trial to have 80% power with a one-sided For each variable, the numbers and percentages
alpha of 10%, a total of 190 deaths would need of patients with missing observations are preto occur, with the upper one-sided 90% confi- sented.
dence interval for the hazard ratio (sentinel-node
The time to an event was calculated from thebiopsy only vs. completion axillary-lymph-node randomization date to the date of recurrence ordissection) being below 1.44. Owing to its clini- death or to the date of last recorded visit forcal significance, the secondary end point of patients without an event. Recurrence-free surrecurrence-free survival is being reported before vival was descriptively evaluated with the use of
the primary end point of overall survival, for Kaplan–Meier curves. The effect of the omission
which statistical power has not yet been ob- of completion axillary-lymph-node dissection ontained.
5-year recurrence-free survival was assessed with
For the secondary end point of recurrence- the use of a Cox proportional-hazards model.
free survival (reported here), the sample-size Final analyses were adjusted for the stratification
calculation was added to the protocol in June 2020, factor of country. Hazard ratios (sentinel-node
under an assumption that 5-year recurrence-free biopsy only vs. completion axillary-lymph-node
survival would be 90% in the dissection group, dissection) are presented with 95% confidence
on the basis of the safety analysis of May 2020. intervals. The proportional-hazards assumpWith an unchanged threshold for the upper tion was evaluated with the use of Schoenfeld
boundary of the confidence interval for the haz- residuals.
The per-protocol population was used for theard ratio for recurrence or survival of 1.44, resulting in a prespecified noninferiority margin main analysis because such a population is moreof 4.1 percentage points, we concluded that the conservative in the context of a noninferiority
trial would have sufficient power (80%) to con- analysis.14,15 The upper boundary of the conficlude noninferiority once 190 events of recurrence dence interval was required to be below thenoninferiority margin of 1.44 for the analysis
or death had occurred.
of the hazard ratio for recurrence or death. A
Definitions of Trial Populations
complementary one-sided noninferiority statistiAmong all the patients who underwent random- cal test was performed, and a P value of lessization, the modified intention-to-treat popula- than 0.025 was considered to indicate that thetion excluded those who withdrew their informed result was significantly below the noninferiority
consent within 21 days after randomization — margin. Clinically relevant subgroups were asthat is, before a potential second surgery with sessed in the per-protocol population. These
completion axillary-lymph-node dissection. Pa- subgroup analyses were not prespecified, so retients who withdrew consent later had their data sults are presented as hazard ratios with 95%
censored at the date of withdrawal of consent.
confidence intervals that were not adjusted for1166

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Omit ting Axillary Dissection in Breast Cancer

multiplicity, without any formal statistical test.
Sensitivity analyses were performed with the useof a model adjusted for calendar period as apotential factor that may predict nonadherence
to the assigned treatment, in the modified intention-to-treat population, and with introduction of the requirement that at least nine lymph
nodes were removed in the dissection group (ascompared with the overall sentinel-node biopsy–
only group).16

R e sult s
Characteristics of the Patients and Tumors

Trial enrollment opened on January 31, 2015,
and closed on December 31, 2021. Overall, 6637
patients underwent screening at 67 sites internationally, and 2766 patients underwent randomization. The modified intention-to-treat population consisted of 2624 patients, and the perprotocol population of 2540 patients, of whom1335 had been assigned to undergo sentinelnode biopsy only and 1205 to undergo completion axillary-lymph-node dissection (dissectiongroup) (Fig. 1). The per-protocol population included 1553 patients (61.1%) from Sweden, 803(31.6%) from Denmark, 86 (3.4%) from Germany, 52 (2.0%) from Greece, and 46 (1.8%) from
Italy.
The median follow-up was 46.8 months(range, 1.5 to 94.5). A total of 17 patients (9 inthe sentinel-node biopsy–only group and 8 in
the dissection group) left the trial before thereporting of radiation therapy was due. Most of
the patients who remained in the trial until atleast 1 year of follow-up underwent postoperative radiation therapy targeting regional lymph
nodes (1192 of 1326 [89.9%] in the sentinel-nodebiopsy–only group and 1058 of 1197 [88.4%] in
the dissection group), and all but 26 patients
received some systemic treatment. Patients 65
years of age or older were well represented in thetrial (529 patients [39.6%] in the sentinel-nodebiopsy–only group and 496 [41.2%] in the dissection group). Table 1 shows the characteristicsof the patients and tumors in the per-protocol
population. Corresponding data for the modified intention-to-treat population are provided in

2766 Patients underwent randomization

1382 Were assigned to undergo
sentinel-node biopsy only

1384 Were assigned to undergo completion
axillary-lymph-node dissection

11 Withdrew consent within
21 days

131 Withdrew consent within
21 days1371 Were included in the modified
intention-to-treat population

1253 Were included in the modified
intention-to-treat population

32 Had violation of inclusion
criteria
3 Were excluded within 21 days
1 Did not undergo sentinel-nodebiopsy36 Had violation of inclusion
criteria
7 Were excluded within 21 days
5 Did not undergo completion
axillary-lymph-node dissection

1335 Were included in the per-protocol
population

1205 Were included in the per-protocol
population

Figure 1. Randomization of the Patients and the Analysis Populations.
The modified intention-to-treat population excluded patients who withdrew their informed consent within 21 days
after randomization (i.e., before a potential second surgery with completion axillary-lymph-node dissection). The
per-protocol population consisted of patients who underwent axillary surgery corresponding to their randomized
group assignment. Patients who did not meet all the inclusion criteria or who met any of the exclusion criteria at thetime of randomization, even if discovered later, were excluded from the per-protocol analyses.

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T h e n e w e ng l a n d j o u r na l o f m e dic i n eTable 1. Characteristics of the Patients and Tumors (Per-Protocol Population).*Sentinel-NodeBiopsyOnly(N = 1335)

Characteristic

Completion
Axillary-LymphNode Dissection(N = 1205)

Age
Mean — yr

61.0±12.0

60.9±11.7

Median (range) — yr

61 (20–94)

61 (34–90)

Distribution — no. (%)<40 yr37 (2.8)

32 (2.7)

40–49 yr

220 (16.5)

194 (16.1)

50–64 yr549 (41.1)

483 (40.1)

65–74 yr

334 (25.0)

342 (28.4)≥75 yr195 (14.6)

154 (12.8)

Mean

24.4±15.524.2±16.9

Median (range)

20 (0.2–155)

20 (1–155)

T1

710 (53.2)

651 (54.0)

T2

552 (41.3)

480 (39.8)

T3

73 (5.5)

74 (6.1)

1 or 2934 (70.0)856 (71.0)

3 or 4349 (26.1)

303 (25.1)

Tumor size — mm†

Tumor stage — no. (%)‡

No. of removed sentinel lymph nodes — no. (%)>4

52 (3.9)46 (3.8)

Mean

2.1±1.2

2.1±1.2

Median (range)

2 (1–11)

2 (1–9)11143 (85.6)

1008 (83.7)

2

192 (14.4)

197 (16.3)

Mean

1.3±0.5

2.3±3.0

Median (range)

1 (1–5)

1 (1–42)

Breast-conserving surgery

845 (63.3)

775 (64.3)

Mastectomy

490 (36.7)

430 (35.7)

Invasive carcinoma, no special type

997 (74.7)

939 (77.9)

Lobular carcinoma

278 (20.8)

226 (18.8)

Other

60 (4.5)

40 (3.3)

Grade 1243 (18.2)

211 (17.5)

Grade 2786 (58.9)

717 (59.5)

Grade 3298 (22.3)

263 (21.8)

8 (0.6)14 (1.2)

No. of sentinel lymph-node macrometastases — no. (%)

No. of axillary metastases

Type of breast surgery — no. (%)

Tumor histologic type — no. (%)

Nottingham histologic grade — no. (%)§

Missing data1168

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Omit ting Axillary Dissection in Breast Cancer

Table 1. (Continued.)
Sentinel-NodeBiopsyOnly(N = 1335)

Completion
Axillary-LymphNode Dissection(N = 1205)

ER-positive, HER2-negative

1166 (87.3)

1034 (85.8)

ER-positive, HER2-positive

84 (6.3)

88 (7.3)

ER-negative, HER2-positive

23 (1.7)

34 (2.8)

ER-negative, HER2-negative

57 (4.3)

46 (3.8)

Missing data

5 (0.4)3 (0.2)

Mean — %24.6±17.2

24.8±17.7

Median (range) — %20 (1–98)

20 (1–98)

Missing data — no. (%)

13 (1.0)

18 (1.5)

Characteristic
Tumor subtype — no. (%)¶

Ki-67 proliferation index*	Plus–minus values are means ±SD. The per-protocol population consisted of patients who underwent axillary surgery
corresponding to their randomized group assignment. Patients who did not meet all the inclusion criteria or who met
any of the exclusion criteria at the time of randomization, even if discovered later, were excluded from per-protocol
analyses. Percentages may not total 100 because of rounding.
†	A total of 55 patients (17 in the sentinel-node biopsy–only group and 38 in the dissection group) who received primarysystemic treatment were excluded from this analysis.
‡	Tumor stage was deduced from the histopathological tumor size in the context of primary surgery and from the clinicaltumor size in the context of primary systemic treatment. A stage of T1 indicates that the tumor size was no more than
20 mm in the largest dimension, T2 that the size was 21 to 50 mm, and T3 that the size was greater than 50 mm.
§	Nottingham histologic grades are based on information about the degree of tubular formation, nuclear pleomorphism,and mitosis. Grades range from 1 to 3, with higher grades indicating a higher risk of recurrence.
¶	Tumor subtype was based on estrogen receptor (ER) status and human epidermal growth factor receptor 2 (HER2;
Erb2-neu) gene amplification. HER2 positivity was defined as a result of 3+ on immunohistochemical testing or a resultof 2+ on immunohistochemical testing with a subsequent in situ hybridization test showing gene amplification.

Table S1 in the Supplementary Appendix, available at NEJM.org.
Approximately one third of the patients had
extracapsular extension in the sentinel-node biopsy sample. Sentinel-node biopsy only removed
a mean of 2 lymph nodes per patient, whereas
sentinel-node biopsy followed by completion
axillary-lymph-node dissection removed a meanof 15 lymph nodes per patient. Lymphovascularinvasion in the primary tumor was present inapproximately 28% of the patients. Approximately 65% of the patients received adjuvant chemotherapy, with endocrine therapy used in approximately 93% and human epidermal growth factor
receptor 2 (HER2)–targeted therapy in approximately 9%. Approximately 88% of the patients
received radiation therapy to the breast or chestwall plus regional lymph nodes. Details are provided in Table S2.
For radiation-therapy quality control, data fromall 1360 patients in the per-protocol populationn engl j med 390;13

who had undergone randomization in Sweden
or Denmark until May 31, 2019, were considered, and 1154 radiation-therapy plans were
evaluated (Fig. S1). Reported data from the electronic case-report form matched the radiationtherapy plan in 1146 patients (99.3%) with regard to radiation therapy to the breast or chestwall and in 1115 patients (96.6%) with regard to
nodal target volumes.
Given that additional sentinel-node micrometastases were allowed, 49 patients in the trial had
a total of three metastatic sentinel nodes, and 3
patients had four. On preoperative ultrasonography, 177 patients (13.3%) in the sentinel-nodebiopsy–only group and 170 patients (14.1%) in thedissection group had axillary lymph nodes thatwere suspicious for cancer. Fine-needle aspiration
was confirmatory for lymph-node metastasis in
18 patients (1.3%) in the sentinel-node biopsy–
only group and in 18 (1.5%) in the dissectiongroup.

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T h e n e w e ng l a n d j o u r na l o f m e dic i n e

Owing to the varying use of intraoperative
frozen section, completion axillary-lymph-nodedissection was performed either during a second
surgery (in 930 patients [77.2%]) or during thesame session as the sentinel-node biopsy (in 275
patients [22.8%]). Additional non–sentinel-nodemetastases were found on completion axillarylymph-node dissection in 403 of 1167 patients(34.5%) who had undergone primary surgery.
Among patients with one sentinel-node macrometastasis, 31.3% had additional non–sentinel-nodemetastases; among patients with two sentinelnode macrometastases, 51.3% had additional non–sentinel-node metastases. The final pathologicalnodal classification among the 2485 patients undergoing primary surgery was pN1 (1 to 3 metastases) in 1311 patients (99.5%) in the sentinel-nodebiopsy–only group and in 1016 patients (87.1%)
in the dissection group, pN2 (4 to 9 metastases)in 7 (0.5%) and in 116 (9.9%), respectively, and pN3(≥10 metastases) in 35 patients (3.0%) in the dissection group.

deaths according to trial group in the per-protocol
population during the entire follow-up period.
Most deaths (117) occurred within 5 years after
randomization, with 50 of those deaths being
due to breast cancer. The estimated 5-year overall survival was 92.9% (95% confidence interval[CI], 91.0 to 94.9) in the sentinel-node biopsy–
only group and 92.0% (95% CI, 89.9 to 94.1) inthe dissection group. The estimated 5-year breast
cancer–specific survival was 97.1% (95% CI, 95.8
to 98.3) in the sentinel-node biopsy–only group
and 96.6% (95% CI, 95.3 to 97.9) in the dissection group.
Regional recurrences were in the ipsilateralaxilla in three patients, in the ipsilateral axilla
and infraclavicular nodes in two patients, and in
the supra- or infraclavicular, internal mammary,or parasternal nodes in one patient each. In four
patients, the location of the regional recurrence
was unknown.
The calculation of the estimated 5-year recurrence-free survival was based on 180 patients(7.1%) who had an event within 5 years after
End Points
randomization: 89 patients (6.7%) in the sentinelRecurrence or death occurred in 191 patients. node biopsy–only group and 91 (7.6%) in the disTable 2 shows the numbers of recurrences and section group. The estimated 5-year recurrencefree survival was 89.7% (95% CI, 87.5 to 91.9) inthe sentinel-node biopsy–only group and 88.7%
Table 2. Recurrence-free Survival Analyses (Per-Protocol Population).*(95% CI, 86.3 to 91.1) in the dissection group(Fig. 2). After adjustment for the stratification
Sentinel-NodeCompletion
factor of country, the hazard ratio for recurrence
BiopsyAxillary-LymphOnly
Node Dissection
or death in the sentinel-node biopsy–only group
Variable(N = 1335)(N = 1205)
as compared with the dissection group was 0.89
Recurrence — no. (%)(95% CI, 0.66 to 1.19), which was significantly(P<0.001) below the noninferiority margin. The
Local
12 (0.9)
10 (0.8)
proportional-hazards assumption of the Cox
Regional
6 (0.4)6 (0.5)model was not violated (P = 0.48). The result inDistant
44 (3.3)
53 (4.4)
the modified intention-to-treat population (hazDeath — no. (%)
62 (4.6)
69 (5.7)
ard ratio, 0.89; 95% CI, 0.67 to 1.19) was similar
Cause of death — no./total no. (%)
to that in the per-protocol population. The nonBreast cancer
24/62 (39)31/69 (45)inferiority of sentinel-node biopsy only to comOther cause
30/62 (48)
30/69 (43)pletion axillary-lymph-node dissection was confirmed in sensitivity analyses (Fig. 3).
Unknown
8/62 (13)8/69 (12)Subgroup analyses were performed in cliniRecurrence or death as first event— no. (%)
cally relevant subgroups (Fig. 3). Too few malepatients (10 [0.4%]) had been enrolled for subNo
1240 (92.9)
1109 (92.0)
group analysis to be possible. The hazard ratio forYes
95 (7.1)
96 (8.0)
recurrence or death in the sentinel-node biopsy–*	Shown are analyses of recurrence-free survival (secondary end point) in the
only group as compared with the dissection groupper-protocol population during the entire follow-up period. Some patients
included 1.00 in all the subgroups except in the
may have more than one recurrence of breast cancer.
subgroup of patients with estrogen receptor–

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Omit ting Axillary Dissection in Breast Cancer

Proportion of Patients Alive and Free
from Recurrence

positive, HER2–positive disease, in which sentinel- sion; in the ACOSOG Z0011 trial, matted nodes
node biopsy only appeared to be better.
and gross extranodal disease were an exclusion
criterion, and extracapsular extension was notreported in the AMAROS trial. This lack of inDiscussion
formation resulted in substantial clinical uncerIn this randomized, controlled trial, the estimat- tainty, which the results of the present trial may
ed 5-year recurrence-free survival after sentinel- now resolve. Third, whereas the SENOMAC trial
node biopsy only was noninferior to that after included a relevant proportion of patients withcompletion axillary-lymph-node dissection among T3 tumors, only one such patient was enrolled inpatients with breast cancer and one or two sentinel- the previous two trials together, so our trial adnode macrometastases. Most of the patients, re- dressed an important knowledge gap. Fourth,gardless of trial-group assignment, received adju- mastectomy was not an eligible intervention invant systemic treatment and radiation therapy, the ACOSOG Z0011 trial, and the AMAROS trial
included only 248 such patients (17.4%). In our
including nodal target volumes.
The current results are in line with those of trial, more than one third of the patients underthe ACOSOG Z0011 and AMAROS trials,1,7 which went mastectomy, which corroborates the exterenrolled patients in the periods of 1999–2004 nal validity of our trial, given that 34% of theand 2001–2010, respectively. The SENOMAC trial patients with breast cancer in Sweden and 31%
differs from these earlier trials in several as- of those in Denmark undergo mastectomy.18,19
pects. First, patients who had only sentinel-node
Results from two further trials evaluating the
micrometastases were not enrolled, on the basis omission of completion axillary-lymph-node disof the results of the International Breast Cancer section in patients who had a sentinel node with
Study Group (IBCSG) 23-01 trial.17 In the ACOSOG metastases have been reported. The Optimal
Z0011 and AMAROS trials, however, patients with Treatment of the Axilla–Surgery or Radiotherapy
sentinel-node micrometastases constituted near- (OTOASOR) trial, in which patients with a breast
ly 40% of the trial population, a notably higher cancer up to 3 cm in the largest dimension werepercentage than has been observed in the clinical randomly assigned to completion axillary-lymphbreast cancer population. Second, the SENOMAC node dissection or regional nodal irradiation,
trial allowed sentinel-node extracapsular exten- showed no significant between-group difference

1.0

Sentinel-node biopsy only

0.9
Completion axillary-lymph-node dissection

0.8
0.7
0.6
0.5

Sentinel-NodeBiopsy Only
Dissection

0.4
0.3
0.2

Recurrence-free
Survival (95% CI)
percent

8989.7 (87.5–91.9)

91

88.7 (86.3–91.1)

Hazard ratio for recurrence or death, 0.89
(95% CI, 0.66–1.19)
P<0.001 for noninferiority

0.1
0.0

No. of
Events

0

12

24

36

48

60

Months since Randomization
No. at Risk
Sentinel-nodebiopsy only
Dissection

1335

1276

1069

832

577

307

1205

1159

1009

772

544

274

Figure 2. Recurrence-free Survival (Per-Protocol Population).
Shown are Kaplan–Meier curves for the secondary end point of recurrence-free survival.

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T h e n e w e ng l a n d j o u r na l o f m e dic i n e

in disease-free survival.20 However, more than
one third of the patients in that trial had only
sentinel-node micrometastases or isolated tumor
cells, extracapsular extension was not reported,and few patients underwent mastectomy. The
SINODAR-ONE trial, in which patients with T1
or T2 tumors and sentinel-node macrometastases
were randomly assigned to completion axillarylymph-node dissection or sentinel-node biopsy

Subgroup

only, showed equivalent recurrence-free survivalin the two groups.21 A subgroup analysis that
included 218 patients undergoing mastectomy
was confirmatory. Therefore, previous trials had
certain clinical limitations regarding eligibility
and the size of included subgroups but also hadsigns of selection bias toward a more low-risk
population than the underlying population of
persons with breast cancer. This situation has

Completion
Sentinel-Node Axillary-LymphBiopsy Only Node Dissection

Hazard Ratio for Recurrence or Death (95% CI)

no. of patients with event/total no.
Overall, per-protocol population
89/1335Age<65 yr36/806≥65 yr53/529Tumor stage
T1 or T2
84/1262T3
5/73
No. of macrometastases
1
76/11432
13/192Tumor type19/278Lobular70/1057
Nonlobular
Surgery type
48/845
Breast-conserving
41/490Mastectomy
Extracapsular extension
34/461
Yes
55/871No
Tumor subtype
73/1166
ER-positive, HER2-negative
3/84
ER-positive, HER2-positive
2/23
ER-negative, HER2-positive
10/57
ER-negative, HER2-negative
Sensitivity analysis
89/1335
Model adjusted for calendar period
Modified intention-to-treat population 91/1371
89/1335
At least 9 lymph nodes removed if
patient was randomly assigned
to dissection group

91/1205

0.89 (0.66–1.19)

41/70950/4960.77 (0.49–1.20)
1.02 (0.69–1.51)

81/113110/74

0.94 (0.69–1.28)
0.47 (0.16–1.39)

72/1008
19/1970.92 (0.67–1.27)
0.79 (0.39–1.59)

17/22674/9790.91 (0.47–1.76)
0.88 (0.64–1.23)

46/77545/4300.98 (0.65–1.47)
0.79 (0.52–1.21)

31/40960/7910.94 (0.58–1.54)
0.86 (0.60–1.25)

68/1034
10/88
3/34
10/46

0.95 (0.68–1.32)
0.26 (0.07–0.96)
1.04 (0.17–6.35)
0.95 (0.39–2.30)

91/1205
93/1253
83/1036

0.89 (0.66–1.19)
0.89 (0.67–1.19)
0.82 (0.61–1.10)
0.5

1.0

1.5

2.0

Sentinel-Node Biopsy Completion AxillaryOnly Better
Lymph-NodeDissection Better

Figure 3. Subgroup Analysis of Recurrence-free Survival.
Subgroup analyses were conducted in the per-protocol population. Sensitivity analyses were conducted in a modelthat was adjusted for calendar year (as a potential factor that may predict nonadherence to the assigned treatment),
in the modified intention-to-treat population, and with introduction of the requirement that at least nine lymph
nodes were removed in the dissection group (with the overall sentinel-node biopsy–only group as the comparator).
Arrows indicate that the 95% confidence interval exceeds the graphed area. Diamonds represent the overall estimate,with the width of the diamond indicating the 95% confidence interval. ER denotes estrogen receptor, and HER2
human epidermal growth factor receptor 2.

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Omit ting Axillary Dissection in Breast Cancer

resulted in uncertainties about which patientsshould be offered the possibility of omitting
completion axillary-lymph-node dissection. The
present trial had highly representative proportions of such subgroups, a larger trial population,and extended eligibility criteria.
A common problem in clinical trials is theunderrepresentation of older patients. Even
though, of the trials mentioned above, only
SINODAR-ONE had an age limit for enrollment,
the reported populations in previous trials have
had mean ages between 54 years and 56 years,
which is lower than in a typical breast cancer
population. Our trial enrolled a substantial number of older patients, and the median ages of 65
years in the Swedish breast cancer population
and 62 years in the Danish breast cancer population support the external validity of our trial
results.18,22
Other prospective randomized trials evaluating the omission of completion axillary-lymphnode dissection have been initiated. The Borstkanker Onderzoek Groep (BOOG) 2013-07 trial
in the Netherlands was closed prematurely owing
to slow enrollment.23 The second randomizationof the Intergroup-Sentinel-Mamma (INSEMA)
trial in Germany (ClinicalTrials.gov number,
NCT02466737) had not met the target enrollment when the trial closed enrollment in 2019,
when its first randomization, in which patientswere assigned to sentinel-node biopsy or its
omission, had reached full enrollment. The results of the Positive Sentinel Node (POSNOC)
trial in the United Kingdom, in which 1900 patients with cN0 breast cancer with a tumor stageof T1 or T2 were randomly assigned either to axillary treatment (completion axillary-lymph-nodedissection or axillary radiation therapy) or to noaxillary treatment, are awaited.24
Our trial has some limitations. First, the useof radiation therapy followed national guidelines, which led to a high proportion of patients
undergoing nodal field irradiation, which is thestandard care in Sweden and Denmark. Thus,
the results of our trial are comparable with thoseof the AMAROS and OTOASOR trials rather thanwith those of the POSNOC, SINODAR-ONE, and
ACOSOG Z0011 trials. The concordance between
the data from the registered electronic case-reportforms and the actual radiation-therapy plans
was high. Detailed information about radiation-n engl j med 390;13

therapy target volumes and doses to specificnodal levels are not yet available. Second, therecruitment of male patients aimed to fill an
important knowledge gap, but only 10 male patients could be enrolled over a 7-year period — asituation that prevented subgroup analysis according to sex. Third, given that most of theenrolled patients had breast cancer of the luminal subtype, and also given the predilection ofthis subtype to recur late, the current follow-up
is relatively short. Fourth, as in previous trials,
enrollment ran short of the prespecified target.
However, statistical power relies on the occurrence of events rather than on the target sample
size, and given the high number of events, thenarrow confidence intervals, and the large distance between the noninferiority margin and theobserved upper boundary of the confidence interval, the presented results reflect a high precision of estimates. Fifth, the incidence of withdrawal was clearly higher in the dissection groupthan the sentinel-node biopsy–only group, a situation that reflects patients’ awareness and desire to avoid completion axillary-lymph-nodedissection. Given the large size of the trial population and the balanced distribution of important variables between the two trial groups,
however, this situation should not have affected
the trial results.
This trial provides robust evidence that theomission of completion axillary-lymph-node dissection was safe in patients with clinically nodenegative T1, T2, or T3 breast cancer and one or
two sentinel-node macrometastases who received
adjuvant systemic treatment and radiation therapy
according to national guidelines.
Presented in part at the San Antonio Breast Cancer Symposium,
San Antonio, TX, on December 7, 2023.
Supported by the Swedish Research Council (grant numbers,
2015-00760 and 2021-02128), the Swedish Cancer Society (grant
numbers, CAN 2015/437 and 22 2061 Pj), the Nordic Cancer
Union (grant numbers, R217-A13260 and R241-A14982), and theSwedish Breast Cancer Association.
Disclosure forms provided by the authors are available withthe full text of this article at NEJM.org.
A data sharing statement provided by the authors is available
with the full text of this article at NEJM.org.
We thank the staff of the Clinical Trials Office at Karolinska
University Hospital for data management and the monitoring of
Swedish sites, the staff of the Good Clinical Practice unit at Aarhus
University Hospital for the monitoring of Danish sites, the staff
of CRO Dr. med. Kottmann for the monitoring of German and
Italian sites, and the staff of CROS&S for the monitoring of Greek
sites, all the study nurses and supporting staff at the participating
hospitals, and the patients who participated in the trial.

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Appendix
The authors’ full names and academic degrees are as follows: Jana de Boniface, M.D., Ph.D., Tove Filtenborg Tvedskov, M.D., Ph.D.,
Lisa Rydén, M.D., Ph.D., Robert Szulkin, Ph.D., Toralf Reimer, M.D., Ph.D., Thorsten Kühn, M.D., Ph.D., Michalis Kontos, M.D.,
Oreste D. Gentilini, M.D., Roger Olofsson Bagge, M.D., Ph.D., Malin Sund, M.D., Ph.D., Dan Lundstedt, M.D., Ph.D., Matilda Appelgren, O.C.N., Johan Ahlgren, M.D., Ph.D., Sophie Norenstedt, M.D., Ph.D., Fuat Celebioglu, M.D., Ph.D., Helena Sackey, M.D., Ph.D.,
Inge Scheel Andersen, M.D., Ph.D., Ute Hoyer, M.D., Per F. Nyman, M.D., Eva Vikhe Patil, M.D., Ph.D., Elinore Wieslander, Ph.D.,
Henrik Dahl Nissen, Ph.D., Sara Alkner, M.D., Ph.D., Yvette Andersson, M.D., Ph.D., Birgitte V. Offersen, M.D., Ph.D., Leif Bergkvist,
M.D., Ph.D., Jan Frisell, M.D., Ph.D., and Peer Christiansen, M.D., D.M.Sc.
The authors’ affiliations are as follows: the Departments of Molecular Medicine and Surgery (J.B., M.A., H.S., J.F.) and Medical Epidemiology and Biostatistics (R.S.), Karolinska Institutet, the Department of Surgery, Capio St. Göran’s Hospital (J.B., M.A., S.N.), Cytel(R.S.), the Department of Surgery, Södersjukhuset (F.C.), and Breast Center Karolinska, Karolinska Comprehensive Cancer Center,
Karolinska University Hospital (H.S., J.F.), Stockholm, the Faculty of Medicine, Institute of Clinical Sciences, Lund University (L.R.,
S.A.), and the Department of Hematology, Oncology, and Radiation Physics, Skåne University Hospital Lund (S.A.), Lund, the Department of Gastroenterology and Surgery (L.R.), and Radiation Physics, Department of Hematology, Oncology, and Radiation Physics(E.W.), Skåne University Hospital Lund, Malmö, the Departments of Surgery (R.O.B.) and Oncology (D.L.), Institute of Clinical Sciences, Sahlgrenska Academy at Gothenburg University, and the Departments of Surgery (R.O.B.) and Oncology (D.L.), Sahlgrenska
University Hospital, Gothenburg, the Department of Diagnostics and Intervention–Surgery, Umeå University, Umeå (M.S.), the Department of Oncology, Faculty of Medicine and Health, Örebro University, Örebro (J.A.), Regional Cancer Center of Mid-Sweden, Uppsala(J.A.), the Department of Surgery, Skaraborg Hospital, Lidköping (P.F.N.), the Department of Biomedical and Clinical Sciences (E.V.P.),
Linköping University, and the Department of Surgery, Linköping University Hospital (E.V.P.), Linköping, and the Department of Surgery(Y.A.) and the Center for Clinical Research, Uppsala University and Region Vastmanland, Vastmanland Hospital (Y.A., L.B.), Vasteras— all in Sweden; the Faculty of Health and Medical Sciences, University of Copenhagen (T.F.T.), the Department of Breast Surgery,
Gentofte Hospital, Gentofte (T.F.T.), the Department of Surgery, Breast Clinic, Viborg Hospital, Viborg (I.S.A.), the Department of
Plastic and Breast Surgery, Aalborg University Hospital, Aalborg (U.H.), the Department of Oncology, Vejle Hospital, University Hospital of Southern Denmark, Vejle (H.D.N.), and the Departments of Oncology (B.V.O.) and Plastic and Breast Surgery (P.C.), Aarhus
University Hospital, the Departments of Oncology (B.V.O.) and Clinical Medicine (P.C.), Aarhus University, and the Department ofExperimental Clinical Oncology, Danish Center for Particle Therapy (B.V.O.), Aarhus — all in Denmark; the Department of Obstetrics
and Gynecology, University of Rostock, Rostock (T.R.), the Breast Center, Die Filderklinik, Filderstadt (T.K.), and the Department of
Gynecology and Obstetrics, University of Ulm, Ulm (T.K.) — all in Germany; the First Department of Surgery, National and Kapodistrian University of Athens, Athens (M.K.); the Department of Breast Surgery, IRCCS Ospedale San Raffaele (O.D.G.), and Vita-Salute
San Raffaele University (O.D.G.) — both in Milan; and the Department of Surgery, University of Helsinki and Helsinki University
Hospital, Helsinki (M.S.).

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Double Take Video: What Is Rheumatoid Arthritis?
In this video, Drs. Schubach, Gravallese,and Firestein review the epidemiology, clinicalfeatures, pathogenesis, and diagnostic evaluation of rheumatoid
arthritis. The video also
explores available therapeutic approaches to thedisease, including strategies to manage flares.

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