Keywords
level III dissection - locally advanced breast cancer - neoadjuvant chemotherapy -
axillary dissection - level III positivity rate
Introduction
Breast cancer is the most common female cancer in India.[1] As per a recent Indian study, locally advanced breast cancer (LABC) accounts for
46% of all the newly diagnosed breast cancers.[2] The current concept of breast surgery is of conservation both in the breast and
the axilla. The standard of care in breast surgery is currently breast conservation
surgery in the primary and in the post-neoadjuvant chemotherapy (NACT) setting.[3]
[4] The extent of axillary dissection has decreased drastically in the primary surgery
in early, node-negative breast cancer with the advent of sentinel lymph node biopsy
(SLNB).[5] In patients with cN0 status pre NACT with nonprogression on chemotherapy, SLNB using
dual tracer is adequate.[6] In node-positive patients who receive NACT, the role of de-escalation is still not
proven with level 1 evidence. Multiple trials like Sentinel-lymph-node biopsy in patients
with breast cancer before and after neoadjuvant chemotherapy (SENTINA), American College
of Surgeons Oncology Group Z1071 (ACOSOGZ1071), and Sentinel node biopsy after neoadjuvant
chemotherapy in biopsy-proven node-positive breast cancer (SNFNAC) have a high false-negative
rate and low identification rate.[7]
[8]
[9] Newer techniques like targeted axillary dissection using various targeting agents
have a low false-negative rate but the evidence is in the form of small trials.[10]
[11]
[12] Even with these techniques, if the targeted node or SLNB is positive, complete axillary
dissection is advised.
As per the European Breast Cancer Research association of Surgical Trialist (EUBREAST)
survey, there is no consensus on axillary management after NACT in patients with clinically
node-positive breast cancer.[13] During the axillary dissection, the level I and II are routinely cleared with or
without level III dissection. As per the NCCN guidelines for clinical practice in
breast cancer, in the absence of gross disease in level II or III, level I and II
dissection should be done.[14]
In the primary surgery setting, the level III positivity was 27.3% as per a recent
Indian study.[15] The current pathological complete response (pCR) rate is 12% in hormone receptor
(HR)-positive, HER2-negative, 36% in HR-positive, HER2-positive, 38% in triple-negative,
and 55% in HR-negative, HER2-positive cancer.[16] Thus, there is possibility of residual disease in level III in a significant proportion
of patients. In our institute, we routinely perform complete axillary dissection of
all III levels in the post-NACT setting.
We analyzed our retrospective data of level III positivity in post-NACT patients.[17] The level III node was positive in 15.5% as per our study. In a retrospective study
by Fan et al, the level III positivity rate was 9%.[18] With this high rate, level III dissection is unavoidable as these are the nodes
that have not responded to the primary chemotherapy and represent residual tumor cells
that can later cause relapse and distant metastasis. As per studies, presence of residual
nodes post-NACT is a predictor of poorer survival and increased relapse in ER negative
and HER2-positive patients.[19]
[20]
There are no prospective studies that have analyzed the level III positivity rate
in post-NACT breast cancer patients. We aim to prospectively assess the rate of level
III positivity in LABC patients post-NACT and identify any subgroup in which level
III dissection can be avoided.
Materials and Methods
This is a prospective observational study of female patients with LABC who received
NACT and underwent surgery including level III nodal clearance from November 2019
to October 2021 at a tertiary cancer center in Kerala, India. This study was conducted
after institutional review board clearance. Inclusion criteria were women aged 18
years to 80 years with LABC (defined as cT3N1–3M0 or cT4N0–3M0 or cTanyN2,3M0) and who received NACT with anthracyclines and/or taxanes. Women with history
of previous malignancy, who progressed on NACT, who were HER2 positive and did not
receive neoadjuvant trastuzumab, who had inflammatory breast cancer, and who did not
complete their planned NACT were excluded. Data collected included age, menopausal
status, T and N stage at presentation, grade, estrogen, progesterone and HER2 receptor
status, response to treatment (response evaluation criteria in solid tumors (RECIST),
criteria version 1.1), post-chemotherapy clinical stage, and final histopathology
report.[21] Age was subdivided into less than or equal to 40 years, 41 to 60 years and over
60 years. Menopausal status was divided into premenopausal or postmenopausal. Patients
with either estrogen or progesterone receptor Allred score greater than 2 were considered
HR positive. RECIST 1.1 criteria weas used to assess the response to NACT. No imaging
of the axilla was done post-NACT. The cT and cN stage include both clinical and radiological
examination (mammogram and computed tomography, CT, scan [for internal mammary nodes
staging]). In patients planned for mastectomy, we do not routinely perform mammogram
of the ipsilateral breast. In such cases, cT and cN are based on clinical findings
and CT scan for the internal mammary node staging. Level III nodes were defined as
nodes identified in the space bounded laterally by the medial margin of pectoralis
minor muscle, superiorly by the axillary vein and medially by the thoracic inlet (costoclavicular
ligament).[22] Levels I, II, and III nodes were dissected and sent for histology separately. A
subgroup analysis based on age, menopausal status, prechemotherapy T and N stage,
grade, HR status, HER2 status, response to NACT, and post-NACT clinical stage was
done. Categorical variables were analyzed using Pearson's chi-squared test. Univariate
and multivariate analyses were done using Fisher's exact test and logistic regression
model, respectively. A p-value of less than or equal to 0.05 was considered significant.
Results
There were 1532 women with breast cancer who underwent breast surgery during the study
period, of whom 669 were post-neoadjuvant therapy. The inclusion criteria were met
by 598 patients as shown in the consort diagram ([Fig. 1]).
Fig. 1 Consort diagram of the study population.
[Table 1] summarizes the patient and pre-surgery tumor characteristics.
Table 1
Patient and tumor characteristics
Characteristic
|
Patient number
|
Percentage
|
Age
|
|
|
≤ 40years
|
69
|
11.5
|
41–60 years
|
435
|
72.7
|
>60 years
|
94
|
15.8
|
Menopausal status
|
|
|
Premenopausal
|
220
|
36.8
|
Postmenopausal
|
378
|
63.2
|
Clinical stage (cTNM) prechemotherapy
|
|
|
cT0N2M0
|
4
|
0.6
|
cT1N2M0
|
23
|
3.9
|
cT1N3M0
|
4
|
0.7
|
cT2N2M0
|
191
|
31.9
|
cT2N3M0
|
13
|
2.2
|
cT3N1M0
|
95
|
15.9
|
cT3N2M0
|
8
|
1.3
|
cT3N3M0
|
11
|
1.8
|
cT4N0M0
|
24
|
4.1
|
cT4N1M0
|
135
|
22.6
|
cT4N2M0
|
54
|
9
|
cT4N3M0
|
36
|
6
|
Grade
|
|
|
2
|
143
|
23.9
|
3
|
455
|
76.1
|
Hormone receptor status
|
|
|
Positive
|
408
|
68.2
|
Negative
|
190
|
31.8
|
HER2 status
|
|
|
Positive
|
212
|
35.5
|
Negative
|
386
|
64.5
|
Biology
|
|
|
Hormone receptor positive, HER2 negative
|
256
|
42.8
|
Triple positive
|
152
|
25.4
|
Hormone receptor negative, HER2 positive
|
65
|
10.9
|
Triple negative
|
125
|
20.9
|
Clinical response assessment
|
|
|
Complete response
|
215
|
36
|
Partial response
|
350
|
58.5
|
Stable disease
|
33
|
5.5
|
Post-chemotherapy clinical stage (ycTNM)
|
|
|
ycT0N0M0
|
215
|
36
|
ycT0N1M0
|
67
|
11.2
|
ycT0N2M0
|
4
|
0.6
|
ycT1N0M0
|
74
|
12.4
|
ycT1N1M0
|
36
|
6
|
ycT2N0M0
|
35
|
5.9
|
ycT2N1M0
|
26
|
4.5
|
ycT2N2M0
|
3
|
0.5
|
ycT2N3M0
|
1
|
0.2
|
ycT3N0M0
|
3
|
0.5
|
ycT3N1M0
|
11
|
1.7
|
ycT3N2M0
|
2
|
0.3
|
ycT4N0M0
|
71
|
11.8
|
ycT4N1M0
|
38
|
6.4
|
ycT4N2M0
|
10
|
1.7
|
ycT4N3M0
|
2
|
0.3
|
The most common age group was 41 to 60 years (72.7%) and 63.2% were postmenopausal.
The most common stage at presentation was cT2N2 (31.9%). cN3 disease was seen in 10.5%
of the cases. Grade 3 was most common, seen in 76.1% of patients. HR positivity was
present in 68.2% and HER2 was positive in 35.5%. HR positive, HER2 negative was the
most common biology (42.8%) followed by triple positive (25.4%), triple negative (20.9%),
and HR negative and HER2 positive (10.9%). No patient received pertuzumab. [Table 2] summarizes the surgery and post-surgery histopathology.
Table 2
Surgery and histopathology characteristics
Characteristic
|
Patient number
|
Percentage
|
Type of surgery
|
|
|
Breast conservation surgery
|
175
|
29.3
|
Modified radical mastectomy
|
423
|
70.7
|
T stage on final histopathology (ypT)
|
|
|
ypT0
|
233
|
39.0
|
ypT1
|
215
|
36.0
|
ypT2
|
120
|
20.0
|
ypT3
|
28
|
4.7
|
ypT4
|
2
|
0.3
|
N stage on final histopathology (ypN)
|
|
|
ypN0
|
346
|
57.9
|
ypN1
|
133
|
22.2
|
ypN2
|
67
|
11.2
|
ypN3
|
52
|
8.7
|
ypTN stage on final histopathology
|
|
|
ypT0N0
|
188
|
31.4
|
ypT0N1
|
25
|
4.2
|
ypT0N2
|
15
|
2.5
|
ypT0N3
|
5
|
0.8
|
ypT1N0
|
103
|
17.2
|
ypT1N1
|
70
|
11.7
|
ypT1N2
|
24
|
4
|
ypT1N3
|
21
|
3.5
|
ypT2N0
|
44
|
7.4
|
ypT2N1
|
31
|
5.2
|
ypT2N2
|
25
|
4.2
|
ypT2N3
|
16
|
2.6
|
ypT3N0
|
7
|
1.2
|
ypT3N1
|
6
|
1
|
ypT3N2
|
3
|
0.5
|
ypT3N3
|
10
|
1.7
|
ypT4N0
|
1
|
0.2
|
ypT4N1
|
1
|
0.2
|
ypT4N2
|
3
|
0.5
|
Level I on final histopathology
|
|
|
Positive
|
242
|
40.5
|
Negative
|
356
|
59.5
|
Level II on final histopathology
|
|
|
Positive
|
72
|
12
|
Negative
|
526
|
88
|
Level III on final histopathology
|
|
|
Positive
|
50
|
8.4
|
Negative
|
548
|
91.6
|
Most of the patients underwent modified radical mastectomy (70.7%). Using the RECIST
1.1 criteria, the clinical complete response rate was 36%. The overall pathological
complete response rate was 31.4% (188/598). The overall nodal pathological complete
response rate was 57.9%. The level III positivity rate was 8.4%. The association between
level III positivity and the various subsets is depicted in [Table 3].
Table 3
Univariate analysis of factors and level III nodal status
Characteristic
|
Level III positive patients
|
p-Value
|
Age
|
0.133
|
≤ 40 years
|
10/69 (14.5%)
|
41–60 years
|
34/435 (7.8%)
|
>60 years
|
6/94 (6.4%)
|
Menopausal status
|
Premenopausal
|
20/220 (9.1%)
|
0.677
|
Postmenopausal
|
30/378 (7.9%)
|
Clinical T stage (cT)
|
cT0
|
0/4 (0%)
|
0.096
|
cT1
|
2/28 (7.1%)
|
cT2
|
11/213 (5.2%)
|
cT3
|
7/105 (6.7%)
|
cT4
|
30/248 (12.1%)
|
Clinical N stage (cN)
|
cN0
|
1/42 (2.4%)
|
0.056
|
cN1
|
17/281 (6.1%)
|
cN2
|
24/212 (11.3%)
|
cN3
|
8/63 (12.7%)
|
Grade
|
2
|
19/143 (13.3%)
|
0.064
|
3
|
31/455 (6.8%)
|
Hormone receptor status
|
Positive
|
50/485 (10.3%)
|
0.176
|
Negative
|
10/113 (8.9%)
|
HER2 status
|
Positive
|
12/215 (5.6%)
|
0.181
|
Negative
|
38/383 (9.9%)
|
Biology
|
Hormone receptor positive, HER2 negative
|
28/228 (12.3%)
|
0.254
|
Triple positive
|
10/152 (6.6%)
|
Hormone receptor negative, HER2 positive
|
5/65 (7.7%)
|
Triple negative
|
7/125 (5.6%)
|
Clinical response assessment
|
Complete response
|
11/215 (5.1%)
|
<0.01
|
Partial response
|
35/350 (10%)
|
Stable disease
|
4/33 (12.1%)
|
Post-chemotherapy clinical T stage (ycT)
|
ycT0
|
15/286 (5.3%)
|
0.001
|
ycT1
|
6/110 (5.5%)
|
ycT2
|
6/65 (9.2%)
|
ycT3
|
1/16 (6.3%)
|
ycT4
|
22/121 (18.2%)
|
Post-chemotherapy clinical N stage (ycN)
|
ycN0
|
31/397 (7.8%)
|
0.028
|
ycN1
|
13/178 (7.3%)
|
ycN2
|
5/20 (25%)
|
ycN3
|
1/3 (33.3%)
|
Type of surgery
|
Modified radical mastectomy
|
35/423 (8.3%)
|
0.056
|
Breast conservation surgery
|
15/175 (8.6%)
|
T stage on final histopathology (ypT)
|
ypT0
|
5/233 (2.2%)
|
0.001
|
ypT1
|
21/217 (9.7%)
|
ypT2
|
15/117 (12.8%)
|
ypT3
|
9/26 (34.6%)
|
ypT4
|
0/2 (0%)
|
N stage on final histopathology (ypN)
|
ypN0
|
0/346 (0%)
|
0.001
|
ypN1
|
3/133 (2.3%)
|
ypN2
|
3/67 (4.5%)
|
ypN3
|
44/52 (84.6%)
|
In patients with ycN0, the level III positivity was 7.8%. In patients with complete
clinical response, the level III positivity was only 5.1%. Level III node positivity
was 10.9% in HR + HER2-, 6.6% in triple positive, 7.7% in HR- HER2 + , and 5.6% in
triple-negative subset. Level III was the only positive node in six patients (1%).
On univariate analysis, a significant association was present between level III node
positivity and complete clinical response (p < 0.01), ycT0 stage (p = 0.001), ycN0 stage (p = 0.028), ypT stage (p = 0.001), ypN stage (p = 0.001), and level II node positivity (p = 0.001). On multivariate analysis, significant association was present between level
III node positivity ycT stage (p < 0.001), ypT stage (p = 0.001), and ypN stage (p = 0.001). No significant association was seen between level III positivity and age,
menopausal status, clinical T stage, HR status, HER2 receptor status, biology, or
type of surgery.
Discussion
The current trend in breast cancer surgery is of de-escalation. The breast conservation
surgery has been accepted for the breast primary with evidences with 20 years follow-up
data proving its equivalence to mastectomy.[21]
[22] SLNB has revolutionalized the management of N0 axilla in the primary surgery setting.[5] In the post-NACT setting, the role of SLNB is not proven in node-positive axilla.[7]
[8]
[9] Newer techniques like targeted axillary dissection, radioisotope tagging of the
positive node, Magseed, Radio Frequency Identification (RFID) tags, and activated
carbon injection into the positive node have been tried in small series.[10]
[11]
[12]
[23]
[24]
[25]
[26] These techniques have their pros and cons and there is no level 1 evidence to support
their use in current practice.
A recent study has shown the level III positivity rate in case of primary surgery
is 27.3% in clinically node-positive axilla.[15] Even if we consider the best pCR rate of 60% as in a recent meta-analysis, there
is the possibility of residual disease in approximately 11% of the patients in the
level III nodes.[27] In the post-NACT setting, these are the tumor cells that are resistant to the chemotherapy.
There is risk of local and systemic that may be resistant to standard chemotherapy
if these nodes are not removed surgically. There is role of adjuvant chemotherapy
based on the presence or absence of residual disease.[28]
[29] These level III nodes may contain the only residual tumor cells as was present in
six patients in our study. Thus, if these nodes are not removed, the patient may be
wrongly diagnosed as to have achieved pCR and may not receive adjuvant therapy that
has shown survival advantage.[28]
[29] The presence of level III node positivity upstages the cancer to N3a that has prognostic
implications. The current NCCN guidelines do not specify any difference in the axillary
dissection in the primary and post-NACT setting. The dissection of level III nodes
is at the discretion of the surgeon depending on the presence of clinically suspicious
level II and III nodes during surgery that is subjective. In the post-NACT setting,
the axillary tissues undergo fibrosis due to chemotherapy and it is difficult to differentiate
the tumor from fibrosis. The clinicopathological correlation in the post-NACT setting
of the axilla is low.[17] As per previous studies, there is no survival benefit with level III dissection,
but presence of tumor in the level III nodes is an essential factor that causes distant
recurrence and has prognostic implications.[30]
[31] A recent propensity matched study has advised discretion in de-escalation of axilla
in patients who have a heavy nodal burden.[31]
Complete axillary dissection including all three levels is routinely practiced our
institute in the post-NACT setting. A retrospective study of the level III dissection
in post-NACT from our institute revealed at level III positivity rate of 15.5%.[17] The retrospective study by Fan et al had a level III positivity of 9%.[18] As both these studies have the inherent drawbacks due to their retrospective nature,
a prospective study was conducted to identify the level III positivity rate and to
identify any subset in which level III dissection can be avoided. Literature review
did not reveal any prospective studies of role of level III dissection in the post-NACT
setting.
In this study, all the three levels were sent separately for histopathological analysis.
The level III positivity was 8.4% that is less than that of our previous study. Level
III node positivity was low in patients with ycT0 stage, ycN0 stage, and clinical
complete response on univariate analysis. On multivariate analysis, advanced ycT stage
was associated with significantly with level III positivity. Thus, level III dissection
may be avoided in patients with complete clinical response, ycT0 and ycN0 stage, and
must be done in patients with advanced ycT stage post-NACT. It is understandable that
in patients with complete clinical response to NACT in the breast and axilla would
have a good response in the level III nodes as well. However, a patient with poor
response with persistence T4 disease in the breast would be more likely to have residual
nodal disease including at level III. There was a significant association with the
higher final pathological T and N stage and level III positivity, but this has no
clinical benefit in planning the level III dissection.
With the advent of pertuzumab and newer agents like immunotherapy and cell cycle inhibitors,
the pCR rate may increase and the level III positivity may further decrease. None
of our study patients received pertuzumab. In our resource restricted setting, the
use of these agents is limited due to economic constraints. The response to such agents
may further reduce the indications for level III dissection in the future.
Conclusion
Level III positivity rate in LABC post-NACT is high. In patients with advanced ycT
stage, it would be advisable to offer complete axillary dissection including level
III. Level III dissection may be avoided in patients with ycT0 or ycN0 or with complete
clinical response.