1000

Disease-Free and Overall Survival after Pathologic

Complete Disease Remission of Cytologically Proven
Inammatory Breast Carcinoma Axillary Lymph Node
Metastases after Primary Systemic Chemotherapy
Bryan T. Hennessy, M.D.1
Ana Maria Gonzalez-Angulo,
Gabriel N. Hortobagyi, M.D.1
Massimo Cristofanilli, M.D.1
Shu Wan Kau, B.S.N., M.D.1
Kristine Broglio, M.S.2
Bruno Fornage, M.D.3
S. Eva Singletary, M.D.4
Aysegul Sahin, M.D.3
Aman U. Buzdar, M.D.1
Vicente Valero, M.D.1

BACKGROUND. Breast carcinoma axillary lymph node (ALN) pathologic complete

M.D.

Department of Breast Medical Oncology, University of Texas M. D. Anderson Cancer Center, Houston, Texas.

Department of Biostatistics, University of Texas

M. D. Anderson Cancer Center, Houston, Texas.

Department of Pathology, University of Texas

M. D. Anderson Cancer Center, Houston, Texas.

Department of Surgical Oncology, University of

Texas M. D. Anderson Cancer Center, Houston,
Texas.

Department of Radiology, University of Texas

M. D. Anderson Cancer Center, Houston, Texas.

response (pCR) after primary chemotherapy is associated with signicantly higher

recurrence-free survival (RFS) and overall survival (OS) rates. The purpose of the
current study was to determine long-term outcome in patients achieving a pCR of
cytologically proven inammatory breast carcinoma ALN metastases after primary
chemotherapy.

METHODS. Patients with cytologically documented ALN metastases from inammatory breast carcinoma were treated in three prospective primary chemotherapy
trials. After surgery, patients were subdivided into those patients with and those
patients without residual ALN carcinoma. Survival was calculated using the
KaplanMeier method.
RESULTS. Of 175 patients treated, 61 had cytologically conrmed ALN metastases.
Fourteen patients (23%) achieved a pCR of the ALNs after primary chemotherapy.
The 5-year OS and RFS rates were found to be improved in those patients achieving
a pCR of the ALNs (82.5% [95% condence interval (95% CI), 62.8 100%] and 78.6%
[95%CI, 59.8 100%], respectively, vs. 37.1% [95%CI, 25.4 54.2%] and 25.4%
[95%CI, 15.5 41.5%], respectively) (P 0.01 [for OS] and P 0.001 [for RFS]).
Combination anthracycline and taxane-based primary chemotherapy resulted in
signicantly more patients achieving an ALN pCR (45% vs. 16%; P 0.01).
CONCLUSIONS. pCR of ALN metastases is associated with an excellent prognosis in
patients with inammatory breast carcinoma. The rates of ALN pCR are nearly 50%
in patients with inammatory breast carcinoma who are treated with anthracyclines and weekly paclitaxel before surgery. However, those patients with residual
ALN disease at the time of surgery greatly require the introduction of novel
therapeutic strategies. Cancer 2006;106:1000 6. 2006 American Cancer Society.
KEYWORDS: inammatory, breast carcinoma, primary tumor, chemotherapy, pathologic complete response.

Address for reprints: Bryan Hennessy, M.D., Department of Breast Medical Oncology, Unit 424;
The University of Texas M. D. Anderson Cancer
Center; 1515 Holcombe Blvd., Houston, TX 77030;
Fax: (713) 792-3708; E-mail: bhennessy@
mdanderson.org
Received August 3, 2005; accepted August 24,
2005.

etastases to axillary lymph nodes (ALNs) are the most signicant

prognostic factor in breast carcinoma. Therefore, pathologic
complete response (pCR) of axillary lymph node metastases may
affect the long-term course of patients with high-risk breast carcinoma and provide an early surrogate marker of recurrence-free survival (RFS) and overall survival (OS).
Primary or neoadjuvant systemic chemotherapy is the standard
treatment for patients with inammatory breast carcinoma, and for
those patients with locally advanced breast carcinoma and large,
operable breast tumors who desire breast-conserving surgery; it also

2006 American Cancer Society

DOI 10.1002/cncr.21726
Published online 27 January 2006 in Wiley InterScience (www.interscience.wiley.com).

pCR of Breast Ca LN Metastases/Hennessy et al.

currently is being assessed in patients with earlier

stage disease as well as in other types of cancer.112
Although randomized studies, including the National
Surgical Adjuvant Breast and Bowel Project (NSABP)
B-18 trial, have to our knowledge not demonstrated a
survival advantage for patients with operable breast
carcinoma who are treated with primary chemotherapy compared with postoperative chemotherapy, patients who achieve a pCR of the primary tumor are
reported to have a signicantly better outcome than
those with residual disease.11,12 We have similarly
shown that the long-term outcome in patients with a
pCR of cytologically conrmed ALN metastases after
primary chemotherapy for breast carcinoma is significantly better than in those patients who do not
achieve a pCR of ALN metastases; in addition, pCR of
ALN metastases may be a better predictor of outcome
than a pCR of the breast primary tumor.13
Inammatory breast carcinoma is the most biologically aggressive form of primary breast carcinoma.
It has a reported incidence rate of 1 6% in the U.S.14
However, data from the Surveillance, Epidemiology,
and End Results (SEER) Program has reported that the
incidence of inammatory breast carcinoma has increased from 0.3 to 0.7 cases per 100,000 personyears.14 Inammatory breast carcinoma is a clinical
diagnosis, with tumor cells penetrating dermal lymphatic channels, causing the inammatory signs.15,16
Primary chemotherapy is considered to be a major
component of treatment.17 Because to our knowledge
the outcome of patients who achieve a pCR of cytologically proven ALN metastases from inammatory
breast carcinoma has not been well documented to
date, particularly compared with the outcomes of patients achieving a pCR of cytologically proven ALN
metastases from noninammatory breast carcinoma,
we attempted to determine the long-term outcome in
patients achieving a pCR of cytologically proven ALN
metastases from inammatory breast carcinoma and
compared their outcomes with those of patients with
cytologically proven ALN metastases from noninammatory breast carcinoma.

MATERIALS AND METHODS

Between 1987 and 2001, 175 patients with inammatory breast carcinoma (classied as T4 disease using
the 2002 American Joint Committee on Cancer [AJCC]
classication18) were treated in 3 prospective Institutional Review Board-approved trials of anthracyclinebased or anthracycline and taxane-based primary
chemotherapy. Patients provided written informed
consent and were registered prospectively. Of the 175
patients, 140 had a clinically suspicious axilla; after

1001

needle sampling, 61 had cytologically documented

ALN metastases.
A clinical diagnosis of inammatory breast carcinoma required the presence of erythema, heat, ridging, and peau dorange, with or without evidence of
dermal lymphatic invasion on pathologic evaluation.
Patients were examined by a multidisciplinary team to
evaluate the clinical stage of disease at the time of
presentation and response after four chemotherapy
cycles. Staging included history and physical examination, complete blood count, blood chemistries,
electrocardiography, chest radiology, abdominal computed tomography or ultrasonography, bone scan, bilateral mammography, and ultrasonography of the
breast and/or regional lymph nodes. Patients were
entered prospectively into the protocol database and
data were added with follow-up. The complete medical records of all patients were available for review at
the time of the current analysis.
In all patients being treated with the older 2 protocols (50 of the total of 61 patients), the primary
chemotherapy per protocol was comprised of an anthracycline-based regimen including 5-uorouracil at
a dose of 500 mg/m2, doxorubicin at a dose of 50
mg/m2, and cyclophosphamide at a dose of 500
mg/m2 (FAC) every 21 days for 3 4 cycles; 3 of these
patients received preoperative paclitaxel because of a
lack of response to FAC-based therapy. Eleven patients (18%) treated on the third and most recent
protocol received 4 cycles of primary FAC chemotherapy followed by weekly high-dose paclitaxel (175 mg/
m2) before surgery. The majority of patients underwent a subsequent modied radical mastectomy
(MRM) (n 57 patients); 2 patients developed disease
progression while receiving primary chemotherapy
precluding surgery, 1 patient declined surgery, and 1
patient received radiation therapy but did not undergo surgery.
The ALN dissection specimens were evaluated
completely to identify all lymph nodes. All lymph
nodes that appeared to demonstrate no residual carcinoma were submitted in toto for histologic evaluation. The blocks were processed by routine methods
and only one representative hematoxylin and eosinstained section was obtained. Immunohistochemistry
for keratin was performed when suspicious cells were
identied. A histologic response was considered to be
an ALN pCR when there was no evidence of residual
tumor in the ALNs. A pCR of the breast tumor was
dened as the absence of all invasive disease in the
breast, but ductal/lobular carcinoma in situ was allowed. Immunohistochemistry for the estrogen receptor (ER) and progesterone receptor (PR) was performed using the avidin biotinperoxidase complex

1002

CANCER March 1, 2006 / Volume 106 / Number 5

method using 6F11 and 1A6 antibodies (Novocastra

Laboratories Ltd., Newcastle-upon-Tyne, U.K.), respectively.19
Postoperative radiotherapy was delivered to the
chest wall and internal mammary and supraclavicular/high ALNs. Locoregional radiotherapy was initiated within 6 weeks of the completion of chemotherapy. Tamoxifen was initiated after chemotherapy in
those patients with hormone receptor-positive tumors.

Data Analysis
Patient characteristics were tabulated or described using the median and range for all patients and by ALN
pCR group. Patient characteristics were compared between ALN pCR groups by using the Fisher exact test
or Wilcoxon rank-sum test as appropriate. OS was
calculated from the date of diagnosis to the date of
death or last follow-up. RFS was calculated from the
date of diagnosis to the date of local disease recurrence or metastasis. Patients who died before developing a local disease recurrence or metastasis were
considered censored at their date of death. The median follow-up time was calculated as the median
observation time among all patients. Survival curves
were estimated with the KaplanMeier method and
the log-rank statistic was used to compare groups.20,21
Cox proportional hazards models were t for OS and
RFS that included variables identied a priori as being
associated with survival. The t of the model and the
proportional hazards assumption was assessed visually with residual plots.

RESULTS
Table 1 summarizes the characteristics of the patients
overall and by ALN pCR group. The median age at
diagnosis among all 61 patients was 50 years. Approximately half of the patients had ER- and/or PR-positive disease, and 79% had Blacks Nuclear Grading
(modied) Grade 3 disease. Fourteen patients (23%)
achieved an ALN pCR at the time of surgery; with the
exception of 1 patient who achieved an ALN pCR and
who had received preoperative radiation therapy in
addition to chemotherapy (with a subsequent residual
0.1-cm focus in the breast), 13 patients (21%) achieved
a pCR of the ALNs (and breast) after primary chemotherapy. Of the 11 patients treated on the third protocol with preoperative paclitaxel in addition to FAC, 5
patients (45% [excluding the sixth patient who
achieved a pCR of the ALNs after preoperative FAC/
paclitaxel/radiation therapy]) achieved a pCR of the
ALNs, and this was statistically superior to the rate of
ALN pCRs observed among those patients treated with
preoperative FAC only (8 of 50 patients [16%]; P

0.05), even with the limited number of patient in the

current study. None of the patient and/or tumor characteristics were found to be signicantly different between the two ALN pCR groups (Table 1). Patients who
achieved a pCR of the ALNs tended to be younger and
to have ER/PR-negative disease and lower grade disease more frequently compared with patients who did
not achieve a pCR of the ALNs, although these differences did not reach statistical signicance, perhaps
because of the limited numbers of patients. Those
patients who achieved a pCR of the ALNs signicantly
more often were found to have less residual disease in
the breast at the completion of primary chemotherapy; only 1 of these 14 patients was found to have
residual invasive disease in the breast (a 0.1-cm focus),
and this patient was free of disease recurrence at 55
months.
Table 2 shows the OS and RFS rates among all
patients and by ALN pCR group. Among all patients,
the median follow-up was 48 months (range, 6 170
months). Thirty-six patients had died at the time of
last follow-up and the median overall survival was 47.4
months. Figure 1 shows the OS by ALN pCR group.
Among those patients who did not achieve a pCR of
the ALNs, 33 patients had died at the time of last
follow-up and the OS rate at 5 years was 37%. Among
those patients who did achieve a pCR of the ALNs,
only 3 patients had died at the time of last follow-up,
and the OS rate at 5 years was 82.5%. The OS was
found to be signicantly different between the two
groups (P 0.01).
Figure 2 shows RFS by ALN pCR group. Among
patients who did not achieve a pCR of the ALNs, 35
patients had experienced disease recurrence at the
time of last follow-up and the RFS rate at 5 years was
25%. Among those patients who did achieve a pCR of
the ALNs, only 3 patients had experienced a disease
recurrence at the time of last follow-up, and the RFS
rate at 5 years was 78.6%. The RFS was found to be
signicantly different between the two ALN pCR
groups (P 0.001).
Table 3 shows OS and RFS rate estimates by ER
and ER/PR group in the subgroup of patients who did
not achieve an ALN pCR. In the subgroup of patients
who did achieve a pCR of the ALNs, only two patients
had a known ER or ER/PR status and experienced
either a disease recurrence or death; therefore, a subgroup analysis was not performed among these patients. Figure 3 shows the OS by ER/PR group. Within
the subgroup of patients who did not achieve a pCR of
the ALNs, the OS rates were found to be similar between the two ER/PR groups and between the two ER

pCR of Breast Ca LN Metastases/Hennessy et al.

1003

TABLE 1
Patient Characteristics
All

No.
Age in yrs
Minimum
Median
Maximum
ERa
Negative
Positive
PRa
Negative
Positive
ER/PRa
Both negative
Either positive
Histologya
Ductal
Lobular
LVIa
No
Yes
MNG a
2
3
N classication
N0
N1
N2
N3
Total no. of lymph nodes at surgery
Minimum
Median
Maximum
Residual tumor in the breast
Minimum
Median
Maximum

No ALN pCR

ALN pCR

Frequency

Frequency

Percent

Frequency

Percent

P value

61

47

14

32
50
78

32
50
78

35
43.5
68

0.16

36
13

26
12

68%
32%

10
1

91%
9%

0.25

35
10

27
9

75%
25%

8
1

89%
11%

0.66

27
18

20
16

56%
44%

7
2

78%
22%

0.28

52
3

39
3

93%
7%

13
0

100%
0%

1.00

2
33

1
30

3%
97%

1
3

25%
75%

0.22

15
44

10
37

21%
79%

5
7

42%
58%

0.26

1
26
23
11

1
20
19
7

2%
43%
40%
15%

0
6
4
4

0%
43%
29%
29%

0.60

3
13
32

3
14
32

4
12
29

0.54

0
0.35
8.5

0
0.8
8.5

0
0
0.1

0.0001

ALN: axillary lymph node; pCR: pathologic complete response; ER: estrogen receptor; PR: progesterone receptor; LVI:lymphovascular invasion; MNG: modied Blacks nuclear grade; N: lymph node.
a
Numbers may not add up to total in categories because of unknown data.

groups. Figure 4 shows RFS by ER/PR group. Among

patients who did not achieve a pCR of the ALNs, RFS
rates were found to be similar between the two ER/PR
groups and between the two ER groups.

Cox Proportional Hazards Model

After adjustment for ER/PR group, nuclear grade, and
clinical N classication, patients who achieved a pCR
of the ALNs were found to have 0.18 times the risk of
death and 0.09 times the risk of disease recurrence
compared with patients who did not achieve a pCR of
the ALNs (P 0.03 and P 0.003, respectively).

Patients with Cytologically Conrmed ALN Metastases

from Noninammatory Breast Carcinoma
We previously analyzed 403 patients with cytologically
conrmed ALN metastases from noninammatory
breast carcinoma, 144 of whom (36%) were treated
with primary FAC/paclitaxel, 226 of whom were
treated with primary FAC chemotherapy (56%), and 33
of whom were treated with primary paclitaxel alone
(8%).13 A total of 89 patients (22%) achieved a pCR of
the ALNs after primary chemotherapy. Similar to inammatory breast carcinoma, the 5-year OS and RFS
rates in patients with noninammatory breast carcinoma who achieved a pCR of the ALNs (93% [95%

1004

CANCER March 1, 2006 / Volume 106 / Number 5

TABLE 2
Survival among All Patients and by Axillary Lymph Node Pathologic Complete Response Group

Overall survival
All patients
ALN pCR
No
Yes
Recurrence-free survival
All patients
ALN pCR
No
Yes

No.

No. of
events

Median
(mos)

5-year
estimate, %

95% CI

10-year
estimate, %

95% CI

61

36

47.4

46.7

(35.3%61.8%)

30.8

(18.9%50.3%)

47
14

33
3

40.9

37.1
82.5

(25.4%54.2%)
(62.8%100%)

21.8
68.8

(10.9%43.4%)
(43.9%100%)

61

38

22.9

37.4

(26.9%51.9%)

37.4

(26.9%51.9%)

47
14

35
3

19.8

25.4
78.6

(15.5%41.5%)
(59.8%100%)

25.4
78.6

(15.5%41.5%)
(59.8%100%)

P value

0.01

0.001

95% CI: 95% condence interval; ALN pCR: axillary lymph node pathologic complete response.

FIGURE 1.

Overall survival by axillary lymph node pathologic complete

response (pCR) group. E: events; N: number.

FIGURE 2.

condence interval (95% CI), 87.598.5] and 87%

[95%CI, 79.794.3], respectively) were signicantly
higher than the rates in those patients who did not
achieve a pCR of the ALNs (72% [95%CI, 66.577.5]
and 60% [95%CI, 54.1 65.9], respectively). Combination anthracycline/taxane-based primary chemotherapy resulted in signicantly more ALN pCRs occurring
among noninammatory breast carcinoma patients
than the use of anthracycline chemotherapy alone
(29% vs. 19%; P 0.03).

ported after primary chemotherapy (22%) in patients

with noninammatory breast carcinoma with cytologically conrmed ALN metastases. The rate of ALN
negativity after primary chemotherapy in patients
with clinically suspicious ALNs is reported to vary
from 25% to 38%.11,14,2225 Signicantly more noninammatory breast carcinoma and inammatory
breast carcinoma patients are reported to achieve a
pCR of the ALNs when a taxane is used in addition to
an anthracycline, a nding that is consistent with the
NSABP B-27 study.23 Although the current inammatory breast carcinoma study has relatively small numbers of patients, the data suggest that the ALN pCR
rates are nearly 50% in inammatory breast carcinoma patients with cytologically conrmed ALN metastases who are treated with anthracycline/taxanebased primary chemotherapy. Because up to 23% of
patients with inammatory breast carcinoma achieve
a pCR of the ALNs after primary chemotherapy, axil-

DISCUSSION
Primary systemic chemotherapy is reported to completely eradicate cytologically conrmed ALN metastases in up to 23% of patients with inammatory
breast carcinoma. The data from the current study
excluded patients with clinically suspicious axillary
ndings in whom the cytology was negative or nondiagnostic. This is similar to the rate of ALN pCR re-

Recurrence-free survival by axillary lymph node pathologic

complete response (pCR) group. E: events; N: number.

pCR of Breast Ca LN Metastases/Hennessy et al.

1005

TABLE 3
Survival by ER and ER/PR Group among Patients Who Did Not Achieve an Axillary Lymph Node Pathologic Complete Response

Overall survival
ER/PR
Negative
Positive
ER
Negative
Positive
Recurrence-free survival
ER/PR
Negative
Positive
ER
Negative
Positive

No.

No. of
events

Median
(mos)

5-year
estimate, %

95% CI

10-year
estimate, %

95% CI

P value

20
16

15
12

25.7
42.9

32.1
31.3

(16.4%63.1%)
(15.1%64.6%)

16.1
0.0

(4.9%52.8%)

0.43

26
12

19
9

34.4
40.9

36.7
25.0

(21.8%61.8%)
(9.4%66.6%)

13.1
25.0

(2.8%61.9%)
(9.4%66.6%)

0.93

20
16

17
12

14.8
20.7

13.3
25.0

(4.1%43.7%)
(10.7%58.4%)

13.3
25.0

(4.1%43.7%)
(10.7%58.4%)

0.35

26
12

21
9

19.3
19.8

18.5
25.0

(8.1%42.2%)
(9.4%66.6%)

18.5
25.0

(8.1%42.2%)
(9.4%66.6%)

0.77

ER: estrogen receptor; PR: progesterone receptor; 95% CI: 95% condence interval.

FIGURE 3. Overall survival among patients who did not achieve a pathologic
complete response of the axillary lymph nodes by estrogen receptor (ER)/
progesterone receptor (PR) group. E: events; N: number.

FIGURE 4. Recurrence-free survival among patients who did not achieve a

pathologic complete response of the axillary lymph nodes by estrogen receptor
(ER)/progesterone receptor (PR) group. E: events; N: number.

lary lymph node dissection, currently the standard

approach, might not be necessary in certain patients
with ALN-positive breast carcinoma who are treated
with primary chemotherapy. Sentinel lymph node biopsy may be an alternative in those patients with a
clinically negative axilla after primary chemotherapy.26 29 We and others are prospectively evaluating
sentinel lymph node biopsy in patients with ALNpositive breast carcinoma treated on our current primary chemotherapy protocols.
ALN pCR is associated with a good prognosis in
patients with inammatory breast carcinoma and in
patients with noninammatory breast carcinoma.
However, as would be expected, the prognosis is poor
for noninammatory breast carcinoma patients with

cytologically conrmed ALN metastases who do not

achieve a pCR of the ALNs with primary chemotherapy, and is very poor in patients with cytologically
conrmed, ALN-positive inammatory breast carcinoma who do not achieve a pCR of the ALNs.
ALN pCR is an excellent prognostic factor in patients with inammatory breast carcinoma. A pCR in
the ALNs after primary chemotherapy has the potential to become an early surrogate marker of long-term
benet with experimental adjuvant treatments. Furthermore, the use of conventional primary chemotherapy will allow us to determine those biologic features that are predictive of whether a particular
patient will benet from standard adjuvant chemotherapy. The rates of ALN pCR may be as high as 50%

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CANCER March 1, 2006 / Volume 106 / Number 5

in inammatory breast carcinoma who are patients

treated with anthracyclines and taxanes before surgery. However, those inammatory breast carcinoma
patients with residual ALN disease at the time of surgery greatly require the introduction of new effective
therapies.

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