Triple negativity and young age as prognostic factors in lymph node-negative invasive ductal carcinoma of 1 cm or less.

Abstract

Whether a systemic adjuvant treatment is needed is an area of controversy in patients with node-negative early breast cancer with tumor size of ≤1 cm, including T1mic.
We performed a retrospective analysis of clinical and pathology data of all consecutive patients with node-negative T1mic, T1a, and T1b invasive ductal carcinoma who received surgery between Jan 2000 and Dec 2006. The recurrence free survival (RFS) and risk factors for recurrence were identified.
Out of 3889 patients diagnosed with breast cancer, 375 patients were enrolled (T1mic:120, T1a:93, T1b:162). Median age at diagnosis was 49. After a median follow up of 60.8 months, 12 patients developed recurrences (T1mic:4 (3.3%), T1a:2 (2.2%), T1b:6 (3.7%)), with a five-year cumulative RFS rate of 97.2%. Distant recurrence was identified in three patients. Age younger than 35 years (HR 4.91; 95% CI 1.014-23.763, p = 0.048) and triple negative disease (HR 4.93; 95% CI 1.312-18.519, p = 0.018) were significantly associated with a higher rate of recurrence. HER2 overexpression, Ki-67, and p53 status did not affect RFS.
Prognosis of node-negative breast cancer with T1mic, T1a and T1b is excellent, but patients under 35 years of age or with triple negative disease have a relatively high risk of recurrence.

Full text

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RESEARCH ARTICLEOpen Access
Triple negativity and young age as prognostic
factors in lymph node-negative invasive ductal
carcinoma of 1 cm or less
Ji Hyun Kwon1,2, Yu Jung Kim1, Keun-Wook Lee1, Do-Youn Oh2, So Yeon Park3, Jee Hyun Kim1*, Eui Kyu Chie4,
Sung-Won Kim5, Seock-Ah Im2, In-Ah Kim6, Tae-You Kim2, In Ae Park7, Dong-Young Noh8, Yung-Jue Bang2,
Sung Whan Ha4
Abstract
Background: Whether a systemic adjuvant treatment is needed is an area of controversy in patients with node-
negative early breast cancer with tumor size of ≤1 cm, including T1mic.
Methods: We performed a retrospective analysis of clinical and pathology data of all consecutive patients with
node-negative T1mic, T1a, and T1b invasive ductal carcinoma who received surgery between Jan 2000 and Dec
2006. The recurrence free survival (RFS) and risk factors for recurrence were identified.
Results: Out of 3889 patients diagnosed with breast cancer, 375 patients were enrolled (T1mic:120, T1a:93,
T1b:162). Median age at diagnosis was 49. After a median follow up of 60.8 months, 12 patients developed
recurrences (T1mic:4 (3.3%), T1a:2 (2.2%), T1b:6 (3.7%)), with a five-year cumulative RFS rate of 97.2%. Distant
recurrence was identified in three patients. Age younger than 35 years (HR 4.91; 95% CI 1.014-23.763, p = 0.048)
and triple negative disease (HR 4.93; 95% CI 1.312-18.519, p = 0.018) were significantly associated with a higher rate
of recurrence. HER2 overexpression, Ki-67, and p53 status did not affect RFS.
Conclusions: Prognosis of node-negative breast cancer with T1mic, T1a and T1b is excellent, but patients under 35
years of age or with triple negative disease have a relatively high risk of recurrence.
Background
Owing to the increased use of screening mammogra-
phy, the proportion of early stage breast cancer is
increasing internationally [1-3]. In Korea, an increase
in the percentage of stage 0 and I types of breast can-
cer has also been reported. The proportion of stage 0
breast cancer was 7.5% in 2002 and increased to 11.3%
in 2003. For stage I breast cancer, the proportion of
patients increased from 29.5% to 36.5% over the same
period [4,5].
Generally, it has been reported that the prognosis of
small-sized, node-negative breast cancer is excellent
with complete surgical resection of the primary tumor,
even without systemic adjuvant therapy [6]. For patients
with microinvasive breast cancer, which is defined as
tumor foci of 0.1 cm or less, a very small percentage of
women relapse or die of breast cancer [7]. According to
an analysis of the Surveillance Epidemiology and End
Results (SEER) data from 1998 to 2001, the ten-year
overall breast cancer specific mortality of patients with
T1a, bN0M0 disease was 4% [8].
Nevertheless, certain subgroups of patients who were
initially diagnosed with small, node-negative breast can-
cer tumors have a risk of recurrence. Some authors have
reported that young patients under 35 years old had
poor prognosis [9]. The biological factors of a high
grade of tumor [8,10,11] and high Ki-67 [12] were asso-
ciated with a high relapse or high mortality rate.
There have been few clinical studies with large numbers
of patients over a long duration of observation sufficient
for the evaluation of the prognosis of node-negative breast
cancer of 1cm or less in size. In addition, few studies
* Correspondence: jhkimmd@snu.ac.kr
1Department of Internal Medicine, Seoul National University College of
Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
Full list of author information is available at the end of the article
Kwon et al. BMC Cancer 2010, 10:557
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© 2010 Kwon et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons
Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.

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have evaluated the long-term prognosis according to
the hormone receptor and human epidermal growth
factor receptor 2 (HER2) statuses because many
patients were not examined for estrogen receptor (ER),
progesterone receptor (PR), or HER2 status before
these tests became widely available. Therefore, some
controversy remains regarding treatment decisions for
these patients.
The features of breast cancer vary among Asian coun-
tries, but there is a common tendency of younger age-
onset and a large proportion of premenopausal women
[5,13]. Some studies have reported higher rates of hormone
receptor negative or high-grade breast tumor in Asian
populations [14]. However, the ethnic differences asso-
ciated with recurrence or mortality remain unclear, espe-
cially in node-negative early breast cancer of 1cm or less.
The aim of this study was to evaluate the overall prog-
nosis of lymph node negative invasive ductal carcinoma
of the breast of ≤ 1 cm in size, including microinvasive
carcinoma (T1mic) in a Korean population. Moreover,
through identification of subgroups of patients with a
high risk of recurrence and their characteristics, we set
out to determine which subgroup of patients would be
candidates for systemic adjuvant therapies.
Methods
Study population
We identified the study population from a prospectively
maintained hospital-based cancer registry and collected
information from all consecutive women diagnosed as
invasive breast carcinoma at Seoul National University
Hospital and Seoul National University Bundang Hospital
from January 2000 to December 2006. Eligibility criteria
included complete surgical resection, histologic diagnosis
of invasive ductal carcinoma of 1 cm or less (T1a, T1b),
or microinvasive carcinoma (T1mic) and no lymph node
metastasis (N0) according to the fifth and sixth editions
of the American Joint Committee on Cancer (AJCC)
Cancer Staging Manual [15]. Both the fifth and sixth edi-
tions were used because T staging did not differ between
the two staging systems. Patients with a history of pre-
vious malignancy of the breast or other sites and who
received neoadjuvant chemotherapy were excluded.
Clinical and biological data acquisition
Data on patient’s baseline characteristics and symptoms,
mammography results, type of operation and axillary
lymph node examinations were collected. The type of
operation was divided into mastectomy and breast-
conserving surgery, and breast-conserving surgery
included lumpectomy, quadrantectomy and excision of
the primary tumor. Methods of axillary lymph node
examination were classified into sentinel lymph node
biopsies and axillary lymph node dissections.
Pathologic information was obtained by reviewing
pathology reports on the following variables: tumor size,
histologic subtype, modified Bloom-Richardson histologic
grade (tubule formation, nuclear pleomorphism, mitotic
counts), extent of intraductal carcinoma, lymphatic inva-
sion, venous invasion and tumor border. Immunohisto-
chemical data for standard prognostic biomarkers (ER,
PR, HER-2, p53 and Ki-67) were also collected. Immuno-
histochemical staining was determined from microinva-
sive foci in cases of T1mic disease. For ER and PR, cases
with 10% or more positive staining were grouped as posi-
tive. For HER-2, 3+ staining by immunohistochemistry
was considered positive. For Ki-67 status, we grouped the
cases with 10% or more positive staining as a positive
[16]. A 10% cutoff value was also used for p53 expression.
Information about treatment undertaken as an adjuvant
therapy was also retrieved.
Recurrence free survival (RFS) was calculated as the
time from operation to diagnosis of a recurrent disease
in the ipsilateral breast, local, regional or distant site.
For patients who remained alive and recurrence-free,
data were censored at the date of the last follow up.
The information of recurrent disease included time of
diagnosis, sites of disease (local, regional, systemic), and
histologic features of recurrent tumor (ductal carcinoma
in situ or invasive ductal carcinoma). Diagnosis of con-
tra-lateral breast cancer was not included in the cate-
gory of recurrent disease. Overall survival was measured
as the time from operation to death.
Statistical analysis
Pearson’s chi-square test was used to assess differences
in clinical and biological characteristics between T stage
subgroups. The RFS curves were constructed using the
Kaplan-Meier method, and the log-rank test was used
for a comparison of the survival curves between sub-
groups according to prognostic factors. We also com-
pared the five-year cumulative survival rate and
investigated the association between the probability of
death or recurrence and the clinical and biologic fea-
tures. Multivariate analysis was conducted using Cox’s
proportional hazard regression model, and our data was
shown to satisfy the proportional hazard assumption. A
significance level of 0.05 was used for covariate entry.
All statistical analyses were performed using SPSS for
Windows software, version 15.0 (SPSS Inc., Chicago, IL).
The study was approved by an independent review
board at the Seoul National University Bundang Hospi-
tal and Seoul National University Hospital.
Results
Clinical and histologic characteristics
From January 2000 to December 2006, we identified a
total of 3889 women with invasive breast cancer who
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were diagnosed at the Seoul National University Hospi-
tal and Seoul National University Bundang Hospital
using the hospital cancer registry. Among these, we
excluded 2907 patients (74.7%) with more advanced
stage cancer than T1bN0, 76 patients (1.9%) who
received neoadjuvant chemotherapy, and 81 patients
(2.1%) with recurrent breast cancer. Rest of the patients
(n = 450, 11.6%) received diagnosis but did not undergo
operation in our hospital therefore were excluded from
the study. A total of 375 (9.6%) women were eligible,
and 120 patients were classified as T1mic, 93 as T1a,
and 162 as T1b. Median age was 49 years (range, 24 to
77 years), and 23 patients (6.1%) were under 35. The
majority of the study population (182 patients, 48.5%)
was asymptomatic at the time of diagnosis, and these
patients were diagnosed by screening mammography.
Isolated microcalcification was the most common mam-
mographic finding (149 patients, 40.9%). Pathologic
information including hormone receptor and HER2 sta-
tus was available in 99% of patients. Twenty six percent
of patients had HER2 positive tumors, defined by 3+
staining on immunohistochemistry; 67.3% had hormone
receptor positive disease; and 15.1% had triple negative
disease.
Table 1 shows the baseline characteristics of the three
T stage sub-groups. The age distribution between each
patient T stage group was similar. In the microinvasive
(T1mic) group, there were significantly higher percen-
tages of negative ER and negative PR disease compared
to the T1a and T1b groups (57.6% vs. 34.4%, 22.2% for
ER, 68.6% vs. 48.4%, 37.7% for PR; p < 0.0001). T1mic
tumor also had a higher proportion of HER2 positivity
(p < 0.0001); 54 patients (45.8%) in the T1mic group, 21
(22.8%) in T1a, and 21 (13.0%) in T1b. The frequency of
positive immunohistochemical staining for p53 was also
highest in the T1mic group (p = 0.080 by chi-square,
p = 0.037 by Linear-by-Linear association). Ki-67 did
not show significant differences between each patient
group. Among the 255 patients with T1a or T1b tumor,
data of associated DCIS was available in 248 patients.
One-hundred and ninety-eight (79.8%) had associated
DCIS around the invasive portion, 79 (88.8%) in T1a
and 119 (73.6%) in T1b.
Loco-regional and adjuvant treatment
178 patients (47.5%) received a mastectomy, and breast-
conserving surgery was performed in 197 women
(52.5%). For axillary lymph node examinations, more
patients (255 patients, 68%) received axillary lymph
node dissection than sentinel lymph node biopsies.
Among patients who received breast-conserving surgery,
135 patients (68.5%) were treated with adjuvant radio-
therapy after surgical resection. The proportion of
patients receiving adjuvant whole breast radiotherapy
was different in each T stage group: 30 (56.6%) in
T1mic, 30 (63.8%) in T1a, and 75 (77.3%) in T1b (p =
0.007).
278 patients (74.1%) received systemic adjuvant ther-
apy. Among patients with hormone-receptor positive
disease, 232 (92.4%) received adjuvant endocrine ther-
apy. No differences were observed in the percentage of
patients undergoing endocrine therapy between T stage
subgroups. Adjuvant chemotherapy was given to 61
(16.3%) patients. Forty-two patients, 34.4% of the
patients with ER and PR negative disease, received adju-
vant chemotherapy. An anthracycline-based regimen
was given to thirty-three patients (54.1% of these 61
patients), and 25 patients were treated with combination
Table 1 Baseline characteristics of all patients according
to T stage
All
patients
(N = 375) (N = 120) (N = 93) (N = 162)
T1micT1a T1b
P
value
Age at diagnosis
Median
Range
Grade¶
1
2
3
ERa
Negative
Positive
PRb
Negative
Positive
HER2c
Negative
Positive
HR/HER2
HR+HER2-
HR+HER2+
HR-HER2+
HR-HER2-
p53d
<10%
≥10%
Ki-67d
<10%
≥10%
49 4947500.297
24 - 77 27 - 7429 - 7724 - 73
28(11.2)
152(60.6)
71(28.3)
.
.
.
8(9.0)
49(55.0)
32(36.0)
20(12.3)
103(63.6)
39(24.1)
0.126
136(36.5)
237(63.5)
68(57.6)
50(42.4)
32(34.4)
61(65.6)
36(22.2)
126(77.8)
<0.001
187(50.1)
186(49.9)
81(68.6)
37(31.4)
45(48.4)
48(51.6)
61(37.7)
101(62.3)
<0.001
276(74.2)
96(25.8)
64(54.2)
54(45.8)
71(77.2)
21(22.8)
141(87.0)
21(13.0)
<0.001
220(59.1)
31(8.3)
65(17.5)
56(15.1)
42(35.6)
11(9.3)
43(36.4)
22(18.6)
56(60.9)
9(9.8)
12(13)
15(16.3)
122(75.3)
11(6.8)
10(6.2)
19(11.7)
<0.001
220(60.6)
143(39.4)
60(52.2)
55(47.8)
56(63.6)
32(36.4)
104(65.0)
56(35.0)
0.080
275(75.8)
88(24.2)
82(71.3)
33(28.7)
72(81.8)
16(18.2)
121(75.6)
39(24.4)
0.223
¶Nuclear/histologic grade was assessed only in T1a and T1b patients.
a,bData of hormone receptor status was available in 373 patients. ;<10%;
negative, ≥10%;positive.
cHER2 status was determined by immunohistochemistry and was available in
372 patients.; 0,1+,2+;negative, 3+;positive.
dData of p53 and Ki-67 was available in 363 patients.
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chemotherapy of cyclophosphamide, methotrexate,
fluorouracil. No patients received adjuvant trastuzumab.
T1mic patients were more likely to be candidates for
observation without any systemic adjuvant therapy
(75.8% in T1mic group, 53.6% in T1a, and 38.7% in
T1b, P < 0.0001).
Recurrence and prognosis
Median follow up duration for all patients was 60.8
months while median RFS duration was not reached as
of the time of this writing. The five-year cumulative RFS
rate was 97.2%, and recurrent disease was diagnosed in
12 patients during this follow up period. There was no
difference in five-year RFS between T1mic, T1a and
T1b patients (97.4% for T1mic, 97.8% for T1a, and
96.9% for T1b, p = 0.681) (Table 2). The rate of local or
regional recurrence did not show a statistically signifi-
cant difference between patients who received or not
received adjuvant radiotherapy among the patients who
received breast conserving surgery (p = 0.871).
Table 2 Number of events and five year recurrence free survival according to prognostic factors
Variable No. of patientsNo. of eventsProportion surviving to 5 years (%) p value
T stage
T1mic
T1a
T1b
120
93
162
4
2
6
97.4
97.8
96.9
0.681
Age
≤ 35
>35
23
352
3
9
90.9
97.7
0.002
Grade¶
1 (low)
2
3 (high)
28
152
71
1
5
2
96.3
96.6
98.6
0.696
ERa
negative
positive
136
237
7
5
95.1
98.2
0.123
PRb
negative
positive
187
186
9
3
96.0
98.2
0.126
HR
ER-PR-
ER+ and/or PR+
122
251
7
5
94.9
98.4
0.069
HER2c
Negative
Positive
276
96
8
3
97.4
97.9
0.772
HR/HER2
HR+HER2-
HR+HER2+
HR-HER2+
HR-HER2-
220
31
65
56
4
1
2
4
98.6
96.8
98.5
92.6
0.225
HR/HER2
HR+ and/or HER2+
HR-HER2-
316
56
7
4
98.4
92.6
0.018
p53d
<10%;
≥10%
220
143
4
6
97.9
97.1
0.543
Ki-67d
<10%
≥10%
275
88
6
4
98.4
95.5
0.148
¶Only T1a, T1b patients were analyzed using nuclear/histolgogic grade.
a,bData of hormone receptor status was available in 373 patients. ;<10%;negative, ≥10%;positive.
cHER2 status was determined by immunohistochemistry and was available in 372 patients.; 0,1+,2+;negative, 3+;positive.
dData of p53 and i-67 was available in 363 patients.
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On the univariate analysis, age younger than 35 years
and hormone receptor negative disease were risk factors
of recurrence. The five-year cumulative RFS rate was
90.9% vs. 97.7% in patients ≤35 and >35 years of age
(p = 0.002, Figure 1 A). Each of ER and PR status did
not show a significant association with recurrence, but
negative status of both ER and PR tend to be associated
with shorter RFS (p = 0.069). Patients with both ER and
PR negative disease showed a five-year cumulative RFS
rate of 94.9%; hormone receptor-positive patients
showed a rate of 98.4%. Patients with triple negative dis-
ease had a significantly lower RFS rate compared to hor-
mone receptor-positive and/or HER2-positive patients (p
= 0.018, Figure 1 B). HER2 status alone, Ki-67 and p53
status were not prognostic factors of RFS. Whether
adjuvant chemotherapy was given was not associated
with the development of systemic recurrence (p= 0.422).
Cox proportional hazard regression model was con-
structed using the variables of age, triple negativity, p53
and Ki-67. The independent prognostic factors of recur-
rence were triple negativity (HR 4.93; 95% CI 1.312-
18.519, p = 0.018), and age younger than 35 years (HR
4.91; 95% CI 1.014-23.763, p = 0.048) (Table 3).
In the analysis of distant disease-free survival, age
younger than 35 (p = 0.029) and negative hormone
receptor status (p = 0.011) were the convincing poor
prognostic factors. Univariate analysis on HER2, Ki67,
p53 status and multivariate analysis could not be per-
formed due to the small number of distant metastasis
events.
There were twelve patients who experienced recur-
rence of disease, and their median RFS time was 29.5
months (range 6.1-121.2 months, Table 4). Four patients
were diagnosed as T1micN0M0 initially, two patients
were T1a, and six were T1b. Three patients were less
than 35 years old. Three of 12 patients developed sys-
temic recurrence. All three patients had ER/PR negative
disease and developed lung metastases. One patient died
during the follow up period. This patient, initially diag-
nosed with T1bN0M0 breast cancer with ER-PR- and
positive HER2, received quadrantectomy with radiation
therapy and adjuvant chemotherapy. At 29.5 months
after surgical resection, she developed multiple metas-
tases in the lung, skin, and chest wall. She died from
breast cancer progression at 40.6 months after surgery.
Discussion
The results of this study confirmed an excellent short-
term prognosis of lymph-node-negative invasive ductal
carcinoma of the breast of 1 cm or less in a Korean
population. Among 375 patients, only one patient died
of breast cancer and only twelve cases of recurrence
were reported. The overall five-year cumulative RFS rate
was 97%. Univariate and multivariate analyses revealed
that triple negative status and age younger than 35 years
were significantly associated with shorter RFS.
There are a number of studies that focus on the prog-
nosis and predictors of recurrence of node-negative
early breast cancer. Though many reviews were retro-
spective and had small populations, high tumor grade
was the most consistent factor associated with poor out-
come in these studies [6,17-19]. Chia et al. surveyed
430, a relatively large number of patients with T1a,b
breast cancer. They noted that patients with grade 3
tumor had shorter 10-year RFS compared to grade 1, 2
patients (with 74% vs. 82%, p = 0.007) [10]. Age, tumor
size, lymphovascular invasion and estrogen receptor
negativity were also commonly found to be poor prog-
nostic factors [20-23]. In another report, Ki-67 and p53
were considered as significant prognostic factors of sur-
vival [24]. More recently, reports have shown that
Figure 1 Recurrence-free survival by (a) age (b) breast cancer
subtype according to HR and HER2 status.
Table 3 Multivariate analysis: prognostic value of
selected factors on recurrence
P valueHazard ratio 95% Confidence interval
Triple negative
Age (≤35)
KI-67
p53
0.018
0.048
0.481
0.819
4.93
4.91
1.67
1.18
1.312 - 18.519
1.014 - 23.763
0.400 - 6.995
0.285 - 4.896
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