Ultrasound and clinicopathological characteristics of triple receptor-negative breast cancers.

Abstract

Triple receptor-negative (TRN) breast cancer is associated with high risk of recurrence and poor prognosis. The present study assessed the clinicopathologic characteristics and ultrasound (US) features of TRN breast cancers.
Pathological and biological data were reviewed for 558 breast cancer patients treated at Kangbuk Samsung Hospital, between January 2003 and December 2009. The patients were separated into TRN breast cancer and non-TRN breast cancer groups, based on the results of immunohistochemical prognostic panels. Clinical and pathologic features were compared for the two groups. US features, including shape, orientation, margins, boundaries, echo patterns, posterior acoustic features, surrounding tissues, and microcalcifications, were determined for 41 TRN patients and 189 non-TRN controls (ER+/PR+/HER2-).
Of 558 cases, 58 (10.4%) had the TRN phenotype. Four hundred and thirty-four cases (77.8%) were invasive ductal carcinomas. TRN cancer was significantly associated with specific characteristics of tumor size, nuclear grade, histologic grade, venous invasion, and lymphatic invasion. With respect to US features, TRN cancers were more likely to have an oval shape, a circumscribed margin, and marked hypoechogenicity.
Tumor characteristics were different between TRN and non-TRN breast cancers, although US cannot differentiate the subtype of breast cancers TRN cancer tend to show somewhat different US morphology.

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© 2011 Korean Breast Cancer Society
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INTRODUCTION
Oncologists subcategorize breast cancer patients into those
that are hormone-receptor positive, HER2-positive, or both
hormone-receptor and HER2-negative, and treatment varies
with subcategory. Triple receptor-negative (TRN) breast can-
cer is a subcategory that lacks expression of estrogen receptors
(ER-), progesterone receptors (PR-), and human epidermal
growth factor receptor 2 (HER2-) [1-4]. This subtype, which
comprises 15% of all breast cancers [5], currently lacks effec-
tive targeted therapies. TRN breast cancers are typically char-
acterized by large, high-grade tumors that have relatively high
rates of recurrence and distant metastasis, and low overall sur-
vival rates [4,6-8]. TRN breast cancers are not identical to bas-
al-like breast cancers, but have similar clinical and pathologi-
cal features. Both types of breast cancer are associated with poor
overall prognosis and response to chemotherapy, such as an-
thracycline- and taxane-based regimens [3,5,6,9,10].
Cohort studies have shown that TRN breast cancers occur
at high frequencies in relatively young women and in African
American women [1,2,7,11]. In Asia, TRN breast cancers oc-
cur at rates similar to those reported for Western countries [12],
and are often characterized by young age of onset and dense
breast tissues.
The incidence of breast cancer in Korea has been increasing
over time, and is characterized by a young age of onset in com-
parison to Western countries [13-15]. Molecular profiling has
revealed that Korean women are more likely to have the aggres-
sive basal cell type of breast cancer than TRN breast cancer,
which may account for worse prognoses of Korean women,
compared to young women of European descent [15,16]. How-
ever, data specifically concerning phenotypes of TRN breast
cancer in Korea are very limited. Furthermore, only a few pre-
vious reports have described the imaging features of TRN breast
cancers [17,18]. The goals of the present study were to describe
the TRN phenotypes of Korean breast cancer patients and to
evaluate high-resolution ultrasound (HR-US) imaging features
Ultrasound and Clinicopathological Characteristics of Triple Receptor-
Negative Breast Cancers
Yoon Jung Choi, Min Hyun Seong1, Seon Hyeong Choi, Shin Ho Kook, Hyon Joo Kwag, Yong Lai Park2, Chan Heun Park2
Departments of Radiology and 2Surgery, Breast and Thyroid Cancer Center, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine,
Seoul; 1Department of Radiology, Dream Hospital, Daegu, Korea
ORIGINAL ARTICLE
J Breast Cancer 2011 June; 14(2): 119-123 DOI: 10.4048/jbc.2011.14.2.119
Purpose: Triple receptor-negative (TRN) breast cancer is associ-
ated with high risk of recurrence and poor prognosis. The pre-
sent study assessed the clinicopathologic characteristics and ul-
trasound (US) features of TRN breast cancers. Methods: Pathol-
ogical and biological data were reviewed for 558 breast cancer
patients treated at Kangbuk Samsung Hospital, between Janu-
ary 2003 and December 2009. The patients were separated into
TRN breast cancer and non-TRN breast cancer groups, based
on the results of immunohistochemical prognostic panels. Clini-
cal and pathologic features were compared for the two groups.
US features, including shape, orientation, margins, boundaries,
echo patterns, posterior acoustic features, surrounding tissues,
and microcalcifications, were determined for 41 TRN patients and
189 non-TRN controls (ER+/PR+/HER2-). Results: Of 558 cases,
58 (10.4%) had the TRN phenotype. Four hundred and thirty-four
cases (77.8%) were invasive ductal carcinomas. TRN cancer was
significantly associated with specific characteristics of tumor size,
nuclear grade, histologic grade, venous invasion, and lymphatic
invasion. With respect to US features, TRN cancers were more
likely to have an oval shape, a circumscribed margin, and marked
hypoechogenicity. Conclusion: Tumor characteristics were differ-
ent between TRN and non-TRN breast cancers, although US can-
not differentiate the subtype of breast cancers TRN cancer tend
to show somewhat different US morphology.
Key Words: Breast neoplasms, Hormone receptor, Pathology, Ultrasouography
Correspondence: Yoon Jung Choi
Department of Radiology, Breast and Thyroid Cancer Center, Kangbuk
Samsung Hospital, Sungkyunkwan University School of Medicine, 108
Pyeong-dong, Jongno-gu, Seoul 110-746, Korea
Tel: +82-2-2001-2438, Fax: +82-2-2001-1736
E-mail: yoonchoi99@gmail.com
Received: October 28, 2010 Accepted: February 21, 2011
Journal of
Breast
Cancer

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? Yoon?Jung?Choi,?et?al.
http://ejbc.kr DOI: 10.4048/jbc.2011.14.2.119
that could be used to discriminate TRN breast cancers from
non-TRN breast cancers.
METHODS
Patient selection
This retrospective study consisted of 622 consecutive patients
who had surgery for breast cancer at Kangbuk Samsung Hos-
pital between March 2003 and December 2009, 467 underwent
modified radical mastectomy (MRM), 65 underwent either
partial mastectomy or quadrantectomy, and 26 underwent
lumpectomy (BCS) or wide excision. Of the 622 total patients,
485 underwent axillary dissection, and 73 underwent sentinel
lymph node dissections. Of the total patients, 558 underwent
HR-US breast examination within one month prior to surgery.
Ten patients that presented with bilateral breast cancer (n = 10),
and 54 who had not undergone preoperative assessment or
immunohistochemical tests for ER, PR, HER2, were excluded
from the image evaluations. The age range of the 588 patients
was 24-88 years, and the mean age was 49.8 years. Patients who
were examined from screening center were not included in this
study.
Clinical pathology
All TRN and non-TRN patients were examined for the type
of pathology, tumor size, nuclear grade, histologic grade, venous
invasion, lymphatic invasion, lymph node metastasis, associ-
ated ductal carcinomas in situ (DCIS), distant metastasis state,
and recurrence. The tumor grades of invasive carcinomas were
classified as grade 1 (low), grade 2 (moderate), or grade 3 (high)
based on the frequency of cell mitosis, tubule formation, and
nuclear pleomorphism. DCIS cases were divided into grade 1
(low), grade 2 (moderate), or grade 3 (high) based on nuclear
grade, architecture, and necrosis.
Immunohistochemistry and fluorescence in situ hybridiza-
tion (FISH) performed on breast tissue specimens were used
to evaluate ER, PR, and HER-2/neu status. Immunohistochem-
istry was performed for all breast carcinomas. Overexpression
of the HER-2/neu gene (HER2+) was defined as level 3 staining
intensity. Carcinomas with 0 or 1 staining intensity were con-
sidered negative for overexpression. Carcinomas with level 2
staining intensity were defined as indeterminate, and HER-2/
neu overexpression was then evaluated by FISH. Based on re-
sults of the analyses, 58 of the 558 patients (10.4%) were clas-
sified as TRN, and 500 (89.6%) were classified as non-TRN.
HR-US evaluations
HR-US features were analyzed for 41 TRN patients and 189
non-TRN patients, who were ER+/PR+/HER2-. In each case,
one of three board-certified breast radiologists, with 5-20 years
of experience in breast US, performed a preoperative HR-US
examination of the breast lesion, using an HDI 5000 unit (ATL,
Bothell, USA) or an IU-22 (Philips Medical Systems, Best, The
Netherlands) and a 12-5 MHz linear-array transducer. Imag-
ing data were analyzed retrospectively: images from more than
two different planes per lesion were saved as a bitmap file, and
a radiologist blinded to the immunophenotypes analyzed the
images according to the Breast Imaging Reporting and Data
System (BI-RADS) lexicon. Tumor shape (oval, round, irregu-
lar), orientation (parallel, not parallel), margins (circumscribed,
indistinct, angular, microlobulated, spiculated), boundaries
(abrupt interface, echogenic halo), echo patterns (hypoechoic,
complex, markedly hypoechoic), posterior acoustic features
(none, enhancement, shadowing), surrounding tissues (duct
changes, Cooper’s ligament changes or architectural distortion,
skin thickening or edema), and microcalcifications were eval-
uated.
Statistical analyses
The chi-squared test or Fisher exact test was used to compare
parameters for TRN and non-TRN patients. Student’s t-test
and Mann-Whitney U-test were used. The normal distribu-
tion of data in each group was confirmed with a Kolmogorov-
Smirnov test before the t-test was run. A two-tailed p<0.05
indicated a significant difference between groups. Data analy-
ses were performed with SPSS for Windows, version 16.0 (SPSS
Inc., Chicago, USA).
RESULTS
Of the 558 breast tumors examined, there were 434 (77.8%)
invasive ductal carcinomas, 72 DCIS, 16 mucinous carcinomas,
10 invasive lobular carcinomas, 7 microinvasive carcinomas, 3
papillary carcinomas, 3 medullary carcinomas, 3 mixed ductal
and lobular carcinomas, 2 metaplastic carcinomas, 2 tubular
carcinomas, 2 invasive cribriform carcinomas, 2 invasive mi-
cropapillary carcinomas, 1 acinic cell carcinoma, and 1 apo-
crine carcinoma.
The 58 patients in the TRN group had a mean age of 48 years
(range, 30-82 years), and the 500 patients in the non-TRN group
had a mean age of 50 years (range, 24-88 years). There was no
significant difference between the two groups in the percent-
age of patients <40 years (Table 1). Tumors <1 cm were signif-
icantly less frequent in the TRN group than in the non-TRN
group, while the opposite was true for tumors >2 cm.
Tumors with high histologic and nuclear grades were signif-
icantly more prevalent in the TRN group than in the non-TRN
group (Table 1). The frequencies of venous and lymphatic in-

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vasion were also significantly higher in TRN patients than in
non-TRN patients. However, the frequencies of a positive re-
section margin, lymph node metastasis, microcalcifications,
associated DCIS, distant metastasis, and recurrence did not
differ significantly between the two groups.
HR-US evaluations showed that TRN cancers were more like-
ly to have an oval shape or circumscribed margin, were more
markedly hypoechoic and less likely to have posterior shadow-
ing than non-TRN cancers (e.g., Table 2). The other HR-US
features did not differ significantly between the TRN and non-
TRN groups.
DISCUSSION
Results of the present study found some pathologic features
that was different between TRN from non-TRN tumors: tumor
size was significantly larger, nuclear and histologic grades were
significantly higher, venous and lymphatic invasion were sig-
nificantly more common in the TRN group than in the non-
TRN group. However, previous clinical studies found that over-
expression of the HER-2/neu gene (HER2+) is associated with
some of the same pathologic features, including large tumor
size, axillary lymph node metastasis, negative hormone recep-
Table 2. Comparison of ultrasound features of TRN and non-TRN tu-
mors
US features
TRN
(n=41)
No. (%)
Non-TRN
(n=189)
No. (%)
p-value
Shape
Oval
Round
Irregular
Orientation
Parallel
Not parallel
Margin
Circumscribed
Indistinct, angular,
microlobulated
Spiculated
Lesion boundary
Abrupt interface
Echogenic halo
Echo pattern
Hypoechoic
Complex
Markedly hypoechoic
Posterior features
No posterior
Enhancement
Shadowing
Surrounding tissue change
Negative
Duct changes
Architectural distortion,
Cooper’s ligament change
Skin thickening, edema
Microcalcification
No
Yes
Assessment category
C3 (probably benign)
C4 (suspicious)
C5 (highly suggestive)

15 (36.6)
2 (4.9)
24 (58.5)

22 (53.7)
19 (46.3)

9 (22.0)
11 (26.8)
21 (51.2)

34 (18.0)
15 (7.9)
140 (74.1)

74 (39.2)
115 (60.8)

16 (8.5)
58 (30.7)
115 (60.8)
0.030
NS
0.042

19 (46.3)
22 (53.7)

17 (41.5)
20 (48.8)
4 (9.8)

30 (73.2)
7 (17.1)
4 (9.8)

17 (41.5)
6 (14.6)
15 (36.6)

3 (7.3)

32 (78.0)
9 (22.0)

2 (4.9)
15 (36.6)
24 (58.5)

78 (41.3)
111 (58.7)

131 (69.3)
57 (30.2)
1 (0.5)

127 (67.2)
16 (8.5)
46 (24.3)

64 (33.9)
48 (25.4)
76 (40.2)

1 (0.5)

143 (75.7)
46 (24.3)

3 (1.6)
64 (33.9)
122 (64.6)
NS
NS
0.051
NS
NS
NS
TRN=triple receptor negative; US=ultrasound; NS=not significant.
Table 1. Pathologic features of TRN and non-TRN breast cancer
Parameters
TRN
(n=58)
Non-TRN
(n=500)
p-
value
No. (%)
No. of
avail-
able
cases
No. (%)
No. of
avail-
able
cases
Age (yr)
<40
≥40
Size (cm)
<1
≥1, <2
≥2, <5
≥5
Nuclear grade (n=423)*
I
II
III
Histologic grade (n=477)*
I
II
III
Resection margin
Negative
Positive
Venous invasion (n=320)*
No
Yes
Lymphatic invasion (n=369)*
No
Yes
LN metastasis
Negative
Positive
Microcalcifications (n=314)*
No
Yes
Associated DCIS
No
Yes
Distant metastasis (n=342)*
No
Yes
Recurrence (n=337)*
No
Yes

11 (19.0)
47 (81.0)

3 (5.2)
20 (34.5)
29 (50.0)
6 (10.3)

1 (2.3)
15 (34.9)
27 (62.8)

3 (5.8)
11 (21.2)
38 (73.1)

56 (96.6)
2 (3.4)

26 (78.8)
7 (21.2)

19 (48.7)
20 (51.3)

56 (11.2)
444 (88.8)

104 (20.8)
176 (35.2)
193 (38.6)
27 (5.4)

59 (15.5)
215 (56.6)
106 (27.9)

120 (28.2)
188 (44.2)
117 (27.5)

484 (96.8)
16 (3.2)

268 (93.4)
19 (6.6)

221 (67.0)
109 (33.0)
NS
0.015
43380<0.001
52425<0.001
NS
33287 0.010
393300.024
37 (63.8)
21 (36.2)

13 (50.0)
13 (50.0)

50 (86.2)
8 (13.8)
333 (66.6)
167 (33.4)

117 (40.6)
171 (59.4)

432 (86.4)
68 (13.6)

272 (90.7)
28 (9.3)

290 (97.6)
7 (2.4)
NS
26228NS
NS
37 (88.1)
5 (11.9)

39 (97.5)
1 (2.5)
42300NS
40 297NS
TRN=triple receptor negative; LN=lymph node; DCIS=ductal cancer
in situ; NS=not significant.
*Number of available cases.

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?Yoon?Jung?Choi,?et?al.
http://ejbc.kr DOI: 10.4048/jbc.2011.14.2.119
tors, and high tumor grade [6,16]. Although these characteris-
tics suggest poor prognoses, the limited data on treatment re-
sponses and survival of women with TRN breast cancer make
it difficult to conclude that the factors do contribute to lower
survival rates.
We cannot differentiate TRN breast cancers based on US
imaging but it is important that the radiologist will be aware
of such subtypes and that radiologist anticipate thorough pre-
operative examination for multifocal breast cancers, or contra-
lateral breast cancer and associated axillary lymph node me-
tastasis or distant metastasis. By comparing HR-US features in
TRN and ER+/PR+/HER2- patients, the present study found
imaging differences that may be useful for identifying TRN
breast cancers but was not specific of the subtype. In this study
we noticed that many TRN breast cancers, due to their oval
shape, circumscribed margins, and low echogenicity, the TRN
tumors resembled benign nodules more closely than the non-
TRN tumors did (Figure 1). These features of TRN tumors may
lead a radiologist to conclude that the lesion is probably be-
nign, and have the patient wait six months before a follow-up
US exam or US-guided biopsy. Furthermore, a prior study re-
ported that ER-/PR-/HER2+ breast cancers are commonly as-
sociated with some of the same features as the TRN cancers in
the present study, specifically calcifications (79%), circumscribed
margins (57%), markedly low echogenicity (57%), and lack of
posterior shadowing (5%), and are sometimes depicted as non-
mass lesions (32%) [19]. Although, a tumor with an oval shape,
a fairly well circumscribed margin, and low echogenicity could
be confused with a cystic mass, results of the present study in-
dicate that TRN breast cancer should be suspected when the
tumor has those US features and is also large, palpable, and ex-
hibits rapid growth. Biopsy should be recommended for such
nodules, even if the echogenicity is not extremely low.
Results of the present study found a high incidence of mi-
crocalcifications in TRN and non-TRN groups, both of which
were HER2-negative. However, Wang et al. [18] found that
ER-/HER2+ breast cancers were more likely to be associated
with calcifications than TRN cancers. Another previous study
found that 75% of HER2+ carcinomas were associated with cal-
cifications [16,20]. We analyzed the incidence of DCIS in the
TRN and non-TRN groups, because microcalcifications previ-
ously found in TRN patients during mammography may have
been psamomma bodies associated with DCIS. However, we
did not find a significant association between TRN and DCIS.
The present study had several limitations. First, identification
of TRN tumors was predominantly based on immunohisto-
chemical results, and FISH analysis was only used in a limited
number of cases. FISH analysis provides a more accurate deter-
mination of HER2+, due to false positives in weakly positive
immunohistochemical results [21-23]. Another limitation was
that the imaging analyses were limited to malignant nodules,
which may have influenced interpretation by the radiologists.
Third, the non-TRN group was limited to ER+/PR+/HER2-
patients, because based on our experience, most young breast
cancer patients are HER2-.
Although results of the present study indicate that it may be
possible to differentiate TRN cancers from non-TRN cancers
on the basis of specific US features, further research is needed
to confirm our findings and to provide a more reliable “alarm”
for cancers with very poor prognoses.
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