Journal of Surgical Oncology 2009;100:89–94

Characteristics and Prognosis for Molecular

Breast Cancer Subtypes in Chinese Women

JING ZHAO, MD,1,2 HONG LIU, MD, PhD,1 MENG WANG, MD,3 LIN GU, MD, PhD,1

XIAOJING GUO, MD, PhD,2 FENG GU, MD, PhD,2 AND LI FU, MD, PhD2*

1Department of Breast Cancer, Cancer Institute & Hospital, Tian Jin Medical University, Tian Jin, PR China2Department of Breast Cancer Pathology and Research Laboratory, State Key Laboratory of Breast Cancer Research,

Cancer Institute & Hospital, Tian Jin Medical University, Tian Jin, PR China3Department of Lung Cancer, Cancer Institute & Hospital, Tian Jin Medical University, Tian Jin, PR China

Background:Breast cancer is regarded as a heterogeneous disease with four molecular subtypes. However, the clinicopathological characteristics

among the different subtypes have not been studied in Chinese demographic. This study clarifies the prevalence and clinicopathological features

of each subtype and investigates the independent prognosis factors in the Chinese population.

Methods:A retrospective review of 1,820 Chinese breast cancer women were classified into different molecular subtypes based on the IHC-based

definitions for ER, PR, and HER-2/neu to evaluate the clinicopathological features and prognosis.

Results: Luminal A subtype was the most prevalent with the oldest median age at first full-term birth. The basal cell-like subtype was associated

with early onset, higher percentage of node positivity, family history of breast cancer, increased tumor size, advanced tumor grade, higher

prevalence in the premenopausal group, and the earlier age at menarche. Univariate and multivariate analysis of OS and RFS identified the basal

cell-like and HER-2/neu subtypes as negative prognostic factors. A family history was an independent predictor of shorter RFS and OS in only the

basal cell-like subtype.

Conclusions: The basal cell-like subtype is associated with a poor prognosis and a family history was a negative predictor in the basal cell-like

subtype.

J. Surg. Oncol. 2009;100:89–94. � 2009 Wiley-Liss, Inc.

KEY WORDS: molecular subtypes; risk factor; clinicopathological feature; Chinese population

INTRODUCTION

Breast cancer (BC) is a leading cause of morbidity and mortality

among female cancer patients both in China and worldwide [1]. With

the development of DNA microarray analysis for gene expression

profiling, BC is now regarded as a heterogeneous disease classified into

four molecular subtypes (luminal A, luminal B, basal cell-like, and

HER-2/neu). These four subtypes of breast tumors are characterized

by distinct clinical and pathological features and respond in an

accordingly distinct manner to chemotherapy [2–5]. When comparing

the prognosis of tumors within each of the different subtypes, it was

shown that basal cell-like or HER-2/neu tumors showed a more

aggressive clinical behavior, whereas luminal A tumors were

associated with an excellent prognosis in Western populations [6].

However, the clinical and histopathological features of BC molecular

subtypes in the Chinese population have not yet been described.

Furthermore, studies on patients with basal cell-like BCs have been

limited by small sample sizes and short follow-up times.

There are differences in BC stages, treatment, and mortality rates

around the world that are specific to race and ethnicity [7]. The

differences result from multiple factors, including socio-economical

factors, access to insurance, screening, treatments, and biological

differences between BC types. Whether or not the clinical and

histopathological features of BC molecular subtypes in the Chinese

population differed from those in Western countries is still unknown.

Further studies in the Chinese population are required.

To investigate the prevalence and clinicopathological features of

each BC subtype in the Chinese population, immunohistochemical

(IHC) stains were performed on tumor tissue to identify the molecular

subtype and clinicopathological features. Subsequent to subtype

identification, clinical behaviors were evaluated among 1,820 women

in the Chinese population. Here, the independent prognosis factor of

the basal cell-like subtype of BC was identified in the Chinese

population.

MATERIALS AND METHODS

A retrospective chart review analysis was conducted on patients

diagnosed with and surgically treated for BC at the Cancer Hospital of

Tianjin Medical University between January 2002 and June 2003.

Expression of estrogen receptor (ER), progesterone receptor (PR), and

the HER-2/neu receptor was detected by IHC. The exclusion criteria

were: patients lost to follow-up, postoperative mortality, and non-

tumor-mediated mortality. In total, 1,820 patients were identified and

contributed to this study.

Subjects

All patients underwent preoperative mammography and ultrasound

of the breast and abdomen, X-ray or computed tomography (CT) scan

of the thorax. If there were any signs of metastasis to the bone or brain,

bone scintigraphy or brain CTwas performed as a standard procedure.

Abbreviations: BC, breast cancer; IHC, immunohistochemistry; ER,estrogen receptor; PR, progesterone receptor; OS, overall survival; RFS,relapse-free survival.

*Correspondence to: Li Fu, MD, PhD, Department of Breast Cancer,Cancer Institute & Hospital, Tian Jin Medical University, Tian Jin 300060,PR China. Fax: 86-22-23537796. E-mail: ezxwm@163.com

Received 7 November 2008; Accepted 7 April 2009

DOI 10.1002/jso.21307

Published online 18 June 2009 in Wiley InterScience(www.interscience.wiley.com).

� 2009 Wiley-Liss, Inc.

If the no metastasis to the bone or brain was detected, the patients

underwent breast-conserving therapy or mastectomy.

Immunohistochemistry of ER, PR, and HER-2

IHC was performed on formalin-fixed, paraffin-embedded samples

obtained from the pathology registry. The expression of ER and PR on

tumor tissue was detected by IHC using rabbit anti-ER monoclonal

antibody (1:50 dilution; clone SP1, Zymed, San Francisco, CA)

and rabbit anti-PR monoclonal antibody (1:50 dilution; clone SP2,

Zymed). The definition of ER or PR positive was >15% positive

staining. Expression of HER2 on tumor tissues was detected by IHC

using mouse anti-c-erbB-2 monoclonal antibody (1:50 dilution; clone

CB11, Zymed) following guidance from the HecepTest. Scores of

0 and 1 were considered negative, while scores of 2 and 3 were

considered positive [8]. Detection of ER, PR, and HER2 has been

widely used in clinical study since 2001. According to the IHC-based

definitions BCs were classified into four molecular subtypes including:

luminal A (ERþ and/or PRþ, HER2�), luminal B (ERþ and/or PRþ,

HER2þ), basal cell-like (ER�, PR�, HER2�), and HER2/neu(ER�,

PR�, HER2þ) [9–11].

Treatments

All patients underwent local and/or systemic treatments. Local

treatment included surgery and radiotherapy. Systemic treatments

included chemotherapy and endocrine therapy. Surgical procedures

consisted of breast-conserving therapy and mastectomy. Breast-

conserving therapy was defined as: lumpectomy, quadrantectomy,

segmental mastectomy (partial mastectomy), and wedge resection

with radiation therapy; mastectomy was defined as: total (simple)

mastectomy and modified radical mastectomy. All patients involved in

this study were diagnosed based on either the frozen biopsy during the

operation or core-biopsy before operation. The local and systemic

treatment is compliant with the Clinical Practice Guidelines on

Oncology of National Comprehensive Cancer Network (NCCN).

Endocrine therapy was performed on ER- and PR-positive patients; as

a result, the basal cell-like and HER2/neu subtype patients did not

accept endocrine therapy.

Evaluation

BC stages were diagnosed according to the American Joint

Committee on Cancer Staging Manual (6th edition), and the data

were obtained from the medical records. Histological grade of the

tumors were classified into grades I–III according to the Nottingham

combined histological grade.

Clinicopathological features of each subtype were evaluated in the

same manner, including age at diagnosis, tumor size, lymph nodes

status, tumor stage, tumor grade, menopausal status, age at menarche,

age at first full-term birth, family history (family history of BC within

first- and second-degree relatives), and treatment (surgery, chemother-

apy, and radiation treatment). Patients were considered premenopausal

if still menstruating and postmenopausal if menstruation had stopped at

the time of interview. Survival periods were calculated from the time of

surgery. Relapse was defined as radiographic or pathological evidence

of local-regional tumor recurrence or distant metastasis at any time

after initial therapy. Primary endpoints of the study were relapse-free

survival (RFS) and overall survival (OS). Factors in the univariate and

multivariate analysis included age at diagnosis, tumor size, lymph

nodes status, tumor stage, tumor grade, menopausal status, age at

menarche, family history of BC, and treatment (surgery, chemotherapy,

and radiation treatment).

Follow-up data were collected directly from the outpatient clinic

records. All patients followed a standardized program of clinical and

instrumental examinations. Median follow-up time was 66.7 months

(range: 10–78 months).

Statistics

Differences between BC molecular subtypes with regard to

clinicopathological features were evaluated using analysis of variance,

w2 tests for the categorical variables, and one-way ANOVA for

continuous variables. Actuarial survival analysis was conducted using

the Kaplan–Meier method. The log-rank test was used to compare

mean survival among IHC subtypes. To identify independent

prognostic significance and relative risk, multivariate analysis was

performed by the Cox model and logistic regression including all

variables. P< 0.05 was considered statistically significant. All

statistical analyses were performed using SPSS software (Version

13.0 for Windows).

RESULTS

Molecular Subtypes and Profiles of Patients

Of the 1,820 patients involved in this study, 1,016 (55.8%) were of

the luminal A subtype, 240 (13.2%) were of the luminal B subtype, 336

(18.5%) were of the basal cell-like subtype, and 228 (12.5%) were of

the HER-2/neu subtype.

Patient profiles and tumor features as a function of the BC

molecular subtypes are presented in Table I. The basal cell-like subtype

was associated with early onset, higher percentage of node positivity,

family history of BC, larger tumor size, higher tumor grade, higher

prevalence in the premenopausal group, and earlier age at menarche.

The median age at first full-term birth of luminal A type BC patients

was the oldest.

Of the 1,820 cases involved in this study, 1,675(92.1%) were treated

with mastectomy and 145(7.9%) were treated with breast-conserving

therapy, 91.54% received chemotherapy and 46.48% received radio-

therapy. There was no significant difference in the treatments among

the four subtypes.

Survival of Breast Cancer Subtypes

Univariate analysis of OS and RFS identified the basal cell-like

and HER-2/neu subtypes as negative prognostic factors. The 5-year

actuarial OS of luminal A, luminal B, basal cell-like, and HER-2/neu

subtype were 94.69%, 93.33%, 86.90% and 85.09%, respectively

(Fig. 1). The 5-year actuarial RFS of luminal A, luminal B, basal cell-

like, and HER-2/neu subtype were 89.37%, 86.67%, 71.43%, and

72.81% respectively (Fig. 2). Using the Cox multivariate analysis, BC

subtypes were demonstrated to be independent risk factors for OS and

RFS (Table II).

Prognostic Factors of the Basal Cell-Like and the Non-

Basal Cell-Like Breast Cancer Subtypes

Using the Cox multivariate analysis, AJCC tumor stage, tumor size,

nodal status, family history, and age at menarche were identified to be

independent risk factors for OS in the basal cell-like subtype BC, while

menopausal status and tumor grade did not affect OS. For non-basal

cell-like BC subtypes, AJCC tumor stage, tumor size, nodal status,

tumor grade, menopausal status, and age at menarche were proved to

be independent risk factors for OS, while family history did not affect

OS (Table III). Using the Cox multivariate analysis, AJCC tumor stage,

tumor size, nodal status, family history, tumor grade, menopausal

status, and age at menarche were shown to be independent risk factors

for RFS in the basal cell-like BC subtype. In non-basal cell-like

subtypes AJCC tumor stage, tumor size, nodal status, tumor grade,

Journal of Surgical Oncology

90 Zhao et al.

menopausal status, and age at menarche were shown to be independent

risk factors for RFS, while family history did not affect RFS (Table III).

The types of treatment did not affect OS or RFS in either the basal

cell-like or non-basal cell-like BC subtypes (Table III).

DISCUSSION

BC is a major cause of morbidity and mortality worldwide. For

many years, different classifications of the disease (anatomoclinical,

pathological, prognostic, genetic) have been used to guide patient

management. Most classifications are based on clinical and patholo-

gical factors, which unfortunately fail to reflect the whole clinical

heterogeneity of breast tumors. Consequently, distinct molecular

diseases are grouped in similar clinical classes and selection of the

most appropriate diagnostic or therapeutic strategy for each patient

cannot be performed accurately. In fact, BC is a complex,

heterogeneous disease at the molecular level, which displays strikingly

distinct clinical characteristics in different ethnic populations [12].

Individual breast tumors exhibit a wide array of clinical presentation,

aggressiveness, and response to treatments [13]. Therefore, an accurate

classification of BC which can reveal its heterogeneity and biological

behavior would play a key role in diagnosis and treatment. Current

Journal of Surgical Oncology

TABLE I. Patient and Tumor Characteristics as a Function of Molecular Breast Cancer Subtypes

Characteristics

HER-2/neu

(n¼ 228)

Basal cell-like

(n¼ 336)

Luminal B

(n¼ 240)

Luminal A

(n¼ 1,016) P-valuesa

Age, mean, years (SD) 52.3 (10.1) 51.8 (10.9) 52.8 (10.7) 53.7 (10.6) <0.001

Age at menarche, mean, years (SD) 14.5 (1.2) 13.7 (1.0) 14.2 (1.5) 14.4 (1.2) <0.001

Age at first full-term birth, mean, years (SD) 25.0 (3.2) 25.8 (3.2) 26.5 (2.6) 27.0 (3.9) <0.001

Tumor size, cm (SD) 3.9 (2.2) 3.9 (2.5) 3.5 (1.7) 3.3 (1.4) <0.001

Tumor stage, n (%) 0.08

AJCC stage 0/I/II 190 (83.3) 268 (79.8) 206 (85.8) 868 (85.4)

AJCC stage III 38 (16.7) 68 (20.2) 34 (14.2) 148 (14.6)

Nodal status, n (%) 0.006

Positive 100 (43.9) 166 (49.4) 102 (42.5) 394 (38.8)

Negative 128 (56.1) 170 (50.6) 138 (57.5) 622 (61.2)

Tumor grade, n (%) <0.0001

Grade I/II 132 (57.9) 142 (42.3) 158 (65.8) 712 (70.1)

Grade III 96 (42.1) 194 (57.7) 82 (34.2) 304 (29.9)

Menopausal status, n (%) 0.006

Postmenopausal 118 (51.8) 140 (41.7) 128 (53.3) 528 (52.0)

Premenopausal 110 (48.2) 196 (58.3) 112 (46.7) 488 (48.0)

Family history, n (%) <0.0001

Yes 14 (6.1) 36 (10.7) 8 (3.3) 45 (4.4)

No 214 (93.9) 300 (89.3) 232 (96.7) 971 (95.6)

Type of surgery, n (%) 0.88

BCS 16 (7.0) 25 (7.4) 19 (7.9) 85 (8.4)

Mastectomy 212 (93.0) 311 (92.6) 221 (92.1) 931 (91.6)

Chemotherapy, n (%) 0.79

Yes 210 (92.1) 308 (91.7) 223 (92.9) 925 (91.1)

No 18 (7.9) 28 (8.3) 17 (7.1) 91 (8.9)

Radiotherapy, n (%) 0.26

Yes 109 (47.8) 171 (50.9) 111 (46.2) 455 (44.8)

No 119 (52.2) 165 (49.1) 129 (53.8) 561 (55.2)

BCS, breast-conserving surgery.aP-values were calculated to compare the four tumor subgroups.

Fig. 1. Relapse-free survival of the patients in four breast cancermolecular subtypes. Kaplan–Meier actuarial relapse-free survival wascalculated after surgery.

Fig. 2. Overall survival of patients in four breast cancer molecularsubtypes.

Molecular Subtype Profiles of BC in China 91

advances in human genome research and high-throughput technologies

have allowed for insights into the molecular complexity of cancers.

With the DNA microarrays techniques, comprehensive gene expres-

sion profiles show a great transcriptional heterogeneity in mammary

tumors and revealed new tumor groups. These technologies have been

used to develop intrinsic gene sets to classify BCs into four molecular

subtypes with distinct prognoses and responses to treatment [2–4]

(including luminal A, luminal B, basal cell-like, and HER2/neu

subtypes).

The molecular subtypes have also been recognized at the protein

level, using IHC on tissue microarrays or other methods. Carey et al.

[6] have recently reported the population-based prevalence of intrinsic

subtypes of breast tumors. They refined an IHC-based assay to identify

subtypes instead of using gene expression profiling. This IHC-based

assay has been verified against gene expression profiles to estimate the

prevalence of intrinsic subtypes [14]. Thus, in our study, four intrinsic

subtypes were identified by the IHC-based assay to reveal the

clinicopathological characteristics and prognosis in Chinese women.

Journal of Surgical Oncology

TABLE II. Statistical Analysis for Risk Factor of OS and RFS

Variables

Overall survival Relapse-free survival

HR 95% CI P-valuesa HR 95% CI P-valuesa

AJCC tumor stage

Stage 0/I/II vs. III 0.15 0.142–0.158 <0.0001 0.22 0.214–0.229 <0.0001

Tumor size

�2 cm vs. >2 cm 0.28 0.239–0.319 <0.0001 0.18 0.159–0.197 <0.0001

Nodal status

Negative vs. positive 0.62 0.575–0.660 <0.0001 0.61 0.578–0.635 <0.0001

Tumor grade

Grade I/II vs. grade III 0.15 0.138–0.163 <0.0001 0.20 0.189–0.209 <0.0001

Type of surgery

BCS vs. mastectomy 0.78 0.45

Chemotherapy

Yes vs. no 0.15 0.60

Radiotherapy

Yes vs. no 0.45 0.21

Molecular subtypes

Luminal Ab

Luminal B 1.49 1.383–1.605 <0.0001 1.55 1.464–1.632 <0.0001

Basal cell-like 1.53 1.448–1.620 <0.0001 2.16 2.074–2.241 <0.0001

HER-2/neu 3.21 3.017–3.405 <0.0001 3.46 3.314–3.614 <0.0001

aP-values were calculated to compare the two tumor subgroups.bReferent group.

TABLE III. Statistical Analysis for Risk Factors of OS and RFS in the Basal-Cell-Like and Non-Basal-Cell-Like Type Breast Cancer

Variables

Risk factors of overall survival Risk factors of relapse-free survival

Basal-cell like Non-basal-cell like Basal-cell like Non-basal-cell like

HR 95% CI P-valuea HR 95% CI P-valuea HR 95% CI P-valuea HR 95% CI P-valuea

AJCC tumor stage

(stage 0/I/II vs. III)

0.08 0.072–0.091 <0.0001 0.24 0.225–0.254 <0.0001 0.22 0.201–0.230 <0.0001 0.25 0.241–0.263 <0.0001

Nodal status (negative

vs. positive)

0.08 0.068–0.093 <0.0001 0.58 0.533–0.624 <0.0001 0.53 0.468–0.589 <0.0001 0.69 0.649–0.725 <0.0001

Tumor grade

(grade I/II vs. III)

0.300 0.18 0.166–0.199 <0.0001 0.17 0.150–0.203 <0.0001 0.23 0.214–0.240 <0.0001

Tumor size

(�2 cm vs. >2 cm)

0.57 0.523–0.612 <0.0001 0.17 0.142–0.203 <0.0001 0.26 0.245–0.287 <0.0001 0.16 0.151–0.170 <0.0001

Family history

(no vs. yes)

0.18 0.166–0.199 <0.0001 1.07 0.947–1.204 0.282 0.23 0.210–0.243 <0.0001 1.09 0.995–1.193 0.065

Menopausal status

(premenopausal vs.

postmenopausal)

0.261 0.26 0.237–0.276 <0.0001 0.63 0.589–0.682 <0.0001 0.39 0.369–0.405 <0.0001

Age at menarche

(<14 vs. �14)

2.84 2.576–3.135 <0.0001 1.22 1.159–1.288 <0.0001 1.54 1.442–1.640 <0.0001 1.05 1.010–1.091 0.013

Type of surgery (BCS

vs. mastectomy)

0.68 0.78 0.42 0.45

Chemotherapy

(yes vs. no)

0.11 0.10 0.62 0.66

Radiotherapy

(yes vs. no)

0.39 0.45 0.18 0.21

aP-values were calculated to compare the two tumor subgroups.

92 Zhao et al.

To date, a limited number of studies have investigated the pre-

valence of intrinsic subtypes via racial demographic. The prevalence of

basal cell-like tumors was 22% in the Carolina Breast Cancer Study

[6], 16% in a large series of patients in the UK [15], 26% in

conservatively managed patients in the USA [16], 31% in consecutive

patients in Korea [17], and only 10% in Japan [18]. In our study, we

provided an estimates of the prevalence of ‘‘intrinsic’’ BC in China.

Compared to other countries, the basal cell-like tumor subtype

prevalence was 18.5% in China. Differences in genetic influences or

lifestyle may explain the prevalence of intrinsic subtypes among

different races [19], and socioeconomic status is also strongly

associated with incidence. This combinatorial origin, the heterogeneity

of malignant cells, and the variability of the host background create

distinct molecular subgroups of tumors. However, the investigation of

causative factors leading to differences in the prevalence of intrinsic

subtypes in different demographics remains to be further investigated.

Meanwhile, when comparing the prevalence of molecular subtypes

across patient populations, it is important to take into account the

laboratory methods and the definitions that are employed, as well as

patient demographics and risk factor profiles that may affect the

distribution of different molecular subtypes of BC. Our study shows

that the basal cell-like subtype is associated with larger tumor size,

higher histological grade, higher prevalence of node positivity, and

higher prevalence among premenopausal, associations that have been

noted by other studies [3,4,6,14,20,21].

Our results are consistent with previous studies that reported an

association between the expression of basal cell-like or HER-2/neu

markers and shorter OS and RFS in the whole series [22,23]. Rolland

et al. [24] showed that tumors expressed the phenotype P53(þ),

Bcl-2(�) were associated with younger patients, larger tumors, more

advanced lymph node stage, higher grade and a marked reduction in

survival. Another study [25] showed high correlations between co-

expression of p53 and under-expression of Bcl-2 in basal cell-like and

HER-2/neu subtypes, which may partially explain the aggressive

behavior and poor prognosis of the basal cell-like and HER-2/neu

subtypes.

To date, no large epidemiological studies have been performed to

identify risk factors for the intrinsic BC subtypes. Such studies could

provide important information for identifying and reducing the

behavioral risk factors in different types of BCs. Our data demonstrate

that the basal cell-like subtype is associated with younger age at

diagnosis, earlier age at menarche, and first full-term birth. Usually, an

early first full-term birth is a preventative factor in BC; unfortunately, it

had no effect on basal cell-like type BC. This is the first report that a

family history of BC is statistically associated with risk for the basal

cell-like subtype of BC in the Chinese population. A family history of

BC remains a significant independent predictor of a shorter RFS and

OS in only the basal cell-like subtype, but not in non-basal cell-like

subtypes. It has been reported that a younger age at diagnosis for basal-

like tumors is associated with germ line BRCA1/2 mutations [4,26–

29], and the prognosis of this type of BC with a family history is

increasingly poor. In summary, these findings imply a firm link

between genetics and the etiology of these tumors.

Lastly, our data show treatment types did not affect OS or RFS in

the basal cell-like or non-basal cell-like BC subtypes, which are

consistent with other studies [30,31]. In our study, the selection of all

patients’ treatment types are based on the tumor size, tumor stage, and

node status, and these variables were the independent prognostic

factors for RFS or OS. Therefore, treatment types directly based on

these prognostic factors (tumor size, tumor stage, and node status)

could not be independent prognostic factors themselves for RFS or OS

in the basal cell-like or non-basal cell-like BC subtypes.

In conclusion, our study demonstrates that BC molecular subtypes

can provide additional prognostic information on BC. Family history is

a predictor of a poor prognosis only in the case of the basal cell-like

subtype. With our findings, a specific subgroup of patients can be

identified for a more aggressive approach to adjuvant therapy. Further

studies to investigate the effects of cancer therapy on survival outcome

among different molecular subtypes are required. It is also essential to

perform prospective studies of long-term survival among patients with

specific BC molecular subtypes.

ACKNOWLEDGMENTS

We thank Dr. Hong Yang and Mr. Christopher Spring for their kind

help in editing this manuscript. We also thank for the Division of the

medical record, Cancer Institute & Hospital, Tian Jin Medical

University for all technical supports of the project.

This work supported by program for Changjiang Scholors and

Innovative Research Team in University (IRT 0743), National ‘‘863’’

Program of China (2006AA02A249).

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