Translational Cancer Mechanisms and Therapy Clinical

Cancer
Research
Impact of Breast Cancer Subtypes on Prognosis
of Women with Operable Invasive Breast Cancer:
A Population-based Study Using SEER Database
Ki-Tae Hwang1, Jongjin Kim1, Jiwoong Jung2, Ji Hyun Chang3, Young Jun Chai1,
So Won Oh4, Sohee Oh5, Young A. Kim6, Sung Bae Park7, and Kyu Ri Hwang8

Abstract
Purpose: To determine the prognostic roles of breast cancer (83.9% and 76.5%, respectively). HRc()/HER2() showed
subtypes in females with operable invasive breast cancer. the worst BCSS irrespective of race, age, or stage. Although

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Experimental Design: Data of 321,958 patients from proportions of HRc()/HER2() in the subgroup with negative
Surveillance, Epidemiology, and End Results (SEER) database event regarding BCSS and OS were 10.4% and 10.2%, respec-
were analyzed. Breast cancer subtypes were classified into four tively, they were 34.2% and 22.7%, respectively, in the subgroup
categories according to the status of hormone receptor (HRc) with positive event. Subtype was a significant factor in both
and HER2: HRc(þ)/HER2(), HRc(þ)/HER2(þ), HRc()/ univariable and multivariable analyses regarding both BCSS
HER2(þ), and HRc()/HER2(). and OS (all P < 0.001).
Results: Proportions of HRc(þ)/HER2(), HRc(þ)/HER2(þ), Conclusions: Breast cancer subtype was a significant inde-
HRc()/HER2(þ), HRc()/HER2(), and unknown subtype pendent prognostic factor regarding both BCSS and OS in
were 70.3%, 9.4%, 3.9%, 10.4%, and 6.0%, respectively. HRc multivariable analyses. HRc(þ) subtypes showed better prog-
(þ)/HER2() showed the highest 5-year breast cancer–specific nosis compared with HRc() subtypes regarding both BCSS
survival (BCSS) rate (95.5%), followed by HRc(þ)/HER2(þ) and OS. HRc()/HER2(þ) showed better prognosis than
(94.1%), HRc()/HER2(þ) (89.3%), and HRc()/HER2() HRc()/HER2() but worse prognosis than HRc(þ) subtypes
(83.1%). HRc(þ)/HER2() and HRc(þ)/HER2(þ) showed regarding both BCSS and OS. The triple-negative subtype
higher 5-year overall survival (OS) rates (88.4% and 88.2%, showed the worst BCSS compared with the other subtypes
respectively) than HRc()/HER2(þ) and HRc()/HER2() irrespective of race, age, or stage.

Introduction mated incidence cases of female breast cancer were 1.68 million
(95% uncertainty intervals, 1.61–1.78 million) and 535,000
Breast cancer is the most common female cancer and the
(95% uncertainty intervals, 506,000–573,000) deaths were
leading cause of female cancer-related deaths. In 2016, the esti-
caused by female breast cancer (1). The TNM staging system
developed by the American Joint Committee on Cancer (AJCC)
1 has become the global standard in prognosis prediction of various
Department of Surgery, Seoul Metropolitan Government Seoul National Uni-
versity Boramae Medical Center, Seoul, Republic of Korea. 2Department of
cancers including breast cancer. Since Perou and colleagues shed
Surgery, Seoul Medical Center, Seoul, Republic of Korea. 3Department of light on the existence of intrinsic subtypes in breast cancer
Radiation Oncology, Seoul Metropolitan Government Seoul National University according to the expression microarray patterns in 1999 and
Boramae Medical Center, Seoul, Republic of Korea. 4Department of Nuclear 2000 (2, 3), subsequent studies have reported the clinical impor-
Medicine, Seoul Metropolitan Government Seoul National University Boramae tance of breast cancer subtypes (4–6). The St. Gallen guideline
Medical Center, Seoul, Republic of Korea. 5Department of Biostatistics, Seoul
partially incorporated the concept of intrinsic subtypes into
Metropolitan Government Seoul National University Boramae Medical Center,
Seoul, Republic of Korea. 6Department of Pathology, Seoul Metropolitan
clinical guidelines (7–9). The National Comprehensive Cancer
Government Seoul National University Boramae Medical Center, Seoul, Republic Network guideline (https://www.nccn.org/) classifies breast can-
of Korea. 7Department of Neurosurgery, Seoul Metropolitan Government cer subtypes into the following four categories according to the
Seoul National University Boramae Medical Center, Seoul, Republic of Korea. status of hormone receptor (HRc) and HER2: HRc(þ)/HER2(),
8
Department of Obstetrics and Gynecology, Seoul Metropolitan Government HRc(þ)/HER2(þ), HRc()/HER2(þ), and HRc()/HER2().
Seoul National University Boramae Medical Center, Seoul, Republic of Korea.
This four-subtype classification is practically crucial to decide
Note: Supplementary data for this article are available at Clinical Cancer systemic treatment plans for patients with breast cancer. The
Research Online (http://clincancerres.aacrjournals.org/). proportion of each breast cancer subtype has been reported in
The institutional review boards approved this study (Seoul Metropolitan Gov- previous studies. We reviewed five main previous studies, and the
ernment Seoul National University Boramae Medical Center, 07-2018-7). proportion of each subtype in subtype-known breast cancer was
Corresponding Author: Ki-Tae Hwang, Department of Surgery, Seoul Metro- 66.3% (range, 54.8%–72.9%), 12.6% (range, 5.9%–16.6%),
politan Government Seoul National University Boramae Medical Center, 425, 6.2% (range, 4.7%–7.2%), and 15.0% (range, 11.4%–21.5%)
Shindaebang-2-dong, Dongjak-gu, Seoul 156-707, Republic of Korea. for HRc(þ)/HER2(), HRc(þ)/HER2(þ), HRc()/HER2(þ),
Phone: 822-870-2275; Fax: 822-831-2826; E-mail: [email protected]
and HRc()/HER2(), respectively (10–14). Although various
doi: 10.1158/1078-0432.CCR-18-2782 factors could cause variation in the proportion rate of each
2018 American Association for Cancer Research. subtype, main causality might be explained by methodologic

1970 Clin Cancer Res; 25(6) March 15, 2019

 Breast Cancer Subtype and Prognosis

the objective of this study was to perform holistic analyses on

Translational Relevance prognostic roles of four breast cancer subtypes in females with
This population-based study aimed to determine prognos- operable invasive breast cancer using population-based SEER
tic roles of breast cancer subtypes in women with operable database. We also analyzed survivals and proportions of each
invasive breast cancer. This study analyzed data of 321,958 subtype in various subgroups according to race, age, stage,
patients with breast cancer from Surveillance, Epidemiology, and more.
and End Results (SEER) database and found that breast cancer
subtype was a significant independent prognostic factor in
breast cancer. Hormone receptor (HRc)-positive subtypes Materials and Methods
showed better prognosis compared with HRc -negative sub- Study subjects
types. HRc -positive and HER2-negative subtype showed better The total number of subjects who had been diagnosed as breast
prognosis than HRc -negative and HER2-negative subtype but cancer and registered in SEER incidence data (1973–2015) was
worse prognosis than HRc-positive subtypes. The triple- 1,631,572. Of these subjects, females with operable invasive
negative subtype showed the worst prognosis compared with breast cancer who had information of breast cancer subtype were
other subtypes irrespective of race, age, or stage. Breast cancer target subjects of this study. Male patients with breast cancer
subtypes are important prognostic factors in women with (N ¼ 10,848) were excluded. Patients without information of
operable breast cancer, and triple-negative breast cancer subtype (N ¼ 1,151,840), patients with carcinoma in situ

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shows the worst prognosis of all subtypes. Clinicians should (N ¼ 94,209) or initial stage IV (N ¼ 20,691), and patients with
consider breast cancer subtypes carefully in clinical setting unknown stage (N ¼ 15,591) were also excluded in sequence.
and further studies are needed to identify long term prog- After further exclusion of patients without surgery or unknown
nostic impact of each subtype on breast cancer. about surgery status (N ¼ 16,435), the final number of subjects
was 321,958 (Supplementary Fig. S1). As SEER database has
provided information of breast cancer subtype since 2010, all
subjects were enrolled between 2010 and 2015.
variation for the diagnosis of HR and HER2, demographic vari- SEER collects cancer incidence data from population-based
ation of enrolled subjects, and chronologic changes regarding cancer registries covering approximately 34.6% of the U.S. pop-
breast cancer screening, diagnosis, and treatment. ulation. The SEER registries collect data on patient demographics,
The prognostic influence of these four subtypes on breast primary tumor site, tumor morphology, stage at diagnosis, and
cancer has been occasionally reported by researchers, showing first course of treatment, and they follow up with patients for vital
that HRc(þ)/HER2() subtype has the best prognosis, whereas status. This database collects data from Atlanta, Connecticut,
HRc()/HER2(þ) and HRc()/HER2() subtypes has adverse Detroit, Hawaii, Iowa, New Mexico, San Francisco–Oakland,
prognoses compared with other subtypes (10–14). Previous Seattle–Puget Sound, Utah, San Jose–Monterey, Los Angeles,
studies have also reported that HRc(þ)/HER2() subtype repre- Rural Georgia, Alaska Natives, Greater California, Kentucky,
sents the majority of breast cancer cases, and HRc()/HER2() Louisiana, New Jersey, and greater Georgia (https://seer.cancer.
subtype, also known as triple-negative breast cancer, has unfavor- gov/).
able clinicopathologic features and poor prognosis (10, 15–18).
Regarding breast cancer, the prognostic roles of HRc and HER2 Clinicopathologic parameters
have been widely acknowledged. As a result, HRc and HER2 were T category, N category, and anatomic stage group were
finally incorporated into main factors to determine prognostic described according to the seventh edition of the AJCC. Status
stage groups as well as TNM classification and histologic grade in of estrogen receptor (ER) or progesterone receptor (PR) was
eighth edition of the AJCC Cancer Staging Manual (19). Although defined based on result of IHC test (20). HRc status was de-
prognostic roles of these four breast cancer subtypes have been fined as positive when IHC test for either ER or PR was
partly unveiled in previous studies, most previous studies positive. HRc was defined as negative when both ER and PR
enrolled relatively small numbers of subjects from a single insti- were negative. HER2 status was defined as positive or negative
tute, making it difficult to extrapolate their results to the general according to the algorithm used for deriving HER2 summary
population. Although there have been significant chronologic variable based on the results of IHC test and in situ hybridiza-
changes in standard treatment modalities for patients with breast tion tests (21). Race was classified into three groups: Caucasian,
cancer, results of some previous studies could not reflect recent African-American, and other races including American
changes of treatment modalities. For example, adjuvant HER2- Indian/Alaska Native and Asian/Pacific Islander. Age was clas-
targeted therapy was introduced in practice since the second half sified into three groups: age 50 years, 50 < age  65 years, and
of the period between 2001 and 2010. Some studies that enrolled age >65 years. Breast cancer subtypes were classified into four
subjects before that period could not adequately reflect treatment groups: HRc(þ)/HER2(), HRc(þ)/HER2(þ), HRc()/HER2(þ),
impact of HER2-targeted therapy. Some previous studies had and HRc()/HER2(þ).
relatively short follow-up periods with only short-term results of All data and parameters were utilized from SEER Program
survival analyses (14). Research Data (1973–2015), NCI, Division of Cancer Control
Recently, the Surveillance, Epidemiology, and End Results and Population Sciences, Surveillance Research Program, released
(SEER) program released SEER incidence data (1973–2015) April 2018, based on the November 2017 submission.
including data of more than 1.6 million breast cancer cases
(https://seer.cancer.gov/). As SEER program has provided infor- Statistical analyses
mation for HER2 status and breast cancer subtype since 2010, Pearson x2 test was used to determine statistical differences
the maximal follow-up period could reach almost 6 years. Thus, in clinicopathologic parameters between groups. Survival

www.aacrjournals.org Clin Cancer Res; 25(6) March 15, 2019 1971

 Hwang et al.

analyses were carried out with respect to breast cancer–specific All tests were two-sided. Statistical significance was considered
survival (BCSS) and overall survival (OS). Time duration of when P value was less than 0.05.
BCSS was calculated as the time from initial diagnosis of
primary breast cancer to death from breast cancer. Time dura-
tion of OS was calculated as the time from initial diagnosis of Results
primary breast cancer to death from any cause. The event of Clinicopathologic characteristics of study subjects
each subject regarding both BCSS and OS was defined as yes, The total number of subjects was 321,958. Their mean age was
when the subject was dead or no, when the subject was alive at 61.4  13.3 years (median, 62.0 years). The mean follow-up
the time of the last follow-up. Kaplan–Meier estimator was period was 32.0  20.5 months (median, 31.0 months; range,
used to analyze survival rates whereas log-rank test was used to 0–71 months). Total numbers of deaths from breast cancer and
determine the significance of differences between two or more any cause during this period were 8,320 (2.6%) and 22,100
survival curves. Cox proportional hazards model was used for (6.9%), respectively. Clinicopathologic characteristics of study
univariable and multivariable analyses. HR and 95% confi- subjects are summarized in Table 1. Numbers of subjects with
dence interval (CI) were calculated. All statistical analyses were HRc(þ)/HER2(), HRc(þ)/HER2(þ), HRc()/HER2(þ), HRc()/
carried out using IBM SPSS Statistics, version 20.0 (IBM Corp.). HER2(), and unknown subtype were 226,326 (70.3%),

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Table 1. Clinicopathologic characteristics of subjects according to breast cancer subtypes
Subtypes
HRc(þ)/HER2() HRc(þ)/HER2(þ) HRc()/HER2(þ) HRc()/HER2() Unknown Total
Characteristics No. (%) No. (%) No. (%) No. (%) No. (%) P No. (%)
All 226,326 (70.3%) 30,295 (9.4%) 12,592 (3.9%) 33,497 (10.4%) 19,248 (6.0%) 321,958 (100%)
Mean age (years) 62.4  13.0 58.0  13.5 58.2  13.1 59.0  13.9 62.2  13.6 61.4  13.3
T category <0.001
T1 152,442 (67.4%) 16,263 (53.7%) 6,124 (48.7%) 15,779 (47.2%) 12,936 (67.4%) 203,544 (63.3%)
T2 59,760 (26.4%) 10,915 (36.1%) 4,604 (36.6%) 13,735 (41.1%) 4,727 (24.6%) 93,741 (29.1%)
T3 10,557 (4.7%) 2,023 (6.7%) 1,078 (8.6%) 2,559 (7.7%) 1,046 (5.4%) 17,263 (5.4%)
T4 3,437 (1.5%) 1,071 (3.5%) 767 (6.1%) 1,374 (4.1%) 490 (2.6%) 7,139 (2.2%)
N category <0.001
N0 165,465 (73.1%) 19,144 (63.2%) 7,523 (59.8%) 23,016 (68.7%) 14,950 (77.8%) 230,098 (71.5%)
N1 45,790 (20.2%) 8,035 (26.5%) 3,452 (27.4%) 7,274 (21.7%) 3,175 (16.5%) 67,726 (21.0%)
N2 9,974 (4.4%) 2,017 (6.7%) 922 (7.3%) 1,917 (5.7%) 738 (3.8%) 15,568 (4.8%)
N3 5,031 (2.2%) 1,090 (3.6%) 692 (5.5%) 1,271 (3.8%) 354 (1.8%) 8,438 (2.6%)
Anatomic stage group <0.001
Stage I 134,608 (59.5%) 13,513 (44.6%) 4,991 (39.6%) 13,505 (40.3%) 11,791 (61.3%) 178,408 (55.4%)
Stage II 70,592 (31.2%) 12,132 (40.0%) 5,032 (40.0%) 15,039 (44.9%) 5,746 (29.9%) 108,541 (33.7%)
Stage IIII 21,126 (9.3%) 4,650 (15.3%) 2,569 (20.4%) 4,953 (14.8%) 1,711 (8.9%) 35,009 (10.9%)
ER <0.001
Negative 2,126 (0.9%) 831 (2.7%) 12,592 (100.0%) 33,497 (100.0%) 2,068 (15.8%) 51,114 (16.2%)
Positive 224,102 (99.1%) 29,423 (97.3%) 0 (0.0%) 0 (0.0%) 11,054 (84.2%) 264,579 (83.8%)
PR <0.001
Negative 26,298 (11.7%) 7,901 (26.2%) 12,592 (100.0%) 33,497 (100.0%) 3,493 (27.4%) 83,781 (26.6%)
Positive 199,225 (88.3%) 22,272 (73.8%) 0 (0.0%) 0 (0.0%) 9,275 (72.6%) 230,772 (73.4%)
HER2 <0.001
Negative 226,326 (100.0%) 0 (0.0%) 0 (0.0%) 33,497 (100.0%) 337 (81.0%) 260,160 (85.8%)
Positive 0 (0.0%) 30,295 (100.0%) 12,592 (100.0%) 0 (0.0%) 79 (19.0%) 42,966 (14.2%)
Histologic grade <0.001
Well differentiated 68,178 (31.0%) 2,091 (7.2%) 206 (1.7%) 747 (2.3%) 3,871 (23.7%) 75,093 (24.2%)
Moderately differentiated 110,056 (50.0%) 12,225 (41.9%) 2,846 (23.9%) 5,826 (18.0%) 7,114 (43.5%) 138,067 (44.5%)
Poorly differentiated 41,652 (18.9%) 14,721 (50.5%) 8,737 (73.5%) 25,556 (78.9%) 5,148 (31.5%) 95,814 (30.9%)
Undifferentiated 315 (0.1%) 108 (0.4%) 99 (0.8%) 245 (0.8%) 214 (1.3%) 981 (0.3%)
Race <0.001
Caucasian 184,857 (82.2%) 23,475 (78.0%) 9,167 (73.2%) 24,237 (72.7%) 15,150 (79.5%) 256,886 (80.3%)
African-American 19,997 (8.9%) 3,403 (11.3%) 1,716 (13.7%) 6,628 (19.9%) 2,089 (11.0%) 33,833 (10.6%)
Other races 20,163 (9.0%) 3,233 (10.7%) 1,635 (13.1%) 2,472 (7.4%) 1,810 (9.5%) 29,313 (9.2%)
Age group (years) <0.001
50 45,767 (20.2%) 9,265 (30.6%) 3,520 (28.0%) 9,594 (28.6%) 4,023 (20.9%) 72,169 (22.4%)
>50, 65 86,641 (38.3%) 12,291 (40.6%) 5,581 (44.3%) 13,149 (39.3%) 7,385 (38.4%) 125,047 (38.8%)
>65 93,915 (41.5%) 8,737 (28.8%) 3,490 (27.7%) 10,754 (32.1%) 7,839 (40.7%) 124,735 (38.7%)
Year of diagnosis <0.001
2010 34,393 (15.2%) 4,605 (15.2%) 1,995 (15.8%) 5,590 (16.7%) 4,143 (21.5%) 50,726 (15.8%)
2011 36,584 (16.2%) 4,613 (15.2%) 2,053 (16.3%) 5,840 (17.4%) 3,580 (18.6%) 52,670 (16.4%)
2012 37,791 (16.7%) 4,894 (16.2%) 2,062 (16.4%) 5,628 (16.8%) 3,027 (15.7%) 53,402 (16.6%)
2013 38,833 (17.2%) 5,050 (16.7%) 2,038 (16.2%) 5,462 (16.3%) 2,879 (15.0%) 54,262 (16.9%)
2014 38,897 (17.2%) 5,491 (18.1%) 2,179 (17.3%) 5,490 (16.4%) 2,894 (15.0%) 54,951 (17.1%)
2015 39,828 (17.6%) 5,642 (18.6%) 2,265 (18.0%) 5,487 (16.4%) 2,725 (14.2%) 55,947 (17.4%)

1972 Clin Cancer Res; 25(6) March 15, 2019 Clinical Cancer Research
 Breast Cancer Subtype and Prognosis

A B
1.0 1.0

0.8 0.8

0.6 HRc(+)/HER2(-) 0.6 HRc(+)/HER2(-)

BCSS
HRc(+)/HER2(+) HRc(+)/HER2(+)

OS
HRc(-)/HER2(+) HRc(-)/HER2(+)
0.4 HRc(-)/HER2(-) 0.4 HRc(-)/HER2(-)
NS between HRc(+)/HER2(-)
0.2 0.2
Figure 1. P < 0.001 among all the subtypes and HRc(+)/HER2(+)

Survival curves and subject P < 0.001 among all the others
proportions according to breast 0.0 0.0
cancer subtypes. BCSS (A) and 0 20 40 60 80 0 20 40 60 80
OS (B) according to breast cancer
Follow-up months Follow-up months
subtypes were depicted. Subject
proportions according to breast

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cancer subtypes without the
unknown subtype (C) and with
C HRc(+)/HER2(-)
D Unknown HRc(+)/HER2(-)
HRc(-)/HER2(-) N = 19,248 (6.0%)
the unknown subtype (D) were N = 226,326 (74.8%) N = 226,326 (70.3%)
N = 33,497 (11.1%)
also depicted. HRc(-)/HER2(-)
HRc(-)/HER2(+) N = 33,497 (10.4%)
N = 12,592 (4.2%)
HRc(-)/HER2(+)
N = 12,592 (3.9%)

HRc(+)/HER2(+)
N = 30,295 (10.0%)
HRc(+)/HER2(+)
N = 30,295 (9.4%)

30,295 (9.4%), 12,592 (3.9%), 33,497 (10.4%), and 19,248 there was no significant difference in BCSS rate between these
(6.0%), respectively. two subtypes. HRc()/HER2() subtype showed the worst BCSS
in these subgroups.
Survival analysis of all subjects according to breast cancer The subgroup of age between 50 and 65 years showed the
subtypes highest BCSS rate among all three age groups (Fig. 3). In subgroup
Among the four breast cancer subtypes, HRc(þ)/HER2() analysis for those with age  50 years, HRc(þ)/HER2() and
subtype showed the highest five-year BCSS rate (95.5%). HRc(þ)/HER2(þ) subtypes showed the highest BCSS rates, fol-
HRc(þ)/HER2(þ) subtype showed a higher 5-year BCSS lowed by HRc()/HER2(þ) and HRc()/HER2() subtypes in
(94.1%) than HRc()/HER2(þ) (89.3%) and HRc()/ order. In subgroup analysis for those with age between 50 and
HER2() (83.1%). HRc()/HER2() subtype showed the 65 years and those with age > 65 years, HRc(þ)/HER2() subtype
lowest BCSS (Fig. 1A). Regarding OS, HRc(þ)/HER2() and showed the highest BCSS rate, followed by HRc(þ)/HER2(þ),
HRc(þ)/HER2(þ) subtypes showed higher five-year OS rates HRc()/HER2(þ), and HRc()/HER2() subtypes in order.
(88.4% and 88.2%, respectively) than HRc()/HER2(þ) and Stage I showed the highest BCSS rate, followed by stage II and
HRc()/HER2() subtypes (83.9% and 76.5%, respectively). stage III in order (Fig. 4). In stage I, HRc(þ)/HER2() showed
There was no significant difference in OS between the two the highest BCSS rate, followed by HRc(þ)/HER2(þ), HRc()/
HRc(þ) subtypes. The triple-negative subtype showed the HER2(þ), and HRc()/HER2() subtypes in order. In stage II
lowest OS (Fig. 1B). Detailed BCSS and OS rates of each and stage III, HRc(þ)/HER2() and HRc(þ)/HER2(þ) subtypes
subtype for every 1-year interval are summarized in Supple- showed higher BCSS rates than HRc()/HER2(þ) and HRc()/
mentary Table S1. HER2() subtypes. HRc()/HER2() subtype showed the worst
BCSS in stage II and III.
Survival analysis for subgroups according to race, age, and stage
In this study, race was classified into three groups: Caucasian, Survival analysis for subgroups according to other factors
African-American, and other races. Other races showed the highest including ER, PR, HER2, T category, N category, and histologic
BCSS rate, whereas African-American showed the lowest BCSS grade
(Fig. 2). In Caucasian women, HRc(þ)/HER2() subtype showed Subgroups with ER(þ), PR(þ), and HER2() showed better
the highest BCSS rate, followed by HRc(þ)/HER2(þ), HRc()/ BCSS rates than subgroups with ER(), PR(), and HER2(þ),
HER2(þ), and HRc()/HER2() in order. In African- respectively (Supplementary Fig. S2). The proportion of HRc(þ)/
American women and other races, HRc(þ)/HER2() and HER2() was 4.3% in the subgroup with ER(), whereas
HRc(þ)/HER2(þ) subtypes showed the highest BCSS rates and it was 32.8% in the subgroup with PR(). Proportions of

www.aacrjournals.org Clin Cancer Res; 25(6) March 15, 2019 1973

 Hwang et al.

A Race groups B Caucasian C African-American D Other races

1.0 1.0 1.0 1.0

0.8 0.8 0.8 0.8

HRc(+)/HER2(-) HRc(+)/HER2(-) HRc(+)/HER2(-)
0.6 White 0.6 0.6 0.6
BCSS

BCSS
BCSS

BCSS
HRc(+)/HER2(+) HRc(+)/HER2(+) HRc(+)/HER2(+)
Black HRc(-)/HER2(+) HRc(-)/HER2(+) HRc(-)/HER2(+)
Other races HRc(-)/HER2(-) HRc(-)/HER2(-) HRc(-)/HER2(-)
0.4 0.4 0.4 0.4

P < 0.001among all race groups NS between HRc(+)/HER2(-) NS between HRc(+)/HER2(-)

0.2 0.2 P < 0.001among all the subtypes 0.2 and HRc(+)/HER2(+) 0.2 and HRc(+)/HER2(+)
P < 0.001among all the others P < 0.001among all the others
0.0 0.0 0.0 0.0
0 20 40 60 80 0 20 40 60 80 0 20 40 60 80 0 20 40 60 80
Follow-up months Follow-up months Follow-up months Follow-up months

E Race groups (N = 320,032) F Caucasian (N = 256,886) G African-American (N = 22,833) H Other races (N = 29,313)
Other races Caucasian HRc(-)/HER2(-) HRc(+)/HER2(-) HRc(+)/HER2(-) HRc(-)/HER2(-) HRc(+)/HER2(-)
N = 29,313 (9.2%) N = 256,886 (80.3%) N = 33,497 (10.0%) N = 184,857 (76.5%) N = 19,997 (63.0%) N = 2,472 (9.0%) N = 20,163 (73.3%)
HRc(-)/HER2(-)
HRc(-)/HER2(+) N = 6,628 (20.9%) HRc(-)/HER2(+)
African-American N = 12,592 (3.8%) N = 1,635 (5.9%)
N = 33,833 (10.6%)

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HRc(+)/HER2(+) HRc(-)/HER2(+)
N = 30,295 (9.7%) N = 1,716 (5.4%) HRc(+)/HER2(+)
N = 3,233 (11.8%)

HRc(+)/HER2(+)
N = 3,403 (10.7%)

Figure 2.
BCSS curves according to the race groups (A) and subject proportions of the race groups (E). Survival curves of each subtype for Caucasian (B), African-
American (C), and other races (D) and subject proportions of each subtype for Caucasian (F), African-American (G), and other races (H) were depicted.

HRc()/HER2() subtype in the subgroup with ER() and 10.2%, respectively, but they were 34.2% and 22.7%, respectively,
PR() were 68.3% and 41.7%, respectively. BCSS curves and in the subgroup with positive event (Supplementary Fig. S4).
subtype proportions in each subgroup according to T category,
N category, and histologic grade are depicted in Supplementary Univariable and multivariable analyses
Fig. S3. The proportions of HRc()/HER2() in the subgroup Regarding BCSS, all eleven clinicopathologic factors including
with negative event regarding BCSS and OS were 10.4% and subtype, T category, N category, anatomic stage group, ER, PR,

A Age groups B Age ≤ 50 years C 50 < Age ≤ 65 years D Age > 65 years
1.0 1.0 1.0 1.0

0.8 0.8 0.8 0.8

HRc(+)/HER2(-) HRc(+)/HER2(-) HRc(+)/HER2(-)
0.6 Age ≤ 50 years 0.6 0.6 0.6
BCSS

BCSS

BCSS

HRc(+)/HER2(+) HRc(+)/HER2(+)
BCSS

HRc(+)/HER2(+)
50 < Age ≤ 65 years HRc(-)/HER2(+) HRc(-)/HER2(+) HRc(-)/HER2(+)
Age > 65 years HRc(-)/HER2(-) HRc(-)/HER2(-)
0.4 0.4 0.4 HRc(-)/HER2(-) 0.4
NS between HRc(+)/HER2(-) P = 0.001 between HRc(-)/HER2(+)
0.2 P < 0.001 among all age groups 0.2 and HRc(+)/HER2(+) 0.2 P < 0.001 among all the subtypes 0.2 and HRc(-)/HER2(-)
P < 0.001 among all the others P < 0.001 among all the others
0.0 0.0 0.0 0.0
0 20 40 60 80 0 20 40 60 80 0 20 40 60 80 0 20 40 60 80
Follow-up months Follow-up months Follow-up months Follow-up months

E Age groups (N = 321,951) F Age ≤ 50 years (N = 72,169) G 50 < Age ≤ 65 years (N = 125,047) H Age > 65 years (N = 124,735)
Age ≤ 50 years HRc(+)/HER2(-) HRc(+)/HER2(-) HRc(-)/HER2(-) HRc(+)/HER2(-)
Age > 65 years N = 72,169 (22.4%) HRc(-)/HER2(-) N = 45,767 (67.2%) HRc(-)/HER2(-)
N = 86,641 (73.6%) N = 10,754 (9.2%) N = 93,915 (80.3%)
N = 124,735 (38.7%) N = 9,594 (14.1%) N = 13,149 (11.2%)
HRc(-)/HER2(+)
HRc(-)/HER2(+) N = 3,490 (3.0%)
HRc(-)/HER2(+) N = 5,581 (4.7%)
N = 3,520 (5.2%)
HRc(+)/HER2(+)
N = 8,737 (7.5%)
HRc(+)/HER2(+)
N = 12,291 (10.5%)
HRc(+)/HER2(+)
N = 9,265 (13.6%)

50 < Age ≤ 65 years

N = 125,047 (38.8%)

Figure 3.
BCSS curves according to the age groups (A) and subject proportions of the age groups (E). Survival curves of each subtype for age 50 years (B), 50 < age 
65 years (C), and age >65 years (D) and subject proportions of each subtype for age 50 years (F), 50 < age  65 years (G), and age >65 years (H) were
depicted.

1974 Clin Cancer Res; 25(6) March 15, 2019 Clinical Cancer Research
 Breast Cancer Subtype and Prognosis

A Stage groups B Stage I C Stage II D Stage III

1.0 1.0 1.0 1.0

0.8 0.8 HRc(+)/HER2(-) 0.8 0.8

HRc(+)/HER2(+) HRc(+)/HER2(-)
Stage I HRc(-)/HER2(+)
BCSS

0.6 0.6 0.6 HRc(+)/HER2(+) 0.6

BCSS

BCSS

BCSS
Stage II HRc(-)/HER2(-) HRc(-)/HER2(+) HRc(+)/HER2(-)
Stage III HRc(-)/HER2(-) HRc(+)/HER2(+)
0.4 0.4 P = 0.001 between HRc(+)/HER2(-) 0.4 0.4 HRc(-)/HER2(+)
and HRc(+)/HER2(+) NS between HRc(+)/HER2(-) HRc(-)/HER2(-)
0.2 P < 0.001 among all stage groups 0.2 P = 0.001 between HRc(+)/HER2(+) 0.2 and HRc(+)/HER2(+) 0.2 NS between HRc(+)/HER2(-)
and HRc(-)/HER2(+)
P < 0.001 among all the others and HRc(+)/HER2(+)
P< 0.001 among all the others P < 0.001 among all the others
0.0 0.0 0.0 0.0
0 20 40 60 80 0 20 40 60 80 0 20 40 60 80 0 20 40 60 80
Follow-up months Follow-up months Follow-up months Follow-up months

E Stage groups (N = 321,958) F Stage I (N = 178,408) G Stage II (N = 108,541) H Stage III (N = 35,009)
Stage I HRc(-)/HER2(-) HRc(+)/HER2(-) HRc(+)/HER2(-) HRc(+)/HER2(-)
Stage III HRc(-)/HER2(-)
N = 178,408 (55.4%) N = 13,505 (8.1%) N = 134,608 (80.8%) HRc(-)/HER2(-) N = 70,592 (68.7%) N = 21,126 (63.5%)
N = 35,009 (10.9%) N = 4,953 (14.9%)
N = 15,039 (14.6%)
HRc(-)/HER2(+)
N = 4,991 (3.0%)
HRc(-)/HER2(+)

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N = 5,032 (4.9%) HRc(-)/HER2(+)
HRc(+)/HER2(+) N = 2,569 (7.7%)
N = 13,513 (8.1%)

HRc(+)/HER2(+)
Stage II N = 12,132 (11.8%)
HRc(+)/HER2(+)
N = 108,541 (33.7%)
N = 4,650 (14.0%)

Figure 4.
BCSS curves according to the stage groups (A) and subject proportions of the stage groups (E). Survival curves of each subtype for stage I (B), stage II (C), and
stage III (D) and subject proportions of each subtype for stage I (F), stage II (G), and stage III (H) were depicted.

HER2, histologic grade, race, age group, and year of diagnosis were summary of current and previous studies for prognostic influence
significant in univariable analyses (Table 2). HRs for HRc(þ)/ of breast cancer subtypes). The British Columbia Cancer Agency
HER2(þ), HRc()/HER2(þ), and HRc()/HER2() were 1.305 (BCCA) study analyzed data of 4,046 female patients with invasive
(95% CI: 1.203–1.415; P < 0.001), 2.652 (95% CI: 2.431–2.894; breast cancer who had been referred to the BCCA between 1986
P < 0.001), and 4.755 (95% CI: 4.527–4.995; P < 0.001), respec- and 1992. With a median follow-up time of 12.5 years, it reported
tively, with HRc(þ)/HER2() as reference. Subtype was a signi- that 5-year BCSS rates of HRc(þ)/HER2(), HRc(þ)/HER2(þ),
ficant independent prognostic factor in multivariable analysis HRc()/HER2(þ), and HRc()/HER2() were 91%, 75%, 60%,
after adjusting for six basic clinicopathologic factors including and 73%, respectively (10, 15). The Carolina Breast Cancer Study
T category, N category, histologic grade, race, age group, and year (CBCS) analyzed the data of 496 breast cancer cases diagnosed
of diagnosis. HRs for HRc(þ)/HER2(þ), HRc()/HER2(þ), and between 1993 and 1996 with a maximal follow-up period of 11.2
HRc()/HER2() were 0.810 (95% CI: 0.745–0.881; P < 0.001), years. It reported that HRc()/HER2(þ) subtype showed worse
1.212 (95% CI: 1.105–1.330; P < 0.001), and 2.528 (95% CI: 10-year BCSS rate (52%) compared with other subtypes [84% for
2.390–2.674; P < 0.001), respectively, with HRc(þ)/HER2() as HRc(þ)/HER2(), 87% for HRc(þ)/HER2(þ), and 75% for
reference. Regarding OS, ten clinicopathologic factors except triple-negative subtype] (11). The California Cancer Registry study
for HER2 were significant in univariable analyses. Subtype was analyzed data of 61,309 patients with invasive breast cancer
also a significant independent prognostic factor in multivariable who were registered between 1999 and 2004. It reported that
analysis after adjustment (P < 0.001). HRc()/HER2(þ) and HRc()/HER2() subtypes showed the
worst and essentially identical 5-year relative cumulative survival
rates of 75.9% and 76.2%, respectively (12). The authors of that
Discussion study mentioned that their results could reflect the natural history
This study investigated the prognostic roles of four breast cancer of HER2(þ) breast cancers as the subject enrollment period was
subtypes based on the status of HRc and HER2 in female patients prior to the era of routine trastuzumab therapy (12). Another
with operable invasive breast cancer by analyzing the data of study analyzed data of 12,052 patients with primary nonmeta-
321,958 subjects from population-based SEER database. This static invasive breast cancer who had been registered in the
study revealed that HRc(þ) subtypes had better prognosis than regional cancer registry of Saxony-Anhalt from Germany between
HRc() subtypes. Although there was a minor difference in both 2000 and 2016. With a median follow-up time of 80.8 months,
BCSS and OS rates between HRc(þ)/HER2() and HRc(þ)/ it reported that 10-year OSs for HRc(þ)/HER2(þ), HRc()/
HER2(þ) subtypes, HRc()/HER2(þ) subtype showed superior HER2(þ), and HRc()/HER2() subtypes were 79.6%, 74.4%,
prognosis than HRc()/HER2() subtype. Breast cancer subtype and 75.8%, respectively (13). Another study analyzed data of
was a significant prognostic factor in univariable analysis and it 196,094 patients with invasive breast cancer from SEER database
still remained a significant independent factor in multivariable (2010–2013) with a maximum follow-up time of 59 months. It
analyses regarding both BCSS and OS. reported that 4-year BCSS rates of HRc(þ)/HER2(), HRc(þ)/
Some previous studies have reported the prognostic roles of HER2(þ), HRc()/HER2(þ), and HRc()/HER2() subtypes
breast cancer subtypes (Supplementary Table S2 shows review were 92.5%, 90.3%, 82.7%, and 77.0%, respectively (14).

www.aacrjournals.org Clin Cancer Res; 25(6) March 15, 2019 1975

 Table 2. Univariable and multivariable analyses regarding BCSS and OS
BCSS OS
Univariable analysis Multivariable analysisa Univariable analysis Multivariable analysisa
Characteristics HR CI (95%) P HR CI (95%) P HR CI (95%) P HR CI (95%) P
Hwang et al.

Subtype <0.001 <0.001 <0.001 <0.001

HRc(þ)/HER2() Reference Reference Reference Reference
HRc(þ)/HER2(þ) 1.305 1.203 (1.415) <0.001 0.810 0.745 (0.881) <0.001 1.036 0.986 (1.089) 0.161 0.911 0.865 (0.960) <0.001
HRc()/HER2(þ) 2.652 2.431 (2.894) <0.001 1.212 1.105 (1.330) <0.001 1.511 1.419 (1.608) <0.001 1.103 1.032 (1.179) 0.004
HRc()/HER2() 4.755 4.527 (4.995) <0.001 2.528 2.390 (2.674) <0.001 2.488 2.406 (2.573) <0.001 1.882 1.811 (1.956) <0.001
Unknown 1.445 1.316 (1.586) <0.001 1.316 1.191 (1.454) <0.001 1.324 1.257 (1.394) <0.001 1.270 1.202 (1.343) <0.001
T category <0.001 <0.001 <0.001 <0.001
T1 Reference Reference Reference Reference
T2 4.162 3.939 (4.397) <0.001 2.281 2.150 (2.421) <0.001 2.140 2.078 (2.204) <0.001 1.761 1.705 (1.820) <0.001
T3 9.015 8.421 (9.652) <0.001 4.060 3.763 (4.380) <0.001 3.426 3.276 (3.584) <0.001 2.655 2.525 (2.791) <0.001

1976 Clin Cancer Res; 25(6) March 15, 2019

T4 19.828 18.433 (21.329) <0.001 6.115 5.625 (6.649) <0.001 7.227 6.881 (7.592) <0.001 4.152 3.923 (4.394) <0.001
N category <0.001 <0.001 <0.001 <0.001
N0 Reference Reference Reference Reference
N1 2.919 2.770 (3.076) <0.001 1.946 1.840 (2.060) <0.001 1.482 1.436 (1.530) <0.001 1.273 1.229 (1.317) <0.001
N2 6.579 6.172 (7.012) <0.001 3.372 3.144 (3.616) <0.001 2.721 2.602 (2.845) <0.001 1.895 1.804 (1.990) <0.001
N3 12.045 11.284 (12.857) <0.001 5.149 4.784 (5.542) <0.001 4.549 4.337 (4.771) <0.001 2.747 2.605 (2.898) <0.001
Anatomic stage group <0.001 <0.001
Stage I Reference Reference
Stage II 4.300 4.027 (4.591) <0.001 1.935 1.876 (1.996) <0.001
Stage IIII 15.285 14.329 (16.304) <0.001 4.363 4.218 (4.513) <0.001
ER
Negative Reference Reference
Positive 0.242 0.232 (0.253) <0.001 0.453 0.440 (0.466) <0.001
PR
Negative Reference Reference
Positive 0.258 0.246 (0.269) <0.001 0.481 0.468 (0.494) <0.001
HER2
Negative Reference Reference
Positive 1.149 1.082 (1.220) <0.001 0.989 0.950 (1.029) 0.584
Histologic grade <0.001 <0.001 <0.001 <0.001
Well differentiated Reference Reference Reference Reference
Moderately differentiated 2.731 2.462 (3.029) <0.001 1.793 1.613 (1.992) <0.001 1.310 1.257 (1.364) <0.001 1.084 1.040 (1.131) <0.001
Poorly differentiated 9.462 8.575 (10.440) <0.001 3.822 3.440 (4.247) <0.001 2.434 2.339 (2.532) <0.001 1.613 1.542 (1.687) <0.001
Undifferentiated 10.343 8.082 (13.237) <0.001 4.207 3.262 (5.424) <0.001 2.915 2.475 (3.433) <0.001 1.934 1.637 (2.285) <0.001
Race <0.001 <0.001 <0.001 <0.001
Caucasian Reference Reference Reference Reference
African-American 1.886 1.784 (1.994) <0.001 1.305 1.232 (1.384) <0.001 1.402 1.350 (1.457) <0.001 1.254 1.205 (1.305) <0.001
Other races 0.736 0.674 (0.804) <0.001 0.734 0.669 (0.804) <0.001 0.633 0.597 (0.671) <0.001 0.702 0.661 (0.745) <0.001
Age group (years) <0.001 <0.001 <0.001 <0.001
50 Reference Reference Reference Reference
>50, 65 0.823 0.778 (0.871) <0.001 1.102 1.039 (1.168) 0.001 1.055 1.009 (1.104) 0.019 1.260 1.203 (1.319) <0.001
>65 1.238 1.173 (1.307) <0.001 2.106 1.989 (2.229) <0.001 2.888 2.776 (3.005) <0.001 3.922 3.762 (4.088) <0.001
Year of diagnosis 0.016 0.379 0.001 0.040
2010 Reference Reference Reference Reference
2011 0.948 0.895 (1.004) 0.068 0.968 0.912 (1.027) 0.276 0.981 0.947 (1.017) 0.304 0.997 0.962 (1.034) 0.884
2012 0.930 0.872 (0.992) 0.027 0.961 0.900 (1.026) 0.238 0.978 0.939 (1.017) 0.264 0.993 0.953 (1.035) 0.738
2013 0.901 0.835 (0.972) 0.007 0.967 0.895 (1.045) 0.402 0.938 0.895 (0.983) 0.008 0.964 0.918 (1.011) 0.134
2014 0.890 0.803 (0.986) 0.025 0.950 0.855 (1.055) 0.336 0.918 0.862 (0.976) 0.007 0.945 0.887 (1.007) 0.082
2015 0.756 0.602 (0.951) 0.017 0.784 0.618 (0.993) 0.044 0.805 0.711 (0.911) 0.001 0.830 0.731 (0.942) 0.004
a
The subtype factor was adjusted with six basic clinicopathologic factors including T category, N category, histologic grade, race, age, and year of diagnosis.

Clinical Cancer Research

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 Breast Cancer Subtype and Prognosis

Although our study revealed that both HRc(þ) subtypes have reported similar association between the proportion of
showed favorable BCSS with minor prognostic difference subtypes and pathologic findings (13, 14, 17, 28). Weak corre-
between them, the BCCA study reported a prominently worse lation between T category and N category in triple negative or
BCSS of the HRc(þ)/HER2(þ) subtype compared with HRc(þ)/ BRCA-associated breast cancers has been reported in previous
HER2(). Although our results showed superior BCSS and OS studies (18, 29).
rates of the HRc()/HER2(þ) subtype compared with the triple- As breast cancer subtypes were classified according to the
negative subtype, both the BCCA study and the CBCS study re- expression of ER, PR, and HER2, the prognosis of each subtype
ported completely reversed results. Both the California Cancer was also closely associated with the expression of those receptors.
Registry study and the Saxony-Anhalt study reported that HRc()/ Subjects with ER(þ), PR(þ), and HER2() had higher BCSS rates
HER2(þ) and HRc()/HER2() subtypes showed worse surv- than those with ER(), PR(), and HER2(þ), respectively. These
ival rates without survival difference between them. Considering findings could partially explain the basic relationship between
that clinical application of adjuvant HER2-targeted therapy has each subtype and prognosis. Previous studies have reported
been introduced since the second half of the period between favorable prognosis of HRc(þ) breast cancers (11, 12, 14) and
2000 and 2010, the prognosis of HER2(þ) subtypes could be adverse prognosis of HER2(þ) breast cancers (11, 12, 14, 30, 31).
significantly improved by HER2-targeted therapy accordingly. The proportion of the HRc()/HER2() subtype in subjects with
This hypothesis could partially explain the worse prognoses of positive events of BCSS (34.2%) was three times larger than that in
HER2(þ) subtypes in the era before routine HER2-targeted the- subjects with negative events of BCSS (10.4%). Regarding OS, the

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rapy and the improved prognoses of them in the era after that. proportion of triple-negative breast cancer in subjects with pos-
Further studies are needed to prove this plausible hypothesis. itive events (22.7%) was about twice larger than subjects with
In this study, although the proportions of HRc(þ)/HER2(þ) negative events (10.2%). Improving the prognosis of the triple-
and HRc()/HER2(þ) subtypes showed little variance across the negative subtype is crucial to improve the prognosis of unselected
race groups, HRc(þ)/HER2() and HRc()/HER2() subtypes patients with breast cancer.
showed prominent variance; HRc(þ)/HER2() and HRc()/ Although this study performed holistic analyses on the
HER2() subtypes were 76.5% and 10.0% in Caucasian women, prognosis of breast cancer subtypes based on the largest data-
but 63.0% and 20.9% in African-American women. African- base available in the world regarding this issue, it had also
American women showed worse BCSS rate than Caucasian several limitations. First, the follow-up period was still rela-
women, and proportions of triple-negative breast cancers could tively short. Although information of ER and PR has been
be closely linked with this causality. The adverse prognosis of available since 1990, SEER database has presented information
African-American women in breast cancer has been repeatedly of HER2 and breast cancer subtype since 2010. The mean
reported (22–24). It might be associated with many factors follow-up period was 32 months (range, 0–71 months). Fur-
such as early age of onset, unfavorable histologic features, lower ther studies are needed to validate long term follow-up results
socio-economic status, genetic predisposition, and so forth of this issue. Second, this study could not analyze effects of
(16, 24). Some studies have stressed the association between adjuvant treatments on the prognosis of each breast cancer
higher proportion of triple-negative subtype and worse prognosis subtype because no data regarding adjuvant treatments was
in African-American women (11, 16, 25–27). available from the SEER database. Especially, we could not
In this study, although the proportion of HRc(þ)/HER2() analyze the impact of endocrine therapy or HER2-targeted
subtype increased as age increased, the proportion of the triple- therapy, although they are crucial factors for the analysis of
negative subtype increased as age decreased. The proportion the prognostic role of breast cancer subtypes. The prognostic
of triple-negative subtype was larger in the age group with age effect of chemotherapy or radiation therapy could not be
50 years than that in the other two age groups with age >50 years. analyzed either because of data unavailability.
The CBCS reported that the proportion of the triple-negative In conclusion, breast cancer subtype was a significant indepen-
subtype in premenopausal women (26.8%) was larger than that dent prognostic factor in operable female invasive breast cancer
in postmenopausal women (15.9%) with known subtypes (11). regarding both BCSS and OS. HRc(þ) subtypes such as HRc(þ)/
Triple-negative breast cancer was known to be more prevalent in HER2() and HRc(þ)/HER2(þ) showed more favorable BCSS
younger patients. This has been suggested as a factor to explain the and OS rates than HRc() subtypes such as HRc()/HER2(þ)
adverse prognosis of young patients with breast cancer, especially and HRc()/HER2(). HRc()/HER2(þ) subtype showed
that in African-American women (11, 15, 16). With our dataset, better prognosis than HRc()/HER2() but worse prognosis
proportions of triple-negative breast cancer in age groups of than HRc(þ) subtypes regarding both BCSS and OS. The triple-
40 years, 40 < age  60 years, and age >60 years were 18.8% negative subtype showed the worst prognosis among all sub-
(N ¼ 3,179), 12.1 % (N ¼ 15,185), 9.4% (N ¼ 15,133), respec- types irrespective of race, age, or anatomic stage regarding BCSS.
tively (data not shown). Especially, triple-negative subtype repre- Further studies are needed to identify long term prognostic impact
sented 27.0% in African-American women with age <40 years of each subtype on breast cancer.
compared with 18.1% and 14.1% in Caucasian and other races
with same ages, respectively. Disclosure of Potential Conflicts of Interest
This study showed that the proportion of HRc(þ)/HER2() No potential conflicts of interest were disclosed.
subtype decreased as anatomic stage advanced and the proportion
of triple-negative subtype increased as the stage advanced. These
Authors' Contributions
association patterns were also observed regarding T category, Conception and design: K.-T. Hwang, J.H. Chang, S.B. Park
N category, and histologic grade. T category showed a more Development of methodology: K.-T. Hwang, S. Oh, J. Kim
prominent association pattern than N category. Histologic grade Acquisition of data (provided animals, acquired and managed patients,
showed the most prominent association pattern. Previous studies provided facilities, etc.): K.-T. Hwang, S.W. Oh

www.aacrjournals.org Clin Cancer Res; 25(6) March 15, 2019 1977

 Hwang et al.

Analysis and interpretation of data (e.g., statistical analysis, biostatistics, (Department of Surgery), Bumjo Oh (Department of Family Medicine), So
computational analysis): K.-T. Hwang, S. Oh, J. Kim, J. Jung, Y.J. Chai, Won Oh (Department of Nuclear Medicine), Sohee Oh (Department of
J.H. Chang, K.R. Hwang Biostatistics), Jong Yoon Lee (Department of Radiology), Ji Hyun Chang
Writing, review, and/or revision of the manuscript: K.-T. Hwang, J. Kim, (Department of Radiation Oncology), Se Hee Jung (Department of
J. Jung, J.H. Chang, Y.J. Chai, S.W. Oh, S. Oh, Y.A. Kim, S.B.Park, K.R. Hwang Rehabilitation Medicine), Young Jun Chai (Department of Surgery), In
Administrative, technical, or material support (i.e., reporting or organizing Sil Choi (Department of Internal Medicine), A. Jung Chu (Department of
data, constructing databases): K.-T. Hwang, J.H. Chang, S.W. Oh Radiology), and Kyu Ri Hwang (Department of Obstetrics and Gynecology).
Study supervision: K.-T. Hwang, S.B. Park, K.R. Hwang All BBS members are from Seoul Metropolitan Government Seoul National
University Boramae Medical Center (Seoul, Republic of Korea).
Acknowledgments
We appreciate valuable discussion from the following members of the The costs of publication of this article were defrayed in part by the
Boramae hospital Breast cancer Study group (BBS): Ki-Tae Hwang (Depart- payment of page charges. This article must therefore be hereby marked
ment of Surgery), Bo Kyung Koo (Department of Internal Medicine), advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate
Young A. Kim (Department of Pathology), Jongjin Kim (Department of this fact.
Surgery), Eun Youn Roh (Department of Laboratory Medicine), Sejung
Maeng (Department of Surgery), Sung Bae Park (Department of Neuro- Received August 25, 2018; revised November 2, 2018; accepted December 11,
surgery), Jin Hyun Park (Department of Internal Medicine), Cho Won Park 2018; published first December 17, 2018.

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