Observational Study Medicine ®

OPEN

Features of triple-negative breast cancer

Analysis of 38,813 cases from the national cancer database
Magdalena L. Plasilova, MD, PhD, Brandon Hayse, BSc, Brigid K. Killelea, MD, MPH, Nina R. Horowitz, MD,
∗
Anees B. Chagpar, MD, MSc, MPH, MA, MBA, Donald R. Lannin, MD

Abstract
The aim of this study was to determine the features of triple-negative breast cancer (TNBC) using a large national database. TNBC is
known to be an aggressive subtype, but national epidemiologic data are sparse. All patients with invasive breast cancer and known
molecular subtype diagnosed in 2010 to 2011 were identified from the National Cancer Data Base (NCDB). Patients with and without
TNBC were compared with respect to their sociodemographic and clinicopathologic features. TNBC was present in 38,628 of
295,801 (13%) female patients compared to 185 of 3136 (6%) male patients (P < 0.001). The incidence of TNBC varied by region
from 10.8% in New England to 15.8% in the east south central US (P < 0.001), as well as by race with the highest rates in African-
Americans (23.7%), and lowest in Filipino patients (8.9%). The incidence of TNBC also varied by histology, accounting for 76% of
metaplastic cancers, but only 2% of infiltrating lobular carcinomas. TNBCs were significantly larger than non-TNBC (mean 2.8 cm vs
2.1 cm, P < 0.001), and more TNBC were poorly differentiated compared to other subtypes (79.7% vs 25.8%, P < 0.001). On
univariate analysis, TNBC was no more likely than non-TNBC to have node-positive disease (32.0% vs 31.7%, respectively, P =
0.218) but in a multivariable analysis controlling for tumor size and grade, TNBC was associated with significantly less node-positivity
(OR = 0.59; 95% confidence interval [CI]: 0.57–0.60). TNBC has distinct features regarding age, gender, geographic, and racial
distribution. Compared to non-TNBC, TNBC is larger and higher grade, but less likely to have lymph node metastases.
Abbreviations: ER = estrogen receptor, Her2 = human epidermal growth factor receptor 2, NCDB = National Cancer Database,
PR = progesterone receptor, TNBC = triple-negative breast cancer.
Keywords: Breast cancer molecular type, national cancer database, triple-negative breast cancer

1. Introduction published describing its biology, behavior, and treatment, large

scale epidemiologic studies based on national data are sparse.
Triple-negative breast cancer (TNBC) represents a subgroup of
The aim of this study was to determine the features of TNBC
breast tumors defined by lack of expression of the estrogen
using a large national dataset. The National Cancer Database
receptor (ER), progesterone receptor (PR), and human epidermal
(NCDB) is a joint project of the Commission on Cancer of the
growth factor receptor 2 (Her2). It tends to be biologically
American College of Surgeons and the American Cancer
aggressive, and with a lack of commonly utilized targeting agents,
Society and contains data on about 70% of the cancer
it is often associated with a worse prognosis.[1] Despite unique
cases in the United States. Her2 status has been collected since
identifying features, there is significant heterogeneity among
2010, allowing determination of molecular type. In this study,
TNBC patient populations and the results of small studies are
38,813 cases of TNBC diagnosed in 2010 and 2011 were
sometimes contradictory.[2,3] Although many articles have been
compared to non-TNBC diagnosed in the same years with
regard to sex, race/ethnicity, age, geographic distribution,
histologic type, stage, pathologic characteristics, and treatment
Editor: Hisashi Oshiro. patterns.
Presented at the Society of Surgical Oncology, March 26 to 29, 2015, Houston,
TX.
2. Methods
The authors have no conflicts of interest to declare.
Department of Surgery, and Yale Comprehensive Cancer Center, Yale University
The NCDB, established in 1989, is a nationwide, facility-based,
School of Medicine, New Haven, CT. comprehensive data set that captures about 70% of all newly
∗
Correspondence: Donald R. Lannin, Department of Surgery, Yale University diagnosed malignancies in the United States annually. After
School of Medicine, PO Box 208062, New Haven, CT 06520 (e-mail: approval by the NCDB, patient deidentified data were down-
[email protected]). loaded from the website in January 2014 and analyzed in this
Copyright © 2016 the Author(s). Published by Wolters Kluwer Health, Inc. All study. Given the deidentified and retrospective nature of the data
rights reserved. obtained from the NCDB, this study was deemed exempt by the
This is an open access article distributed under the terms of the Creative
Human Investigations Committee of Yale University.
Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-
ND), where it is permissible to download and share the work provided it is
properly cited. The work cannot be changed in any way or used commercially.
2.1. Receptor data and study population
Medicine (2016) 95:35(e4614)
Received: 14 March 2016 / Received in final form: 15 July 2016 / Accepted: 27 The instructions to the tumor registrars in the Collaborative Stage
July 2016 Coding Manual regarding estrogen and progesterone assays were
http://dx.doi.org/10.1097/MD.0000000000004614 to “record the pathologist’s interpretation of the assay value.”

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Plasilova et al. Medicine (2016) 95:35 Medicine

However, it was noted that the College of American 2.3. Race, histology, and treatment variables
Pathologists had issued guidelines in late 2009 that if 1% or The NCDB classified race and histology into many categories,
more of tumor cells stained positive, the ER/PR value was with relatively few cases in each group. To allow a valid analysis,
considered positive.[4] only racial categories with greater than 400 cases and histology
With regard to Her2 assays, the NCDB contains data on categories with greater than 200 cases were included; categories
immunohistochemistry, fluorescence in situ hybridization, and with less than 400 and 200 cases, respectively, were recoded as
chromogenic in situ hybridization, but the field we used for this “other.” For determination of surgical treatment, only cases that
study was one where the individual local tumor registrars had definitive surgery, either mastectomy or lumpectomy, were
determined the best assay result for each individual patient. The included. For patients who had neoadjuvant chemotherapy,
registrars were instructed to use gene amplification assays first, pathologic complete response was defined as no remaining
and then use immunohistochemistry assay for cases where the invasive tumor in either the breast or the axillary lymph nodes.
amplification assay was borderline or not performed.
The population used for this study consisted of all patients
with invasive breast cancer diagnosed in 2010 and 2011 whose 2.4. Statistical analysis
ER, PR, and Her2 were known to be positive or negative. Statistical analysis was performed with IBM SPSS version 22,
This represented 88.4% of all invasive breast cancers in the Chicago, Ill. USA. Bivariate comparisons were performed with
database for those years. Cases were categorized as triple chi-square tests, and multivariable analysis was performed with
negative (TNBC) if all 3 receptors were known to be negative, binary logistic regression. Statistical tests were 2-sided, and
and non-TNBC if any one of the receptors was known to be P values <0.05 were considered significant.
positive.

3. Results
2.2. Tumor size
3.1. Completeness of data
The NCDB variable, “tumor size,” is a combination of clinical
and pathological size. If surgery was performed before any other The Her2 variable was complete for 91% of the 2010 to 2011
treatments, the pathological size was used, but if neoadjuvant cases, and was positive in 14.2%, negative in 83.1%, and
therapy was employed, the clinical tumor size before treatment borderline in 2.7%. The cases of borderline Her2 expression were
was used. The size is coded in 1 mm increments, but for this study excluded, resulting in 88% of all invasive cancers being positive
the size was converted to 1 cm increments, that is, from 1 to or negative for Her2. Essentially all of the cases with complete
10 mm, 11 to 20 mm, 21 to 30 mm, etc, so that positive lymph data on Her2 also had complete data for ER and PR. It appears
node rates could be calculated for each size interval. that the 2009 guidelines changing the definition of hormone

Table 1
Incidence of triple-negative tumors by sex, race/ethnicity, age, and geographic region.
Nontriple-negative number (%)
Total cancer number HR+ Her2 HR+ Her2+ HR Her2+ Triple-negative number (%) P
Sex <0.001
Female 295,801 214,052 (72.4%) 29,794 (10.1%) 13,327 (4.5%) 38,628 (13.1%)
Male 3,136 2587 (82.5%) 315 (10.0%) 49 (1.6%) 185 (5.9%)
Race/ethnicity <0.001
Non-Hispanic white 235,082 175,760 (74.8%) 22,870 (9.7%) 9669 (4.1%).1%) 26,783 (11.4%)
Non-Hispanic black 33,970 20,255 (59.6%) 3744 (11.0%) 1904 (5.6%) 8,067 (23.7%)
Non-Hisp Asian/P.I. 9,294 6519 (70.1%) 1091 (11.7%) 639 (6.9%) 1,045 (11.2%)
Hispanic 15,536 10,476 (67.4%) 1847 (11.9%) 907 (5.8%) 2,306 (14.8%)
Other/unknown 5,055 3629 (71.8%) 557 (11.0%) 257 (5.1%) 612 (12.1%)
Age <0.001
30 2,059 1014 (49.2%) 411 (20.0%) 155 (7.5%) 479 (23.3%)
31–40 15,094 8439 (55.9%) 2494 (16.5%) 978 (6.5%) 3,183 (21.1%)
41–50 51,793 34,894 (67.4%) 6422 (12.4%) 2627 (5.1%) 7,850 (15.2%)
51–60 72,543 49,920 (68.8%) 8051 (11.1%) 4149 (5.7%) 10,423 (14.4%)
61–70 77,870 59,173 (76.0%) 6724 (8.6%) 3061 (3.9%) 8,912 (11.4%)
>70 79,578 63,199 (79.4%) 6007 (7.5%) 2406 (3.0%) 7,966 (10%)
Geographic region <0.001
East South Central 17,319 11,844 (68.4%) 1850 (10.7%) 888 (5.1%) 2,737 (15.8%)
West South Central 23,951 16,634 (69.5%) 2693 (11.2%) 1150 (4.8%) 3,474 (14.5%)
South Atlantic 65,180 46,520 (71.4%) 6502 (10.0%) 3035 (4.7%) 9,123 (14.0%)
East North Central 52,707 38,085 (72.3%) 5162 (9.8%) 2301 (4.4%) 7,159 (13.6%)
Middle Atlantic 46,259 33,908 (73.3%) 4699 (10.2%) 1982 (4.3%) 5,670 (12.3%)
West North Central 21,923 16,223 (74.0%) 2121 (9.7%) 949 (4.3%) 2,630 (12.0%)
Mountain 14,382 10,682 (74.3%) 1377 (9.6%) 619 (4.3%) 1,704 (11.8%)
Pacific 38,647 28,794 (74.5%) 3842 (9.9%) 1699 (4.4%) 4,312 (11.2%)
New England 18,569 13,949 (75.1%) 1863 (10.0%) 753 (4.1%) 2,004 (10.8%)
HR = hormone receptor, Her2 = human epidermal growth factor receptor 2.

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youngest ages (< 30), the 2 racial groups had roughly equivalent
35
proportions of TNBC (Fig. 1A). Based on 9 geographic regions of
30
25
the United States, TNBC was highest in the east south central
% with TNBC

20 (15.8%), the west south central (14.5%), and the south Atlantic
15
White regions (14.0%) and lowest in New England (10.8%, P < 0.001).
10 Black
5
0
3.3. Incidence of triple-negative tumors by detailed racial
<30 31-40 41-50 51-60 61-70 >70 groups
A Age
The NCDB included detailed information on racial group
distribution. Table 2 shows the incidence of triple-negative
% with positive lymph nodes

100
tumors for all racial groups that contained more than 400
80 individuals. Compared to the white population, black, American
60 Indian/Eskimo, and Asian Indian patients had a higher incidence
40 non-TNBC of TNBC, and Filipino patients had a lower incidence of TNBCs.
20 TNBC
0 3.4. Incidence of triple-negative tumors by detailed
<1 2 3 4 5 6 7 8 9 >10 histologic type
B Tumor size in cm
Figure 1. (A) Percentage of cancers that are triple negative by patient age and
Table 3 shows the incidence of TNBC among all histologic types
race. (B) Percentage of cancers that are lymph node positive by tumor size and with more than 200 cases. Infiltrating ductal carcinoma was the
molecular type. most common histologic type and contained 14.6% TNBC.
However, there was an extremely wide range from adenoid cystic,
which was 78% TNBC to tubular that was 0.3%. Histologic types
receptor positivity from 10% to 1% were adopted fairly quickly. with a higher percent TNBC compared to infiltrating ductal were
Out of all invasive cancers diagnosed in 2010 and 2011, 79.1% adenoid cystic, metaplastic, medullary, apocrine adenocarcinoma,
were positive for ER, 18.0% were negative, and 2.9% were and inflammatory carcinoma. Carcinoma not otherwise specified
unknown/not done; whereas for 2004 to 2009, only 73.6% were (NOS) and adenocarcinoma NOS were also more likely to be
positive, 20.1% negative, and 6.3% unknown/not done. TNBC, probably because these categories are used for very
undifferentiated cancers. Histologic types with a lower percent of
TNBC than infiltrating ductal included tubular carcinoma,
3.2. Incidence of triple-negative tumors by sex,
mucinous carcinoma, infiltrating lobular, infiltrating ductal and
race/ethnicity, age, and geographic region
infiltrating lobular, infiltrating lobular mixed with other types,
Table 1 shows incidence data for TNBC based on sex, race/ cribriform carcinoma, micropapillary and papillary carcinoma,
ethnicity, age, and geographic region. TNBC was present in Paget’s disease with infiltrating ductal, intraductal papillary with
38,628 of 295,801 (13%) female patients compared to 185 out of invasion, and infiltrating ductal mixed with other types. To see
3136 (6%) male patients (P < 0.001). Non-Hispanic black and whether differences in histological type may account for the racial
Hispanic patients had higher incidence of TNBC, and TNBC was and age differences observed, Table 4 shows histology by race and
more common amongst younger patients (P < 0.001 for both). age for triple-negative cancers. The racial and age differences were
Across all age groups, African-American women were more likely mainly due to infiltrating ductal cancers and not due to the very
to have TNBC than their white counterparts; however, at the small contribution of other histologic types.

Table 2
∗
Incidence of triple-negative tumors by detailed racial groups .
Nontriple-negative number (%)
Total cancer number HR+ Her2 HR+ Her2+ HR Her2+ Triple-negative number (%) P#
White 249,185 185,265 (74.3%) 24,556 (9.9%) 10,497 (4.2%) 28,867 (11.6%) Ref
Black 34,380 20,529 (59.7%) 3790 (11.0%) 1926 (5.6%) 8,135 (23.7%) <0.001
Asian Indian 576 383 (66.5%) 61 (10.6%) 42 (7.3%) 90 (15.6%) 0.003
American Indian/Eskimo 808 548 (67.8%) 95 (11.8%) 47 (5.8%) 118 (14.6%) 0.008
Korean 679 435 (64.1%) 90 (13.3) 62 (9.1%) 92 (13.5%) 0.111
Asian Indian or Pakistani 849 592 (69.7%) 100 (11.8%) 55 (6.5%) 102 (12.0%) 0.696
Chinese 1,448 1003 (69.3%) 167 (11.5) 105 (7.3%) 173 (11.9%) 0.667
Vietnamese 497 325 (65.4%) 63 (12.7%) 52 (10.5%) 57 (11.5%) 0.936
Japanese 903 696 (77.1%) 74 (8.2%) 31 (3.4%) 102 (11.3%) 0.787
Pacific Islander, NOS 576 419 (72.7%) 66 (11.5%) 29 (5.0%) 62 (10.8%) 0.539
Other Asian, NOS 2,266 1621 (71.5%) 253 (11.2%) 157 (6.9%) 235 (10.4%) 0.072
Filipino 1,579 1102 (69.8%) 226 (14.3%) 111 (7.0%) 140 (8.9%) 0.001
Other 2,030 1396 (68.8%) 248 (12.2%) 112 (5.5%) 274 (13.5%) 0.007
Unknown 3,161 2325 (73.6%) 320 (10.1%) 150 (4.7%) 366 (11.6%) 0.992
∗
Where N > 400.
#
Triple negative vs nontriple negative compared to whites.
HR = hormone receptor, Her2 = human epidermal growth factor receptor.

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Table 3
∗
Incidence of tripl-negative tumors by histologic type .
Nontriple-negative number (%)
Total cancer number HR+ Her2 HR+ Her2+ HR Her2+ Triple-negative number (%) P#
Infiltrating ductal 224,844 155,060 (69.0%) 25,170 (11.2%) 11,788 (5.2%) 32,826 (14.6%) Ref
Adenoid cystic 220 45 (20.5%) 1 (0.5%) 2 (0.9%) 172 (78.2%) <0.001
Metaplastic 1,221 227 (18.6%) 18 (1.5%) 45 (3.7%) 931 (76.2%) <0.001
Medullary 643 178 (27.7%) 33 (5.1%) 43 (6.7%) 389 (60.5%) <0.001
Apocrine adenocarcinoma 480 97 (20.2%) 41 (8.5%) 70 (14.6%) 272 (56.7%) <0.001
Carcinoma NOS 2,186 1179 (53.9%) 252 (11.5%) 154 (7.0%) 601 (27.5%) <0.001
Inflammatory 934 357 (38.2%) 144 (15.4%) 191 (20.4%) 242 (25.9%) <0.001
Adenocarcinoma NOS 1,598 926 (57.9%) 200 (12.5%) 154 (9.6%) 318 (19.9%) <0.001
Neoplasm, malignant 615 440 (71.5%) 56 (9.1%) 23 (3.7%) 96 (15.6%) 0.479
Adenocarcinoma with mixed subtypes 259 195 (75.3%) 19 (7.3%) 5 (1.9%) 40 (15.4%) 0.701
Infiltrating ductular 490 339 (69.2%) 61 (12.4%) 23 (4.7%) 67 (13.7%) 0.562
Inf ductal mixed with other types 9,501 7502 (79.0%) 728 (7.7%) 273 (2.9%) 998 (10.5%) <0.001
Intraductal papillary with invasion 546 445 (81.5%) 36 (6.6%) 11 (2.0%) 54 (9.9%) 0.002
Pagets with infiltrating ductal 345 116 (33.6%) 96 (27.8%) 108 (31.3%) 25 (7.2%) <0.001
Papillary carcinoma 970 861 (88.8%) 43 (4.4%) 8 (0.8%) 58 (6.0%) <0.001
Micropapillary 600 461 (76.8%) 74 (12.3%) 30 (5.0%) 35 (5.8%) <0.001
Cribriform carcinoma 550 493 (89.6%) 27 (4.9%) 5 (0.9%) 25 (4.5%) <0.001
Inf lobular mixed with other types 1,060 951 (89.7%) 52 (4.9%) 10 (0.9%) 47 (4.4%) <0.001
Infiltrating ductal and inf lobular 15,040 13,239 (88.0%) 1197 (8.0%) 162 (1.1%) 442 (2.9%) <0.001
Infiltrating lobular carcinoma 27,799 25,756 (92.7%) 1382 (5.0%) 121 (0.4%) 540 (1.9%) <0.001
Mucinous carcinoma 5,608 5216 (93.0%) 314 (5.6%) 45 (0.8%) 33 (0.6%) <0.001
Tubular carcinoma 1,756 1710 (97.4%) 39 (2.2%) 1 (0.1%) 6 (0.3%) <0.001
Other/unknown 1,672 846 (50.6%) 126 (7.5%) 104 (6.2%) 596 (35.6%) <0.001
∗
Where N > 200.
#
Triple negative vs nontriple negative compared to infiltrating ductal.
HR = hormone receptor, Her2 = human epidermal growth factor receptor.

3.5. Tumor characteristics of triple-negative and have lymphovascular invasion, and to present with clinically
nontriple-negative cancers metastatic disease.
In unadjusted analysis TNBC were more likely than HR+
Tumor characteristics for TNBC and non-TNBCs are shown in
Her2– patients but less likely than Her2+ patients to have positive
Table 5. TNBC and Her2 positive patients had larger tumors
nodes. However, when stratified by tumor size, as seen in Fig. 1B,
than HR+ Her2 patients and were more likely to be high grade,

Table 4
Histology of triple-negative cancers by race and age.
Race number (%) Age number (%)
White Black 50 >50
Infiltrating ductal 24,262 (84.0%) 7,036 (86.5%) 9,398 (87.2%) 21,900 (83.5%)
Adenoid cystic 150 (0.5%) 18 (0.2%) 38 (0.4%) 130 (0.5%)
Metaplastic 738 (2.6%) 159 (2.0%) 192 (1.8%) 705 (2.7%)
Medullary 265 (0.9%) 106 (1.3%) 161 (1.5%) 210 (0.8%)
Apocrine adenocarcinoma 214 (0.7%) 42 (0.5%) 25 (0.2%) 231 (0.9%)
Carcinoma NOS 431 (1.5%) 145 (1.8%) 186 (1.7%) 390 (1.5%)
Inflammatory 184 (0.6%) 47 (0.6%) 66 (0.6%) 165 (0.6%)
Adenocarcinoma NOS 239 (0.8%) 63 (0.8%) 80 (0.7%) 222 (0.8%)
Neoplasm, malignant 76 (0.3%) 14 (0.2%) 20 (0.2%) 70 (0.3%)
Adenocarcinoma with mixed subtypes 34 (0.1%) 6 (0.1%) 8 (0.1%) 32 (0.1%)
Infiltrating ductular 44 (0.2%) 20 (0.2%) 17 (0.2%) 47 (0.2%)
Inf ductal mixed with other types 743 (2.6%) 199 (2.4%) 229 (2.1%) 713 (2.7%)
Intraductal papillary with invasion 40 (0.1%) 14 (0.2%) 10 (0.1%) 44 (0.2%)
Pagets with infiltrating ductal 22 (0.1%) 2 (0%) 6 (0.1%) 18 (0.1%)
Papillary carcinoma 35 (0.1%) 22 (0.3%) 18 (0.2%) 39 (0.1%)
Micropapillary 23 (0.1%) 9 (0.1%) 10 (0.1%) 22 (0.1%)
Cribriform carcinoma 21 (0.1%) 4 (0%) 6 (0.1%) 19 (0.1%)
Inf lobular mixed with other types 41 (0.1%) 3 (0%) 7 (0.1%) 37 (0.1%)
Infiltrating ductal and inf lobular 350 (1.2%) 64 (0.8%) 103 (1.0%) 311 (1.2%)
Infiltrating lobular carcinoma 446 (1.5%) 69 (0.8%) 78 (0.7%) 437 (1.7%)
Mucinous carcinoma 27 (0.1%) 4 (0%) 2 (0%) 29 (0.1%)
Tubular carcinoma 5 (0%) 1 (0%) 0 (0%) 6 (0%)
Other/unknown 477 (1.7%) 88 (1.1%) 121 (%)1.1%) 444 (1.7)

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Table 5
Tumor characteristics of triple-negative and nontriple-negative cancers.
Nontriple-negative number (%)
∗
HR+ Her2 HR+ Her2+ HR Her2+ Triple-negative number (%) P
T stage
cT1 129,150 (68.0%) 13,787 (52.9%) 4,860 (42.9%) 15,923 (46.4%) <0.001
cT2 46,109 (24.3%) 8,677 (33.3%) 4,024 (35.5%) 13,090 (38.1%)
cT3 8,384 (4.4%) 1,846 (7.1%) 1,091 (9.6%) 2,893 (8.4%)
cT4 6,356 (3.3%) 1,774 (6.8%) 1,358 (12.0%) 2,432 (7.1%)
N stage
cN0 164,877 (84.6%) 19,425 (71.9%) 7,644 (63.4%) 25,202 (72.0%) <0.001
cN1 22,921 (11.8%) 5,726 (21.2%) 3,150 (26.1%) 7,021 (20.1%)
cN2 4,535 (2.3%) 1,173 (4.3%) 731 (6.1%) 1,630 (4.7%)
cN3 2,501 (1.3%) 704 (2.6%) 530 (4.4%) 1,139 (3.3%)
M stage
cM0 192,356 (96.0%) 25,643 (92.6$) 11,227 (90.8%) 33,682 (94.1%) <0.001
cM1 8,052 (4.0%) 2,047 (7.4%) 1,131 (9.2%) 2,104 (5.9%)
Grade
1 61,993 (30.1%) 2,397 (8.5%) 210 (1.7%) 888 (2.4%) <0.001
2 102,929 (50.0%) 12,129 (42.9%) 2,996 (24.2%) 6,562 (17.8%)
3 40,741 (19.8%) 13,733 (48.6%) 9,187 (74.1%) 29,353 (79.8%)
LVI
Yes 33,864 (19.0%) 6,847 (29.1%) 3,240 (32.0%) 7,643 (25.0%) <0.001
No 144,162 (81.0%) 16,649 (70.9%) 6,897 (68.0%) 22,881 (75.0%)
Mean tumor size (cm ± SE) 2.04 ± 0.004 2.48 ± 0.012 2.78 ± 0.021 2.78 ± 0.012 <0.001
Positive nodes
>0 57,327 (30.3%) 9,820 (38.2%) 4,502 (40.0%) 10,768 (32.0%) 0.218
0 131,798 (69.7%) 15,874 (61.8%) 6,749 (60.0%) 22,852 (68.0%)
OR unadjusted (95% CI) Reference 1.42 (1.38–1.46) 1.53 (1.48–1.59) 1.08 (1.06–1.11) <0.001
OR adjusted for tumor size and Reference 1.06 (1.02–1.09) 0.95 (0.91–1.00) 0.59 (0.57–0.61) <0.001
grade (95% CI)
Surgery
Lumpectomy 117,468 (58.2%) 12,951 (47.7%) 4,713 (39.5%) 17,809 (50.0%) <0.001
Mastectomy 84,405 (41.8%) 14,182 (52.3%) 7,224 (60.5%) 17,776 (50.0%)
OR unadjusted (95% CI) Reference 0.66 (0.64–0.67) 0.47 (0.45–0.49) 0.72 (0.70–0.74) <0.001
OR adjusted for tumor Reference 0.78 (0.76–0.81) 0.62 (0.60–0.65) 0.96 (0.94–0.99) 0.009
size, nodal status
and grade (95% CI)
Chemotherapy
Yes 67,007 (34.9%) 20,622 (75.2%) 10,407 (84.5%) 28,460 (81.4%) <0.001
No 125,018 (65.1%) 6,799 (24.8%) 1,916 (15.5%) 6,490 (18.6%)
OR unadjusted (95% CI) Reference 5.7 (5.5–5.8) 10.1 (9.6–10.6) 8.2 (7.9–8.4) <0.001
OR adjusted for tumor size, nodal Reference 5.7 (5.5–5.9) 7.6 (7.1–8.2) 5.6 (5.4–5.8) <0.001
status and grade (95% CI)
∗
Triple negative compared to nontriple negative except the rows with odds ratios, where the P value represents triple negative compared to the reference, HR+ Her2 .
CI = confidence interval, HR = hormone receptor, Her2 = human epidermal growth factor receptor, OR = odds ratio, SE = standard error.

patients with TNBC were significantly less likely to have positive chemotherapy, they were more likely to receive neoadjuvant
nodes than their non-TNBC counterparts (P < 0.001). Adjusting chemotherapy (28% vs 22%, P < 0.001) and to have a pathologic
for tumor size and grade in a multivariable logistic regression complete response (40% vs 28%, P < 0.001).
model, TNBCs had a much lower rate of lymph node positivity
than any other molecular type (OR = 0.59; 95% CI: 0.57–0.61).
4. Discussion
To our knowledge, this is the largest study regarding the
3.6. Treatment of triple-negative and nontriple-negative
epidemiology, tumor characteristics, and treatment patterns of
cancers
TNBCs in the United States. We found that the incidence of
Table 5 also shows differences in treatment. On univariate TNBC was 13% among females and 6% among males. The
analysis, TNBC and Her2 positive patients received less breast- incidence of TNBC was highest among non-Hispanic black and
conserving surgery compared with HR+ Her2 patients. Hispanic patients (23.7% and 14.8%). These data are in
However, after adjusting for tumor size, nodal status, and agreement with previously published smaller studies.[1,5,6,7]
grade, Her2+ patients continued to have significantly less breast In addition, however, we found an increased incidence of TNBC
conservation whereas the difference largely disappeared for in American Indian/Eskimo (14.6%) and Asian Indian patients
TNBC patients. TNBC and Her2+ patients were also much more (15.6%). Interestingly, the incidence of TNBC was lowest in
likely to receive chemotherapy; and among patients who received Filipino patients (8.9%). It has been previously reported that

5
Plasilova et al. Medicine (2016) 95:35 Medicine

Filipino woman have an increased risk of Her2 positive breast References

cancers, regardless of ER and PR status.[8] In addition, we found [1] Newman LA, Reis-Filho JS, Morrow M, et al. The 2014 society of
that the highest incidence of TNBC is in the southern regions of surgical oncology susan g. Komen for the cure symposium: triple-
the United States, which might reflect the racial/ethnic distribu- negative breast cancer. Ann Surg Oncol 2015;22:874–82.
tion of the population. [2] Cancello G, Maisonneuve P, Rotmensz N, et al. Prognosis in women with
In all racial/ethnic groups, TNBC was associated with small (T1mic,T1a,T1b) node-negative operable breast cancer by
immunohistochemically selected subtypes. Breast Cancer Res Treat
increased incidence among young patients. However, as seen 2011;127:713–20.
in Fig. 1A, the shape of the curves differs by race. In white [3] Ueno NT, Zhang D. Targeting EGFR in triple negative breast cancer. J
patients, TNBC was highest under age 40, whereas in black Cancer 2011;2:324–8.
patients, it did not really drop off until after age 60. [4] Hammond ME, Hayes DF, Dowsett M, et al. American Society of
Clinical Oncology/College of American Pathologists guideline recom-
The data illustrate the broad histological heterogeneity of mendations for immunohistochemical testing of estrogen and progester-
TNBCs. There were 7 different histologic subtypes where TNBC one receptors in breast cancer. J Clin Oncol 2010;28:2784–95.
was more prevalent and 12 types where it was less prevalent than [5] Duffy MJ, McGowan PM, Crown J. Targeted therapy for triple-negative
infiltrating ductal carcinoma. This is consistent with smaller breast cancer: where are we? Int J Cancer 2012;131:2471–7.
studies that showed TNBC was associated with some special [6] Lin NU, Vanderplas A, Hughes ME, et al. Clinicopathologic features,
patterns of recurrence, and survival among women with triple-negative
histologic subtypes such as adenoid cystic,[9,10] medullary or breast cancer in the National Comprehensive Cancer Network. Cancer
metaplastic subtypes,[11,12] and not with other subtypes such as 2012;118:5463–72.
tubular or lobular carcinoma.[13] [7] Iqbal J, Ginsburg O, Rochon PA, et al. Differences in breast cancer stage
This study clarifies the relationship between TNBC and lymph at diagnosis and cancer-specific survival by race and ethnicity in the
United States. JAMA 2015;313:165–73.
node metastases. Although the overall percentage of positive [8] Gangi A, Chung A, Mirocha J, et al. Breast-conserving therapy for triple-
nodes for TNBC and non-TNBC is equivalent, TNBC tends to be negative breast cancer. JAMA Surg 2014;149:252–8.
larger and of higher grade; hence, it would be predicted to have a [9] Wetterskog D, Lopez-Garcia MA, Lambros MB, et al. Adenoid cystic
higher incidence of lymph node metastases. When adjusted for carcinomas constitute a genomically distinct subgroup of triple-negative
these factors, however, the incidence of positive nodes with and basal-like breast cancers. J Pathol 2012;226:84–96.
[10] Boyle P. Triple-negative breast cancer: epidemiological considerations
TNBC is considerably less than non-TNBC. This is in agreement and recommendations. Ann Oncol 2012;23(suppl 6):vi7–12.
with other recent studies.[14–16] However the finding in this study [11] Amirikia KC, Mills P, Bush J, et al. Higher population-based incidence
of increased lymphovascular invasion in TNBCs is contrary to rates of triple-negative breast cancer among young African-American
previously published reports.[15,16] women: implications for breast cancer screening recommendations.
Cancer 2011;117:2747–53.
We found that TNBC and Her2+ patients were treated more [12] Parise C, Caggiano V. Disparities in the risk of the ER/PR/HER2
frequently with mastectomy than were HR+ Her2 patients. breast cancer subtypes among Asian Americans in California. Cancer
However, upon adjusting for larger tumor size, nodal status, and Epidemiol 2014;38:556–62.
grade, TNBCs had about the same breast conservation rate as HR [13] Anderson KN, Schwab RB, Martinez ME. Reproductive risk factors and
+ Her2 patients. While TNBC patients have a higher risk for breast cancer subtypes: a review of the literature. Breast Cancer Res Treat
2014;144:1–10.
both local and distant recurrence, histologic or molecular [14] Gangi A, Mirocha J, Leong T, et al. Triple-negative breast cancer is not
subtype is not an indication for mastectomy and standard associated with increased likelihood of nodal metastases. Ann Surg
criteria should be applied to select the surgical approach in Oncol 2014;21:4098–103.
TNBC.[1,2,7,17] [15] Wiechmann L, Sampson M, Stempel M, et al. Presenting features of breast
cancer differ by molecular subtype. Ann Surg Oncol 2009;16:2705–10.
The majority (80%) of TNBC patients received systemic [16] Ugras S, Stempel M, Patil S, et al. Estrogen receptor, progesterone
chemotherapy and the odds of receiving chemotherapy were receptor, and HER2 status predict lymphovascular invasion and lymph
much greater for TNBC than for non-TNBC even when node involvement. Ann Surg Oncol 2014;21:3780–6.
adjusted for stage and grade. Furthermore, TNBC was more [17] Abdulkarim BS, Cuartero J, Hanson J, et al. Increased risk of
likely to be treated with neoadjuvant chemotherapy, and more locoregional recurrence for women with T1-2N0 triple-negative breast
cancer treated with modified radical mastectomy without adjuvant
likely to have a pathologic complete response. This is what we radiation therapy compared with breast-conserving therapy. J Clin
would expect based on the biology and clinicopathologic Oncol 2011;29:2852–8.
features of TNBC.[18,19] More detailed analyses of neoadjuvant [18] Cortazar P, Zhang L, Untch M, et al. Pathological complete response and
chemotherapy use in the NCDB have recently been pub- long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis.
Lancet 2014;384:164–72.
lished.[20,21] [19] Foulkes WD, Smith IE, Reis-Filho JS. Triple-negative breast cancer. N
In summary, TNBC has distinct features regarding age, gender, Engl J Med 2010;363:1938–48.
geographic, and racial/ethnic distribution. Compared to non- [20] Killelea BK, Yang VQ, Wang SY, et al. Racial differences in the use and
TNBC, TNBC is larger and higher grade, but less likely to have outcome of neoadjuvant chemotherapy for breast cancer: results from the
lymph node metastases. When the stage is taken into account, the National Cancer Data Base. J Clin Oncol 2015;33:4267–76.
[21] Mougalian SS, Soulos PR, Killelea BK, et al. Use of neoadjuvant
surgical treatment is similar to that of non-TNBC, but treatment chemotherapy for patients with stage I to III breast cancer in the United
with chemotherapy is much more common. States. Cancer 2015;121:2544–52.