Observational Study Medicine ®

OPEN

Association of p53 expression with poor prognosis

in patients with triple-negative breast invasive
ductal carcinoma
Jing-ping Li, MSa, Xiang-mei Zhang, MD, PhDb, Zhenzhen Zhang, PhDc, Li-hua Zheng, MSd,
∗
Sonali Jindal, MDe, Yun-jiang Liu, MD, PhDa,

Abstract
TP53 gene is mutated in approximately 80% of triple-negative breast cancer (TNBC). However, the prognostic significance of
immunohistochemical (IHC)-detected p53 protein expression remains controversial in TNBC. In this study, we retrospectively
analyzed the association between IHC-detected p53 expression and the prognosis in a cohort of 278 patients with stage I-III triple-
negative breast invasive ductal carcinoma (IDC), who received surgery at the department of breast surgery in the Fourth Hospital of
Hebei Medical University from 2010–01 to 2012–12. We found a positive expression ratio of IHC-detected p53 in triple-negative
breast IDC of 58.6% (163/278). Furthermore, levels of expression were significantly associated with vessel tumor emboli and higher
histologic grade (P = .038, P = .043, respectively), with the highest expression level observed in G3 breast cancer (64.7%).
Additionally, Kaplan-Meier analysis showed that p53 expression indicated worse overall survival (OS) in the whole cohort (79.6% vs
89.6%, Log-rank test P = .025) as well as in stratified prognostic stage II patients (90.8% vs 100%, Log-rank test P = .027). The
mortality risk of p53 expression patients was 2.22 times higher than that of p53 negative patients (HR: 2.222; 95%CI: 1.147–4.308).
In addition, p53 expression was also associated with poor disease-free survival (DFS) (76.7% vs 86.8%, P = .020). Cox proportional
hazard ratio model showed p53 expression was an independent risk factor for OS (P = .018) and DFS (P = .018) after controlling for
tumor size, lymph node status, and vessel tumor emboli. Altogether, our data showed that IHC-detected p53 expression is a
promising prognostic candidate for poor survival in triple-negative breast IDC patients. However, more studies are needed to
determine if p53 may be applied to clinical practice as a biomarker and/or novel therapeutic target for TNBC.
Abbreviations: AJCC = American Joint Committee on Cancer, DFS = disease-free survival, ER = estrogen receptor, HER-2 =
human epidermal growth factor receptor 2, IDC = infiltrating ductal carcinoma, IHC = immunohistochemical, OS = overall survival,
PgR = progesterone receptor, TNBC = triple-negative breast cancer.
Keywords: IDC, IHC, p53, progression, TNBC

1. Introduction approximately 15% of all breast cancers, is the most lethal

subtype of breast cancer.[2] With very low or no expression of
Breast cancer is the most frequently diagnosed cancer and the
estrogen receptor (ER), progesterone receptor (PgR), and human
leading cause of cancer-related deaths among females world-
epidermal growth factor receptor 2 (HER2), TNBC is conse-
wide.[1] Triple-negative breast cancer (TNBC), accounting for
quently unresponsive to both endocrine and anti-HER2 therapy,
limiting the therapeutic option for these patients.[3] Moreover,
TNBC is a heterogeneous disease in terms of clinical, histological,
Editor: Undurti N. Das. and molecular aspects,[4,5] Combined, these features make TNBC
The authors have no funding and conflicts of interest to disclose. difficult to treat and study. To date, the molecular drivers of
a
Department of Breast Surgery, the Fourth Hospital of Hebei Medical University, TNBC remain mysterious. For better treatment of TNBC, there is
b
Research Center, the Fourth Hospital of Hebei Medical University, c Division of an urgent need to further identify and understand the signaling
Hematology & Medical Oncology, Oregon Health & Science University,
d
Department of Vascular Surgery, the First Hospital of Hebei Medical University,
pathways driving TNBC tumor progression, relapse and
e
Department of Cell, Developmental & Cancer Biology, Oregon Health & Science treatment resistance.
University, Shijiazhuang, Hebei, China. One of the key reasons for the failure to develop a new therapy
∗
Correspondence: Yun-jiang Liu, Hebei Medical University Fourth Affiliated for TNBC patients is the lack of known highly prevalent,
Hospital and Hebei Provincial Tumor, Hospital, Shijiazhuang, Hebei, China targetable molecular alteration in these tumors. Recently
(e-mail: lyj818326@outlook.com). however, the TP53 gene was found to be mutated in
Copyright © 2019 the Author(s). Published by Wolters Kluwer Health, Inc. approximately 80% of basal-like/TNBC,[6] raising the possibility
This is an open access article distributed under the terms of the Creative
that targeting the mutant p53 protein product might be a new
Commons Attribution-Non Commercial License 4.0 (CCBY-NC), where it is
permissible to download, share, remix, transform, and buildup the work provided approach for the treatment of TNBC. The TP53 gene, known as
it is properly cited. The work cannot be used commercially without permission the “guardian of the genome”, is a tumor suppressor gene that
from the journal. regulates cell cycle progression, DNA repair, cellular senescence,
Medicine (2019) 98:18(e15449) and apoptosis.[7] Conversely, mutant p53 contributes tumor
Received: 18 December 2018 / Received in final form: 24 February 2019 / progression via a dual mechanism, the loss of tumor suppression
Accepted: 5 April 2019 activity and a gain of oncogenic activity.[8] As such, mutant p53 is
http://dx.doi.org/10.1097/MD.0000000000015449 a target of particular interest for TNBC. However, the prognostic

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Figure 1. Flow diagram of the study cohort.

value of p53 expression remains controversial in TNBC.[9–11] 278 patients were retrieved and reassessed by examining
Some studies reported that breast cancers with IHC-detected p53 hematoxylin and eosin-stained histologic sections. The histologic
expression are characterized by an aggressive and metastatic type of all the specimens was reconfirmed as breast IDC,
phenotype with worse outcomes.[12,13] However, other studies according to the World Health Organization (WHO) classifica-
suggested that wild-type p53 protein associated with a strong tion standards. Patients diagnosed with stage IV breast cancer
immunohistochemical signal, because the protein is commonly were excluded. Additionally, patients were excluded if clinico-
overexpressed as a compensatory mechanism to repair DNA pathological information were not available or incomplete
damages that occur during tumorigenesis. These later studies (Fig. 1). All patients were followed up after surgery until the
indicated that IHC-detected p53 protein expression may serve as date of death or October 2018 (median follow-up: 79 months;
a favorable prognostic indicator.[14,15] range of follow-up: 2–105 months). The study was approved by
While the significance of TP53 mutation has been identified at the institutional ethnics committee of the Fourth Hospital of
the basic research level,[7] it remains difficult to interpret IHC Hebei Medical University.
results for clinical applications.[16,17] The purpose of this study is
to further investigate the relationship between p53 expression in
2.1. Histopathological determination of biomarkers
TNBC and clinical outcomes. Thus, we designed this study to
evaluate IHC-detected p53 expression in a cohort of 278 patients The molecular subtype of all the specimens was reconfirmed as
with triple-negative breast invasive ductal carcinoma (IDC), and triple-negative breast IDC by 2 experienced pathologists,
reveal the association between p53 expression and the prognostic according to the 14th St. Gallen International Expert Consensus.
impact in TNBC. Our data showed that IHC-detected p53 They reviewed all pathology specimens of 278 patients to
expression is a promising prognostic candidate for poor survival determine the following tumor characteristics: histologic grade,
in triple-negative breast IDC patients. tumor size, vessel tumor emboli and IHC staining for p53, Ki67,
ER, PgR, and HER2 (all monoclonal antibodies were purchased
from Abcam, Cambridge, UK). The expression of p53 is localized
2. Methods
in the nucleus, and cells with a distribution of pale yellow or
This retrospective study comprised 278 females with stage I-III brownish yellow particles was considered p53-positive. Under
triple-negative breast IDC who underwent primary surgery at the the light microscope, the pathologists observed >5 high power
Department of Breast Surgery in the Fourth Hospital of Hebei fields with over 1000 cells and an observation of ≥10% of
Medical University from 1st January 2010 to 31st December positive cells was considered p53 positive. Intensity of p53 was
2012. These patients underwent surgery without any anticancer not recorded (Fig. 2).[18] Disagreements between the 2 pathol-
therapy before the operation, including radiation therapy, ogists were resolved by repeated examination of the original slide
systemic chemotherapy/neo-adjuvant therapy, or hormone until consensus was achieved. Using a similar IHC scoring
therapy. Formalin-fixed, paraffin-embedded specimens from method, the Ki67 index was scored as high when 30% or more of

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Figure 2. Immunohistochemical p53 staining in TNBC. Representative images of nuclear p53 expression (A, B, magnification,  200,  400, respectively). TNBC =
triple-negative breast cancer.

the tumor cells were expressed.[19] Analyses for ER, PgR, and Anatomic and prognostic staging was evaluated according to the
HER2 were conducted according to the recommended guidelines 8th edition of the American Joint Committee on Cancer (AJCC)
of the American Society of Clinical Oncology and College of staging manual.[22] Appropriate adjuvant cytotoxic chemothera-
American Pathologists.[20,21] Histologic grading was carried out py after the surgery were conducted according to the standard
using the Nottingham-combined histologic grade (Elston-Ellis guidelines. The baseline characteristics of the 278 patients in this
modification of the Scarff-Bloom-Richardson grading system). study are reported in Table 1.

Table 1
p53 expression in TNBC according to clinicopathologic parameters.
p53 expression
Factor N (278) Negative (n = 115) Positive (n = 163) x2-text P
Age (yr)
35 19 8 (42.1%) 11 (57.9%) 1.477 .478
36–64 219 87 (39.7%) 132 (60.3%)
≥65 40 20 (50%) 20 (50%)
Menstrual status
Premenopausal 133 51 (38.3%) 82 (61.7%) 0.960 .327
Postmenopausal 145 64 (44.1%) 81 (55.9%)
Tumor size
2cm 159 67 (42.1%) 92 (57.9%) 0.091 .763
>2cm 119 48 (40.3%) 71 (59.7%)
Lymph node status
N0 169 70 (41.4%) 99 (58.6%) 0.001 .982
N1–3 109 45 (41.3%) 64 (58.7%)
Grade
1 27 17 (63.0%) 10 (37.0%) 6.291 .043
2 183 74 (40.4%) 109 (59.6%)
3 68 24 (35.3%) 44 (64.7%)
Vessel tumor emboli
yes 222 85 (38.3%) 137 (61.7%) 4.307 .038
no 56 30 (53.6%) 26 (46.4%)
Ki67
30% 56 26 (46.4%) 30 (53.6%) 0.741 .389
>30% 222 89 (40.1%) 133 (59.9%)
Anatomic Stage
I 115 51 (44.3%) 64 (55.7%) 1.012 .603
II 121 49 (40.5%) 72 (59.5%) 15
III 42 15 (35.7%) 27 (64.3%)
Prognostic Stage
II 116 51 (44.0%) 65 (56.0%) 0.554 .457
III 162 64 (39.5%) 98 (60.5%)

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2.2. Statistical analysis and G3). The median follow-up of the 278 patients was 79
Data were processed using SPSS for Windows, version 22.0. The months (range, 2 to 105), 46 patients died at data cut-off, 6
association between the p53 expression and pathologic charac- patients with local recurrence and/or distant metastasis, and the
teristics was examined using either Chi square statistical test or 7-year OS and DFS rates were 83.45% and 81.29%, respectively.
Fisher exact test. Overall survival (OS) and disease-free survival Table 1 provides the clinicopathological characteristics of
(DFS) were calculated from the time of diagnosis to the time of patients.
event of interest, death from any cause, recurrence, or the final
follow-up date. The Kaplan-Meier method was used for 3.2. p53 expression and clinical features
calculation of survival probabilities and the unstratified log-
The expression ratio of p53 in 278 specimens was 58.6% (163/
rank test for comparison of the survival curves. Cox proportional
278). There was no statistical difference between p53 (+) and p53
hazards model was used to estimate the hazard ratio (HR) of each
( ) in T stage, N stage and Ki67 expression. However, p53
clinicopathologic variables for OS and DFS. All predictors with P
expression was associated with vessel tumor embolus (61.7% vs
value <.05 in univariate Cox analyses were used in multivariate
41.6%, P = .038) and higher histologic grade (G1 vs G2 vs G3,
analysis. P values were 2-tailed and considered significant when
37.0% vs 59.6% vs 64.7%, respectively; P = .043) Significantly,
<.05.
p53 expression was highest in the G3 group (64.7%).

3. Results
3.3. p53 expression and survival analysis
3.1. Patients characteristics
In the whole cohort of patients, Kaplan-Meier curve showed that
In total, 3380 patients with primary invasive breast cancer were p53 (+) TNBC conferred a significantly lower rate of DFS (76.7%
diagnosed and treated at the Department of Breast Surgery in the vs 86.8%, log-rank P = .020, Fig. 3A) and OS (79.6% vs 89.6%,
Fourth Hospital of Hebei Medical University from 1st January log-rank P = .025, Fig. 4A). After staging by the 8th edition of
2010 to 31st December 2012. Among them, 416 (12.31%) AJCC staging system, 116 had prognostic stage II cancer and 162
patients had the TNBC subtype. After exclusion of patients with had prognostic stage III cancer. It showed that p53 (+) TNBC was
special type breast cancer (N = 94) (medullary carcinoma N = 61, associated with a significantly poorer OS (90.8% vs 100%, Log-
metaplastic carcinoma N = 6, carcinosarcoma N = 6, secretory rank P = .027, Fig. 4B) in the prognostic stage II group. Univariate
carcinoma N = 4, clear cell carcinoma N = 4, apocrine carcinoma Cox analysis of clinicopathological characteristics indicated that
N = 3, spindle cell carcinoma N = 3, papillary carcinoma N = 2, p53 (+) was significantly associated with worse DFS (HR: 2.036;
lobular breast cancer N = 1, neuroendocrine tumor N = 1, mixed 95%CI: 1.103–3.758; P = .023; Table 2) and OS (HR: 2.096;
carcinoma N = 3), incomplete information (N = 9) and stage IV 95%CI: 1.082–4.058; P = .028; Table 3). Multivariate Cox
breast cancer (N = 5), 278 patients with triple-negative breast analysis of all the predictors with P values < .05 in univariate Cox
IDC were enrolled in this study. All patients were female with a analyses indicated that p53 (+) was an independent prognostic
median age of 54 years (range, 23 to 80). About half (159/278) of factor for lower DFS (HR: 2.222; 95%CI: 1.147–4.308; P = .018,
all the patients presented with stage T1 tumor and 38.13% (109/ Table 2) and OS (HR: 2.097; 95%CI: 1.136–3.873; P = .018,
278) had clinically detectable axillary lymph node metastasis. Table 3). In addition, the multivariate analysis showed that vessel
Around one-fifth of the patients presented with vessel tumor tumor emboli, T > 2 cm and positive nodes also appeared to be
embolus, and 90.29% (251/278) with high histologic grade (G2 independent risk factors for poor prognosis (Tables 2 and 3).

Figure 3. p53 prognostic significance. Kaplan-Meier curves for DFS associated with p53 expression in the whole cohort of triple-negative breast invasive ductal
carcinoma patients as well as in different stratified prognostic stage patients according to the AJCC 8th edition. (A) Total TNBC, (B) AJCC prognostic stage II TNBC,
(C) AJCC prognostic stage III TNBC. P values were calculated with use of the log-rank test. AJCC = American Joint Committee on Cancer, DFS = disease-free
survival, TNBC = triple-negative breast cancer.

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Figure 4. p53 prognostic significance. Kaplan-Meier curves for OS associated with p53 expression in the whole cohort of triple-negative breast invasive ductal
carcinoma patients as well as in different stratified prognostic stage patients according to the AJCC 8th edition. (A) Total TNBC, (B) AJCC prognostic stage II TNBC,
(C) AJCC prognostic stage III TNBC. P values were calculated with use of the log-rank test. AJCC = American Joint Committee on Cancer, TNBC = triple-negative
breast cancer.

4. Discussion clinical laboratories to use NGS to determine p53 mutational

state due to high cost and complex interpretation. By contrast,
The TP53 gene, known as the “guardian of the genome”, was IHC is still considered a valuable diagnostic tool with easy
found to be mutated in approximately 50% of human cancer.[23] accessibility and well-established efficacy in investigating target
Mutations of the tumor suppressor TP53 are associated with agents and predicting clinical outcome in cancer. It also
increased tumor cell invasion and metastasis. Several mechanisms overcomes discrepancies between mRNA and protein expression
have been identified for promoting dissemination of cancer cells by transcriptional and translational regulation.
with TP53 mutations.[24,25]TP53 mutation comprised 80% of IHC has provided enormous benefits in evaluating prognostic
TNBC, raising the possibility that targeting the mutant p53 and predictive markers in cancer. Yet until now, the prognostic
protein product might be a new approach for the treatment of this significance of IHC-detected p53 protein remains controversial in
form of breast cancer.[6] It has recently been suggested that anti- TNBC. According to Jin et al,[14] increased IHC expression of
p53 drugs could reactivate mutant p53 and restore the tumor p53 reflected the accumulation of wild-type p53 as a compensa-
suppression activity in a preclinical model.[26–28] It is important tory mechanism of cell’s DNA damage and repair system. They
to select appropriate patients with TP53 mutation to use these demonstrated that strong p53 expression served as a favorable
drugs and ensure successful results in clinical studies. Accurate prognostic indicator for better DFS and OS (P = .012, P = .008) in
detection of TP53 mutation would be a necessary precondition of 305 TNBC cases, but not an independent prognostic factor in the
anti-p53 therapies. Although next generation sequencing (NGS) multivariate analysis (P > .05). Similarly, Coates et al[16]
allows whole genomic evaluation, it is still impractical in most observed that p53 expression was associated with a good

Table 2
Univariate and multivariate analyses (Cox regression) for DFS.
Univariate analysis for DFS Multivariate analysis for DFS
Variable HR 95% CI P value HR 95% CI P value
T (>2 cm) 3.163 1.768–5660 <.001 2.309 1.264–4.217 .006
Positive nodes 3.165 1.799–5.567 <.001 2.091 1.133–3.860 .018
Vessel tumor emboli 3.217 1.846–5.607 <.001 2.116 1.165–3.841 .014
p53 2.036 1.103–3.758 .023 2.097 1.136–3.873 .018
DFS = disease-free survival.

Table 3
Univariate and multivariate analyses (Cox regression) for OS.
Univariate analysis for OS Multivariate analysis for OS
Variable HR 95% CI P value HR 95% CI P value
T (>2 cm) 3.546 1.861–6.758 <.001 2.398 1.229–4.677 .010
Positive nodes 3.919 2.084–7.369 <.001 2.444 1.235–4.840 .010
Vessel tumor emboli 3.920 2.181–7.047 <.001 2.438 1.298–4.580 .006
p53 2.096 1.082–4.058 .028 2.222 1.147–4.308 .018

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prognosis in ER ( ) node-negative breast cancer. However, more Medical University, for her contributions to the study. We are
scholars thought that p53 protein translated from the wild-type also grateful to Dr. Pepper Schedin for critically reviewing our
TP53 gene was typically not observed by IHC staining with a manuscript. The authors also would like to thank Mr. Weston
truncated and unstable structure. Many studies showed that most Anderson, a professional editor in the U.S., for editorial
IHC-detected p53 proteins are thought to be mutant p53, which assistance.
are less susceptible to degradation than wild-type p53.[9–11,29]
Kim et al[29] suggested that patients with TP53 missense
Author contributions
mutations showed high protein expression in contrast to patients
with wild-type TP53 (positivity of IHC: wild type vs missense, Conceptualization: Jing-ping Li, Sonali Jindal, Yun-jiang Liu.
53.6% vs 89.8%, respectively; P < .001). In fact, 3 quarters of Data curation: Jing-ping Li, Li-hua Zheng, Yun-jiang Liu.
TP53 mutations are missense substitutions rather than trunca- Formal analysis: Jing-ping Li, Xiang-mei Zhang, Li-hua Zheng,
tion/deletion mutations.[30] Previous studies reported that IHC- Yun-jiang Liu.
detected p53 reflected the mutant p53 and indicated poor Investigation: Jing-ping Li, Yun-jiang Liu.
prognosis in primary breast cancer.[12,31,32] Bae et al[12] found Methodology: Jing-ping Li, Xiang-mei Zhang, Li-hua Zheng,
that the mortality risk of p53 expression TNBC was 1.84 times Yun-jiang Liu.
higher than that of p53 negative TNBC in the non-chemotherapy Project administration: Jing-ping Li.
group (P = .027). Yang et al[33] also found that p53 predicted Resources: Jing-ping Li, Xiang-mei Zhang, Zhen-zhen Zhang.
poor survival of breast cancer patients with visceral metastasis. Software: Xiang-mei Zhang.
However, there was no prognostic difference between p53 (+) Supervision: Jing-ping Li, Xiang-mei Zhang, Zhen-zhen Zhang,
TNBC and p53 ( ) TNBC in some studies.[17,34] Sonali Jindal, Yun-jiang Liu.
In our research, we only choose patients with triple-negative Validation: Jing-ping Li, Xiang-mei Zhang, Zhen-zhen Zhang,
subtype breast IDC for the study in order to achieve a more Li-hua Zheng, Sonali Jindal, Yun-jiang Liu.
homogeneous study population. We found that p53 expression Visualization: Zhen-zhen Zhang, Li-hua Zheng, Sonali Jindal.
was associated with vessel tumor emboli (61.7% vs 41.6%, Writing – original draft: Jing-ping Li.
P = .038) and higher histologic grade (37.0% vs 59.6% vs Writing – review & editing: Jing-ping Li, Zhen-zhen Zhang,
64.7%, P = .043) significantly, highest in the G3 group (64.7%). Sonali Jindal, Yun-jiang Liu.
Vessel tumor emboli, an independent risk factor for prognosis, is
caused by the dysfunctional cell-cell adhesive junctions and
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