Value of TP53 status for predicting response to neoadjuvant chemotherapy in breast cancer: a meta-analysis.

Abstract

Numerous studies have yielded inconclusive results regarding the relationship between tumor suppressor protein TP53 overexpression and/or TP53 gene mutations and the response to neoadjuvant chemotherapy in patients with breast cancer. The purpose of the current study was therefore to evaluate the relationship between TP53 status and response to chemotherapy in breast cancer.
A total of 26 previously published eligible studies including 3,476 cases were identified and included in this meta-analysis. TP53 status (over expression of TP53 protein and/or TP53 gene mutations) was associated with good response in breast cancer patients who received neoadjuvant chemotherapy (total objective response: risk ratio [RR]= 1.20, 95% confidence interval [CI]= 1.09-1.33, p<0.001; pathological objective response: RR = 1.37, 95% CI = 1.20-1.57, p<0.01; total complete response: RR = 1.33, 95% CI = 1.15-1.53, p<0.001; pathological complete response: RR = 1.45, 95% CI = 1.25-1.68, p<0.001). In further stratified analyses, this association also existed among the studies using anthracycline-based neoadjuvant chemotherapy, and the association between response and the presence of gene alterations was stronger than that between response and immunohistochemistry positivity.
The results of the present meta-analysis suggest that TP53 status is a predictive factor for response in breast cancer patients undergoing neoadjuvant chemotherapy. Further larger and well-designed prospective studies are required to evaluate the predictive role of TP53 status in clinical practice.

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Value of TP53 Status for Predicting Response to
Neoadjuvant Chemotherapy in Breast Cancer: A Meta-
Analysis
Min-Bin Chen1., Ya-Qun Zhu2., Jun-Ying Xu3, Li-Qiang Wang1, Chao-Ying Liu3, Zhang-Yi Ji1, Pei-
Hua Lu4*
1Department of Medical Oncology, Kunshan First People’s Hospital Affiliated to Jiangsu University, Kunshan, People’s Republic of China, 2Department of Radiotherapy
and Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China, 3Department of Medical Oncology, Wuxi People’s Hospital
Affiliated to Nanjing Medical University, Wuxi City, People’s Republic of China, 4Department of General Surgery, Wuxi People’s Hospital Affiliated to Nanjing Medical
University, Wuxi City, People’s Republic of China
Abstract
Background: Numerous studies have yielded inconclusive results regarding the relationship between tumor suppressor
protein TP53 overexpression and/or TP53 gene mutations and the response to neoadjuvant chemotherapy in patients with
breast cancer. The purpose of the current study was therefore to evaluate the relationship between TP53 status and
response to chemotherapy in breast cancer.
Methods and Findings: A total of 26 previously published eligible studies including 3,476 cases were identified and
included in this meta-analysis. TP53 status (over expression of TP53 protein and/or TP53 gene mutations) was associated
with good response in breast cancer patients who received neoadjuvant chemotherapy (total objective response: risk ratio
[RR] =1.20, 95% confidence interval [CI] =1.09–1.33, p,0.001; pathological objective response: RR=1.37, 95% CI=1.20–
1.57, p,0.01; total complete response: RR=1.33, 95% CI=1.15–1.53, p,0.001; pathological complete response: RR=1.45,
95% CI=1.25–1.68, p,0.001). In further stratified analyses, this association also existed among the studies using
anthracycline-based neoadjuvant chemotherapy, and the association between response and the presence of gene
alterations was stronger than that between response and immunohistochemistry positivity.
Conclusion: The results of the present meta-analysis suggest that TP53 status is a predictive factor for response in breast
cancer patients undergoing neoadjuvant chemotherapy. Further larger and well-designed prospective studies are required
to evaluate the predictive role of TP53 status in clinical practice.
Citation: Chen M-B, Zhu Y-Q, Xu J-Y, Wang L-Q, Liu C-Y, et al. (2012) Value of TP53 Status for Predicting Response to Neoadjuvant Chemotherapy in Breast
Cancer: A Meta-Analysis. PLoS ONE 7(6): e39655. doi:10.1371/journal.pone.0039655
Editor: Sharon A. Glynn, National University of Ireland Galway, Ireland
Received February 1, 2012; Accepted May 24, 2012; Published June 29, 2012
Copyright: ? 2012 Chen et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This work was supported by the Natural Science Foundation of Jiangsu Province (No. BK2010160, BK2011374) and the National Natural Science
Foundation (No.81108676, 81101801). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
* E-mail: lphty1_1@yahoo.com.cn
. These authors contributed equally to this work and should be considered co-first authors.
Introduction
Neoadjuvant chemotherapy, also known as primary or induc-
tion chemotherapy, refers to chemotherapy administered before
locoregional treatment, such as surgery and/or irradiation.
Neoadjuvant chemotherapy has become the standard treatment
for the management of locally advanced breast cancer, primarily
because of its ability to downsize large tumors. Neoadjuvant
chemotherapy is increasingly used for the treatment of early-stage
breast cancer. However, despite generally high response rates, a
small proportion of patients fail to respond to neoadjuvant
chemotherapy, or even progress during therapy. Recent evidence
suggests that biological markers may be useful for identifying those
patients who would benefit from neoadjuvant chemotherapy [1].
The TP53 gene is a prime candidate for predicting the response
of tumors to classic chemotherapy [2]. It is a master gene in the
stress response that plays a critical role in cancer development.
TP53 is the most frequently mutated gene in human cancer, with
mutations occurring in at least 50% of human cancers [1]. It
mediates checkpoint or stress responses to several insults and
suppresses tumor formation through several mechanisms, includ-
ing apoptosis, senescence, and autophagy [3]. Experimental
evidence suggests a key role for TP53 in apoptosis in response to
genotoxic agents [4,5].
The use of TP53 status as a biological marker to predict the
response of breast cancer to neoadjuvant chemotherapy, however,
is disappointing, and the findings to date have shown conficting
results [6–10]. Several studies [6,9–11] found that patients with
TP53 mutations often had better responses to therapy than those
with normal TP53 status. Other studies [7,8,12,13], however,
evaluated TP53 status in breast cancer patients and drew different
conclusions. The relevance of this gene to clinical therapy thus
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remains unknown. We therefore performed a meta-analysis of the
value of TP53 status for predicting response to neoadjuvant
chemotherapy in breast cancer.
Materials and Methods
Publication Search
PubMed, Embase, and Web of Science databases were searched
(up to December 20, 2011) using the search terms: ‘TP53’, ‘p53’,
‘p53 protein’, ‘p53 mutation’, ‘17p13 gene’, ‘chemotherapy’ and
‘breast cancer’. All potentially eligible studies were retrieved and
their bibliographies were carefully scanned to identify other
eligible studies. Additional studies were identified by a hand search
of the references cited in the original studies. When multiple
studies of the same patient population were identified, we included
the published report with the largest sample size. Only studies
published in English were included in this meta-analysis.
Inclusion and Exclusion Criteria
Studies included in this meta-analysis had to meet all of the
following criteria: (a) evaluation of TP53 status for predicting the
response to neoadjuvant chemotherapy in early-stage breast
cancer, locally-advanced breast cancer, (b) described therapeutic
response, (c) retrospective or prospective cohort study, (d) inclusion
of sufficient data to allow the estimation of a risk ratio (RR) with
95% confidence intervals (95% CI), and (e) studies published in
English. Letters to the editor, reviews, and articles published in
books, or papers published in a language other than English were
excluded.
Data Extraction and Definitions
According to the inclusion criteria listed above, the following
data were extracted for each study: the first author’s surname,
publication year, country of origin, number of patients analyzed,
types of measurement, and treatment. Data on the main outcomes
were entered in tables showing the clinical and pathological
responses to chemotherapy with respect to TP53 status. Informa-
tion was carefully and independently extracted from all eligible
publications by two of the authors (Chen and Zhu). Any
disagreement between the researchers was resolved by discussions
until a consensus was reached. If they failed to reach a consensus, a
third investigator (Lu) was consulted to resolve the dispute.
We used the definitions and standardizations for ‘TP53’ and
‘response to chemotherapy’ as reported by Pakos et al. [14]. For
consistency, we used ‘TP53’ to denote the gene, ‘TP53’ for the
expressed protein, and ‘TP53 status’ to refer to both the gene and
protein markers. The correlation between protein and gene
detection is not straightforward [9,15]. TP53 alterations increase
the half-life of the TP53 protein, leading to nuclear accumulation
of mutant TP53, which can be detected by immunohistochemistry
(IHC). However TP53 protein accumulation measured by IHC
does not necessarily correspond to TP53 mutations. Thus, the
overall analysis considered all studies, regardless of whether
protein expression or gene mutation was being evaluated. Separate
analyses for TP53 protein expression and TP53 gene alterations
were also performed. For studies using both protein and gene
detection, we used the protein data but also examined the gene
detection data, and found similar results (data not shown). TP53
status positive means patients with over expression of TP53
protein and/or TP53 gene mutations. Response was defined as
complete response (CR), partial response (PR), or objective
response (OR) (OR = CR +PR). Non-response was defined as
stable disease (SD) or progressive disease (PD), according to WHO
criteria [16] or RECIST (Response Evaluation Criteria in Solid
Tumors) criteria [17].
Statistical Analysis
RR with 95% CIs was used to estimate the association between
TP53 status and response to neoadjuvant chemotherapy in breast
cancer patients. Subgroup analyses were performed to evaluate the
effects of treatment regimens (anthracycline-based) and different
methods of TP53 gene determination (protein and gene).
Heterogeneity assumption was checked using the Q test, and a p
value .0.10 indicated a lack of heterogeneity among studies. The
pooled RR was calculated using a fixed-effects model (the Mantel–
Haenszel method) or a random-effects model (the DerSimonian
and Laird method), according to the heterogeneity. Funnel plots
and the Egger’s test were employed to estimate the possible
publication bias. We also performed sensitivity analysis by
omitting each study or specific studies to find potential outliers.
Statistical analyses were conducted using Stata (version SE/10;
StataCorp, College Station, TX). p values for all comparisons were
two-tailed and statistical significance was defined as p,0.05 for all
tests, except those for heterogeneity.
Results
Eligible Studies
A total of 1,223 articles were retrieved by a literature search of
the PubMed, Embase, and Web of Science databases, using
different combinations of key terms. As indicated in the search
flow diagram (Figure. S1), 26 studies reported at least one of the
outcomes of interest and were finally included in the meta-analysis
[2,6–13,15,18–33]. The characteristics of the eligible studies are
summarized in Table 1. Twenty-one of the studies employed IHC,
eight employed gene detection (including genomic sequencing,
DNA microarray, Functional Analysis of Separated Allele in Yeast
[FASAY]), two employed both methods and one employed three
methods (Table 1). The sample sizes in all the eligible studies
ranged from 20–1,469 patients (median =73 patients, mean
=134 patients, standard deviation [SD] =54). Overall, the eligible
studies included 3,476 patients. Eighteen of the studies were
conducted in European or North American populations with
mixed but mostly white participants (1,460 patients), whereas eight
were conducted in East Asian populations (748 patients).
Correlation of TP53 Status with Response to Neoadjuvant
Chemotherapy in Breast Cancer Patients
Among the studies of breast cancer patients who received
neoadjuvant therapy, 26 studies involving 3,476 patients contrib-
uted data on total OR (clinical OR + pathological OR). TP53
status-positivity was significantly associated with improved total
OR among patients treated with neoadjuvant therapy (RR=1.20;
95% CI=1.09–1.33; p,0.001, Figure S2). Thirteen studies
involving 2,761 patients contributed data on pathological OR.
TP53 status-positivity was significantly associated with improved
pathological response (RR=1.37; 95% CI=1.20–1.57; p,0.001).
Fifteen studies involving 2,736 patients contributed data on total
CR. TP53 status-positivity was significantly associated with
improved total CR (RR=1.33; 95% CI=1.15–1.53; p,0.001).
Finally, 12 studies involving 2,434 patients provided information
on pathological CR. TP53 status-positivity was significantly
associated with significant improvements in pathological CR
(RR=1.45; 95% CI=1.25–1.68; p,0.001, Figure. S3). For
studies using both clinical and pathological responses, we used
the pathological-response data, but also examined the clinical-
response data and found similar results (data not shown).
TP53 Status for Predicting Chemotherapy Response
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Table 1. Characteristics of studies included in the meta-analysis.
Author
Year
Country
Cases
Treatment
Subgroup
of treatment
Detection
Response
Makris et al. [18]
1997
UK
80
mitoxantrone, methotrexate (6 mitomycin
C) and tamoxifen
N
IHC
clinical response
CR + PR
Kandioler-Eckersberger et al. [9]
2000
Austria
67
FEC or paclitaxel
N
PCR amplification sequencing and IHC
clinical response
CR + PR
Geisler et al. [20]
2001
Norway
90
weekly doxorubicin scheduled for 16 weeks
A-b
IHC, TTGE and sequencing
clinical response
PR
Schneider et al. [19]
2001
Spain
52
FAC or CMF
N
IHC
clinical response
CR + PR
Aas et al. [11]
2003
Norway
90
doxorubicin
A-b
IHC
clinical response
PR+SD
Anelli et al. [6]
2003
Brazil
73
AT
A-b
IHC
clinical response
CR + PR
Bonnefoi et al. [22]
2003
Switzerland
179
FEC,EC + G-CSF
A-b
IHC
clinical response
CR
Martin-RIHCard et al.[]
2003
Spain
38
FAC or FEC
A-b
IHC
clinical response
CR + PR
Geisler et al. [21]
2003
Norway
35
FUMI regimen
N
IHC
clinical response
PR
Mathieu et al. [24]
2004
France
129
AVCMF or FAC/FEC
A-b
IHC
Pathologic response
CR
Deissler et al. [23]
2004
Germany
50
anthracycline/taxane
A-b
FASAY
clinical response
CR
Kim et al. [26]
2005
Japan
63
docetaxel
N
IHC
Pathologic response
RR
Learn et al. [25]
2005
USA
121
AC vs. AC+D
A-b
IHC
Pathologic response
CR
Bertheau et al. [29]
2007
France
80
EC
A-b
FASAY
Pathologic response
CR
Tiezzi et al. [8]
2007
Brazil
60
CMF or FEC
N
IHC
clinical response
CR + PR
Keam et al. [27]
2007
Korea
145
docetaxel and doxorubicin
A-b
IHC
Pathologic response
CR + PR
Lee et al. [28]
2008
Korea
61
AT
A-b
IHC
clinical response
RR
Pathologic response
CR
Zhou et al. [7]
2008
China
135
taxanes and anthracycline
A-b
IHC
Pathologic response
CR
Yonemori et al. [12]
2009
Japan
44
trastuzumab-containing neoadjuvant
N
IHC
Pathologic response
CR
Shekhar et al. [30]
2009
USA
20
AC, AT, FAC, FAT
A-b
IHC
clinical and pathologic
response
CR + PR
Silver et al. [32]
2010
USA
22
DDP
N
IHC
clinical and pathologic
response
CR + PR
Masuda et al. [31]
2010
Japan
33
FEC100 and taxanes
A-b
IHC
Pathologic response
CR
Sanchez-Munoz et al. [10]
2010
Spain
73
EC followed by GP (+ trastuzumab
in Her2 patients)
A-b
IHC
Pathologic response
CR
Bonnefoi et al. [2]
2011
Europe
1469
FEC VS. T-ET
A-b
FASAY
clinical and pathologic
response
CR
Ono et al. [33]
2011
Japan
179
anthracycline-based regimens
A-b
IHC
Pathologic response
CR
Oshima et al. [15]
2011
Japan
88
P-FEC
A-b
genomic sequencing, DNA
microarray and IHC
Pathologic response
CR
IHC, immunohistochemistry; FEC, 5-fluorouracil, epirubicin, and cyclophosphamide; FAC, 5-fluorouracil, doxorubicin, and cyclophosphamide; CMF, cyclophosphamide, mitomycin C and 5-fluorouracil; AVCMF, doxorubicin,
vincristine, cyclophosphamide, methotrexate and 5-fluorouracil; P-FEC, sequential paclitaxel and 5-FU/epirubicin/cyclophosphamide; FUMI regimen, 5-fluorouracil (1,000 mg/m2on days 1 and 2) and mitomycin; EC, epirubicin and
cyclophosphamide; A, doxorubicin; E, epirubicin; T, docetaxel; P, paclitaxel; G, gemcitabine; FASAY, RNA-based functional assay in yeast; TTGE, temporal temperature gradient gel electrophoresis. N, can not be grouped; A-b,
anthracycline-based neoadjuvant chemotherapy.
doi:10.1371/journal.pone.0039655.t001
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Subgroup Analysis
Among the 26 studies in the neoadjuvant subgroup, 18 used
anthracycline-based neoadjuvant chemotherapy,while the remain-
ing studies can not be grouped (table 1). The results of the
anthracycline-based neoadjuvant chemotherapies were therefore
calculated. TP53 status-positivity was associated with improved
response in breast cancer patients who received anthracycline-
based neoadjuvant chemotherapy (total OR: RR=1.18, 95%
CI=1.04–1.33,p=0.010,Figure.
RR=1.33, 95% CI=1.19–1.62, p=0.005; total CR: RR=1.33,
95% CI=1.15–1.54, p,0.001; pathological CR: RR=1.45, 95%
CI=1.24–1.69, p,0.001). For studies using both clinical and
pathological responses, we used the pathological-response data,
but also examined the clinical-response data, and similar results
were obtained (data not shown).
Different measurements of TP53 status (either by protein or
gene detection) have been used to evaluate associations with
favorable responses to neoadjuvant chemotherapy. We therefore
calculated the associations using both protein and gene statuses of
TP53. The results of subgroup analysis are presented in Table 2.
For gene detection, TP53 status-positivity was significantly
associated with increased total OR (RR=1.41, 95% CI=1.20–
1.65, p,0.001, Figure S5), total pathological response (patholog-
ical response: RR=1.49; 95% CI=1.24–1.79; p,0.001), total
CR (RR=1.46; 95% CI=1.22–1.75; p,0.001) and pathological
CR (RR=1.49; 95% CI=1.24–1.79; p,0.001) among patients
treated with neoadjuvant chemotherapy. For protein-based
detection, TP53 status-positivity was significantly associated with
increased total OR (RR=1.22; 95% CI=1.01–1.48; p=0.041)
and total CR (RR=1.32; 95% CI=1.02–1.69; p=0.032) among
patients treated with neoadjuvant chemotherapy, but not with
total OR (RR=1.06; 95% CI=0.94–1.20; p=0.310) or total CR
(RR=1.15; 95% CI=0.92–1.43; p=0.235). For studies using
both clinical and pathological responses, we used the pathological-
response data, but also examined the clinical response data, and
the results were similar (data not shown).
S4;pathologicalOR:
Publication Bias
Begg’s funnel plot and Egger’s test were used to estimate the
publication bias of the included literature. The shapes of the
funnel plots showed no evidence of obvious asymmetry(Figure S6),
and Egger’s test indicated the absence of publication bias
(p.0.05). Moreover, sensitivity analysis was carried out to assess
the influence of individual studies on the summary effect.
Trastuzumab would likely have increased the chances of response
when combined with a taxane in two of the studies which included
patients with HER-2 positive disease, there may be some
discordance in response rates in the newer studies compared to
the older studies prior to the advent of trastuzumab, this may have
falsely credited the anthracycline for the benefit seen and
introduced confounding. However, the corresponding pooled
RRs were not substantially altered whether or not these studies
were included. No individual study dominated this meta-analysis,
and the removal of any single study had no significant effect on the
overall results (total OR: RR ranged from 1.12[95% CI=1.01–
1.25] to 1.22 [95% CI=1.10–1.35]; pathological OR: RR ranged
from 1.42 [95% CI=1.22–1.66] to 1.51 [95% CI=1.18–1.93];
total CR: RR ranged from 1.24 [95% CI=1.01–1.56] to 1.37
[95% CI=1.18–1.59]; pathological CR: RR ranged from 1.42
[95% CI=1.22–1.66] to 1.47 [95% CI=1.26–1.76]).
Table 2. Risk ratio for the association between TP53 status and response to neoadjuvant chemotherapy.
Comparison
Total OR*
Pathological OR
Total CR*
Pathological CR
N
RR (95%CI)
p value
Ph
N
RR (95%CI)
p value
Ph
N
RR (95%CI)
p value
Ph
N
RR (95%CI)
p value
Ph
All studies
26
1.20 (1.09–1.33)
,0.001
0.292
15
1.37 (1.20–1.57)
,0.001
0.329
15
1.33 (1.15–1.53)
,0.001
0.095
12
1.45 (1.25–1.68)
,0.001
0.391
Treatment
Anthracycline-based
17
1.18 (1.04–1.33)
0.010
0.298
10
1.33 (1.19–1.62)
0.005
0.109
12
1.33 (1.15–1.54)
,0.001
0.031
9
1.45 (1.24–1.69)
,0.001
0.175
Type of measurement
Protein
21
1.06 (0.94–1.20)
0.310
0.796
12
1.22 (1.01–1.48)
0.041
0.637
12
1.15 (0.92–1.43)
0.235
0.209
9
1.32 (1.02–1.69)
0.032
0.659
Gene
8
1.41 (1.20–1.65)
,0.001
0.207
4
1.49 (1.24–1.79)
,0.001
0.089
5
1.46 (1.22–1.75)
,0.001
0.076
4
1.49 (1.24–1.79)
,0.001
0.089
Subgroup analysis was performed when there were at least two studies in each subgroup.
N, number of studies; Ph, p value of Q-test for heterogeneity.
*For studies using both clinical and pathological responses, we used the pathological response data, but also examined the clinical response data, and found similar results (data not shown).
#One study (Oshima et al. [15]) used both genomic sequencing and DNA microarray analysis for gene measurement; we used genomic sequencing data, but also also examined the DNA microarray data, and found similar results
(data not shown).
doi:10.1371/journal.pone.0039655.t002
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Discussion
TP53 status had been shown to play a pivotal role in the
response to a large panel of anticancer drugs. Previous studies
suggested that breast cancers with TP53 mutations might be either
resistant or sensitive to anticancer drugs. However, the issue could
not be resolved, because most of the available clinical reports
involved small sample sizes, and the results were therefore unable
to determine the value of TP53 status for predicting the response
to chemotherapy. Additionally, IHC, which lacks sensitivity and
specificity, or various DNA sequencing techniques, some of which
also lack sensitivity, were the main techniques used in these
studies. We therefore concluded that a meta-analysis was the best
way of evaluating the association between TP53 status and
response to neoadjuvant chemotherapy in a large population.
The current meta-analysis of 26 studies systematically evaluated
the association between TP53 status and response to neoadjuvant
chemotherapy in a large population. The results indicate that
altered TP53 status may predict good response rates to
neoadjuvant chemotherapy in patients with breast cancer. TP53
status was associated with total and pathologically relevant
increases in OR and CR. Stratification according to different
treatments showed that altered TP53 status was significantly
associated with increased OR and CR in patients who received
anthracycline-based neoadjuvant chemotherapy. Further stratifi-
cation by gene detection revealed imprecise results, but amplifi-
cation of the TP53 gene was also associated with relevant increases
in OR and CR (both total and pathological); however, although
overexpression of TP53 was associated with relevant increases in
pathological OR and CR, it was not associated with total OR and
CR. Gene detection was associated with advantages regarding
response rates to neoadjuvant chemotherapy in patients with
breast cancer. Gene detection may thus be a useful approach in
future prospective studies.
Despite our attempts to perform a comprehensive analysis, there
were some limitations associated with this meta-analysis. First, the
meta-analysis may have been influenced by publication bias, we
limited the search to studies performed in English, and we did not
search conference proceedings and abstract books, which may
have introduced publication bias to meta-analysis. We tried to
identify all relevant data and retrieve additional unpublished
information, some missing data were unavoidable. Second, the
studies used different measurements of TP53 status (either protein
or gene detection), and the cut-off values for TP53 for
overexpression by IHC and for gene amplification differed
between studies. Standardization is therefore of great importance
for obtaining an accurate assessment of the clinical significance of
TP53 status. Although we made considerable efforts to standardize
definitions, some variability in definitions of methods, measure-
ments, and outcomes among studies was inevitable. Third, our
analysis was observational in nature, and we therefore cannot
exclude confounding as a potential explanation of the observed
results. Despite these limitations, this meta-analysis had several
strengths. First, a substantial number of cases were pooled from
different studies, and 3,476 subjects represent a sizeable number,
significantly increasing the statistical power of the analysis.
Secondly, no publication biases were detected, indicating that
the pooled results may be unbiased.
This study is the first meta-analysis to assess the usefulness of
TP53 status for predicting the response of breast cancer patients to
neoadjuvant chemotherapy. Our data support TP53 status as a
useful predictive factor for assessing treatment response to
neoadjuvant chemotherapy in breast cancer patients. However,
future prospective studies with large sample sizes and better study
designs are required to confirm our findings. Moreover, the
interactions of this marker with other molecular markers such as
HER-2 [34] or estrogen receptor [35] remain unknown, and
should be topics for further investigation.
Supporting Information
Figure S1
analyses of randomized controlled trials; the Quality of
Reporting of Meta-Analyses (QUOROM) statement flow
diagram.
(EPS)
Improving the quality of reports of meta-
Figure S2
ation between TP53 and total OR among breast cancer
patients treated with neoadjuvant therapy.
(EPS)
Forest plots of RR were assessed for associ-
Figure S3
ation between TP53 and pathological CR among breast
cancer patients treated with neoadjuvant therapy.
(EPS)
Forest plots of RR were assessed for associ-
Figure S4
evaluation of total OR in anthracycline-based settings.
(EPS)
Forest plots of RR were assessed for the
Figure S5
evaluation of total OR in gene-based detection settings.
(EPS)
Forest plots of RR were assessed for the
Figure S6
obvious indication of publication bias for the outcome of
total OR.
(EPS)
The funnel plot shows that there was no
Author Contributions
Conceived and designed the experiments: M-BC Y-QZ P-HL. Performed
the experiments: M-BC J-YX L-QW C-YL. Analyzed the data: M-BC Y-
QZ P-HL. Contributed reagents/materials/analysis tools: Y-QZ J-YX L-
QW. Wrote the paper: M-BC Y-Q Z. Helped edit the manuscript C-YL Z-
YJ.
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PLoS ONE | www.plosone.org5 June 2012 | Volume 7 | Issue 6 | e39655